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Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Scope
The Atlas of Genetics and Cytogenetics in Oncology and Haematology is a peer reviewed on-line journal in
open access, devoted to genes, cytogenetics, clinical entities in cancer, and cancer-prone diseases.
It presents structured review articles ("cards") on genes, leukaemias, solid tumours, cancer-prone diseases, more
traditional review articles on these and also on surrounding topics ("deep insights"), case reports in hematology, and
educational items in the various related topics for students in Medicine and in Sciences.
Editorial correspondance
Jean-Loup Huret
Genetics, Department of Medical Information,
University Hospital
F-86021 Poitiers, France
tel +33 5 49 44 45 46 or +33 5 49 45 47 67
[email protected] or [email protected]
Staff
Mohammad Ahmad, Mélanie Arsaban, Mikael Cordon, Isabelle Dabin, Marie-Christine Jacquemot-Perbal, Maureen
Labarussias, Anne Malo, Catherine Morel-Pair, Laurent Rassinoux, Sylvie Yau Chun Wan - Senon, Alain Zasadzinski.
Database Director: Philippe Dessen, and the Chairman of the on-line version: Alain Bernheim (Gustave Roussy
Institute, Villejuif, France).
The Atlas of Genetics and Cytogenetics in Oncology and Haematology (ISSN 1768-3262) is published 6 times a year
by ARMGHM, a non profit organisation, and by the INstitute for Scientific and Technical Information of the French
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Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Editor-in-Chief
Jean-Loup Huret
(Poitiers, France)
Editorial Board
Sreeparna Banerjee
Alessandro Beghini
Anne von Bergh
Judith Bovée
Vasantha Brito-Babapulle
Charles Buys
Anne Marie Capodano
Fei Chen
Antonio Cuneo
Paola Dal Cin
Louis Dallaire
Brigitte Debuire
François Desangles
Enric Domingo-Villanueva
Ayse Erson
Richard Gatti
Ad Geurts van Kessel
Oskar Haas
Anne Hagemeijer
Nyla Heerema
Jim Heighway
Sakari Knuutila
Lidia Larizza
Lisa Lee-Jones
Edmond Ma
Roderick McLeod
Cristina Mecucci
Yasmin Mehraein
Fredrik Mertens
Konstantin Miller
Felix Mitelman
Hossain Mossafa
Stefan Nagel
Florence Pedeutour
Elizabeth Petty
Susana Raimondi
Mariano Rocchi
Alain Sarasin
Albert Schinzel
Clelia Storlazzi
Sabine Strehl
Nancy Uhrhammer
Dan Van Dyke
Roberta Vanni
Franck Viguié
José Luis Vizmanos
Thomas Wan
(Ankara, Turkey)
(Milan, Italy)
(Rotterdam, The Netherlands)
(Leiden, The Netherlands)
(London, UK)
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(Lund, Sweden)
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(Braunschweig, Germany)
(Nice, France)
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(Memphis, Tennesse)
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(Villejuif, France)
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(Hong Kong, China)
Atlas Genet Cytogenet Oncol Haematol. 2008;12(3)
Solid Tumours Section
Genes Section
Genes / Leukaemia Sections
Solid Tumours Section
Leukaemia Section
Deep Insights Section
Solid Tumours Section
Genes / Deep Insights Sections
Leukaemia Section
Genes / Solid Tumours Section
Education Section
Deep Insights Section
Leukaemia / Solid Tumours Sections
Solid Tumours Section
Solid Tumours Section
Cancer-Prone Diseases / Deep Insights Sections
Cancer-Prone Diseases Section
Genes / Leukaemia Sections
Deep Insights Section
Leukaemia Section
Genes / Deep Insights Sections
Deep Insights Section
Solid Tumours Section
Solid Tumours Section
Leukaemia Section
Deep Insights / Education Sections
Genes / Leukaemia Sections
Cancer-Prone Diseases Section
Solid Tumours Section
Education Section
Deep Insights Section
Leukaemia Section
Deep Insights / Education Sections
Genes / Solid Tumours Sections
Deep Insights Section
Genes / Leukaemia Section
Genes Section
Cancer-Prone Diseases Section
Education Section
Genes Section
Genes / Leukaemia Sections
Genes / Cancer-Prone Diseases Sections
Education Section
Solid Tumours Section
Leukaemia Section
Leukaemia Section
Genes / Leukaemia Sections
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Volume 12, Number 3, May-June 2008
Table of contents
Gene Section
AIFM1 (apoptosis-inducing factor, mitochondrion-associated, 1)
Victor J Yuste, Hans K Lorenzo, Santos A Susin
190
BNIP3 (Bcl-2/adenovirus E1B 19kD-interacting protein 3)
Sang-Gi Paik, Hayyoung Lee
195
BRCA1 (breast cancer 1, early onset)
Sreeparna Banerjee
197
CD97 (CD97 molecule)
Gabriela Aust
201
CDH1 (cadherin 1, type 1, E-cadherin (epithelial))
Marilia de Freitas Calmon, Paula Rahal
204
GRN (granulin)
Hongyong Zhang, Chong-xian Pan, Liang Cheng
208
HTATIP (HIV-1 Tat interacting protein, 60kDa)
Lise Mattera
213
HYAL1 (hyaluronoglucosaminidase 1)
Demitrios H Vynios
217
MAML2 (mastermind-like 2)
Kazumi Suzukawa, Jean-Loup Huret
220
MUC16 (mucin 16, cell surface associated)
Shantibhusan Senapati, Moorthy P Ponnusamy, Ajay P Singh, Maneesh Jain, Surinder K Batra
223
MUC17 (mucin 17, cell surface associated)
Wade M Junker, Nicolas Moniaux, Surinder K Batra
226
PTHLH (parathyroid hormone-like hormone)
Sai-Ching Jim Yeung
234
SOCS2 (suppressor of cytokine signaling 2)
Leandro Fernández-Pérez, Amilcar Flores-Morales
240
Leukaemia Section
del(11)(p12p13)
Pieter Van Vlierberghe, Jules PP Meijerin
243
t(3;5)(q26;q34)
Jean-Loup Huret
244
t(3;9)(q26;p23)
Jean-Loup Huret
245
t(3;17)(q26;q22)
Jean-Loup Huret
246
Atlas Genet Cytogenet Oncol Haematol. 2008;12(3)
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
t(6;7)(q23;q34)
Emmanuelle Clappier, Jean Soulier
248
Solid Tumour Section
Soft tissue tumors: Alveolar soft part sarcoma
Jean-Loup Huret
250
Bone: Subungual exostosis with t(X;6)(q13;q22)
Clelia Tiziana Storlazzi, Fredrik Mertens
253
Cancer Prone Disease Section
Glomuvenous malformation (GVM)
Virginie Aerts, Pascal Brouillard, Laurence M Boon, Miikka Vikkula
255
Case Report Section
Translocation t(1;6)(p35;p25) in B-cell lymphoproliferative disorder with evolution
to Diffuse Large B-cell Lymphoma
Elvira D Rodrigues Pereira Velloso, Cristina Ratis, Sérgio AB Brasil, João Carlos Guerra,
Nydia S Bacal, Cristóvão LP Mangueira
258
Educational Item Section
How human chromosome aberrations are formed
Albert Schinzel
Atlas Genet Cytogenet Oncol Haematol. 2008;12(3)
260
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
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Atlas Genet Cytogenet Oncol Haematol. 2008;12(3)
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Gene Section
Review
AIFM1 (apoptosis-inducing factor, mitochondrionassociated, 1)
Victor J Yuste, Hans K Lorenzo, Santos A Susin
Cell Death, Senescence and Survival Research Group, Institut de Neurociencies, Universitat Autonoma de
Barcelona, Edifici M, Campus de Bellaterra, 08193 Bellaterra Cerdanyola del Valles, Spain (VJY);
University of Paris XI, School of Medicine, Hospital Paul Brousse, INSERM U542, 14, av. Paul Vaillant
Couturier, 94807 Villejuif, France (HKL); Apoptosis and Immune System, Institut Pasteur, URA 1961CNRS, 25, rue du Dr. Roux, 75724 Paris Cedex 15, France (SAS)
Published in Atlas Database: October 2007
Online updated version: http://AtlasGeneticsOncology.org/Genes/AIFM1ID44053chXq25.html
DOI: 10.4267/2042/38516
This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence.
© 2008 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Location: Xq25
Local order: Centromere (59,500 Kbp)- ARHGEF9 (…) - RAB33A - AIFM1 - ELF4 - (…) - IL9R telomere (154,914 Kbp).
Identity
Hugo: AIFM1
Other names: AIF; PDCD8; MGC111425
AIF gene structure and known isoforms. Genomic organization of AIF and resulting AIF, AIF-exB, AIFsh, AIFsh2, and AIFsh3 mRNA
transcripts (schemas in the left). Translation start (ATG, in green) and stop (TGA/TAA, in red) codons are indicated, and the predicted
protein product is shown at the right. Numbers in AIF designate exons (in mRNA transcripts) and amino acids (in the predicted proteins).
Mitochondria localization signal (MLS), Pyridoxin-redox (Pyr-Redox), nuclear localization sequence (NLS), and C-terminal domains are
indicated. I9 (in green) indicates intron 9. The inclusion of the 203-bp exon 9b (lettering in red) produces AIFsh2 and AIFsh3, which
encodes 324- and 237-amino acid proteins, respectively. AIFsh2 contains the MLS and the Pyr-Redox domain, but lacks the C-terminal
portion of AIF. AIFsh3 has a similar structure as AIFsh2 with the splicing of exon 2, leading to the loss of MLS. Blue lines indicate the
splicing of the different isoforms.
Atlas Genet Cytogenet Oncol Haematol. 2008;12(3)
190
AIFM1 (apoptosis-inducing factor, mitochondrion-associated, 1)
Yuste VJ, et al.
Description
DNA/RNA
16 exons spanning 36.471 Kb.
Note: AIF (Apoptosis-Inducing Factor). Total gene
size 36.471 Kb with a transcribed region of 2.215 Kb
which codes for 613 amino acids. To date, five
isoforms from AIF gene have been described (AIF,
AIFexB, AIFsh, AIFsh2, and AIFsh3).
Transcription
2,215 bp mRNA.
Pseudogene
Not known.
Figure 1: Schematic model representing the three different AIF forms: precursor, mature, and truncated. AIF is a flavoprotein (with an
oxidoreductase enzymatic activity) containing a FAD-bipartite domain (yellow, amino-acids 128-262 and 401-480), a NADH-binding motif
(violet, amino-acids 263-400), and a C-terminal domain (red, amino-acids 481-608) where the proapoptotic activity of the protein resides.
In addition, it has a Mitochondria Localization Sequence (MLS, in green, amino-acids 1-41) placed in its N-terminal region. Between the
first-N-terminal FAD motif and the MLS, AIF possesses a potential Transmembrane Domain (TM, in green, amino-acids 67-83). This TM
is flanked by two peptidase-processing positions: a Mitochondrial Processing Peptidase (MPP)-cleavage site (in blue, amino-acid 54)
and a calpains- and/or cathepsins-cleavage site (in red, amino-acid 103). Hsp70 (Heat Shock Protein-70) and CypA (Cyclophilin A) bind
AIF in amino-acids 150-228 and 367-369, respectively. AIF also possesses two DNA-binding sites, which are located in amino-acids
255-265 and 510-518, respectively. AIF precursor protein has 613 amino-acids. The MPP-mediated cleavage generates the
mitochondrial mature AIF (amino-acids 55-613). After an apoptotic insult, calpains or cathepsins cleave AIF to produce truncated-AIF
(tAIF), which is released from mitochondria to cytosol (amino-acids 104-613).
Figure 2: Ribbon structure of mouse AIF in its mature form (pdb id: 1GV4). As depicted here, three domains are present in the protein.
The FAD-binding domain and the NAD-binding domain (yellow) are both similar to oxidoreductase domains from members of the
glutathione reductase family. In contrast, the C-terminal domain (blue) displays a particular folding with a specific insertion, which
includes residues 580 to 610. This picture also includes the AIF cofactor Flavin Adenine Dinucleotide (FAD; magenta).
Atlas Genet Cytogenet Oncol Haematol. 2008;12(3)
191
AIFM1 (apoptosis-inducing factor, mitochondrion-associated, 1)
Yuste VJ, et al.
Protein
programmed cell death: chromatin condensation and
large-scale approximatively 50 kb DNA fragmentation.
Note: 613 amino acids long protein whose structure
may be divided into three domains: a FAD-binding
domain (residues 128-262 and 401-480), a NADHbinding domain (residues 263-400), and a C-terminal
domain (residues 481-608).
Expression
Description
Function
AIF was initially identified as a protein released from
the mitochondrial intermembrane space during the
apoptotic process. First studies showed that upon an
apoptotic stimulus AIF translocates from mitochondria
to cytosol and further to the nucleus where it triggers
caspase-independent programmed cell death. AIF,
expressed as a precursor of 67 kDa, is addressed to
mitochondria by the two MLS placed within the Nterminal prodomain of the protein. Once in
mitochondria, this precursor is processed to a mature
form of 62 kDa by a first proteolytic cleavage. In this
configuration, AIF is an inner-membrane-anchored
protein in which the N-terminus is exposed to the
mitochondrial matrix and the C-terminal portion to the
mitochondrial intermembrane space. AIF is here
required for maintenance or maturation of the
mitochondrial respiratory chain complex I. After a cell
death insult, the 62 kDa AIF-mitochondrial form is
cleaved by activated calpains and/or cathepsins to yield
a soluble proapoptotic protein with an apparent
molecular weight of 57 kDa tAIF (truncated AIF). tAIF
is released from mitochondria to cytosol and nucleus to
generate two typical hallmarks of caspase-independent
AIF has a double life/death function.
In its vital role, AIF is required to maintain and/or
organize the mitochondrial respiratory complex I, and
displays NADH oxidoreductase and peroxide
scavenging activities. In addition to this vital function,
AIF has been shown to be implicated in programmed
cell death (PCD) induction in several experimental
models (see bibliography section). In the two most
studied AIF-dependent PCD models, AIF death activity
is associated with the increase of intracellular Ca2+
(e.g., ischemia/reperfusion injury), or relates with
extensive DNA-damage (e.g., treatment with alkylating
agents). In the first model, increased intracellular Ca2+
levels trigger depolarization of mitochondrial
membrane, subsequent loss of membrane potential,
generation of reactive oxygen species (ROS), and AIF
mitochondrial release. In the second model, extensive
DNA damage, provoked by high doses of alkylating
agents such as MNNG or MNU, triggers poly(ADPribose) polymerase-1 (PARP-1) over-activation and
AIF release from the mitochondrial intermembrane
space. This cell death pathway sequentially involves
PARP-1, calpains, Bax, and AIF.
Ubiquitously expressed.
Localisation
Mitochondrion.
Figure 3: Phylogenetic tree representing the relationship between AIF and other oxidoreductases from different species. Note the
proximity of the AIF family (red branch) to the NADH-oxidase family from Archaea. The PIR accession codes are enumerated following
the abbreviation of each specie: AA: Aquifex aeolicus; AC: Acinetobacter calcoaceticus; AF: Archaeoglobus fulgidus; AT: Arabidopsis
thaliana; BC: Burkholderia cepacia; BS: Bacillus subtilis; CE: Caenorhabditis elegans; DD: Dictyostelium discoideum; DM: Drosophila
melanogaster; EC: Escherichia coli; HS: Homo sapiens; LS: Lycopersicon esculentum; MJ: Methanocaldococcus jannaschii; MM: Mus
musculus; MTH: Methanobacterium thermoautotrophicum; N A: Novosphingobium aromaticivorans; PF: Pseudomonas fluorescens; PH:
Pyrococcus horikoshii; PO: Pseudomonas oleovorans; PP: Pseudomonas putida; PS: Pseudomonas sp.; PSA: Pisum sativum; SP:
Schizosaccharomyces pombe; SS: Sphingomonas sp.; RE: Rhodococcus erythropolis; RG: Rhodococcus globerulus; XL: Xenopus
laevis.
Atlas Genet Cytogenet Oncol Haematol. 2008;12(3)
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AIFM1 (apoptosis-inducing factor, mitochondrion-associated, 1)
Yuste VJ, et al.
Homology
References
AIF is a highly conserved protein ubiquitously present
in all primary kingdoms, Bacteria, Archaea and
Eucaryota. The aif gene is inherited from the last
universal common ancestor and follows the tree
topology with the primary radiation of the archaeoeukaryotic and bacterial clades. AIF also has a highly
significant homology with different families of
oxidoreductases, including NADH oxydases, Ascorbate
reductases, Glutathione reductases and many NADHdependent ferredoxin reductases from Archaea and
Bacteria to invertebrates and vertebrates.
Mouse, Rat homology.
Susin SA, Lorenzo HK, Zamzami N, Marzo I, Snow BE,
Brothers GM, Mangion J, Jacotot E, Costantini P, Loeffler M,
Larochette N, Goodlett DR, Aebersold R, Siderovski DP,
Penninger JM, Kroemer G. Molecular characterization of
mitochondrial
apoptosis-inducing
factor.
Nature
1999;397(6718):441-446.
Joza N, Susin SA, Daugas E, Stanford WL, Cho SK, Li CY,
Sasaki T, Elia AJ, Cheng HY, Ravagnan L, Ferri KF, Zamzami
N, Wakeham A, Hakem R, Yoshida H, Kong YY, Mak TW,
Zúñiga-Pflücker JC, Kroemer G, Penninger JM. Essential role
of the mitochondrial apoptosis-inducing factor in programmed
cell death. Nature 2001;410(6828):549-554.
Miramar MD, Costantini P, Ravagnan L, Saraiva LM, Haouzi D,
Brothers G, Penninger JM, Peleato ML, Kroemer G, Susin SA.
NADH oxidase activity of mitochondrial apoptosis-inducing
factor. J Biol Chem 2001;276(19):16391-16398.
Mutations
Ravagnan L, Gurbuxani S, Susin SA, Maisse C, Daugas E,
Zamzami N, Mak T, Jäättelä M, Penninger JM, Garrido C,
Kroemer G. Heat-shock protein 70 antagonizes apoptosisinducing factor. Nat Cell Biol 2001;3(9):839-843.
Note: Several polymorphisms have been identified but
none of them has shown any association with a disease.
Implicated in
Klein JA, Longo-Guess CM, Rossmann MP, Seburn KL, Hurd
RE, Frankel WN, Bronson RT, Ackerman SL. The harlequin
mouse mutation downregulates apoptosis-inducing factor.
Nature 2002;419(6905):367-374.
Various cancers
Note: Upregulated in cancers (colorectal carcinoma,
gastric carcinoma, breast carcinoma and hepatocellular
carcinoma, glioblastoma ).
AIF expression may play a role in tumor formation and
could maintain a transformed state of colon cancer cells
involving mitochondrial complex I function.
Maté MJ, Ortiz-Lombardía M, Boitel B, Haouz A, Tello D, Susin
SA, Penninger J, Kroemer G, Alzari PM. The crystal structure
of the mouse apoptosis-inducing factor AIF. Nat Struct Biol
2002;9(6):442-446.
Ye H, Cande C, Stephanou NC, Jiang S, Gurbuxani S,
Larochette N, Daugas E, Garrido C, Kroemer G, Wu H. DNA
binding is required for the apoptogenic action of apoptosis
inducing factor. Nat Struct Biol 2002;9(9):680-684.
Cell death
Yu SW, Wang H, Poitras MF, Coombs C, Bowers WJ, Federoff
HJ, Poirier GG, Dawson TM, Dawson VL. Mediation of
poly(ADP-ribose) polymerase-1-dependent cell death by
apoptosis-inducing factor. Science 2002;297(5579):259-263.
Disease
AIF has been directly designed as main mediator of cell
death in ischemic injuries after overproduction of
reactive oxygen species. Indeed, blocking the
mitochondrial release of AIF to cytosol and its further
nuclear translocation provides protection against
neuronal and cardiomyocites cell death. AIF-deficient
harlequin mutant mouse presents a significant reduction
of neuronal cell death in brain trauma and cerebral
ischemia. A similar protective effect was observed in
AIF siRNA-treated neurons.
Bidere N, Lorenzo HK, Carmona S, Laforge M, Harper F,
Dumont C, Senik A. Cathepsin D triggers Bax activation,
resulting in selective apoptosis-inducing factor (AIF) relocation
in T lymphocytes entering the early commitment phase to
apoptosis. J Biol Chem 2003;278(33):31401-31411.
Gurbuxani S, Schmitt E, Cande C, Parcellier A, Hammann A,
Daugas E, Kouranti I, Spahr C, Pance A, Kroemer G, Garrido
C. Heat shock protein 70 binding inhibits the nuclear import of
apoptosis-inducing factor. Oncogene 2003;22(43):6669-6678.
Yu SW, Wang H, Dawson TM, Dawson VL. Poly(ADP-ribose)
polymerase-1 and apoptosis inducing factor in neurotoxicity.
Neurobiol Dis 2003;14(3):303-317. (Review).
Degenerative disorders
Disease
AIF is involved in several degenerative disorders. The
elevated production of ROS generated in Amyotrophic
Lateral Sclerosis, Alzheimer's, or Parkinson diseases
concludes in the translocation of AIF. Likewise, AIF
release triggered by calpains and cathepsins was
observed on in vitro models of Epilepsy and
Huntington's disease. AIF-mediated cell death is
involved in the pathogenesis of different retinal
affections such as retinal detachment, retinitis
pigmentosa, or in models of retinal hypoxia. Moreover,
an increase of AIF expression has been reported in
patients affected with diabetic retinopathy.
Atlas Genet Cytogenet Oncol Haematol. 2008;12(3)
Candé C, Vahsen N, Kouranti I, Schmitt E, Daugas E, Spahr
C, Luban J, Kroemer RT, Giordanetto F, Garrido C, Penninger
JM, Kroemer G. AIF and cyclophilin A cooperate in apoptosisassociated chromatinolysis. Oncogene 2004;23(8):1514-1521.
Gallego MA, Joseph B, Hemström TH, Tamiji S, Mortier L,
Kroemer G, Formstecher P, Zhivotovsky B, Marchetti P.
Apoptosis-inducing factor determines the chemoresistance of
non-small-cell lung carcinomas. Oncogene 2004;23(37):62826291.
Vahsen N, Candé C, Brière JJ, Bénit P, Joza N, Larochette N,
Mastroberardino PG, Pequignot MO, Casares N, Lazar V,
Feraud O, Debili N, Wissing S, Engelhardt S, Madeo F,
Piacentini M, Penninger JM, Schägger H, Rustin P, Kroemer
G. AIF deficiency compromises oxidative phosphorylation.
EMBO J 2004;23(23):4679-4689.
193
AIFM1 (apoptosis-inducing factor, mitochondrion-associated, 1)
Yuste VJ, et al.
Otera H, Ohsakaya S, Nagaura Z, Ishihara N, Mihara K. Export
of mitochondrial AIF in response to proapoptotic stimuli
depends on processing at the intermembrane space. EMBO J
2005;24(7):1375-1386.
analysis of apoptosis-inducing factor (AIF) in colorectal
carcinomas. APMIS 2006;114(12):867-873.
Modjtahedi N, Giordanetto F, Madeo F, Kroemer G. Apoptosisinducing factor: vital and lethal. Trends Cell Biol
2006;16(5):264-272. (Review).
Polster BM, Basañez G, Etxebarria A, Hardwick JM, Nicholls
DG. Calpain I induces cleavage and release of apoptosisinducing factor from isolated mitochondria. J Biol Chem
2005;280(8):6447-6454.
Ruchalski K, Mao H, Li Z, Wang Z, Gillers S, Wang Y, Mosser
DD, Gabai V, Schwartz JH, Borkan SC. Distinct hsp70
domains mediate apoptosis-inducing factor release and
nuclear accumulation. J Biol Chem 2006;281(12):7873-7880.
Urbano A, Lakshmanan U, Choo PH, Kwan JC, Ng PY, Guo K,
Dhakshinamoorthy S, Porter A. AIF suppresses chemical
stress-induced apoptosis and maintains the transformed state
of tumor cells. EMBO J 2005;24(15):2815-2826.
Stambolsky P, Weisz L, Shats I, Klein Y, Goldfinger N, Oren M,
Rotter V. Regulation of AIF expression by p53. Cell Death
Differ 2006;13(12):2140-2149.
Yuste VJ, Moubarak RS, Delettre C, Bras M, Sancho P, Robert
N, d'Alayer J, Susin SA. Cysteine protease inhibition prevents
mitochondrial apoptosis-inducing factor (AIF) release. Cell
Death Differ 2005;12(11):1445-1448.
Vahsen N, Candé C, Dupaigne P, Giordanetto F, Kroemer RT,
Herker E, Scholz S, Modjtahedi N, Madeo F, Le Cam E,
Kroemer G. Physical interaction of apoptosis-inducing factor
with DNA and RNA. Oncogene 2006;25(12):1763-1774.
Artus C, Maquarre E, Moubarak RS, Delettre C, Jasmin C,
Susin SA, Robert-Lézénès J. CD44 ligation induces caspaseindependent cell death via a novel calpain/AIF pathway in
human erythroleukemia cells. Oncogene 2006;25(42):57415751.
Yu SW, Andrabi SA, Wang H, Kim NS, Poirier GG, Dawson
TM, Dawson VL. Apoptosis-inducing factor mediates
poly(ADP-ribose) (PAR) polymer-induced cell death. Proc Natl
Acad Sci USA 2006;103(48):18314-18319.
Boujrad H, Gubkina O, Robert N, Krantic S, Susin SA. AIFMediated Programmed Necrosis: A Highly Regulated Way to
Die. Cell Cycle 2007 Nov 1;6(21):2612-2619.
Cheung EC, Joza N, Steenaart NA, McClellan KA, Neuspiel M,
McNamara S, MacLaurin JG, Rippstein P, Park DS, Shore GC,
McBride HM, Penninger JM, Slack RS. Dissociating the dual
roles of apoptosis-inducing factor in maintaining mitochondrial
structure and apoptosis. EMBO J 2006;25(17):4061-4073.
Lorenzo HK, Susin SA. Therapeutic potential of AIF-mediated
caspase-independent programmed cell death. Drug Resist
Updat 2007 December;10(6):235-255
Delettre C, Yuste VJ, Moubarak RS, Bras M, Lesbordes-Brion
JC, Petres S, Bellalou J, Susin SA. AIFsh, a novel apoptosisinducing factor (AIF) pro-apoptotic isoform with potential
pathological relevance in human cancer. J Biol Chem
2006;281(10):6413-6427.
Moubarak RS, Yuste VJ, Artus C, Bouharrour A, Greer PA,
Menissier-de Murcia J, Susin SA. Sequential activation of
poly(ADP-ribose) polymerase 1, calpains, and Bax is essential
in apoptosis-inducing factor-mediated programmed necrosis.
Mol Cell Biol 2007;27(13):4844-4862.
Delettre C, Yuste VJ, Moubarak RS, Bras M, Robert N, Susin
SA. Identification and characterization of AIFsh2, a
mitochondrial apoptosis-inducing factor (AIF) isoform with
NADH oxidase activity. J Biol Chem 2006;281(27):1850718518.
This article should be referenced as such:
Yuste VJ, Lorenzo HK, Susin SA. AIFM1 (apoptosis-inducing
factor, mitochondrion-associated, 1). Atlas Genet Cytogenet
Oncol Haematol.2008;12(3):190-194.
Jeong EG, Lee JW, Soung YH, Nam SW, Kim SH, Lee JY,
Yoo NJ, Lee SH. Immunohistochemical and mutational
Atlas Genet Cytogenet Oncol Haematol. 2008;12(3)
194
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Gene Section
Mini Review
BNIP3 (Bcl-2/adenovirus E1B 19kD-interacting
protein 3)
Sang-Gi Paik, Hayyoung Lee
Department of Biology, School of Biosciences and Biotechnology, Chungnam National University, Daejeon
305-764, Korea
Published in Atlas Database: October 2007
Online updated version: http://AtlasGeneticsOncology.org/Genes/BNIP3ID822ch10q26.html
DOI: 10.4267/2042/38517
This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence.
© 2008 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Expression
Identity
BNIP3 is detected in mouse oviduct, uterus, spleen,
lung, stomach, brain, seminal, lacrimal, submaxillary,
heart, kidney, liver. It can be detected in cell lines such
as HeLa, 293T, RAW264.7 and K562 cells. Its
expression can be induced in both normal and cancer
tissues that experience hypoxia or hypoxia-like
conditions. Other stimuli, such as nitric oxide or arsenic
trioxide, are also reported to induce BNIP3 expression.
Hugo: BNIP3
Other names: NIP3
Location: 10q26.3
DNA/RNA
Localisation
Outer mitochondrial membrane.
Description
Function
14.23 kb on reverse strand; 6 exons
Proapoptotic protein;
BNIP3 leads to opening of the mitochondrial
permeability transition pore (PTP) thereby abolishing
the proton electrochemical gradient and this is followed
by chromatin condensation and DNA fragmentation.
BNIP3 leads necrosis-like apoptosis. Unusually to the
other Bcl-2 family proteins, the BNIP3-induced cell
death depends not on BH3 domain but on C-terminal
TM domain. BNIP3-induced cell death is known to be
independent the nuclear translocation of AIF. However,
whether caspase activation and cytochrome c release
are involved in the cell death remains controversial.
BNIP3 can induce autophagy. However whether the
consequence of the autophagy is the cell death or
survival remains to be established.
Since BNIP3 is induced by hypoxia through
transcription factor HIF-1, it was postulated to play a
role in hypoxia-induced cell death. Hypoxia-induced
acidosis augments the proapoptotic function of BNIP3.
Transcription
mRNA in MCF-7 cells are 1.7kb (major) and 1.5 kb
(minor) and 1.3 kb (minor).
Protein
Domain map of BNIP3 protein; BH3 domain (Bcl-2 holomogy 3
domain); TM domain (transmembrane domain)
Description
194 amino acids; 1 BH3 domain and 1 TM domain;
BH3 only Bcl2 family member. The TM domain and
C-terminal tail are essential for mitochondrial
membrane localization and proapoptotic function. The
predicted molecular weight is 21.5 kDa. BNIP3
migrates as 30 kDa monomeric form and 60 kDa
dimeric form on SDS-PAGE.
Atlas Genet Cytogenet Oncol Haematol. 2008;12(3)
Homology
The close
(8q21).
195
homologue:
BNIP3L/BNIP3a/Nix/B5
BNIP3 (Bcl-2/adenovirus E1B 19kD-interacting protein 3)
Paik SG, Lee H
necrosis-like cell death through the mitochondrial permeability
transition pore. Mol Cell Biol 2000;20:5454-5468.
The BH3-only Bcl2 family members: BBC3/PUMA
(19q13), BCL2L11/BIM/BOD (2q13), BID (22q11),
BIK/NBK/BBC1 (22q13), BLK (8q23), BMF (15q14),
HRK/DP5/BID3 (12q24), PMAIP1/NOXA (18q21).
Kim JY, Cho JJ, Ha J, Park JH. The carboxy terminal C-tail of
BNip3 is crucial in induction of mitochondrial permeability
transition in isolated mitochondria. Arch Biochem Biophys
2002;398:147-152.
Implicated in
Kubasiak LA, Hernandez OM, Bishopric NH, Webster KA.
Hypoxia and acidosis activate cardiac myocyte death through
the Bcl-2 family protein BNIP3. Proc Natl Acad Sci USA
2002;99:12825-12830.
Pancreatic cancer
Prognosis
Pancreatic adenocarcinoma is highly resistant to
chemical and radiation therapy, and has an extremely
poor prognosis. Reduced expression of BNIP3
increased resistance to gemcitabine and 5-fluoro-uracil
(5-FU) and showed a good correlation with reduced
patient survival.
Oncogenesis
In most cases of pancreatic adenocarcinoma, BNIP3
expression was not detected even in response to
hypoxia. The promoter of BNIP3 is located within a
CpG island and is methylated in most pancreatic cancer
cell lines. Restoration of BNIP3 expression by the
methyltransferase
inhibitor,
5-aza-deoxycytidine,
induced death of pancreatic cancer cells in response to
hypoxia.
Okami J, Simeone DM, Logsdon CD. Silencing of the hypoxiainducible cell death protein BNIP3 in pancreatic cancer.
Cancer Res 2004;64:5338-5346.
Yook YH, Kang KH, Maeng O, Kim TR, Lee JO, Kang KI, Kim
YS, Paik SG, Lee H. Nitric oxide induces BNIP3 expression
that causes cell death in macrophages. Biochem Biophys Res
Commun 2004;321:298-305.
Abe T, Toyota M, Suzuki H, Murai M, Akino K, Ueno, M,
Nojima M, Yawata A, Miyakawa H, Suga T, Ito H, Endo T,
Tokino T, Hinoda Y, Imai K. Upregulation of BNIP3 by 5-aza-2'deoxycytidine sensitizes pancreatic cancer cells to hypoxiamediated cell death. J Gastroenterol 2005;40:504-510.
Akada M, Crnogorac-Jurcevic T, Lattimore S, Mahon P, Lopes
R, Sunamura M, Matsuno S, Lemoine NR. Intrinsic
chemoresistance to gemcitabine is associated with decreased
expression of BNIP3 in pancreatic cancer. Clin Cancer Res
2005;11:3094-3101.
Erkan M, Kleeff J, Esposito I, Giese T, Ketterer K, Buchler MW,
Giese NA, Friess H. Loss of BNIP3 expression is a late event
in pancreatic cancer contributing to chemoresistance and
worsened prognosis. Oncogene 2005;24:4421-4432.
Colorectal cancer
Oncogenesis
Methylation of BNIP3 in 66% of primary colorectal
cancer.
Murai M, Toyota M, Satoh A, Suzuki H, Akino K, Mita H,
Sasaki Y, Ishida T, Shen L, Garcia-Manero G, Issa JP, Hinoda
Y, Tokino T, Imai K. Aberrant DNA methylation associated with
silencing BNIP3 gene expression in haematopoietic tumours.
Br J Cancer 2005;92:1165-1172.
References
Murai M, Toyota M, Suzuki H, Satoh A, Sasaki Y, Akino K,
Ueno M, Takahashi F, Kusano M, Mita H, Yanagihara K, Endo
T, Hinoda Y, Tokino T, Imai K. Aberrant methylation and
silencing of the BNIP3 gene in colorectal and gastric cancer.
Clin Cancer Res 2005;11:1021-1027.
Boyd JM, Malstrom S, Subramanian T, Venkatesh LK,
Schaeper U, Elangovan B, D'Sa-Eipper C, Chinnadurai G.
Adenovirus E1B 19 kDa and Bcl-2 proteins interact with a
common set of cellular proteins. Cell 1994;79:341-351.
Webster KA, Graham RM, Bishopric NH. BNip3 and signalspecific programmed death in the heart. J Mol Cell Cardiol
2005;38:35-45.
Chen G, Ray R, Dubik D, Shi L, Cizeau J, Bleackley RC,
Saxena S, Gietz RD, Greenberg AH. The E1B 19K/Bcl-2binding protein Nip3 is a dimeric mitochondrial protein that
activates apoptosis. J Exp Med 1997;186:1975-1983.
An HJ, Maeng O, Kang KH, Lee JO, Kim YS, Paik SG, Lee H.
Activation of Ras upregulates pro-apoptotic BNIP3 in nitric
oxide-induced cell death. J Biol Chem 2006;281:33939-33948.
Yasuda M, Theodorakis P, Subramanian T, Chinnadurai G.
Adenovirus E1B-19K/BCL-2 interacting protein BNIP3 contains
a BH3 domain and a mitochondrial targeting sequence. J Biol
Chem 1998;273:12415-12421.
Lee H, Paik SG. Regulation of BNIP3 in normal and cancer
cells. Mol Cells 2006;21:1-6. (Review).
Bruick RK. Expression of the gene encoding the proapoptotic
Nip3 protein is induced by hypoxia. Proc Natl Acad Sci USA
2000;97:9082-9087.
Bacon AL, Fox S, Turley H, Harris AL. Selective silencing of
the hypoxia-inducible factor 1 target gene BNIP3 by histone
deacetylation and methylation in colorectal cancer. Oncogene
2007;26:132-141.
Ray R, Chen G, Vande Velde C, Cizeau J, Park JH, Reed JC,
Gietz RD, Greenberg AH. BNIP3 heterodimerizes with Bcl2/Bcl-X(L) and induces cell death independent of a Bcl-2
homology 3 (BH3) domain at both mitochondrial and
nonmitochondrial sites. J Biol Chem 2000;275:1439-1448.
This article should be referenced as such:
Paik SG, Lee H. BNIP3 (Bcl-2/adenovirus E1B 19kDinteracting protein 3). Atlas Genet Cytogenet Oncol
Haematol.2008;12(3):195-196.
Vande Velde C, Cizeau J, Dubik D, Alimonti J, Brown T, Israels
S, Hakem R, Greenberg AH. BNIP3 and genetic control of
Atlas Genet Cytogenet Oncol Haematol. 2008;12(3)
196
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Gene Section
Review
BRCA1 (breast cancer 1, early onset)
Sreeparna Banerjee
Department of Biology, Middle East Technical University, Ankara 06531, Turkey
Published in Atlas Database: October 2007
Online updated version: http://AtlasGeneticsOncology.org/Genes/BRCA1ID163ch17q21.html
DOI: 10.4267/2042/38518
This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence.
© 2008 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Description
Identity
According to Entrez-Gene, BRCA1 gene maps to
NC_000017.9 in the region between 38449840 and
38530994 on the minus strand and spans across 81.1
kilo bases. According to Spidey (mRNA to genomic
sequence
alignment
tool,
http://www.ncbi.nlm.nih.gov/spidey), BRCA1 has 24
exons, the sizes being 181, 99, 54, 78, 89, 140, 105, 47,
77, 89, 172, 127, 191, 311, 88, 78, 41, 84, 55, 74, 61,
1506.
Hugo: BRCA1
Other names: BRCAI; BRCC1; IRIS; PSCP; RNF53
Location: 17q21.31
Local order: According to NCBI Map Viewer, genes
flanking BRCA1 in centromere to telomere direction
on 17q21 are: VAT1 17q21 (vesicle amine transport
protein 1 homolog (T californica)); RND2 17q21 Rho
family GTPase 2; RPL21P4 17q21 ribosomal protein
L21 pseudogene 4; BRCA1 17q21 breast cancer 1,
early onset; NBR2 17q21 neighbour of BRCA1 gene;
BRCA1P1 17q21 BRCA1 pseudogene 1; NBR1
17q21.31 neighbour of BRCA1 gene.
Note: BRCA1 is a tumour suppressor phosphoprotein
that combines with other tumour suppressors, DNA
damage and repair proteins, and signal transducers to
form a large multi-subunit protein complex known as
BRCA1-associated genome surveillance complex
(BASC). Truncating mutations and missence mutations
in the BRCA1 gene are found in a large number of
familial breast cancer cases. Individuals who inherit a
germline mutation of BRCA1 or BRCA2 have a
significantly increased lifetime risk for the
development of breast and/or ovarian cancer.
Transcription
BRCA1 mRNA NM_007302.3 has 7388 bps. The
BRCA1 gene contains two separate promoters that
induce transcription of mRNAs with different 5'UTRs,
a shorter 5'UTRa and a longer 5'UTRb. The
downregulation of BRCA1 gene expression in certain
breast cancers is caused by a switch from expression of
a 5'UTRa, which enables efficient translation, to
expression of 5'UTRb, which contains secondary
structure and upstream open reading frames that
strongly inhibit translation.
Pseudogene
According to Entrez Gene the BRCA1 pseudogene 1
(BRCA1P1) is located on 17q21.
DNA/RNA
Protein
Note: The subcellular localization and physiological
function of this gene is greatly modulated by the
several alternately splices isoforms that are found.
Several of these alternatively spliced transcript variants
have been described, however, not all have had their
full-length natures identified.
Atlas Genet Cytogenet Oncol Haematol. 2008;12(3)
Note: BRCA1 sequence is not well conserved between
mammals, however, two domains, the C terminal
BRCT (BRCA1 C Terminal) motifs and the N-terminal
RING domain are highly conserved.
197
BRCA1 (breast cancer 1, early onset)
Banerjee S
The BRCA1 protein showing the RING finger domain, the Nuclear Localisation Signal domain and the BRCT domains. AA- amino acids.
Description
Expression
BRCA1 is an 1863 amino acid 220kDa protein with an
E3 ubiquitin ligase activity as well as a phosphopeptide binding activity. It has several domains that are
essential for its function as depicted in the figure. The
RING finger domain of BRCA1, commonly found in
many DNA repair proteins, consists of a conserved
core of approximately 50 amino acids in a pattern of
seven cysteine residues and one histidine residue to
form a structure that can bind to two Zn++ ions. This
motif aids in mediating protein-protein interaction, as
exemplified by the interaction of BRCA1 with BARD1
(BRCA1 associated RING domain). This interaction is
critical since mutations in the Zn++ binding regions,
crucial for heterodimerization with BARD1, have been
found in tumours. BRCA1 accumulates in distinct foci
in the nucleus during S phase and this transfer is aided
by its Nuclear Localisation Signal (NLS) domain. A
further role of BARD1 is also implicated whereby its
association with the RING finger domain of BRCA1 is
necessary for the transfer of BRCA1 to the nucleus.
BRCA1 interacts with Rad50 of the MRN complex
through the region AA 341-748 and can directly bind to
branched, flap and four way DNA structures through a
central domain spanning residues 452-1079. The
protein inhibits the nucleolytic activities of the
Mre11/Rad50/Nbs1 complex as a result of this direct
DNA binding. The C terminus of BRCA1, which can
function as a transcriptional activation domain, consists
of two tandemly arranged elements called BRCT
(BRCA1 C- terminal). This motif specifically binds to
phosphorylated proteins, an event that is commonly
associated with DNA damage response. BRCA1 is
capable of interacting directly with BRCA2 and with
Rad51 via BRCA2 through this motif. Another protein
that interacts with BRCA1 via BRCT is the BRCA1
associated C-terminal helicase (BACH1). BACH1 is
said to aid BRCA1 in the DNA damage response and
maintain the protein at the nuclear foci formed after
DNA damage response. Other proteins that can interact
with BRCA1 through the BRCT domains are C
terminal Interacting protein /CtIP), RNA Polymerase II,
BACH 1 (a member of DEAH helicase family) and
p53.
BRCA1 is ubiquitously expressed in humans with the
highest levels observed in the ovaries, testis and
thymus. It is a tumour suppressor and a reduced
expression is correlated with the transformation
procedure and aetiology of sporadic breast cancer. This
reduction is expression is said to be transcriptionally
regulated with implications of aberrant promoter
methylation at CpG dinucleotides as well as CREB
binding sites.
Atlas Genet Cytogenet Oncol Haematol. 2008;12(3)
Localisation
Located in the nucleus.
Function
Role of BRCA1 in DNA repair: BRCA1 is a part of a
large complex of proteins, the BASC, which monitors
the genome for damage and signals downstream
effectors. BRCA1 has been implicated in two pathways
of DNA double strand break repair: homologous
recombination (HR) and non homologous end joining
(NHEJ). Upon exposure to DNA damaging agents,
BRCA1 becomes hyperphosphorylated and is rapidly
relocated, along with Rad51, to sites of DNA synthesis
marked by proliferating cell nuclear antigen (PCNA).
Rad51, a homolog of the bacterial RecA, is a central
player in HR, catalyzing the invasion of the single
stranded DNA in a homologous duplex and facilitating
the homology search during the establishment of joint
molecules. A recent study, however, has indicated that
BRCA1 deficient breast cancer cells compensate for
this deficiency by upregulating Rad51. The resultant
HR may be erroneous and thereby lead to
tumorigenesis. In addition, BRCA1 is said to inhibit the
MRN complex which is is implicated in bringing
together two DNA strands together for the error prone
NHEJ. BRCA1-deficient cells are sensitive to ionizing
radiation and DNA damaging drugs, such as mitomycin
C.
Transcriptional regulation: BRCA1 is capable of
transcriptional regulation and chromatin remodelling
when tethered to promoters of genes important in the
DNA repair process and breast cancer markers. It is a
198
BRCA1 (breast cancer 1, early onset)
Banerjee S
many of which are rare. These mutations are distributed
uniformly along the entire coding region and intronic
sequences flanking each exon. The mutations are at a
high penetrance therefore women who carry these
mutations have a lifetime risk of 80-90% to develop
breast cancer. Founder mutations such as the BRCA1185delAG and 5382insC are found among Ashkenazi
Jews. Larger and complex genomic rearrangements in
the exons 21 and 22 of the BRCA1 gene, resulting in a
lack of the BRCT motif have been reported.
member of the core RNA polymerase II transcriptional
machinery, a feature exploited by the DNA damage
recognition process. In addition, BRCA1 interacts with
p300/CBP, transcriptional coactivators for CREB.
p300/CBP are inhibited by the viral oncoprotein E1A
and the functionality of E1A as an oncogene could be
in part caused by an obstruction of BRCA1:p300/CBP
cooperation resulting in the loss of the tumoursuppressing function of BRCA1. BRCA1 can act as a
transcriptional coactivator or co repressor of proteins
implicated in chromatin remodelling, such as the
histone deacetylase complexes or components of the
SWI/SNF-related chromatin-remodelling complex.
Cell Cycle Regulation by BRCA1: BRCA1, based on
its phosphorylation status, elicits DNA damage induced
cell cycle arrest at several stages through modulation of
specific
downstream
target
genes.
BRCA1
transactivates p21cip1/WAF1, which contributes to an
arrest at the G1/S boundary. ATM phosphorylation of
BRCA1 appears to be important for its role in the intra
S phase checkpoint activation. BRCA1 is also
implicated in the transcriptional regulation of several
genes such as cyclinB, 14-3-3sigma, GADD45, wee-1
kinase and PLK1 associated with the G2/M checkpoint.
p53-dependent apoptosis: The BRCA1 protein is
capable of physically interacting with the p53 tumour
suppressor gene, and can stimulate p53-dependent
transcription from the p21WAF1/CIP1 mdm2 and
promoters. In addition, the BRCA1-BARD1 complex is
required for the phosphorylation of p53 at Ser15 by
ATM/ATR following DNA damage by IR or UV
radiation. The phosphorylation of p53 at Ser-15 is
essential for the G(1)/S cell cycle arrest via
transcriptional induction of the cyclin-dependent kinase
inhibitor p21 after DNA damage.
Ubiquitination: BRCA1 and BARD1 interact together
to form an E3 ubiquitin ligase. RNA polII stalled at
sites of DNA damage is a target for this ubiquitin ligase
mediated degradation following DNA damage, thereby
allowing access to the repair machinery. BRCA1
ubiquitinates the transcriptional preinitiation complex,
not for proteasomal degradation, but to prevent a stable
association of TFIIE and TFIIH; thereby blocking the
initiation of mRNA synthesis.
Implicated in
Breast cancer
Disease
Heterozygous carriers of high-risk mutations in the
general Caucasian population have been estimated to
be about one in 1000 for the BRCA1 gene. The lifetime
risk of the development of hereditary breast cancer with
the presence of BRCA1 mutations is very high. In
addition, for sporadic breast cancer, a reduction in the
expression of BRCA1 rather than the presence of
mutations has been observed. The lack of a functional
BRCA1 leads to impaired repair of DNA double strand
breaks, cell cycle progression and transcriptional
regulation, thereby causing the development of
neoplasms.
Ovarian cancer
Disease
Mutations of the BRCA1 gene is the major cause for
familial breast and ovarian cancer incidence. The
lifetime risks of ovarian cancer associated with a
BRCA1 gene mutation carrier has been estimated as 40
to 50%. The most common mutations are frameshift
and nonsense mutations that are predicted to cause
premature truncation of the BRCA1 protein. In
addition, mutations that are predicted to affect splicesite consensus sequences as well as missense mutation
have also been seen in ovarian cancer. Large genomic
alterations, such as the gains in copy number of exon
13 as well as deletion of exons in the BRCA1 gene is
also associated with the development of ovarian cancer.
Other cancers
Homology
Disease
An increased relative risk to the development of cancer
of the colon, cervix, uterus, pancreas and prostate has
been suggested in BRCA1-mutation carriers.
Dog (Canis familiaris): BRCA1;
Chimpanzee (Pan troglodytes): BRCA1;
Rat (Rattus norvegicus): Brca1;
Mouse (Mus musculus): Brca1;
Chicken (Gallus gallus): BRCA1.
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Yabuki Y, Ogata H, Ohta T. The RING heterodimer BRCA1BARD1 is a ubiquitin ligase inactivated by a breast cancerderived mutation. J Biol Chem 2001;276(18):14537-14540.
Ramus SJ, Harrington PA, Pye C, Dicioccio RA, Cox MJ,
Garlinghouse-Jones K, Oakley-Girvan I, Jacobs IJ, Hardy RM,
Whittemore AS, Ponder BA, Piver MS, Pharoah PD, Gayther
SA. Contribution of BRCA1 and BRCA2 mutations to inherited
ovarian cancer. Hum Mutat 2007;28(12):1207-1215.
Paull TT, Cortez D, Bowers B, Elledge SJ, Gellert M. Direct
DNA binding by BRCA1. Proc Natl Acad Sci USA
2001;98:6086-6091.
Zikan M, Pohlreich P, Stribrna J, Kleibl Z, Cibula D. Novel
complex genomic rearrangement of the BRCA1 gene. Mutat
Res 2007; 637 (1-2):205-208.
Fabbro M, Rodriguez JA, Baer R, Henderson BR. BARD1
induces BRCA1 intranuclear foci formation by increasing
RING-dependent BRCA1 nuclear import and inhibiting BRCA1
nuclear export. J Biol Chem 2002;277(24):21315-21324.
Jasin M. Homologous repair
tumorigenesis:
the
BRCA
2002;21(58):8981-8993.
This article should be referenced as such:
of DNA damage and
connection.
Oncogene
Atlas Genet Cytogenet Oncol Haematol. 2008;12(3)
Banerjee S. BRCA1 (breast cancer 1, early onset). Atlas Genet
Cytogenet Oncol Haematol.2008;12(3):197-200.
200
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Gene Section
Review
CD97 (CD97 molecule)
Gabriela Aust
University of Leipzig, Faculty of Medicine, Research Laboratories, Center of Surgery, Liebigstr. 20, Leipzig,
D-04103, Germany
Published in Atlas Database: October 2007
Online updated version: http://AtlasGeneticsOncology.org/Genes/CD97ID996ch19p13.html
DOI: 10.4267/2042/38519
This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence.
© 2008 Atlas of Genetics and Cytogenetics in Oncology and Haematology
DNA/RNA
orientation; 2508 bp open reading frame. Human CD97
exists in three isoforms that result from alternative
splicing of exons 5 and 6 and thus contain different
numbers of EGF domains in the extracellular part of
the molecule. The isoforms are designated as CD97
(EGF1,2,5), CD97 (EGF1,2,3,5) and CD97 (EGF1-5)
in human.
Description
Pseudogene
DNA contains 27.322 kb composed of 20 coding
exons. Exons 1-2 encode the 5' untranslated region and
the signal peptide, exons 3-7 the five EGF domains,
exons 8-13 the extracellular stalk, exons 14-18 the
seven-span transmembrane (TM7) domains and exons
19-20 the intracellular part and the 3' untranslated
region.
No pseudogenes reported.
Identity
Hugo: CD97
Other names: TM7LN1
Location: 19p13
Protein
Description
CD97 belongs to the B family of G protein-coupled
receptors (GCPRs). Subfamily B2 contains cell surface
molecules with long extracellular N-termini (LNBTM7) known also as adhesion class of heptahelical
receptors.
Transcription
3247 bp mRNA transcribed in telomeric to centromeric
Genomic organization of CD97 (drawn to scale), boxes represent exons.
Structure of CD97. Three isoforms containing 3, 4, or 5 EGF domains exist. N-glycosylation sites in the EGF domains are indicated.
Atlas Genet Cytogenet Oncol Haematol. 2008;12(3)
201
CD97 (CD97 molecule)
Aust G
CD97 is the founding member of a small subfamily
within the adhesion class called EGF-TM7 family. All
EGF-TM7 receptors (CD97, EMR1, EMR2, EMR3,
EMR4) consist of extracellular tandemly arranged EGF
domains, a stalk, the seven-span transmembrane (TM7)
und a short intracellular part. They are expressed as
heterodimers of a non-covalently bound alpha- and
beta-chain resulting from intracellular autocatalytic
cleavage at a conserved GCPR proteolytic site (GPS).
The alpha-chain represents the extracellular region with
the varying numbers of EGF domains and the main part
of the stalk and the beta-chain consists of the stalk
residue, the TM7 and intracellular part.
Three CD97 isoforms containing 3, 4 or 5 EGF
domains are described. The mature full length proteins
contain either 722, 766 or 815 amino acids (aa). After
cleavage the (secretory) alpha-chains contain 420, 464,
or 513 aa. The beta-chain theoretically contains 305 aa
with a molecular weight of 34.3 kDa. However,
immunoprecipitation of the beta-chain yielded a
molecular weight of approximately 28 kDa. The
discrepancy between the theoretical and actual
molecular weight of the beta-chain is not yet clarified.
Depending on the cell type and transformation status of
the cell, CD97 is completely or partly N-glycosylated
or naked. In normal muscle cells CD97 is not or only
slightly N-glycosylated. The molecular weight for the
respective naked alpha-chain of the various CD97
isoforms are 45.6, 50.5 and 55.8 kDa. In hematopoetic
cells CD97 is N-glycosylated at the EGF domains
resulting in molecular weights of 74-78, 80-82, and 8689 kDa for the alpha-chains of the respective isoform.
During tumor transformation CD97 may get Nglycosylated. Although the CD97 stalk contains many
Ser or Thr residues the molecule seems not to be Oglycosylated.
Function
CD97 has the ability to bind cellular and extracellular
matrix ligands. The first two EGF domains of CD97
bind CD55 (decay accelerating factor). The fourth EGF
domain of CD97 and thus only the longest CD97
isoform interacts with the glycosaminoglycan
chondroitin sulfate B. CD97 binds to alpha5beta1 and
alphavbeta3 integrins through interaction with the
CD97 stalk region.
- Hematopoetic cells: Functional studies indicate a role
of CD97 in leukocyte trafficking. CD97 antibodies
block tissue localization of immune cells in vivo
leading to impaired protection against bacteria and
amelioration of autoimmune pathology.
- Tumor cells: In vitro CD97 increases single cell
random motility and directed migration and invasion of
tumor cells in 2D and 3D matrices. CD97 enhances
proteolytic activity of matrix metalloproteinases
(MMPs) and secretion of chemokines in an isoformspecific manner. CD97 (EGF 1,2,5) overexpression
promotes tumor growth in scid mice.
The alpha-chain of the longest CD97 (EGF1-5) isoform
(sCD97) enhances angiogenesis in in vivo tumor
models.
- Muscle, fat, duct cells: function unknown.
Homology
H. sapiens: CD97
P. troglodytes: CD97
B. taurus: CD97
S. scrofa: CD97
C. lupus: CD97
M. musculus: CD97
R. norvegicus: CD97
Exists only in mammals.
Mutations
Expression
Broad, not cell-type specific.
- Hematopoetic system: strong in peripheral blood
myeloid cells and activated lymphocytes, moderately in
subsets of tissue-derived leukocytes;
- Strong in smooth muscle cells (except for arterial
vascular smooth muscle cells), skeletal muscle cells
(stronger in slow-twitch fibers), heart muscle cells;
- Fat cells;
- Low in normal intestinal, thyroidal epithelial cells,
moderately in duct cells of the pancreas, parotis gland
and in bile duct cells of the liver.
Note: unknown.
Implicated in
Note: Note for all tumors:
Antibodies to various epitopes of CD97 vary strongly
in their staining pattern and cross-reactivity to other
EGF-TM7 molecules. The first group of monoclonal
antibodies, which includes BL-Ac/F2, VIM-3b and
CLB-CD97/1, binds to the EGF domains of CD97
(CD97EGF/ antibodies). These antibodies also detect
EMR2, another member of the EGF-TM7 family. In
most cases, this cross-reactivity will not influence the
results obtained for CD97 staining in tumors since
EMR2 is strongly restricted to myeloid cells. CD97
antibodies MEM-180 and CLB-CD97/3 bind to the
stalk region of CD97 (CD97stalk) and do not bind
EMR2.
Localisation
Usually at the cell membrane; soluble CD97 (sCD97)
representing the CD97 alpha-chain in body fluids;
Skeletal muscle cells: at the sarcolemm and
intracellularly in the sacroendoplasmatic reticulum
(SR).
Atlas Genet Cytogenet Oncol Haematol. 2008;12(3)
202
CD97 (CD97 molecule)
Aust G
CD97EGF epitope accessibility depends on cell typespecific N-glycosylation (see above). CD97EGF
antibodies detect only N-glycosylated CD97. During
tumor transformation, not only the CD97 protein
expression level but also the degree of CD97 Nglycosylation varies. Thus, the selection of the CD97
antibody strongly influences the result in
immunohistological studies focused on the correlation
between CD97 and histopathological subtypes,
diagnosis, progression, or prognosis of tumors.
CD97 in tumors is strongly regulated at the posttrancriptional level.
gastric mucosa. It is stronger expressed by most gastric
carcinomas. Half of the tumors show scattered tumor
cells at the invasion front with stronger CD97
expression than tumor cells located in solid tumor
formations.
Prognosis
Not determined.
Cytogenetics
Not determined.
Leiomyosarcoma
Note: Normal smooth muscle cells are CD97-positive.
In this cell type CD97 is not N-glycosylated. Thus,
monoclonal antibodies that detect an N-glycosylation
dependent epitop of CD97 do not react with normal
smooth muscle cells (CD97EGF antibodies). During
transformation CD97 get partly N-glyocosylated in
most uterine leiomyoma and or completely Nglyocosylated in nearly 25% of the leiomyosarcomas.
These tumors are now positive for CD97EGF antibodies.
However, one third of leiomyosarcomas are completely
devoid of CD97.
Prognosis
Not determined.
Cytogenetics
Not determined.
Thyroid cancer
Note: In normal thyroid tissue, no or low
immunoreactivity of CD97 is found. In differentiated
follicular thyroid carcinoma or papillary thyroid
carcinoma, CD97 expression is also either lacking or
low. Most undifferentiated anaplastic carcinomas
reveal high CD97 presentation. CD97 is absent or only
weakly present in patients with postoperative T1
tumors but increased greatly with the progression to
postoperative T4 tumors. Until now, only antibodies
against CD97 EGF domains (CD97EGF antibodies, see
above) have been used in studies of thyroid
carcinomas.
Prognosis
Not determined.
Cytogenetics
Not determined.
Oncogenesis
Overexpression of CD97 might be important for the
progression of thyroid cancer.
References
Aust G, Eichler W, Laue S, Lehmann I, Heldin NE, Lotz O,
Scherbaum WA, Dralle H, Hoang-Vu C. CD97: A
dedifferentiation marker in human thyroid carcinomas. Cancer
Res 1997;57:1798-1806.
Aust G, Steinert M, Schütz A, Wahlbuhl M, Hamann J, Wobus
M. CD97, but not its closely related EGF-TM7 family member
EMR2, is expressed on gastric, pancreatic and esophageal
carcinomas. Am J Clin Pathol 2002;118:699-707.
Colorectal cancer
Note: Normal human colorectal epithelium is slightly
CD97-positive. Most colorectal carcinomas express
CD97. The strongest staining for CD97 occurs in
scattered tumor cells at the invasion front compared to
cells located within solid tumor formations of the same
tumor. Carcinomas with more strongly CD97-stained
scattered tumor cells show a poorer clinical stage as
well as increased lymph vessel invasion compared to
cases with uniform CD97 staining.
Prognosis
Not determined.
Cytogenetics
Not determined.
Oncogenesis
Overexpression of CD97 might be important for
invasion and metastasis of colorectal cancer.
Steinert M, Wobus M, Boltze C, Schütz A, Wahlbuhl M,
Hamann J, Aust G. Expression and regulation of CD97 in
colorectal carcinoma cell lines and tumor tissues. Am J Pathol
2002;161:1657-1667.
Wang T, Ward Y, Tian L, Lake R, Guedez L, Stetler-Stevenson
WG, Kelly K. CD97, an adhesion receptor on inflammatory
cells, stimulates angiogenesis through binding integrin counter
receptors on endothelial cells. Blood 2004;105:2836-2844.
Aust G, Wandel E, Boltze C, Sittig D, Schutz A, Horn LC,
Wobus M. Diversity of CD97 in smooth muscle cells (SMCs).
Cell Tissue Res 2006;323:1-9.
Galle J, Sittig D, Hanisch I, Wobus M, Wandel E, Loeffler M,
Aust G. Individual cell - based models of tumor - environment
interactions. Multiple effects of CD97 on tumor invasion. Am J
Pathol 2006;169:1802-1811.
This article should be referenced as such:
Aust G. CD97 (CD97 molecule). Atlas Genet Cytogenet Oncol
Haematol.2008;12(3):201-203.
Gastric cancer
Note: CD97 is present in normal parietal cells of
Atlas Genet Cytogenet Oncol Haematol. 2008;12(3)
203
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Gene Section
Review
CDH1 (cadherin 1, type 1, E-cadherin (epithelial))
Marilia de Freitas Calmon, Paula Rahal
Laboratory of Genomics studies, São Paulo State University, Department of Biology, São José do Rio Preto SP, Brasil
Published in Atlas Database: October 2007
Online updated version: http://AtlasGeneticsOncology.org/Genes/CDH1ID166ch16q22.html
DOI: 10.4267/2042/38520
This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence.
© 2008 Atlas of Genetics and Cytogenetics in Oncology and Haematology
actin cytoskeleton through an association with various
catenins, such as B-catenin. The protein E-cadherin is a
calcium-dependent cell-cell adhesion molecule
expressed in adherents junctions between epithelial
cells. It is a transmembrane glycoprotein with five
extracellular domains that mediate intercellular
adhesion
through
homophilic
binding.
The
cytoplasmatic domain is bound to the actin
cytoskeleton via intracellular attachment proteins, the
catenins. The actin cytoskeleton forms a transcellular
network mediating structural integrity, cellular polarity
and epithelial morphogenesis.
Identity
Hugo: CDH1
Other names: Arc-1; CD324; CDHE; Cadherin-1; Ecadherin; ECAD; LCAM; UVO; Uvomorulin
Location: 16q22.1
DNA/RNA
Description
DNA contains 98250 bp composed of 16 coding exons.
Transcription
Expression
4828 bp mRNA transcribed in centromeric to telomeric
orientation; 2649 bp open reading frame.
Present tissue specificity for non-neural epithelial
tissues and there are high levels in solid tissues.
Pseudogene
Localisation
Yes, for example, the repeat sequence named c41-cad
is a pseudogene of the cadherin family. c41-cad is
localizated on 5q13.
Cell junction; single-pass type I membrane protein.
Anchored to actin microfilaments through association
with alpha-catenin, beta-catenin and gamma-catenin.
Sequential proteolysis induced by apoptosis or calcium
influx, results in translocation from sites of cell-cell
contact to the cytoplasm.
Function
DNA of CDH1 gene composed of 16 coding exons.
One of the most important and ubiquitous types of
adhesive interactions required for the maintenance of
solid tissues is that mediated by the classic cadherin
adhesion molecules. Cadherins are transmembrane
Ca2+- dependent homophilic adhesion receptors that
are well known to play important roles in cell
recognition and cell sorting during development.
However, they continue to be expressed at high levels
in virtually all solid tissues. There are many members
of the classic cadherin family (which is a subset of the
larger cadherin superfamily), but E-cadherin in
epithelial tissues has been the most studied in the
context of stable adhesions.
Protein
Description
The cadherins are a family of calcium-dependent
transmembrane linker proteins; the first three that were
discovered were named according to their tissue origin
(E-cadherin from epithelium, N-cadherin from neural
tissue and P-cadherin from placenta). The mature Ecadherin protein consists of three major domains: a
large extracellular portion (exons 4-13), which
mediates homophilic cellular interactions; and smaller
transmembrane (exons 13-14) and cytoplasmic
domains (exons 14-16), the latter providing a link to the
Atlas Genet Cytogenet Oncol Haematol. 2008;12(3)
204
CDH1 (cadherin 1, type 1, E-cadherin (epithelial))
Calmon MF, Rahal P
Three-dimensional structure of the beta-catenin arm repeat region in complex with the E-cadherin cytoplasmic domain (Huber and Weis,
2001). The arm repeats are formed by three helices, H1 and H2 (both gray) and H3 (blue). Residues 134-161, which include part of the
alpha-catenin-binding site and a portion of the first arm repeat, form a single helix in this particular crystal structure (cyan). E-cadherin is
divided into five regions of primary structure (1-5) that are indicated in distinct colors (Pokutta S and Weis WI, 2007).
generate secreted E-cadherin fragments, the
functionality of this major cell-cell adhesion protein is
lost. Other cancer-confined E-cadherin mutations also
result in crippled proteins. The distinctive invasive
growth pattern, which is typical for lobular breast
cancers, is fully compatible with this functional
inactivation.
472 human tumors and 15 different cancer cell lines
derived from 10 different tissues have been screened
for CDH1 mutation. So far, frequent somatic mutations
(50%) have been identified only in sporadic diffuse
gastric cancer (DGC), Lobular Breast Cancer. For
sporadic DGC, most somatic mutations are missense
(exons 8, 9) or exon skipping. For sporadic Lobular
Breast Cancer, most somatic mutations are
truncating.472 human tumors and 15 different cancer
cell lines derived from 10 different tissues have been
screened for CDH1 mutation. So far, frequent somatic
mutations (50%) have been identified only in sporadic
Diffuse Gastric Cancer, Lobular Breast Cancer.
Interestingly, there is a major difference between the
mutation types identified in these two carcinoma types.
In diffuse gastric carcinomas, the predominant
mutations are exon skippings causing in-frame
deletions. By contrast, most mutations identified in
lobular breast cancer result in premature stop codons.
In the case of the diffuse gastric carcinomas, a mutation
cluster region is suggested as more than 60% of
mutations cause exon skipping of exon 8 and 9.
Preliminary in vitro studies using transfected cell lines
suggest that tumor-associated E-cadherin mutations
reduce cell adhesion, increase cell motility, and change
cell morphology possibly by dominant negative
mechanisms.
Continued expression and functional activity of Ecadherin are required for cells to remain tightly
associated in the epithelium, and in its absence the
many other cell adhesion and cell junction proteins
expressed in epithelial cells (see below) are not capable
of supporting intercellular adhesion. In its capacity to
maintain the overall state of adhesion between
epithelial cells, E-cadherin is thought to act as an
important suppressor of epithelial tumor cell
invasiveness and metastasis.
Homology
Pan troglodytes - CDH1; Canis lupus familiaris CDH1; Mus musculus - Cdh1; Rattus norvegicus Cdh1; Gallus gallus - LOC415860; Danio rerio - cdh1.
Mutations
Germinal
30 CDH1 germline mutations have been described in
hereditary diffuse gastric cancer families. 25 have been
inactivating (frameshift, nonsense, and splice-site), the
remainders are missense. The mutations are distributed
equally throughout the gene.
Somatic
Somatically acquired mutations in CDH1 were found in
about 56% of lobular breast tumors, generally (>90%)
in combination with loss of the wild-type allele, while
no mutations were found in ductal primary breast
carcinomas. Most of these somatic mutations result in
premature stop codons as a consequence of insertions,
deletions and nonsense mutations. As the majority of
these frameshift and nonsense mutations is predicted to
Atlas Genet Cytogenet Oncol Haematol. 2008;12(3)
205
CDH1 (cadherin 1, type 1, E-cadherin (epithelial))
Calmon MF, Rahal P
57 CDH1 mutations have been found to date. 50 of these are listed in Human Gene Mutation Database. Truncating (27) and splice site
(7) mutations are found above the Schema (34/45, 76%), missense mutations below it (11/45, 24%). Two marked with an asterisk have
been reported as somatic mutations in sporadic diffuse gastric cancer. No Polymorphisms. No Gross deletions/duplications, complex
rearrangements, repeat variations been reported. They spread out all over CDH1 gene (Brooks-Wilson et al., 2004).
On the contrary, the truncating mutations present in
lobular breast cancers are obviously scattered over the
entire E-cadherin gene. In line with this finding is the
observation that the expression of E-cadherin protein is
lost in lobular breast cancers, in contrast to the
retention of expression of the mutant E-cadherin
proteins in diffuse gastric carcinomas. Surprisingly, so
far almost no E-cadherin mutations have been found to
be located in the highly conserved cytoplasmic domain.
In most cases, E-cadherin mutations are found in
combination with loss of the wild-type allele.
Oncogenesis
Reduced E-cadherin expression weakens cell-to-cell
attachment, and tumor cells detach from the primary
tumor, invade vessels, and migrate to lymph nodes.
Once tumor cells reattach to lymph nodes, E-cadherin
is strongly expressed, and lymph nodes are subject to
metastases.
Melanoma
Oncogenesis
The major adhesion mediator between keratinocytes
and normal melanocytes is E-cadherin, which
disappears during melanoma progression. While
normal melanocytes express E-cadherin, this molecule
is not found on nevus or melanoma cells. The loss of Ecadherin likely plays a crucial role in tumor
progression. Cells that have lost epithelial
differentiation, as manifested by the loss of functional
E-cadherin, show increased mobility and invasiveness.
Keratinocytes can no longer control melanoma cells
that have lost E-cadherin. When melanoma cells are
forced to express E-cadherin and are cocultured with
keratinocytes, they dramatically change: melanomas
adhere to keratinocytes, no longer express invasionrelated molecules, and lose their invasive capacities
Implicated in
Non-small cell lung cancer
Prognosis
Reduced E-cadherin correlates with lymph node
metastasis. The rate of vascular invasion was
statistically high in cases with the reduced expression
of E-cadherin. Reduction of E-cadherin is associated
with the degree of differentiation. Bohm et al. found a
correlation between differentiation and E-cadherin
expression in lung squamous cell carcinoma, and
Bongiorno et al. found that well-differentiated lung
cancers express E-cadherin, in a preserved fashion, and
that poorly differentiated tumors exhibited a reduced or
disorganized staining pattern. Sulzer et al. also found
that E-cadherin expression significantly correlated with
increasing tumor differentiation. In general,
undifferentiated or poorly differentiated cancer cells
tend to have a strong potential to invade tissues. These
results suggest that reduction of E-cadherin correlates
with tumor invasion.
Atlas Genet Cytogenet Oncol Haematol. 2008;12(3)
Oesophageal adenocarcinoma
Prognosis
Reduction in the expression of E-cadherin in patients
with OSCC was shown to be strongly associated with
postoperative blood borne recurrence, resulting in a
poorer prognosis than in those patients with tumours
showing normal expression before surgery.
206
CDH1 (cadherin 1, type 1, E-cadherin (epithelial))
Calmon MF, Rahal P
Berx G, Becker KF, Höfler H, Van Roy F. Mutations of the
Human E-Cadherin (CDH1) gene. Human mutation
1998;12:226-237.
This finding suggested that in patients with reduced Ecadherin immunoreactivity, the metastatic potential of
the oesophageal cancer cells may be increased.
Therefore,
the
evaluation
of
E-cadherin
immunoreactivity may be useful in predicting
haematogenous spread and hence recurrence, thus
serving as an aid for planning adjuvant treatment after
surgery in patients with OSCC. It has also been
reported that E-cadherin might be an independent
predictor of micrometastasis in lymph nodes that are
classified as N0 by routine histopathological analysis.
Sulzer MA, Leers M P, Van N JA, Bollen EC, Theunissen PH.
Reduced E-cadherin expression is associated with increased
lymph node metastasis and unfavorable prognosis in non-small
cell lung cancer. Am J Resp Crit Care 1998;157(41):13191323.
Kase S, Sugio K, Yamazaki K, Okamoto T, Yano T, Sugimachi
K. Expression of E-cadherin and ß-Catenin in Human NonSmall Cell Lung Cancer and the Clinical Significance. Clinical
Cancer Research 2000;6:4789-4796.
Berx G, Van Roy F. The E-cadherin/catenin complex: an
important gatekeeper in breast cancer tumorigenesis and
malignant progression. Breast Cancer Res 2001;3(5):289-293.
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(epithelial)).
Atlas
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Cytogenet
Oncol
Haematol.2008;12(3):204-207.
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Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Gene Section
Review
GRN (granulin)
Hongyong Zhang, Chong-xian Pan, Liang Cheng
UC Davis Cancer Center, 2700 Stockton Blvd, Oak Park Research Building, Ste 2301, Univ. of California at
Davis, Sacramento, CA 95817, USA (HZ); Division of Hematology/Oncology, Univ. of California at Davis,
4501 X Street, Rm 3016, Sacramento, CA 95817, USA (CXP); Department of Pathology and Laboratory
Medicine, Indiana University School of Medicine, Clarian Pathology Laboratory Room 4010, 350 West 11th
Street, Indianapolis, IN 46202, USA (LC)
Published in Atlas Database: October 2007
Online updated version: http://AtlasGeneticsOncology.org/Genes/GRNID40757ch17q21.html
DOI: 10.4267/2042/38521
This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence.
© 2008 Atlas of Genetics and Cytogenetics in Oncology and Haematology
kidney, and immune cells; Low levels of GRN
expression on muscle and liver cells. However, overexpressing on some kinds of tumor cells, such as breast
cancer, prostate cancer, ovarian cancer.
Identity
Hugo: GRN
Other names: GEP; GP88; PCDGF; PEPI; PGRN;
acrogranin;
granulin-epithelin;
proepithelin;
progranulin
Location: 17q21.32
Localisation
Nucleus.
Function
DNA/RNA
Progranulin stimulates cell proliferation, migration and
survival. It activates conventional growth factor
signaling pathways including the p44/42 MAPkinase
and phosphatidylinositol 3-kinase pathways and the
Focal Adhesion Kinase pathway. Many experiments
show that increasing the expression of progranulin can
stimulate the tumor growth on immortalized but
otherwise non-tumorigenic cells. SW13 cells
overexpress progranulin (high PGRN), so, they produce
large tumors in nude mice; cells that express less
progranulin (basal PGRN), do not grow as tumors.
However, progranulin is necessary for tumor growth.
Attenuating progranulin (PCDGF) expression in
mammary cancer cells MDA-MB-468 and human
hepatocellular carcinoma cell lines (HepB3) leaded to a
dramatic reduction (90% and 87%, respectively) in the
size of tumors when the cells were grown in nude mice.
Also, some experiments indicated that progranulin
caused an increase of the motility and the invasiveness
of tumor and played an important effect on apoptosis of
tumor cells, reduced the rate of cell death.
Description
13 exons, including 12 protein encoding exons and a
further 5' non-coding exon.
Transcription
Major mRNA: 2323bp
Protein
Description
Granulins are a family of secreted, glycosylated
peptides; Granulins are cleaved from a single precursor
protein with 7.5 repeats of a highly conserved 12cysteine granulin/epithelin motif. The 88 kDa precursor
protein, progranulin, is also called proepithelin and PC
cell-derived growth factor. Cleavage of the signal
peptide produces mature granulin which can be further
cleaved into a variety of active, 6 kDa peptides. These
smaller cleavage products are named granulin A,
granulin B, and granulin C, etc.
Expression
Mutations
Granulins are widely expressed. Normally, high levels
of GRN expression on rapidly proliferating cells, such
as skin cells, deep crypts of gastrointestinal tract,
Note: Mutations in the progranulin (PGRN) gene have
been identified in frontotemporal lobar degeneration
with ubiquitin inclusions linked to chromosome 17q21.
Atlas Genet Cytogenet Oncol Haematol. 2008;12(3)
208
GRN (granulin)
Zhang H, et al.
negative tumors had moderate to strong PCDGF
expression. Positive correlation was found between
PCDGF staining and Ki67 proliferation index.
Similarly, a larger percentage of tumors with
moderate/strong PCDGF expression were p53 positive.
In contrast, PCDGF expression was independent of
cerbB-2 overexpression. This study provides evidence
of the high incidence of PCDGF expression in human
breast cancer with positive correlation with
clinicopathological variables such as tumor grade,
proliferation index, and p53 expression. These
characteristics the absence of expression in benign
breast tissue suggest an important role of PCDGF in
breast cancer pathogenesis and make it a potential
novel target for the treatment of breast cancer.
There are two novel frameshift mutations and three
possible pathogenic missense mutations in the PGRN
gene, and PGRN mutations in familial cases recruited
from a large population-based study of frontotemporal
lobar degeneration carried out in the Netherlands.
However, no mutation was found in the development of
different cancers.
Implicated in
Breast cancer
Disease
Progranulin has been shown to play a major role in
breast tumorigenesis by stimulating proliferation,
mediating survival and conferring resistance to some
chemicals such as tamoxifen and doxorubicin, and its
overexpression account for the resistance to therapeutic
agents. PCDGF/GP88 has metastatic potential in breast
cancer, and tumor cells (such as MCF-7 cells) with a
PCDGF over-expression or treated exogenously with
PCDGF both stimulated anchorage-independent cell
growth and accelerated cell migration through matrigel.
Furthermore, PCDGF/GP88 also can up-regulated the
expression of matrix metalloprotease-9, and stimulated
VEGF expression in some tumor cells. So,
PCDGF/GP88 could act to promote metastasis and
angiogenesis in human breast cancer cells in addition to
stimulating their proliferation and survival.
PCDGF/GP88 activated mitogen-activated protein
kinase (MAP kinase Erk1/Erk2) as well as
phosphatidylinositol 30-kinase (PI-3 kinase) pathways
leading to the stimulation of several cyclins including
Cyclin D1 and Cyclin B. In the adrenal carcinoma SW13 cells, progranulin expression was also a major
determinant of focal adhesion kinase signaling pathway
in addition to MAP kinase and PI-3 kinase.
Prognosis
GRN might play an important role in deciding the
behavior of node-positive breast cancer, so, GRN
maybe provide valuable information for the prognosis
of breast cancer patients. Since all the in vitro studies
indicated the importance of PCDGF/GP88 in breast
tumorigenesis. PCDGF/GP88 expression was then
examined in pathological samples. Correlation studies
between PCDGF expression and prognostic markers
such as ER/PR expression, proliferation index Ki67,
p53, and erbB2 were also conducted. Normally,
PCDGF staining was observed in breast carcinoma,
whereas it was not detected in benign breast
epithelium. In breast carcinoma, PCDGF expression
was more common in ductal carcinoma than in invasive
lobular carcinoma. Moreover, PCDGF staining was
almost never observed in lobular carcinoma in situ,
whereas most of ductal carcinoma in situ (DCIS)
expressed PCDGF. PCDGF expression in DCIS
correlated strongly with nuclear grade in DCIS and
histological grades in IDC. Both ER positive and ER
Atlas Genet Cytogenet Oncol Haematol. 2008;12(3)
Prostate Cancer
Disease
Normal prostate tissue did not express, or expressed
low levels of PCDGF. PCDGF expression could be
detected in more than 50% of cells in all specimens of
prostatic intraepithelial neoplasia (PIN) and invasive
prostate cancer. The expression of PCDGF in normal
prostate tissue was much less intense and in a smaller
fraction of cells than in PIN and invasive
adenocarcinoma (P less than 0.0001). There was no
correlation of PCDGF expression with age, Gleason
score, pathological stage, status of lymph node
metastasis, extraprostatic
extension, perineural
invasion, surgical margins, and vascular invasion. So,
the induction of PCDGF expression occurs during the
development of PIN. PCDGF may be a new molecular
target for the treatment and prevention of prostate
cancer.
Ovarian Carcinoma
Disease
The GEP/PCDGF has been shown to be an important
growth and survival factor induced by low-malignantpotential (LPA) and ET-1 and cAMP/EPAC through
ERK1/2 for ovarian cancer cells, and its expression is a
predictor of patient survival in metastatic ovarian
cancer cells. The prosurvival function of GEP is
important in ovarian cancer tumor progression and
chemoresponse. Overexpression of GEP increased
capacity to migrate and invade their substratum, and
was associated with cisplatin chemoresistance.
Meantime, GEP overexpression increased tumor
formation and protected cells from tumor regression in
response to cisplatin treatment in vivo.
Prognosis
Several experiments discovered and validated the
differential expression of GEP between noninvasive
LPA tumors and invasive epithelial ovarian cancers in
an effort to define a molecular basis for the pathologic
differences between these epithelial tumor subtypes.
Low malignant potential tumors share cytologic
209
GRN (granulin)
Zhang H, et al.
similarities with invasive ovarian cancers but have
epithelial cells that lack the capacity to invade their
underlying stroma. These tumors are slow growing and
rarely metastasize and patients with LMP tumors
present most often with disease limited to the ovary.
This presentation translates into a marked improved
clinical outcome over patients with invasive ovarian
cancers, with over 95% of patients alive at 10 years. In
contrast, patients with invasive ovarian cancers more
commonly present with, and die of, disseminated
disease and have a 40% overall 5-year survival.
GEP expression also was observed in primary and
metastatic epithelial ovarian carcinoma specimens, with
down-regulated expression in tumor cells of malignant
effusions. The poor outcome associated with stromal
GEP expression suggests a prognostic role for this
growth factor in ovarian carcinoma.
Brain tumor-glioblastoma multiforme
Endometrial cancer
Multiple Myeloma
Disease
The majority of endometrial cancers arise as a result of
estrogen stimulation, the molecular targets of which
remain incompletely defined. GEP may be one such
target. GEP co-expression with ER was observed in
most of cancers examined. A two to fivefold increase in
GEP expression with estradiol and/or tamoxifen
treatment was observed in KLE cells. Silencing of GEP
in HEC-1-A cells using shRNA resulted in a decrease
in proliferation among transfected cells. However, coexpression of GEP and ER in endometrial cancer cells,
and the regulation of GEP by estrogen, suggests a role
for GEP in steroid-mediated endometrial cancer cell
growth. Further, characterization of GEP as a steroidmediated growth factor in these cells may help me to
understand endometrial cancer biology very well.
Disease
PCDGF mRNA and protein expression was detected in
human MM cell lines such as ARP-1 and RPMI 8226,
and PCDGF added exogenously stimulated cell growth
and sustained cell survival of both ARP-1 and RPMI
8226 cells in a dose- and time-dependent fashion.
When treated with neutralizing anti-PCDGF antibody,
RPMI 8225 cells growth was inhibited. This indicated
that PCDGF acts as an autocrine growth factor for MM
cells. Studies of signal transduction pathways showed
PCDGF stimulated mitogen-activated protein kinase
and phosphatidylinositol 3'-kinase pathways but not the
Janus-activated kinase-signal transducer and activator
of transcription pathway. Immunohistochemical
analysis of bone marrow smears obtained from MM
patients indicated that PCDGF expression was
associated with myeloma cells from MM patients and
correlated with the presence of MM disease.
Disease
The 2.1-kb granulin mRNA was expressed
predominantly in glial tumors, whereas expression was
not detected in non-tumor brain tissues. Granulin may
be a glial mitogen, as addition of synthetic granulin
peptide to primary rat astrocytes and three different
early-passage human glioblastoma cultures increased
cell proliferation in vitro, whereas increasing
concentrations of granulin antibody inhibited cell
growth in a dose-dependent manner. The differential
expression pattern, tissue distribution, and implication
of this glioma-associated molecule in growth regulation
suggest a potentially important role for granulin in the
pathogenesis and/or malignant progression of primary
brain neoplasms.
Teratoma
Disease
The PC cell line is a highly tumorigenic, insulinindependent, teratoma-derived cell line isolated from
the nontumorigenic, insulin-dependent 1246 cell line.
Studies of the PC cell growth properties have led to the
purification of an 88-kDa secreted glycoprotein called
PC cell-derived growth factor (PCDGF), which has
been shown to stimulate the growth of PC cells as well
as 3T3 fibroblasts. Since PCDGF was isolated from
highly tumorigenic cells, its level of expression was
examined in PC cells as well as in nontumorigenic and
moderately tumorigenic cells from which PC cells were
derived, and the levels of PCDGF mRNA and protein
were very low in the nontumorigenic cells and
increased in tumorigenic cell lines in a positive
correlation with their tumorigenic properties. An
inhibition of PCDGF expression resulted in a dramatic
inhibition of tumorigenicity of the transfected cells
when compared with empty-vector control cells. These
data demonstrate the importance in tumor formation of
overexpression of the novel growth factor PCDGF.
Atlas Genet Cytogenet Oncol Haematol. 2008;12(3)
Laryngeal carcinoma
Disease
The PC cell-derived growth factor protein levels and
mRNA levels of the laryngeal squamous cell
carcinomas were significantly higher than those of
normal laryngeal tissues. Simultaneously, the
difference in the levels of mRNA and protein between
those
of
laryngeal
precancerous
lesions
(papilloma/leukoplakia) and those of normal tissues
was significant, whereas those of laryngeal
precancerous lesions (papilloma/leukoplakia) were
significantly lower than those of laryngeal squamous
cell carcinomas. Strong PC cell-derived growth factor
expression was associated with lymph node metastases
in laryngeal squamous cell carcinoma. Functional
studies on Hep-2 cell lines demonstrated that the
attenuation of PC cell-derived growth factor expression
levels led to diminished cell proliferation rates,
anchorage-independent growth in vitro, tumor forming
in vivo and resistance to apoptosis. PC cell-derived
210
GRN (granulin)
Zhang H, et al.
growth factor is a pivotal autocrine growth factor in the
tumorigenesis of laryngeal squamous cell carcinoma. In
the future, PC cell-derived growth factor may be a
logical and potential target for early diagnosis, specific
therapy and prognosis of laryngeal squamous cell
carcinoma.
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Bladder Cancer
Disease
Proepithelin is overexpressed in bladder cancer cell
lines and clinical specimens of bladder cancer.
Proepithelin did not appreciably affect cell growth, but
it did promote migration of 5637 bladder cancer cells
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Disease
Acrogranin levels were low in benign renal tissue and
increased in malignant renal tissue. In addition, highgrade RCC exhibited higher levels of expression than
low-grade RCC and normal tissue. So, acrogranin may
be a functional important growth factor in RCC and a
potential molecular marker for high-grade RCC.
Lu R, Serrero G. Mediation of estrogen mitogenic effect in
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two protein expression patterns, and the association of
p53 and GEP protein expression was found to be highly
significant only in HCCs with wild-type p53; there was
no association in HCCs with p53 mutation. The GEP
levels in the HepG2 hepatoma cell line with a wild-type
p53 background were modulated by transfection
experiments. Overexpression of the GEP protein
resulted in an increased p53 protein level and
suppression of the GEP protein resulted in a decreased
p53 protein level in HepG2 cells. In summary, p53
wild-type protein nuclei accumulation is associated
with GEP protein expression in human HCC
specimens, and GEP modulates p53 wild-type protein
levels in vitro.
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This article should be referenced as such:
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Atlas Genet Cytogenet Oncol Haematol. 2008;12(3)
212
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Gene Section
Review
HTATIP (HIV-1 Tat interacting protein, 60kDa)
Lise Mattera
Dr Trouche Team, LBCMCP, UMR 5088 CNRS, 118 route de Narbonne, 31062 Toulouse cedex 9, France
Published in Atlas Database: October 2007
Online updated version: http://AtlasGeneticsOncology.org/Genes/HTATIPID40893ch11q13.html
DOI: 10.4267/2042/38522
This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence.
© 2008 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
Protein
Hugo: HTATIP
Other names: Tip60; Tip; 60kDa Tat interacting
protein; HIV-1 Tat interacting protein; cPLA(2)
interacting protein; iTip60; PLIP/Tip60b; Tip60a;
Esa1; Hs.6364
Location: 11q13.1
Description
The Tip60 protein (isoform 2) is 513 amino acids long
and its molecular weight is about 60 kDa. It was cloned
and characterized in 1996 thanks to its interaction with
the HIV-1 transactivator Tat protein.
Isoform 1 produces a 546 amino acids long protein.
Isoform 3 produces a 461 amino acids long protein.
A novel isoform, Tip55, encodes a novel splicing
variant corresponding to 103 amino acids of the Cterminus.
The domain architectures of human TIP60 is similar to
yeast Esa1 protein and consist of a chromodomain and
a MYST domain harboring a zinc finger and an AcetylCoA binding site.
DNA/RNA
Expression
Tip60 is ubiquitously expressed.
In mouse adult tissues Tip60 is expressed in the
following decreasing order of intensity: testis, heart,
brain, kidney, liver, lung, with little to no expression in
spleen and skeletal muscle.
In human, Tip60 (Isoform 2) and PLIP (Isoform 3) are
expressed in human heart, kidney and brain tissue.
With a half-life of approximately 30 minutes, Tip60 is
very unstable. In normal conditions, the proteasome
pathway permits to maintain low protein levels. Tip60
is ubiquitinated and targeted to proteasome-mediated
degradation by Mdm2 but also by p300-associated E4
ubiquitin ligase. Tip60 is stabilized after DNA damage,
and accumulates in cells. Moreover, Tip60 is the target
of several post-translational modifications such as
phosphorylation on serine 86 and 90 by cdc2 but also
acetylation by p300/CBP acetyltransferases.
Description
The HTATIP gene consists of 14 exons. 7,586 bases.
Transcription
The predominant mRNA transcribed from this gene is
2,229 bp long. This is actually the isoform 2 of
HTATIP.
Two others isoforms generated by alternative splicing
have been described:
- Isoform 1 retains the alternatively spliced intron 1,
- Isoform 3 lacks exon 5.
Pseudogene
No pseudogene is currently known.
Atlas Genet Cytogenet Oncol Haematol. 2008;12(3)
213
HTATIP (HIV-1 Tat interacting protein, 60kDa)
Mattera L
Acetylation by p300/CBP occurs in the zinc finger of
Tip60 but consequences of this modification are
currently not known. Finally, a recent report shows that
Tip60 is sumoylated at lysines 430 and 451 via Ubc9.
No data are available about regulation of the Tip60
promoter.
recruited, with TRRAP, to the DSB site. Tip60
interacts with the chromatin surrounding sites of DSBs
and this recruitment is responsible for hyperacetylation
of histone H4.
Homology
Tip60 CHROMO domain has been identified by
sequence homology with the Heterochromatinassociated protein 1 (HP1) chromodomain, which
recognizes methylated lysines. It also harbors the
MYST domain, which is highly conserved from yeast
to human.
Homologs in other species:
- S. Cerevisae: Esa1
- D. Melanogaster: DmeI/Tip60
- M. musculus: Htatip
- R. norvegicus: Htatip
Predicted:
- P.troglodytes: HTATIP
- M. mulatta: HTATIP
Localisation
Tip60 (Isoform 2) is nuclear. PLIP (Isoform 3) is
nuclear but also cytoplasmic.
Function
Tip60 is a Histone Acetyltransferase (HAT), which
belongs to the MYST family. It participates in a
multimolecular complex: The Tip60 complex, which
contains proteins such as p400, Tip49a and Tip49b.
Within this complex, Tip60 exerts its HAT activity on
nucleosomal histone H4. Tip60 is involved in various
cellular mechanisms:
In transcription: Tip60 acts as a coactivator. Indeed,
Tip60 is able to interact with transcription factors, such
as E2F-1 or c-Myc. Tip60 can be recruited to Myc and
E2F-1 target promoters and enhances Myc
transactivation. It also acetylates histone H4 on several
E2F responsive genes. Moreover Tip60 was found to
be involved in nuclear receptor (NR) signaling and to
be a NR-coregulator.
In apoptosis and cell cycle arrest: Tip60 can interact
with and acetylate the tumor suppressor p53. It
enhances p53 binding to pro-apoptotic target genes like
PUMA, Bax or Fas. Moreover, Tip60 is also required
for cell growth arrest via the p21-dependent pathway.
In DNA repair: Tip60 is involved in double strand
breaks (DSB) repair. Interacting and acetylating ATM,
Tip60 participates in DNA damage signaling. But,
Tip60 is also involved directly in DSB repair since it is
Atlas Genet Cytogenet Oncol Haematol. 2008;12(3)
Mutations
Note: No mutation in Tip60 protein has been currently
described.
Implicated in
Acquired Immunodeficiency Syndrome
(AIDS)
Disease
Tip60 interacts with the HIV-1 transactivator Tat and
this interaction inhibits Tip60 HAT activity. Moreover,
in Jurkat cells, Tat enhances Tip60 turnover since it
uses the p300/CBP-associated E4-type ubiquitin-ligase
214
HTATIP (HIV-1 Tat interacting protein, 60kDa)
Mattera L
specifically interacts with the essential cysteine region of the
HIV-1 Tat transactivator. Virology 1996;216(2):357-366.
activity to induce polyubiquitynation and degradation
of Tip60. This targeting by Tat induces an impairment
of Tip60-dependent apoptosis after DNA damage.
Brady ME, Ozanne DM, Gaughan L, Waite I, Cook S, Neal DE,
Robson CN. Tip60 is a nuclear hormone receptor coactivator. J
Biol Chem 1999;274(25):17599-17604.
Neurodegenerative diseases:
Alzheimer’s disease
Creaven M, Hans F, Mutskov V, Col E, Caron C, Dimitrov S,
Khochbin S. Control of the histone-acetyltransferase activity of
Tip60 by the HIV-1 transactivator protein, Tat. Biochemistry
1999;38(27):8826-8830.
Disease
In the nucleus of human H4 neuroglioma cells, TIP60
can interact with a free carboxyl-terminal intracellular
fragment, APP-CT, which is generated by the cleavage
of the Amyloid precursor protein APP by a gammasecretase. This fragment induces apoptosis of
neuroglioma and this cell death is enhanced when a
wild type form of Tip60 is transfected. Thus Tip60
might play a role in Alzheimer’s disease
neurodegeneration.
Ikura T, Ogryzko VV, Grigoriev M, Groisman R, Wang J,
Horikoshi M, Scully R, Qin J, Nakatani Y. Involvement of the
TIP60 histone acetylase complex in DNA repair and apoptosis.
Cell 2000;102(4):463-473.
Ran Q, Pereira-Smith OM. Identification of an alternatively
spliced form of the Tat interactive protein (Tip60), Tip60(beta).
Gene 2000;258(1-2):141-146.
Gaughan L, Brady ME, Cook S, Neal DE, Robson CN. Tip60 is
a co-activator specific for class I nuclear hormone receptors. J
Biol Chem 2001;276(50):46841-46848.
Sheridan AM, Force T, Yoon HJ, O'Leary E, Choukroun G,
Taheri MR, Bonventre JV. PLIP, a novel splice variant of
Tip60, interacts with group IV cytosolic phospholipase A(2),
induces apoptosis, and potentiates prostaglandin production.
Mol Cell Biol 2001;21(14):4470-4481.
Spinocerebellar ataxia type-1
Disease
TIP60 participates in a complex with ATXN1 and
ROR-alpha in a conditional transgenic mouse model of
Spinocerebellar ataxia type-1 (SCA1), one of the nine
inherited polyglutamine neurodegenerative diseases.
Gaughan L, Logan IR, Cook S, Neal DE, Robson CN. Tip60
and histone deacetylase 1 regulate androgen receptor activity
through changes to the acetylation status of the receptor. J Biol
Chem 2002;277(29):25904-25913.
Cancers:
Prostate cancer
Kinoshita A, Whelan CM, Berezovska O, Hyman BT. The
gamma secretase-generated carboxyl-terminal domain of the
amyloid precursor protein induces apoptosis via Tip60 in H4
cells. J Biol Chem 2002;277(32):28530-28536.
Disease
Immunohistochemistry experiments have shown that
Tip60 accumulates in the nucleus of hormonerefractory prostate cancer compared to prostate
hyperplasia and primary prostate cancer.
Legube G, Linares LK, Lemercier C, Scheffner M, Khochbin S,
Trouche D. Tip60 is targeted to proteasome-mediated
degradation by Mdm2 and accumulates after UV irradiation.
EMBO J 2002;21(7):1704-1712.
McAllister D, Merlo X, Lough J. Characterization and
expression of the mouse tat interactive protein 60 kD (TIP60)
gene. Gene 2002;289(1-2):169-176.
Lung cancer and colon cancer
Disease
Real time RT-PCR experiments have shown that Tip60
mRNA is under expressed in colon and lung
carcinomas.
Frank SR, Parisi T, Taubert S, Fernandez P, Fuchs M, Chan
HM, Livingston DM, Amati B. MYC recruits the TIP60 histone
acetyltransferase complex to chromatin. EMBO Rep
2003;4(6):575-580.
Halkidou K, Gnanapragasam VJ, Mehta PB, Logan IR, Brady
ME, Cook S, Leung HY, Neal DE, Robson CN. Expression of
Tip60, an androgen receptor coactivator, and its role in
prostate cancer development. Oncogene 2003;22(16):24662477.
Skin cancer
Disease
The expression levels of TIP60 protein, analyzed by
western blot, were found to be greater in skin tumors as
compared to adjacent non-tumor-bearing skin in a skin
cancer mouse model (K6/ODC mouse). Additionally,
the interaction between Tip60 and E2F1 is enhanced in
these tumors.
Legube G, Trouche D. Identification of a larger form of the
histone acetyl transferase Tip60. Gene 2003;310:161-168.
Lemercier C, Legube G, Caron C, Louwagie M, Garin J,
Trouche D, Khochbin S. Tip60 acetyltransferase activity is
controlled by phosphorylation. J Biol Chem 2003;278(7):47134718.
HTLV-1 induced leukemogenesis
Berns K, Hijmans EM, Mullenders J, Brummelkamp TR, Velds
A, Heimerikx M, Kerkhoven RM, Madiredjo M, Nijkamp W,
Weigelt B, Agami R, Ge W, Cavet G, Linsley PS,
Beijersbergen RL, Bernards R. A large-scale RNAi screen in
human cells identifies new components of the p53 pathway.
Nature 2004;428(6981):431-437.
Disease
Enhancement of c-Myc transforming activity by
HTLV-1 p30II oncoprotein in HeLa cells requires
TIP60 HAT activity.
Legube G, Linares LK, Tyteca S, Caron C, Scheffner M,
Chevillard-Briet M, Trouche D. Role of the histone acetyl
transferase Tip60 in the p53 pathway. J Biol Chem
2004;279(43):44825-44833.
References
Kamine J, Elangovan B, Subramanian T, Coleman D,
Chinnadurai G. Identification of a cellular protein that
Atlas Genet Cytogenet Oncol Haematol. 2008;12(3)
Taubert S, Gorrini C, Frank SR, Parisi T, Fuchs M, Chan HM,
Livingston DM, Amati B. E2F-dependent histone acetylation
215
HTATIP (HIV-1 Tat interacting protein, 60kDa)
Mattera L
and recruitment of the Tip60 acetyltransferase complex to
chromatin in late G1. Mol Cell Biol 2004;24(10):4546-4556.
repair proteins and repair of DNA double-strand breaks. Nat
Cell Biol 2006;8(1):91-99.
Awasthi S, Sharma A, Wong K, Zhang J, Matlock EF, Rogers
L, Motloch P, Takemoto S, Taguchi H, Cole MD, Lüscher B,
Dittrich O, Tagami H, Nakatani Y, McGee M, Girard AM,
Gaughan L, Robson CN, Monnat RJ Jr, Harrod R. A human Tcell lymphotropic virus type 1 enhancer of Myc transforming
potential stabilizes Myc-TIP60 transcriptional interactions. Mol
Cell Biol 2005;25(14):6178-6198.
Serra HG, Duvick L, Zu T, Carlson K, Stevens S, Jorgensen N,
Lysholm A, Burright E, Zoghbi HY, Clark HB, Andresen JM, Orr
HT. RORalpha-mediated Purkinje cell development determines
disease severity in adult SCA1 mice. Cell 2006;127(4):697708.
Sykes SM, Mellert HS, Holbert MA, Li K, Marmorstein R, Lane
WS, McMahon SB. Acetylation of the p53 DNA-binding domain
regulates apoptosis induction. Mol Cell 2006;24(6):841-851.
Col E, Caron C, Chable-Bessia C, Legube G, Gazzeri S,
Komatsu Y, Yoshida M, Benkirane M, Trouche D, Khochbin S.
HIV-1 Tat targets Tip60 to impair the apoptotic cell response to
genotoxic stresses. EMBO J 2005;24(14):2634-2645.
Tang Y, Luo J, Zhang W, Gu W. Tip60-dependent acetylation
of p53 modulates the decision between cell-cycle arrest and
apoptosis. Mol Cell 2006;24(6):827-839.
Sun Y, Jiang X, Chen S, Fernandes N, Price BD. A role for the
Tip60 histone acetyltransferase in the acetylation and
activation
of
ATM.
Proc
Natl
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Sci
USA
2005;102(37):13182-13187.
Tyteca S, Vandromme M, Legube G, Chevillard-Briet M,
Trouche D. Tip60 and p400 are both required for UV-induced
apoptosis but play antagonistic roles in cell cycle progression.
EMBO J 2006;25(8):1680-1689.
Hobbs CA, Wei G, Defeo K, Paul B, Hayes CS, Gilmour SK.
Tip60 Protein Isoforms and Altered Function in Skin and
Tumors that Overexpress Ornithine Decarboxylase. Cancer
Res 2006;66(16):8116-8122.
Cheng Z, Ke Y, Ding X, Wang F, Wang H, Ahmed K, Liu Z, Xu
Y, Aikhionbare F, Yan H, Liu J, Xue Y, Powell M, Liang S,
Reddy SE, Hu R, Huang H, Jin C, Yao X. Functional
characterization of TIP60 sumoylation in UV-irradiated DNA
damage response. Oncogene 2007 Aug 20;[Epub ahead of
print].
Kim MS, Merlo X, Wilson C, Lough J. Co-activation of atrial
natriuretic factor promoter by Tip60 and serum response
factor. J Biol Chem 2006;281(22):15082-15089.
This article should be referenced as such:
LLeonart ME, Vidal F, Gallardo D, Diaz-Fuertes M, Rojo F,
Cuatrecasas M, López-Vicente L, Kondoh H, Blanco C,
Carnero A, Ramón y Cajal S. New p53 related genes in human
tumors: significant downregulation in colon and lung
carcinomas. Oncol Rep 2006;16(3):603-608.
Mattera L. HTATIP (HIV-1 Tat interacting protein, 60kDa).
Atlas Genet Cytogenet Oncol Haematol.2008;12(3):213-216.
Murr R, Loizou JI, Yang YG, Cuenin C, Li H, Wang ZQ, Herceg
Z. Histone acetylation by Trrap-Tip60 modulates loading of
Atlas Genet Cytogenet Oncol Haematol. 2008;12(3)
216
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Gene Section
Mini Review
HYAL1 (hyaluronoglucosaminidase 1)
Demitrios H Vynios
Department of Chemistry, University of Patras, 26500 Patras, Greece
Published in Atlas Database: October 2007
Online updated version: http://AtlasGeneticsOncology.org/Genes/HYAL1ID40903ch3p21.html
DOI: 10.4267/2042/38523
This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence.
© 2008 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Pseudogene
Identity
PHYAL1.
Hugo: HYAL1
Other names: EC 3.2.1.35; HYAL-1; NT6; LUCA1;
LUCA-1;
FUS2;
Hyaluronidase-1
precursor;
Hyaluronoglucosaminidase-1; Hs.75619; MGC45987
Location: 3p21.3
Local order: The gene of Hyal1 is tightly clustered
with HYAL-2 and HYAL-3. The gene for Hyal-2,
HYAL2, the earliest known lysosomal hyaluronidase,
resides immediately centromeric to HYAL1.
Note: The HYAL1 gene was identified as identical
with LUCA-1, a candidate tumour suppressor gene,
especially for tobacco-related cancers.
Protein
Note: HYAL1 is a secreted somatic tissue
hyaluronidase, and the predominant hyaluronidase in
human plasma. Although HYAL1 is predominantly
secreted, it has an acid pH optimum in vitro. HYAL1
can degrade high molecular weight hyaluronan to small
oligomers, primarily to tetrasaccharides, whereas
HYAL2 (the other major human hyaluronidase) high
molecular mass hyaluronan to an approximately 20
kDa product (approximatively 50 saccharide units).
Description
Size: 435 amino acids; Molecular mass: 48368 Da. The
enzyme belongs to the group of carbohydrate-active
enzymes (http://www.cazy.org/CASy), termed glycosyl
hydrolase 56 family.
DNA/RNA
Description
Expression
The HYAL1 gene contains three exons and spans
12,492 bases (start: 50,312,324 bp to end 50,324,816
from 13pter) oriented at the minus strand.
HYAL1 is highly expressed in liver, kidney and heart
and weakly expressed in lung, placenta and skeletal
muscle. No expression is detected in adult brain.
Isoform 1 is expressed only in bladder and prostate
cancer cells, G2/G3 bladder tumor tissues and lymph
node specimens showing tumor invasive tumors cells.
Isoform 3, isoform 4, isoform 5 and isoform 6 are
expressed in normal bladder and bladder tumor tissues.
HYAL1 expression has been described in squamous
cell carcinoma, in small cell lung cancer and glioma
lines.
Transcription
Eight alternatively spliced transcript variants of this
gene encoding six distinct isoforms have been
described. The longest transcript has a length of 2,518
bps, however it is not translated to protein, since, by
retaining intron 1 (occurring within exon 1), it has a
number of stop codons. The longest transcript that
produces active HYAL1 has a length of 2075 bps.
Localisation
It is a secreted enzyme found in plasma and it is also
present in lysosomes.
Atlas Genet Cytogenet Oncol Haematol. 2008;12(3)
217
HYAL1 (hyaluronoglucosaminidase 1)
Vynios DH
Function
References
It is a hydrolytic enzyme (endo-beta-acetyl-Dhexosaminidase) with optimum pH about 3.7, acting on
hyaluronan, chondroitin and chondroitin sulphate. It
possesses also transglycosidase activity using
hyaluronan and chondroitin sulphate or chondroitin as
substrates. This reaction is not well understood, and the
precise enzymatic mechanism is not known.
Csóka AB, Frost GI, Wong T, Stern R. Purification and
microsequencing of hyaluronidase isozymes from human
urine. FEBS Lett 1997;417:307-310.
Frost GI, Csóka AB, Wong T, Stern R. Purification, cloning,
and expression of human plasma hyaluronidase. Biochem
Biophys Res Commun 1997;236:10-15.
Csóka AB, Frost GI, Heng HH, Scherer SW, Mohapatra G,
Stern R. The hyaluronidase gene HYAL1 maps to
chromosome 3p21.2-p21.3 in human and 9F1-F2 in mouse, a
conserved candidate tumor suppressor locus. Genomics
1998;48:63-70.
Homology
The enzyme possesses 70-80% homology to orthologue
hyaluronidases, 40% homology to paralogue
hyaluronidases of the human and high homology with
HYAL1 of other species.
Lepperdinger G, Strobl B, Kreil G. HYAL2, a human gene
expressed in many cells, encodes a lysosomal hyaluronidase
with a novel type of specificity. J Biol Chem 1998;273:2246622470.
Mutations
Csóka AB, Scherer SW, Stern R. Expression analysis of six
paralogous human hyaluronidase genes clustered on
chromosomes 3p21 and 7q31. Genomics 1999;60:356-361.
Somatic
Triggs-Raine B, Salo TJ, Zhang H, Wicklow BA, Natowicz MR.
Mutations in HYAL1, a member of a tandemly distributed
multigene family encoding disparate hyaluronidase activities,
cause
a
newly
described
lysosomal
disorder,
mucopolysaccharidosis IX. Proc Natl Acad Sci USA
1999;96:6296-6300.
There are not extended reports regarding mutations of
HYAL1 gene. The patient with hyaluronidase
deficiency was a compound heterozygote for two
mutations in the HYAL1 gene: a 1412G-A mutation
that introduced a nonconservative amino acid
substitution (glu268 to lys) in a putative active site
residue, and a complex intragenic rearrangement,
1361del37ins14, that resulted in a premature
termination codon. In addition, the mutated HYAL1
gene has a markedly different expression pattern than
the normal one.
Frost GI, Mohapatra G, Wong TM, Csóka AB, Gray JW, Stern
R. HYAL1LUCA-1, a candidate tumor suppressor gene on
chromosome 3p21.3, is inactivated in head and neck
squamous cell carcinomas by aberrant splicing of pre-mRNA.
Oncogene 2000;19:870-877.
Lerman MI, Minna JD. The 630-kb lung cancer homozygous
deletion region on human chromosome 3p21.3: identification
and evaluation of the resident candidate tumor suppressor
genes. Cancer Res 2000;60:6116-6133.
Implicated in
Csóka AB, Frost GI, Stern R. The six hyaluronidase-like genes
in the human and mouse genomes. Matrix Biol 2001;20:499508. (Review).
Mucopolysaccharidosis type IX (MPS9)
Lokeshwar VB, Schroeder GL, Carey RI, Soloway MS, Iida N.
Regulation of hyaluronidase activity by alternative mRNA
splicing. J Biol Chem 2002;277:33654-33663.
Note: Defects in HYAL1 are the cause of
mucopolysaccharidosis
type
IX,
also
called
hyaluronidase deficiency.
Disease
The clinical features are periarticular soft tissue masses,
mild short stature and acetabular erosions, absence of
neurological or visceral involvement and high
hyaluronan concentration in the serum.
Shuttleworth TL, Wilson MD, Wicklow BA, Wilkins JA, TriggsRaine BL. Characterization of the murine hyaluronidase gene
region reveals complex organization and cotranscription of
Hyal1 with downstream genes, Fus2 and Hyal3. J Biol Chem
2002;277:23008-23018.
Junker N, Latini S, Petersen LN, Kristjansen PE. Expression
and regulation patterns of hyaluronidases in small cell lung
cancer and glioma lines. Oncol Rep 2003;10:609-616.
Cancer
Jedrzejas MJ, Stern R. Structures of vertebrate hyaluronidases
and their unique enzymatic mechanism of hydrolysis. Proteins
2005;61:227-238.
Note: HYAL1 is inactivated in most lung cancers in a
conventional manner, by loss of heterozygosity or by
homozygous deletion, at the DNA level. It is also
inactivated in many head and neck carcinomas that are
tobacco-related by aberrant splicing of the mRNA, so
that only the nontranslatable form is transcribed. In
addition, the expression of an alternative spliced
isoform resulting in active enzyme may negatively
regulate bladder tumor growth, infiltration, and
angiogenesis. On the other hand, HYAL1 can function
as oncogene in many cancers of the prostate and
urinary tract and seems to play important role in
squamous cell laryngeal carcinoma.
Atlas Genet Cytogenet Oncol Haematol. 2008;12(3)
Lokeshwar VB, Cerwinka WH, Isoyama T, Lokeshwar BL.
HYAL1 hyaluronidase in prostate cancer: A tumor promoter
and suppressor. Cancer Res 2005;65:7782-7789.
Christopoulos TA, Papageorgakopoulou N, Theocharis DA,
Mastronikolis NS, Papadas TA, Vynios DH. Hyaluronidase and
CD44 hyaluronan receptor expression in squamous cell
laryngeal carcinoma. Biochim Biophys Acta 2006;1760:10391045.
Lokeshwar VB, Estrella V, Lopez L, Kramer M, Gomez P,
Soloway MS, Lokeshwar BL. HYAL1-v1, an Alternatively
Spliced Variant of HYAL1 Hyaluronidase: A Negative
Regulator of Bladder Cancer. Cancer Res 2006;66:1121911227.
218
HYAL1 (hyaluronoglucosaminidase 1)
Vynios DH
Stern R, Jedrzejas MJ. Hyaluronidases: their genomics,
structures, and mechanisms of action. Chem Rev
2006;106:818-839. (Review).
This article should be referenced as such:
Vynios DH. HYAL1 (hyaluronoglucosaminidase 1). Atlas Genet
Cytogenet Oncol Haematol.2008;12(3):217-219.
Chao KL, Muthukumar L, Herzberg O. Structure of human
hyaluronidase-1, a hyaluronan hydrolyzing enzyme involved in
tumor growth and angiogenesis. Biochemistry 2007;46:69116920.
Atlas Genet Cytogenet Oncol Haematol. 2008;12(3)
219
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Gene Section
Mini Review
MAML2 (mastermind-like 2)
Kazumi Suzukawa, Jean-Loup Huret
Department of Hematology, Institute of Clinical Medicine, University of Tsukuba, Japan (KS); Genetics,
Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France (JLH)
Published in Atlas Database: October 2007
Online updated version: http://AtlasGeneticsOncology.org/Genes/MAML2ID472.html
DOI: 10.4267/2042/38524
This article is an update of: Stenman G. MAML2 (mastermind-like 2). Atlas Genet Cytogenet Oncol Haematol.2003;7(3):170-171.
This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence.
© 2008 Atlas of Genetics and Cytogenetics in Oncology and Haematology
target genes HES1 and HES5; functions as a CSLdependent transcriptional coactivator for ligandstimulated Notch.
Identity
Hugo: MAML2
Other names: hMam-3; KIAA1819
Location: 11q21
Homology
MAML1 and MAML3.
DNA/RNA
Implicated in
Description
Mucoepidermoid carcinoma with
t(11;19)(q21-22;p13)
Spans 365 kb; 5 exons.
Transcription
Disease
- Most common type of malignant salivary gland
tumor;
- Second most frequent lung tumor of bronchial gland
origin;
- Rare tumour in the thyroid.
The t(11;19) was found in samples from the three
different sites.
Prognosis
- Mucoepidermoid carcinomas have an unpredictable
behaviour.
- The CRTC1-MAML2 fusion transcript was found
equally in low, intermediate and high grade tumours;
however, tumours lacking the fusion transcript were
significantly associated with metastases; they may
represent a subset of aggressive tumours.
- In another study, the median survival for fusionpositive patients was greater than 10 years compared to
1.6 years for fusion-negative patients.
Hybrid/Mutated Gene
CRTC1-MAML2; exon 1 of CRTC1 fused to exons 2-5
of MAML2. Note: CRTC1 is also known as MECT1,
or WAMTP1.
A major transcript of 7.5 kb.
Protein
Description
1153 aa, 125 kDa; conserved N-terminal basic domain
(aa 29-92) which binds to the ankyrin repeat domain of
Notch receptors; two acidic domains (aa 263-360 and
1124-1153) and a C-terminal transcriptional activation
domain.
Expression
Widely expressed.
Localisation
Nuclear granules.
Function
Mastermind-like coactivator for all four Notch
receptors; forms a complex with the Notch intracellular
domain (Notch ICD) and the CSL family of
transcription factors (CSL: CBF1/RBP-jk, Suppressor
of Hairless, LAG1), resulting in activation of the Notch
Atlas Genet Cytogenet Oncol Haematol. 2008;12(3)
220
MAML2 (mastermind-like 2)
Suzukawa K, Huret JL
Abnormal Protein
CRTC1-MAML2. In the fusion protein, the first 171 aa
including the basic domain of MAML2 are replaced by
42 aa of CRTC1; there are no sequence similarities in
the N-terminal domains of MAML2 and CRTC1. The
fusion protein activates transcription of the Notch
target gene HES1 independently of both Notch ligand
and CSL.
Transforming activity of CRTC1-MAML2 fusion
oncoprotein is mediated by mimicking constitutive
activation of cAMP signaling, by activating CREB
directly.
Hybrid/Mutated Gene
MLL-MAML2; exon 1-7 of MLL fused to exons 2-5 of
MAML2.
Abnormal Protein
Hybrid transcript MLL/MAML2 contains the following
domains:
from
MLL:
AT-hook,
DNAMethyltransferase; from MAML2: Q rich domain,
acidic domain.
To be noted
Note: It is amazing that a similar fusion transcript
(CRTC1-MAML2) can be seen both in a benign and in
a malignant tumour of the same organ: Warthin's
tumor, a benign salivary gland neoplasm, and
mucoepidermoid carcinoma of the salivary gland:
either another event differentiate the two, or the genetic
event takes place in different cell types or in a given
cell type at different states of differenciation.
It has been hypothezised that CRTC1-MAML2 fusion
is etiologically linked to benign and low-grade
malignant tumors originating from diverse exocrine
glands rather than being linked to a separate tumor
entity.
Warthin's tumor with t(11;19)(q2122;p13)
Note: In rare instances mucoepidermoid carcinoma
may arise from or coexist with Warthin's tumors.
Disease
Warthin's tumor is a salivary gland neoplasm consisting
of benign epithelial and lymphoid components;
malignant transformation is extremely rare.
Hybrid/Mutated Gene
CRTC1-MAML2
Clear cell hidradenomas of the skin with
t(11;19)(q21-22;p13)
References
Bullerdiek J, Haubrich J, Meyer K, Bartnitzke S. Translocation
t(11;19)(q21;p13.1) as the sole chromosome abnormality in a
cystadenolymphoma (Warthin's tumor) of the parotid gland.
Cancer Genet Cytogenet 1988;35(1):129-132.
Disease
Clear cell hidradenomas of the skin are benign sweat
gland tumors of eccrine duct origin.
Hybrid/Mutated Gene
CRTC1-MAML2; exon 1 of CRTC1 fused to exons 2
of MAML2.
Mark J, Dahlenfors R, Stenman G, Nordquist A. Chromosomal
patterns in Warthin's tumor. A second type of human benign
salivary gland neoplasm. Cancer Genet Cytogenet
1990;46(1):35-39.
Jhappan C, Gallahan D, Stahle C, Chu E, Smith GH, Merlino
G, Callahan R. Expression of an activated Notch-related int-3
transgene interferes with cell differentiation and induces
neoplastic transformation in mammary and salivary glands.
Genes Dev 1992;6:345-355.
inv(11)(q21q23) in therapy related
leukemias
Disease
Therapy-related acute leukemia and MDS.
Atlas Genet Cytogenet Oncol Haematol. 2008;12(3)
Nordkvist A, Gustafsson H, Juberg-Ode M, Stenman G.
Recurrent rearrangements of 11q14-22 in mucoepidermoid
carcinoma. Cancer Genet Cytogenet 1994;74:77-83.
221
MAML2 (mastermind-like 2)
Suzukawa K, Huret JL
de la Pompa JL, Wakeham A, Correia KM, Samper E, Brown
S, Aguilera RJ, Nakano T, Honjo T, Mak TW, Rossant J,
Conlon RA. Conservation of the Notch signalling pathway in
mammalian neurogenesis. Development 1997;124:1139-1148.
the skin-a third tumor type with a t(11;19)--associated TORC1MAML2 gene fusion. Genes Chromosomes Cancer
2005;43(2):202-205.
Wu L, Liu J, Gao P, Nakamura M, Cao Y, Shen H, Griffin JD.
Transforming activity of MECT1-MAML2 fusion oncoprotein is
mediated by constitutive CREB activation. EMBO J
2005;24(13):2391-2402.
Stenman G, Petursdottir V, Mellgren G, Mark J. A child with a
t(11;19)(q14-21;p12) in a pulmonary mucoepidermoid
carcinoma. Virchows Archiv 1998;433; 579-581.
Wu L, Aster JC, Blacklow SC, Lake R, Artavanis-Tsakonas S,
Griffin JD. MAML1, a human homologue of Drosophila
Mastermind, is a transcriptional co-activator for NOTCH
receptors. Nat Genet 2000;26:484-489.
Behboudi A, Enlund F, Winnes M, Andrén Y, Nordkvist A,
Leivo I, Flaberg E, Szekely L, Mäkitie A, Grenman R, Mark J,
Stenman G. Molecular classification of mucoepidermoid
carcinomas-prognostic significance of the MECT1-MAML2
fusion
oncogene.
Genes
Chromosomes
Cancer
2006;45(5):470-481.
Lin SE, Oyama T, Nagase T, Harigaya K, Kitagawa M.
Identification of new human mastermind proteins defines a
family that consists of positive regulators for notch signaling. J
Biol Chem 2002;277:50612-50620.
Nemoto N, Suzukawa K, Shimizu S, Shinagawa A, Takei N,
Taki T, Hayashi Y, Kojima H, Kawakami Y, Nagasawa T.
Identification of a novel fusion gene MLL-MAML2 in secondary
acute myelogenous leukemia and myelodysplastic syndrome
with
inv(11)(q21q23).
Genes
Chromosomes
Cancer
2007;46(9):813-819.
Wu L, Sun T, Kobayashi K, Gao P, Griffin JD. Identification of a
family of mastermind-like transcriptional coactivators for
mammalian notch receptors. Mol Cell Biol 2002;22:7688-7700.
Tonon G, Modi S, Wu L, Kubo A, Coxon AB, Komiya T, O'Neil
K, Stover K, El-Naggar A, Griffin JD, Kirsch IR, Kaye FJ.
t(11;19)(q21;p13) translocation in mucoepidermoid carcinoma
creates a novel fusion product that disrupts a Notch signaling
pathway. Nat Genet 2003;33:208-213.
Tirado Y, Williams MD, Hanna EY, Kaye FJ, Batsakis JG, ElNaggar AK. CRTC1/MAML2 fusion transcript in high grade
mucoepidermoid carcinomas of salivary and thyroid glands and
Warthin's tumors: implications for histogenesis and biologic
behavior. Genes Chromosomes Cancer 2007;46(7):708-715.
Enlund F, Behboudi A, Andrén Y, Oberg C, Lendahl U, Mark J,
Stenman G. Altered Notch signaling resulting from expression
of a WAMTP1-MAML2 gene fusion in mucoepidermoid
carcinomas and benign Warthin's tumors. Exp Cell Res
2004;292(1):21-28.
Winnes M, Mölne L, Suurküla M, Andrén Y, Persson F, Enlund
F, Stenman G. Frequent fusion of the CRTC1 and MAML2
genes in clear cell variants of cutaneous hidradenomas. Genes
Chromosomes Cancer 2007;46(6):559-563.
Martins C, Cavaco B, Tonon G, Kaye FJ, Soares J, Fonseca I.
A study of MECT1-MAML2 in mucoepidermoid carcinoma and
Warthin's tumor of salivary glands. J Mol Diagn 2004;6(3):205210.
This article should be referenced as such:
Suzukawa K, Huret JL. MAML2 (mastermind-like 2). Atlas
Genet Cytogenet Oncol Haematol.2008;12(3):220-222.
Behboudi A, Winnes M, Gorunova L, van den Oord JJ,
Mertens F, Enlund F, Stenman G. Clear cell hidradenoma of
Atlas Genet Cytogenet Oncol Haematol. 2008;12(3)
222
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Gene Section
Mini Review
MUC16 (mucin 16, cell surface associated)
Shantibhusan Senapati, Moorthy P Ponnusamy, Ajay P Singh, Maneesh Jain, Surinder K Batra
Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, 985870
Nebraska Medical Center, Durham Research center 7005, Omaha, NE 68198-5870, USA
Published in Atlas Database: October 2007
Online updated version: http://AtlasGeneticsOncology.org/Genes/MUC16ID41455ch19q13.html
DOI: 10.4267/2042/38525
This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence.
© 2008 Atlas of Genetics and Cytogenetics in Oncology and Haematology
approximatively 179 kb of genomic DNA.
Identity
Transcription
Hugo: MUC16
Other names: CA125; FLJ14303; Mucin-16
Location: 19p13.2
Note: MUC16 belongs to the subgroup of the
membrane-anchored mucin. It is a type-1 glycopotein
with heavy O- and N-type glycosylation.
As per the present available information, there is a
discrepancy regarding the total number of exons
present in MUC16 genomic DNA. This discrepancy is
due to the absence/presence of some of the genomic
sequences (particularly for the repeat regions) in the
available genomic databases. The terminal nine exons
on both 5' and 3' ends code for the amino- and carboxyterminal domains of MUC16, respectively. At the same
time, it has been proposed that five consecutive exons
code for a single repeat unit (SRU) of the central
tandem repeat domain.
DNA/RNA
Description
In the genome, MUC16 is localized in 19p13.2
chromosome and is coded by sequences present within
Shows the genomic organization of MUC16 gene.
Protein
Shows the structural organization of CA125/MUC16 protein.
Atlas Genet Cytogenet Oncol Haematol. 2008;12(3)
223
MUC16 (mucin 16, cell surface associated)
Senapati S, et al.
Description
Function
MUC16 protein harbors a central tandem repeat region,
N-terminal domain and carboxy terminal domain. The
N-terminal domain has 12070 numbers of amino acids
rich in serine/threonine residues and accounts for the
major O-glycosylation known to be present in CA125.
The MUC16 protein back bone is dominated by tandem
repeat region, which has more than 60 repeat domains,
each composed of 156 amino acids. Though all the
individual repeat units are not similar, most of them
occur more than once in the sequence.
The repeat units are rich in serine, threonine and
proline residues, which are typical for any mucins.
Each repeat unit has some homology to the SEA (Seaurchin sperm protein, Enterokinase and Agrin) module,
whose exact biological function is not known.
The epitopes for known anti-CA125 antibodies (OC125
and M11) are thought to be present on a small cysteine
ring region present in the tandem-repeat region of
MUC16.
The carboxy-terminal domain has 284 aminoacids and
can be divided into three different regions: extra
cellular, transmembrane and cytoplasmic tail. The
extracellular part of the carboxy-terminal domain has
many N-glycosylation sites and some O-glycosyaltion
sites. Several in silico analyses suggest a putative
cleavage site in the extracellular part of carboxyterminal domain. The MUC16 cytoplasmic tail is 31
amino acids long and has many possible
phosphorylation sites.
The phosphorylation of CA125 in WISH cells has been
reported
by
labeling
with
32PO43and
immunoprecipitaion analysis but the exact site of
phosphorylation is yet to be mapped. Interestingly,
CA125 contains a putative tyrosine phosphorylation
site (RRKKEGY), which was first recognized in Src
family protein. This sequence is conserved in the
translated mouse EST (AK003577) that has homology
with CA125/MUC16 at the C-terminal end. Recently, it
has been shown that MUC16 cytoplasmic tail, which
contains a polybasic aminoacid sequence, interacts with
cytoskeleton through ERM (ezrin/radixin/moesin)
actin-binding proteins.
MUC16 provides a disadhesive protective barrier to the
ocular epithelial surface. Overexpression of
CA125/MUC16 in ovarian cancer indicates its possible
role in cancer pathogenesis. Studies have shown that
CA125/MUC16 binds to mesothelin and galectin-1,
which are overexpressed in ovarian cancer. It has also
been shown that mesothelin-MUC16 interaction has
significance in adhesion of ovarian cancer cells to
mesothelial cells present on the inner wall of the
peritoneum and on the surface of other abdominal
organs. This cell to cell adhesion may help in ovarian
cancer metastasis. It has been proposed that galectin-1
bound to MUC16 may cause apoptosis of T cells, and
thus help in the suppression of the host immunity.
Homology
Similar to mucin 16 of Pan troglodytes, Canis lupus
familiaris, Mus musculus, Rattus norvegicus and Gallus
gallus.
Implicated in
Ovarian cancer
Disease
Epithelial ovarian cancer is the most lethal
gynaecologic malignancy in the United States and other
parts of the world. In the United States, ovarian cancer
accounts for approximately 22,000 new cases and
16,000 deaths occurring every year. The epithelial
ovarian carcinomas represent approximately 90% of all
types of ovarian malignant neoplasms. Due to lack of
specific signs and symptoms of this disease, coupled
with lack of reliable screening strategies most patients
are diagnosed in the advanced stage of the disease,
resulting in low overall cure rates. Ovarian cancer
patients are generally treated with surgical resection
and subsequent platinum-based chemotherapy.
Although, many patients initially respond well to
chemotherapy, long term survival remains poor due to
eventual tumor recurrence and emergence of drugresistant disease. Overall, the five year survival rate is
45%.
Prognosis
Since the last 20 years, CA125/MUC16 has been used
as a well-established marker for diagnosis of ovarian
cancer. It is mostly overexpressed in serous type of
ovarian cancers and less likely to be expressed in
mucinous tumors. More than 80% of ovarian cancer
patients have elevated CA125 level during their
treatment period. It has been shown that the disease
progression is associated with an increase in serum
CA125 level, while a decline in serum CA125 level is
associated with response to therapy. In another finding,
Expression
The expression of MUC16 has been reported in human
epithelia of conjunctiva, cornea, middle ear and trachea
under normal physiological conditions. MUC16 is also
expressed in ovarian carcinoma.
Localisation
It is a type I membrane-bound protein and due to
cleavage gets secreted into the extracellular space. On
the ocular surface, MUC16 is expressed on the tips of
the microplicae of the ocular surface.
Atlas Genet Cytogenet Oncol Haematol. 2008;12(3)
224
MUC16 (mucin 16, cell surface associated)
Senapati S, et al.
it has been shown that the trend of serum CA125 level
during the first three courses of chemotherapy is a
strong forecaster of re-examination findings in patients
with ovarian carcinoma at the end of treatment.
Interestingly, it has been shown that a normal CA125
level by the end of second or third chemotherapy is
strongly linked to the survival of patients in stage 3 or
stage 4 conditions. Also, variations in the CA125 value
even within the normal range carry useful information
regarding prediction of time to treatment failure.
Additionally, in patients in stage 1 cancers it has been
suggested that CA125 elevations are not related to the
tumor mass volume. Recently, the potential of
CA125/MUC16 as a therapeutic target has been
harnessed by using an armed human antibody (3A5)
against MUC16 protein.
Oncogenesis
There is no experimental evidence in the scientific
literature for a role of MUC16 in oncogenesis.
However, MUC16 possesses many structural
similarities with other membrane bound mucins, like
MUC1 and MUC4, which are already shown to be
functionally
involved
in
different
cancers.
Transmembrane mucins are hypothesized to serve as
sensors of the external environment and can transduce
signals via the post-translational modifications of their
cytoplasmic tail. Phosphorylation of MUC16 protein
has already been reported. Though the exact interacting
partner and the site of phosphorylation are unknown,
the presence of potential phosphorylation sites in
MUC16 cytoplasmic tail indicates the possible role of
MUC16 in downstream signal transduction. Further, it
has been shown that MUC16 interacts with galectin-1
and mesothelin and these interactions may have a role
in cancer progression.
O'Brien TJ, Beard JB, Underwood LJ, Shigemasa K. The CA
125 gene: a newly discovered extension of the glycosylated Nterminal domain doubles the size of this extracellular
superstructure. Tumour Biol 2002;23(3):154-169.
References
Davies JR, Kirkham S, Svitacheva N, Thornton DJ, Carlstedt I.
MUC16 is produced in tracheal surface epithelium and
submucosal glands and is present in secretions from normal
human airway and cultured bronchial epithelial cells. Int J
Biochem Cell Biol 2007;39(10):1943-1954.
Yin BW, Dnistrian A, Lloyd KO. Ovarian cancer antigen CA125
is encoded by the MUC16 mucin gene. Int J Cancer
2002;98(5):737-740.
Seelenmeyer C, Wegehingel S, Lechner J, Nickel W. The
cancer antigen CA125 represents a novel counter receptor for
galectin-1. J Cell Sci 2003;116(Pt 7):1305-1318.
Maeda T, Inoue M, Koshiba S, Yabuki T, Aoki M, Nunokawa E,
Seki E, Matsuda T, Motoda Y, Kobayashi A, Hiroyasu F,
Shirouzu M, Terada T, Hayami N, Ishizuka Y, Shinya N,
Tatsuguchi A, Yoshida M, Hirota H, Matsuo Y, Tani K,
Arakawa T, Carninci P, Kawai J, Hayashizaki Y, Kigawa T,
Yokoyama S. Solution structure of the SEA domain from the
murine homologue of ovarian cancer antigen CA125 (MUC16).
J Biol Chem 2004;279(13):13174-13182.
Chauhan SC, Singh AP, Ruiz F, Johansson SL, Jain M, Smith
LM, Moniaux N, Batra SK. Aberrant expression of MUC4 in
ovarian carcinoma: diagnostic significance alone and in
combination with MUC1 and MUC16 (CA125). Mod Pathol
2006;19(10):1386-1394.
Duraisamy S, Ramasamy S, Kharbanda S, Kufe D. Distinct
evolution of the human carcinoma-associated transmembrane
mucins, MUC1, MUC4 AND MUC16. Gene 2006;373:28-34.
Gubbels JA, Belisle J, Onda M, Rancourt C, Migneault M, Ho
M, Bera TK, Connor J, Sathyanarayana BK, Lee B, Pastan I,
Patankar MS. Mesothelin-MUC16 binding is a high affinity, Nglycan dependent interaction that facilitates peritoneal
metastasis of ovarian tumors. Mol Cancer 2006;5(1):50.
Blalock TD, Spurr-Michaud SJ, Tisdale AS, Heimer SR,
Gilmore MS, Ramesh V, Gipson IK. Functions of MUC16 in
Corneal Epithelial Cells. Invest Ophthalmol Vis Sci
2007;48(10):4509-4518.
Chen Y, Clark S, Wong T, Chen Y, Chen Y, Dennis MS, Luis
E, Zhong F, Bheddah S, Koeppen H, Gogineni A, Ross S,
Polakis P, Mallet W. Armed antibodies targeting the mucin
repeats of the ovarian cancer antigen, MUC16, are highly
efficacious in animal tumor models. Cancer Res
2007;67(10):4924-4932.
Erratum
in
Cancer
Res
2007;67(12):5998.
O'Brien TJ, Beard JB, Underwood LJ, Dennis RA, Santin AD,
York L. The CA 125 gene: an extracellular superstructure
dominated by repeat sequences. Tumour Biol 2001;22(6):348366.
This article should be referenced as such:
Yin BW, Lloyd KO. Molecular cloning of the CA125 ovarian
cancer antigen: identification as a new mucin, MUC16. J Biol
Chem 2001;276(29):27371-27375.
Atlas Genet Cytogenet Oncol Haematol. 2008;12(3)
Senapati S, Ponnusamy MP, Singh AP, Jain M, Batra SK.
MUC16 (mucin 16, cell surface associated). Atlas Genet
Cytogenet Oncol Haematol.2008;12(3):223-225.
225
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Gene Section
Review
MUC17 (mucin 17, cell surface associated)
Wade M Junker, Nicolas Moniaux, Surinder K Batra
Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, 985870
Nebraska Medical Center, Durham Research Center 7005, Omaha, NE 68198-5870, USA
Published in Atlas Database: October 2007
Online updated version: http://AtlasGeneticsOncology.org/Genes/MUC17ID41456ch7q22.html
DOI: 10.4267/2042/38526
This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence.
© 2008 Atlas of Genetics and Cytogenetics in Oncology and Haematology
repeated in tandem. This sequence was therefore
believed to be part of MUC3 until Gum and
collaborators identified the carboxy terminal sequence
of the 59 aa tandem repeat and identified this sequence
has part of a new mucin called MUC17. Indeed, in
2002, driven with the hypothesis that the 177 bp
tandem repeated sequences were part of a new
unidentified mucin, Gum et al. screened the public
GenBankTM database and the proprietary Lifeseq Gold
database (Incyte Genomics Inc., CA). By database
searching and RT-PCR they extended the partial mucin
sequence found during analysis of MUC3 and cloned a
MUC17 fragment of 3,807 bp (accession number
AF430017) (Gum et al., 2002). In 2006, Moniaux and
Junker reported the complete coding sequence and
organization of the MUC17 gene (Moniaux et al.,
2006).
Identity
Hugo: MUC17
Other names: MUC3; mucin-17; mouse Muc3; small
intestinal mucin MUC3; membrane mucin 17; secreted
mucin 17; intestinal membrane mucin MUC17
Location: 7q22.1
Note: Mucin glycoproteins are a diverse family of high
molecular mass, heavily glycosylated proteins
differentially expressed in epithelial tissues of the
gastrointestinal, reproductive and respiratory tracts.
Membrane mucins such as MUC17 are expressed by
epithelial cells to provide protection, maintain luminal
structure, and provide signal transduction. Often these
molecules are over- or aberrantly expressed in cancers
of epithelial origin. Mucins confer anti-adhesive
properties in cancer cells that lose their apical/basal
polarization. They also provide adhesive properties
towards endothelial cells favoring dissemination of
mucin expressing cancer cells.
MUC17 is a recently fully characterized mucin that
belongs to the membrane-bound subfamily of mucin
(Moniaux et al., 2006). It is a cell surface glycoprotein
that is found on epithelial cells in select tissues of the
body (wade need to precise the know profile). Its
structure consists of an extracellular domain that
extends above the cell surface and an intracellular
domain of 80 amino acid residues. New evidence
suggests its de-regulation in pancreatic cancer
(Moniaux et al., 2006; Moehle et al., 2006). The first
partial length cDNA sequence, now known to
correspond to MUC17, was identified by Van Klinken
et al. (1997). At that time, van klinken isolated a
chimeric cDNA clone overlapping MUC3 specific
tandem repeat sequence and a new 59 aa sequence
Atlas Genet Cytogenet Oncol Haematol. 2008;12(3)
DNA/RNA
Note: MUC17 was identified and localized to
chromosome 7q22 by radiation hybridization mapping
(Gum et al., 2002) where it resided in a gene cluster
with mucins MUC3A, MUC3B, and MUC11/12
(Figure 1). These mucins reside next to each other and
have function in intestinal epithelium integrity, but are
expressed in other different tissues and likely have
different functions as well. The mucin genes within the
cluster are transcribed independent of one another.
MUC17 shows a low degree of VNTR (variable
number of tandem repeats) polymorphism with only
three different genomic DNA sizes detected for the
large tandemly repeated extracellular domain in 24
cancer lines (pancreas, colon, and breast) and in four
healthy individuals control samples (Moniaux et al.,
2006).
226
MUC17 (mucin 17, cell surface associated)
Junker WM, et al.
Figure 1 - Chromosome location within the 7q22 mucin gene cluster.
MUC17 resides in a gene cluster with mucins MUC3A, MUC3B, and MUC11/12 on chromosome 7 in the region q22.1. Upstream of the
gene cluster 50 Kb is a potential open reading frame that shares similarity to MUC3. Approximately 26.7 Kb downstream of MUC17
reside TRIM56 and SERPINE1. Less that 1.2 Kb of genomic distance separates the 3' end of MUC12 from the beginning of MUC17.
Figure 2 - MUC17 genomic and transcript bp size.
The MUC17 gene encompasses (38,587 bp) 38.6 Kb of genomic sequence. The coding sequence contains 13 exons and is transcribed
as a (14,360 bp) 14.4 Kb RNA that gives rise to full-length MUC17. The presence of an alternative splice site results in exclusion of exon
7, and produces a processed RNA that gives rise to a shorter MUC17/SEC.
Description
Transcription
Radiation hybridization mapping was performed using
the GeneBridge4 radiation hybrid panel (Research
Genetics, Huntsville, AL). Following hybridization, the
MUC17 probe was detected in the panel of 93
independent human/hamster fusion clones with
MUC17 specific primers, and data were analyzed using
the GeneBridge4 server. This analysis indicated linkage
to markers on chromosome 7q22 with an LOD score of
15. The presence or absence of MUC17 was
concordant with STS (Sequence Tagged Site) marker
D7S666 in 83 of 84 panel DNA samples that were
unambiguous for both markers, thus positioning
MUC17 near base 101,250,000 of chromosome 7 using
the National Center for Biotechnology Information
(NCBI) STS map. The NCBI electronic PCR server
refined the interval to bases 98,871,000 and 99,054,000
of the STS map and positioned MUC17 approximately
2,000,000 bases telomeric of MUC3A on 7q22 (Gum et
al., 2002).
The MUC17 sequence has now been extended toward
its 5'-extremity to complete the sequence and localize
the promoter and regulatory elements. Rapid
amplification of cDNA ends (RACE) and sequences
from the Human Genome databases were used. The
MUC17 gene is located within a 39-kb DNA fragment
between MUC12 and SERPINE1 on chromosome 7 in
the region q22.1 (Moniaux et al., 2006).
The MUC17 full-length coding sequence is transcribed
as a (14,360 bp) 14.4 Kb mRNA encompassing 13
exons from a (38,587 bp) 38.6 kb genomic fragment
(Figure 2). Alternate splicing generates two variants
coding for a membrane-anchored and a secreted form
of the protein (Moniaux et al., 2006) (Figure 3). The
presence of an alternative splice event/site in the 3'extremity of MUC17 was investigated by RT-PCR.
RT-PCR was carried out on AsPC-1 cDNA. The
generated amplification products were cloned into
pCR® 2.1 and screened. Two distinct fragments were
identified through sequencing. One of the fragments
was 100% identical to the previous referenced
sequence of MUC17 (accession number AJ606307).
The second product revealed the occurrence of an
alternative splice event that resulted in the skipping of
exon 7. This alternative splice event generated a frameshift which coded for the 21 (MUC17/SEC) specific
amino acid residues and introduced a stop codon
positioned 66 nucleotides after the junction. The
resulting protein encodes a secreted form of MUC17
(accession number AJ606308), lacking the second EGF
domain, the transmembrane domain and cytoplasmic
tail (Figure 3). RT-PCR was carried out in four distinct
cell lines, (pancreatic AsPC-1, and colonic LS174T,
CaCo-2, and Ls180), representing different tissues, i.e.
pancreas and colon (Moniaux et al., 2006). Two
Atlas Genet Cytogenet Oncol Haematol. 2008;12(3)
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MUC17 (mucin 17, cell surface associated)
Junker WM, et al.
disease (IBD). The aim of the study was to characterize
changes in the expression profiles of genes related to
intestinal epithelial function by comparing biopsy
samples from patients with Ulcerative Colitis (UC) and
Crohn's disease (CD), to controls; as the loss of
intestinal mucosal integrity is an important factor in
IBD.
DNA-microarray analysis was applied and showed that
mucin genes are differentially regulated in CD and UC.
The loss of intestinal integrity is an important factor in
the pathogenesis of inflammatory bowel disease. A
coordinate down regulation of mucins was observed in
a pool of biopsy RNAs (n=4) taken from affected and
unaffected (control) regions of the terminal ileum and
colon of CD and UC patients. No expression in the
biopsy samples was detected for MUC6, MUC7,
MUC8, MUC9, MUC11, MUC15, MUC16, and
MUC18. Highest mucin expression values were
displayed my MUC2, MUC13, and MUC17 in the
ileum and the colon, while MUC12 was expressed in
the colon. The relative expression levels for MUC1,
MUC2, MUC4, MUC5B, MUC12, MUC13, MUC17,
and MUC20 showed strong down regulation with
decrease factors ranging from -1.3 to -48.5 fold.
MUC17 showed a -4.3 and -2.6 fold decrease in
Crohn’s disease and Ulcerative Colitis respectively in
the colon, but showed an apparent increase of 1.2 and
1.1 fold respectively in the same diseases in the ileum
biopsy pooled RNAs.
Real-time RT-PCR TaqMan assays were conducted to
obtain a specific overview of mucin expression in
human tissues. An initial analysis of nine mucin genes
in a panel of 26 different tissues was completed. The
authors confirmed the relative expression values
(average intensity) of DNA-microarray data (i.e.,
higher expression levels of MUC4, MUC5B, MUC12,
and MUC20 were obtained in the colon compared to
the ileum RNA; MUC17 was expressed higher in the
ileum than in the colon). A meta-analysis of 11
genome-wide linkage studies for IBD revealed 38
significant IBD loci (Brant et al., 2004). Interestingly,
all mucin family member loci reside within or directly
beside these IBD candidate loci. Therefore, Moehle et
al. performed allelic discrimination of one candidate
exonic SNP within each mucin gene in UC (n=220),
CD (n=181), and control (n=250) patient samples.
Significant associations were detected for the MUC2,
MUC4, and MUC13 mucin SNPs. The von Wildebrand
Factor (vWF) domain of MUC2 (11p15, A/G, V116M)
is associated with CD, the vWF domain of MUC4
(3q29, G/T, A585S) with UC, and the cytoplasmic tail
domain of MUC13 (3q13.1, A/C, R502S) with UC.
Unassessed SNPs in the mucin genes may still be
associated and remain unchecked.
The abundance of NFkB sites present in mucin
promoters prompted the authors (Moehle et al., 2006)
to explore regulation of mucin expression in the
Ls174T colon cell line model. The ligands TNF-a,
amplification products were detected. Sequencing of
the major amplification product identified it as the
MUC17 sequence described by Gum et al. (accession
number AF430017), while the other amplicon (minor)
corresponded to an alternatively spliced variant
(skipping of exon 7), the secreted form of MUC17,
referred to as MUC17/SEC. The level of expression of
MUC17/SEC seemed very low in the cell lines
investigated; the intensity of the corresponding band
was very faint as compared to the MUC17 fragment
(Moniaux et al., 2006).
MUC17 is expressed in select cell lines including
pancreatic AsPC-1 and HPAF-II; and colon cancer cell
lines LS174T, Caco-2, NCI-H498, and HM3 (Gum et
al., 2002; Moniaux et al., 2006). Tissue expression was
first shown by RNA dot blot analysis (Clontech
multiple tissue expression blot). MUC17 is expressed
in intestinal tissues, with the highest levels found in the
duodenum (highest level) and in the transverse colon
(85% of the level detected in duodenum). The only
non-intestinal tissues found to express MUC17 in this
analysis were stomach and fetal kidney. Both tissues
showed approximately 7% of the expression level
detected in the duodenum (Gum et al., 2002). In-situ
hybridization was conducted to determine the cell
specificity of MUC17 expression in the small intestine.
In-situ hybridization showed MUC17 expression
predominantly in the apical region of villi absorptive
cells. Barely detectable expression was found in
immature cells of the crypts. No expression was
detected in goblet cells (Gum et al., 2002). Therefore,
MUC17 expression is localized to the mature,
absorptive cells of intestinal villi epithelium and is
expressed in pancreatic cancer tissue (Moniaux et al.,
2006).
The MUC17 gene is located within a 39 kb DNA
fragment between MUC12 and SERPINE1 on
chromosome 7. Approximately 1.2 Kb of sequence lies
between the 3' end of MUC12 and the 5' UTR of the
MUC17 gene. Expression of MUC17 is regulated by
this 1,146-bp fragment upstream of MUC17 which
contains various VDR/RXR, GATA, NFkB, and Cdx-2
response elements. Like mouse Muc3 (mMUC3),
regulation of expression is controlled by both growth
factors and cytokines (unpublished data, Junker and
Batra, 2007). The mMuc3 promoter has consensus
binding sites for AP1, CREB, SP1, NF kappa B, GATA
binding protein, and Cdx. Reporter constructs
demonstrate that IL-4, IL-6, EGF, and PMA increase
mMuc3 promoter activity 35-58% of control levels.
TNF-a and IFN-g showed a lesser degree of stimulation
(Shekels et al., 2003). Regulation of mMuc3 by
cytokines and growth factors suggests an active role of
mouse Muc3 and its human homologue, MUC17 in
intestinal mucosal defense.
A recent study conducted by Moehle et al. (2006)
concerned the aberrant expression and allelic variants
of mucin genes associated with inflammatory bowel
Atlas Genet Cytogenet Oncol Haematol. 2008;12(3)
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MUC17 (mucin 17, cell surface associated)
Junker WM, et al.
TGFb, and LPS induced expression of MUC17 as
assayed by quantitative real-time PCR. TNF-a was able
to induce a time-dependent up-regulation of all the
monitored mucin genes (MUC-1, -2, MUC-5AC, -5B, 12, -13, -17, -20). All monitored mucin genes showed
increased
expression
with
TGFb
treatment.
Cooperation of NFkB with TGFb signaling has been
reported (Jono et al., 2002). Co-incubations of TGFb
with NFkB pathway inhibitors (CAPE and MG132)
resulted in a decrease of mucin expression, thus
demonstrating a link between these two pathways with
regards to mucin gene regulation.
Treatment of the Ls174T colon cancer cell line with
sodium butyrate had little or no effect on induction of
MUC17 expression level but did induce expression of
MUC3 which is not highly expressed in the cell line
(Gum et al., 2002). Similarly, incubation of MUC17
non-expressing cell line, MiaPaCa, with HDAC
inhibitor 5-aza-cytosine had little effect if any on
MUC17 expression.
targets the protein to the plasma membrane. The
majority of the molecule encodes the mucin central
domain that is modified extensively by glycosylation
and is displayed on the extracellular face of the cell.
The central domain of MUC17 contains 63 repeats of
59 amino acid sequence (177 bp) that are repeated in
tandem. This tandem repeat 'central domain' is
followed by a region of unique degenerate tandem
repeats and mucin-like sequences (i.e. that are
repetitive, G/C rich, and contain a high content of
threonine, serine, and proline amino acids). Two EGFlike domains flank both sides of a SEA module and
precede the transmembrane domain. Putative Nglycosylation sites occur near the carboxyl terminus.
The 80 amino acid C-terminal cytoplasmic domain has
potential serine and tyrosine phosphorylation sites.
Expression
RNA blot analysis and RT-PCR suggests MUC17 is
expressed in the digestive tract, primarily in the
duodenum (highest level) and the transverse colon
(85% of the level detected in duodenum) (Gum et al.,
2002). Expression is also reported in the terminal ileum
(Moehle et al., 2006) with MUC17 expressed higher in
the ileum than in the colon (quantitative RT-PCR,
microarray analysis). Many colon and pancreatic
cancer cell lines do express varied levels of MUC17
(Gum et al., 2002; Moniaux et al., 2006). An overexpression of MUC17 by Western blot and
immunohistochemical analyses in pancreatic tumor cell
lines and tumor tissues compared to normal pancreas
samples is seen (Moniaux et al., 2006).
Protein
Note: 4493 aa; 425.5 kDa (note: without modification
such as glycosylation)
Description
MUC17 is classified as a membrane-bound mucin
glycoprotein. The protein may serve as a cellular
receptor. The deduced full-length membrane-bound
amino acid sequence (4493 aa) shows the presence of
various mucin domains (Figure 3). A signal sequence
Figure 3 - full length MUC17 and secreted MUC17/SEC.
Full-length MUC17 contains a 25 amino acid leader peptide (secretion, membrane targeting signal), a central domain with tandemly
repeated sequence, two EGF-like domains, a SEA domain, transmembrane domain, and an 80 amino acid cytoplasmic tail domain.
Usage of an alternative splice site excludes exon 7 and introduces a frame shift that creates a premature stop codon 66 nucleotides
after the splice junction, within the SEA domain coding sequence. This shorter transcript results in a secreted form of the protein,
MUC17/SEC, which has 21 unique C-terminal amino acids, and lacks the second EGF domain, transmembrane domain, and C-terminal
cytoplasmic tail.
Atlas Genet Cytogenet Oncol Haematol. 2008;12(3)
229
MUC17 (mucin 17, cell surface associated)
Junker WM, et al.
transmembrane domain, and the cytoplasmic tail. The
MUC17/SEC protein is believed to be a soluble protein
as the absence of the transmembrane domain would
result in its secretion from the cell. In a mouse model of
human cystic fibrosis, both soluble Muc3 and goblet
cell Muc2 are increased and hyper-secreted
contributing to the excess intestinal mucus of cystic
fibrosis mice (Khatri et al., 2001).
Localisation
Surface localization of the smaller subunit of MUC17
is reported to be dependent on its N-glycosylation
status (Ho et al., 2003). MUC17 contains a SEA
domain, a transmembrane domain, and putative Nglycosylation sites in the carboxyl terminus. Mucins
that possess a SEA domain usually undergo an autoproteolytic cleavage event within the domain (Macao et
al., 2006) to yield two subunits, the smaller of which is
associated with the surface membrane. Ho and
colleagues reported that the ASPC-1 pancreatic cancer
cell line shows three main bands (38, 45, and 49 kDa)
of immunoreactivity with an antibody directed against
a site downstream of the postulated SEA cleavage site
(Ho et al., 2003). Treatment with N-glycan specific
hydrolases showed the 38 kDa band contained high
mannose glycans, whereas the 45 and 49 kDa bands
contained complex-type glycans. Surface biotinylation
studies revealed that only forms possessing complextype N-glycans were localized to the cell surface. Both
tunicamycin (N-glycosylation inhibitor) and brefeldin
A (an inhibitor of protein transport) reduced surface
localization. Surface localization of the smaller subunit
of MUC17 therefore appears to be dependent on its Nglycosylation status in AsPC-1 pancreatic cancer cells.
Immunohistochemical analysis of mouse Muc3 (the
homologue of MUC17) revealed strong staining in
goblet cells and patchy staining of surface columnar
cells in the duodenum, small intestine, caecum, colon
and rectum (Shekels et al., 1998). Northern blot
analysis indicates that the mRNA is approximately 13.5
kb. Highest expression was detected in the caecum with
lesser amounts detected in the colon and small
intestine. No message was found in mouse stomach,
trachea, lung, kidney, esophagus or pancreas (Shekels
et al., 1998). In-situ hybridization studies show
expression at the tips of villi, in the upper crypts, and in
surface cells of the caecum and colon (Shekels et al.,
1998).
Rodent (mouse) mMuc3 and (rat) rMuc3 are assumed
to represent secretory mucins expressed in columnar
and goblet cells of the intestine. In-situ hybridization
with a 3'-probe localized (rat) rMuc3 expression
generally to columnar cells. Two antibodies specific for
the C-termini of rat rMuc3 localized the protein to
apical membranes and cytoplasm of columnar cells. An
antibody to the tandem repeat sequence, however,
localized the protein to both columnar and goblet cells.
Cesium chloride ultracentrifugation was used to isolate
both light- and heavy-density fractions. A full-length
membrane-associated form (light density) was found in
columnar cells, whereas, the carboxyl-truncated soluble
form of rat Muc3 (heavy density) was present in goblet
cells (Wang et al., 2002). A similar localization of
human MUC17 may exist as the splice variant,
MUC17SEC, encodes a truncated protein that is
missing the second EGF-like domain, the
Atlas Genet Cytogenet Oncol Haematol. 2008;12(3)
Function
MUC17 is a membrane-bound glycoprotein that may
serve as a cellular receptor through its extended,
repetitive extracellular glycosylation domain. The
extracellular domain may serve a lubricant
functionality and provide a signal transduction
capability. Membrane mucins, such as MUC17,
function in epithelial cells to provide cytoprotection,
maintain luminal structure, provide signal transduction,
and confer anti-adhesive properties to cancer cells
which lose their apical/basal polarization. Outside-in
signaling may be transduced by the protein's interaction
with extracellular matrix constituents including growth
factors and cytokines and/or potentially binding of
Ca2+ or EGF ligands to extracellular displayed EGFlike domains. The 80 amino acid cytoplasmic domain
has potential serine and tyrosine phosphorylation sites
to convey extracellular signals.
Analysis of mouse Muc3 showed that a definitive
proteolytic cleavage occurs during processing in the
endoplasmic
reticulum.
Recombinant
products
consisted of a V5-tagged 30 kDa extracellular
glycopeptide and a Myc-tagged 49 kDa membraneassociated glycopeptide. Throughout their cellular
transport to the plasma membrane, the two fragments
remained associated by non-covalent SDS-sensitive
interactions.
Site-specific
mutagenesis
showed
requirement for glycine and serine residues in the
cleavage sequence Leu-Ser-Lys-Gly-Ser-Ile-Val-Val,
which is found in the SEA domain between the two
EGF-like motifs of the mucin. A similar cleavage
sequence has been reported in human MUC1 and
analogous sites are present in human MUC3, MUC12,
MUC16 and MUC17. Proteolytic cleavage may be a
conserved characteristic of the membrane-bound
mucins, and possibly precedes the release of their large
extracellular domains at cell surfaces (Wang et al.,
2002).
Homology
The similarity of human MUC17 to rodent Muc3
(mouse and rat) was first reported by JR Gum Jr and
colleagues. This similarity was represented by a
cladogram calculated using sequences initiating at the
start of the second EGF-like domain and continuing
through to the carboxy-termini of the proteins. The
analysis suggests that MUC17 diverged from human
MUC3 earlier in evolution than the divergence of
primates and rodents, and suggests that MUC17 is the
230
MUC17 (mucin 17, cell surface associated)
Junker WM, et al.
true structural homolog of rodent Muc3 (Gum et al.,
2002). Whether MUC17 is the functional homolog of
rodent Muc3 is still unclear, however, and needs to be
experimentally proven. Chromosome computer
analysis assigns mouse Muc3 to mouse chromosome 5,
a region of synteny to human chromosome 7, the
location of the human MUC3, MUC12, and MUC17
mucin genes. NCBI HomoloGene reports MUC17 is
conserved in Coelomata or in organisms higher than
coelenterates and certain primitive worms.
Expression of the mouse Muc3 mucin has been
characterized in terms of regulation of its promoter by
cytokines and growth factors. Mouse Muc3 is now
believed to be the true structural homologue of human
MUC17 due to higher sequence similarity to MUC17
than human MUC3 (Moniaux et al., 2006). The Nterminal domain for MUC17 is coded by two exons,
whereas for MUC3, it is coded by a single exon. Gum
and colleagues (2002) showed that the degree of
sequence homology between the carboxy-extremity of
MUC17 and mMuc3 was higher than that between
MUC3 and mMUC3. An alignment of the aminoextremities of MUC17, MUC3, and mMuc3 is shown.
No similarity is shown by MUC3 and mMuc3, but a
high degree of identity exists between MUC17 and
mMUC3. Their similar structural organization and high
degree of identity show that MUC17 is the human
homologue of mMuc3.
A search of the National Center for Bioinformatics
HomoloGene and UniGene databases returned the
following suggested sequences for comparison.
HomoloGene:88635. Gene conserved in Coelomata
Human
H. sapiens
MUC17
mucin 17, cell surface associated, chromosome 7q22.1, GeneID: 140453
Chimpanzee
(West African)
P. troglodytes
MUC17
mucin 17, chromosome 7, GeneID: 740201
Mouse
M. musculus
Muc3
mucin 3, intestinal
Rhesus monkey
Macaca mulatta
Human
Homo sapiens
CAE54435
Human
Homo sapiens
CAE54436
Human
Homo sapiens
AAL89737
Human
Homo sapiens
AAI26316
Human
Homo sapiens
NP_001035194
Pan troglodytes
XP_001142083
Chimpanzee
(West African)
Opossum (gray
short-tailed)
Opossum (gray
short-tailed)
Monodelphis
domestica
Monodelphis
domestica
chromosome 3
XP_001375221
XP_001371346
Chicken
Gallus gallus
XP_001233667
Mosquito
Aedes aegypti
EAT36316
Opossum (gray
short-tailed)
Monodelphis
domestica
LOC100017948
Chicken
Gallus gallus
LOC770330
Opossum (gray
short-tailed)
Chimpanzee
(West African)
Rat (Brown
Norway)
Monodelphis
domestica
LOC100023779
Pan troglodytes
LOC463614
Rattus norvegicus
Muc17_predicted
Fruit Fly
D. melanogaster
Sgs1
Atlas Genet Cytogenet Oncol Haematol. 2008;12(3)
membrane mucin MUC17 (Homo sapiens)
gi/51869309/emb/CAE54435.1/(51869309)
secreted mucin MUC17 (Homo sapiens)
gi/51869311/emb/CAE54436.1/(51869311)
intestinal membrane mucin MUC17 (Homo sapiens)
gi/19526645/gb/AAL89737.1/AF430017_1(19526645)
MUC17 protein (Homo sapiens)
gi/118835615/gb/AAI26316.1/(118835615)
mucin 17 (Homo sapiens) gi/91982772/ref/NP_001035194.1/(91982772)
PREDICTED: mucin 17 (Pan troglodytes)
gi/114615083/ref/XP_001142083.1/(114615083)
PREDICTED: similar to membrane mucin MUC17 (Monodelphis
domestica) gi/126323716/ref/XP_001375221.1/(126323716)
PREDICTED: similar to MUC17 protein (Monodelphis domestica)
gi/126309309/ref/XP_001371346.1/(126309309)
PREDICTED: similar to intestinal membrane mucin MUC17, partial
(Gallus gallus) gi/118121828/ref/XP_001233667.1/(118121828)
secreted mucin MUC17, putative (Aedes aegypti),
gi/108872091/gb/EAT36316.1/(108872091)
similar to MUC17 protein (Monodelphis domestica) , Chromosome: 2,
GeneID: 100017948
similar to intestinal membrane mucin MUC17 (Gallus gallus),
Chromosome: Un, GeneID: 770330
similar to membrane mucin MUC17 (Monodelphis domestica),
Chromosome: 3, GeneID: 100023779
similar to membrane mucin MUC17 (Pan troglodytes), Chromosome: 7,
GeneID: 463614
Muc17_predicted and Name: mucin 17 (predicted) (Rattus norvegicus),
Chromosome: 7, GeneID: 295035
Salivary gland secretion 1, 25B2-3 puff, salivary glands, third instar
231
MUC17 (mucin 17, cell surface associated)
Junker WM, et al.
Selected Protein Similarities
Comparison of sequences in UniGene with proteins supported by a complete genome. The alignments can suggest function of a gene.
C. elegans
32.92 % / 636 aa ref:NP_505150.1 - reverse transcriptase (Caenorhabditis elegans)
S. cerevisiae
30.55 % / 644 aa pir:S48478 - S48478 glucan 1,4-alpha-glucosidase
R. norvegicus
27.24 % / 647 aa pir:A53577 - A53577 ascites sialoglycoprotein 1 - rat
M. musculus
24.77 % / 633 aa ref:NP_035871.1 - zonadhesin (Mus musculus)
A. thaliana
23.94 % / 531 aa ref:NP_564694.1 - expressed protein (Arabidopsis thaliana)
D. melanogaster 22.31 % / 637 aa sp:Q02910 - CPN_DROME CALPHOTIN
E. coli
18.05 % / 563 aa
ref:NP_287395.1 - putative membrane protein of prophage CP-933X (Escherichia coli O157:H7
EDL933)
tumor mass (weight) in relation to mice injected with
the parental cell line (control group) transfected with a
scrambled RNAi sequence (unpublished data, Junker
and Batra, 2007).
Implicated in
Pancreatic adenocarcinoma
Disease
Worldwide, pancreatic cancer is the eleventh most
common cancer. In the United States of America,
pancreatic cancer is the fourth leading cause of cancer
related death. Pancreatic cancer presents a 5-year
survival rate of just 5%. The incidence and ageadjusted mortality rate (approximatively 95%) are
almost equal, underscoring the aggressive nature of the
disease.
Prognosis
Currently, no approved diagnostic biomarker for
pancreatic cancer is licensed in the United States. The
CA19-9 mucin epitope is used for the diagnosis of
ovarian cancer and other mucins are being developed
for the detection of breast cancer (MUC1) and
pancreatic cancer (MUC1, MUC4, MUC3, MUC17).
The DUPAN-2 antibody recognizes a tumor-associated
antigen carried by the MUC4 protein and is used as a
clinical diagnostic for pancreatic adenocarcinoma in
Japan. MUC4 is aberrantly expressed in 80% of
pancreatic adenocarcinomas and is not expressed in the
normal pancreas or benign pancreatitis. In addition
MUC4 is expressed early in the onset of pancreatic
cancer (detected in pancreatic intraepithelial neoplasia
(PanIN) stage I disease). Similarly, MUC17 is
aberrantly expressed in pancreatic adenocarcinomas as
compared to no expression in the normal pancreas or
benign pancreatitis. MUC17 is expressed early in the
progression of pancreatic cancer with localization to
well defined pancreatic ductal structures undergoing
malignant transformation (Moniaux et al., 2006).
Oncogenesis
In an in vivo model, subcutaneous injection of MUC17
AsPC-1 knock-down cells show slight increase in
tumorigenicity in relation to parental control cells;
although no significant difference was detected due to
large variation in tumor weights. A xenograph model
with knock-down cell lines injected orthotopically into
the pancreas head showed an increased potential to
metastasize to the peritoneal cavity and increased
Atlas Genet Cytogenet Oncol Haematol. 2008;12(3)
To be noted
Note: Conserved in Coelomata. From (HomoloGene:
88635. Gene conserved in Coelomata).
Coelome: the cavity within the body of all animals
higher than the coelenterates and certain primitive
worms, formed by the splitting of the embryonic
mesoderm into two layers. In mammals, the coelome
forms the peritoneal, pleural, and pericardial cavities.
References
Van Klinken BJ, Van Dijken TC, Oussoren E, Buller HA,
Dekker J, Einerhand AW. Molecular cloning of human MUC3
cDNA reveals a novel 59 amino acid tandem repeat region.
Biochem Biophys Res Commun 1997;238(1):143-148.
Shekels LL, Hunninghake DA, Tisdale AS, Gipson IK,
Kieliszewski M, Kozak CA, Ho SB. Cloning and
characterization of mouse intestinal MUC3 mucin: 3' sequence
contains epidermal-growth-factor-like domains. Biochem J
1998;330:1301-1308.
Khatri IA, Ho C, Specian RD, Forstner JF. Characteristics of
rodent intestinal mucin Muc3 and alterations in a mouse model
of human cystic fibrosis. Am J Physiol Gastrointest Liver
Physiol 2001;280:G1321-1330.
Gum JR Jr, Crawley SC, Hicks JW, Szymkowski DE, Kim YS.
MUC17, a novel membrane-tethered mucin. Biochem Biophys
Res Commun 2002;291(3):466-475.
Jono H, Shuto T, Xu H, Kai H, Lim DJ, Gum JR Jr, Kim YS,
Yamaoka S, Feng XH, Li JD. Transforming growth factor-beta Smad signaling pathway cooperates with NF-kappa B to
mediate nontypeable Haemophilus influenzae-induced MUC2
mucin transcription. J Biol Chem 2002;277(47):45547-45557.
Wang R, Khatri IA, Forstner JF. C-terminal domain of rodent
intestinal mucin Muc3 is proteolytically cleaved in the
endoplasmic reticulum to generate extracellular and membrane
components. Biochem J 2002;366:623-631.
Ho JJ, Jaituni RS, Crawley SC, Yang SC, Gum JR, Kim YS. Nglycosylation is required for the surface localization of MUC17
mucin. Int J Oncol 2003;23:585-592.
Shekels LL, Ho SB. Characterization of the mouse Muc3
membrane bound intestinal mucin 5' coding and promoter
regions: regulation by inflammatory cytokines. Biochim Biophys
Acta 2003;1627:90-100.
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Brant SR, Shugart YY. Inflammatory bowel disease gene
hunting by linkage analysis: rationale, methodology, and
present status of the field. Inflamm Bowel Dis 2004;10(3):300311. (Review).
genes associated with inflammatory bowel disease. J Mol Med
2006;84(12):1055-1066.
Moniaux N, Junker WM, Singh AP, Jones AM, Batra SK.
Characterization of human mucin MUC17. Complete coding
sequence and organization. J Biol Chem 2006;281:2367623685.
Macao B, Johansson DG, Hansson GC, Hard T.
Autoproteolysis coupled to protein folding in the SEA domain of
the membrane-bound MUC1 mucin. Nat Struct Mol Biol
2006;13(1):71-76.
This article should be referenced as such:
Moehle C, Ackermann N, Langmann T, Aslanidis C, Kel A, KelMargoulis O, Schmitz-Madry A, Zahn A, Stremmel W, Schmitz
G. Aberrant intestinal expression and allelic variations of mucin
Junker WM, Moniaux N, Batra SK. MUC17 (mucin 17, cell
surface associated). Atlas Genet Cytogenet Oncol
Haematol.2008;12(3):226-233.
Atlas Genet Cytogenet Oncol Haematol. 2008;12(3)
233
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Gene Section
Review
PTHLH (parathyroid hormone-like hormone)
Sai-Ching Jim Yeung
The University of Texas M. D. Anderson Cancer Center, Department of General Internal Medicine,
Ambulatory Treatment and Emergency Care, Department of Endocrine Neoplasia and Hormonal Disorders,
1515 Holcombe Boulevard, Unit 437, Houston, Texas 77030, USA
Published in Atlas Database: October 2007
Online updated version: http://AtlasGeneticsOncology.org/Genes/PTHLHID41897ch12p11.html
DOI: 10.4267/2042/38527
This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence.
© 2008 Atlas of Genetics and Cytogenetics in Oncology and Haematology
28,002,284 bp from pter; End: 28,016,183 bp from
pter).
Orientation: minus strand.
The genomic DNA for the PTHLP gene was isolated
from a human placental genomic library.
Identity
Hugo: PTHLH
Other names: PTHLP (parathyroid hormone-like
protein); PTHRP (parathyroid hormone-related
protein); PTHrP; PTH-rP (PTH-related protein);
PTHR; HHM (humoral hypercalcemia of malignancy);
Osteostatin;
PLP
(parathyroid-like
protein);
MGC14611
Location: 12p11.22
Transcription
DNA/RNA
None.
Description
Protein
The sequence is supported by 3 sequences from 3
cDNA clones.
Pseudogene
PTHLP is encoded by a single gene that is highly
conserved among species. The gene is composed of 7
exons spanning a region of 13,899 bases (Start:
Description
Size: 177 amino acids, 20194 Da.
This diagram represents schematically one possible proteolytic processing pattern of PTHLP into 3 bioactive peptides. The mid-region of
PTHLP contains the nuclear localization signal (NLS).
Atlas Genet Cytogenet Oncol Haematol. 2008;12(3)
234
PTHLH (parathyroid hormone-like hormone)
Yeung SCJ
The PTHLP gene has seven exons, and its transcripts
are processed by alternative splicing into three
isoforms, encoding proteins with 139, 173 and 141
amino acids. The pattern of expression of PTHLP
mRNA isoforms may be cell type-specific. Although
different tumors may have different PTHLP splicing
patterns, there are no tumor-specific transcripts.
PTHLP is processed into a set of distinct peptide
hormones by endoproteolytic cleavage of the initial
translation products: mature N-terminal, mid-region
and C-terminal secretory peptides, each having its own
distinct function. The distribution of the endopeptidase
processing enzymes (PTP (prohormone thiol protease),
prohormone convertases 1 and 2 ( PC1 and PC2 )) may
vary in different tissues. PTP cleaved the PTHLP
precursor at the multibasic, dibasic, and monobasic
residue cleavage sites to generate the NH2-terminal
peptide (residues 1-37, having PTH-like and growth
regulatory activities), the mid-region domain (residues
38-93, regulating calcium transport and cell
proliferation), and the COOH-terminal domain
(residues 102-141, modulating osteoclast activity).
Localisation
PTHLP is a secreted polyhormone and is localized in
the Golgi apparatus in the cytoplasm. However, in
some cells, PTHLP can be detected in the nucleus by
immunochemistry. The growth-inducing effect of NLScontaining mid-region PTHLP peptide in breast cancer
is dependent on both internalization into the cytoplasm
and subsequent translocation to the nucleus. PTHLP
travels from the cytosol to the nucleus with the help of
the nuclear transport factor importin beta1. Importin
beta1 enhanced the association of PTHLP with
microtubules, and the microtubule cytoskeleton plays
an important role in protein transport to the nucleus.
The site of recognition of PTHLP is the N-terminal half
of importin, which can also bind Ran and nucleoporin,
and is sufficient for PTHLP nuclear import.
Function
PTHLP is a growth factor, a PTH-like calciotropic
hormone, a developmental regulatory molecule, and a
muscle relaxant. The diverse activities of PTHLP result
not only from processing of the precursor into multiple
hormones, but from use of multiple receptors.
It is clear that the Type 1 Parathyroid Hormone
Receptor (PTH1R), binding both PTH (1-34) and
PTHLP (1-36), is the receptor mediating the function of
PTHLP (1-36), and it is the only cloned receptor for
PTHLP so far.
PTHLP also binds to a type of receptor in some tissues
that does not bind PTH. PTHLP (67-86) activates
phospholipase C signaling pathways through a receptor
distinct from that activated by PTHLP (1-36) in the
same cells. Unlike PTH, picomolar concentrations of
the PTHLP (107-111) fragment to can activate
membrane-associated PKC in osteosarcoma cells.
PTHLP (107-139) exerts effects through the PKC/ERK
pathway. Thus, it is highly likely that the mid-region
and osteostatin peptides bind other, unique receptors,
but those receptors have yet to be cloned and identified.
In contrast to the receptor-mediated endrocrine and
paracrine action, the mid-region PTHLP peptide
contains a classic bipartite nuclear localization signal
(NLS) which upon entering the nuclear compartment
confers 'intracrine' actions. Details of the nuclear action
of PTHLP are still lacking, but overall, nuclear PTHLP
appears to be mitogenic. The translation of PTHLP
initiates from both the methionine-coding AUG and a
leucine-coding CUGs further downstream in its signal
sequence. It appeared that when translation was
initiated from CUGs, PTHLP accumulated in the
nucleoli, and that when translation was initiated from
AUG, PTHLP localized in both the Golgi apparatus
and nucleoli. Thus, nucleolar PTHLP appears to be
derived from translation initiating from both AUG and
CUGs. Modulation of cell adhesion by PTHLP
localized in the nucleus is a normal physiological
action of PTHLP, mediated by increasing integrin gene
Expression
PTHLP is a protein polyhormone produced by most if
not all tissues in the body. It is secreted during both
fetal and postnatal life. Although PTHLP is found in
the circulation, most of its activity appears to be
paracrine. A complex of transcription factors and
coactivators (CREB, Etsl and CBP) regulates PTHLP
transcription and may contribute to the alterations
associated with the promotion of carcinogenesis.
Disruption of the normal regulation during cancer
progression may in part be associated with TGF-beta1 induced changes in PTHLP mRNA isoform expression
and stability. TGF-beta activates PTHLP expression
increasing transcription from the P3 promoter through a
synergistic interaction of Smad3 and Ets1.
ERK1/ERK2 -dependent Ets2/PKCepsilon synergism
also appears to regulate PTHLP expression in breast
cancer cells.
The PTHLP gene is also under the transcriptional
control of glucocorticoids and vitamin D. 1,25dihydroxy vitamin D3 treatment increases PTHLP
mRNA expression and blocks the stimulatory effect of
TGF-beta on PTHLP mRNA expression. Glucocortical
steroid hormone can suppress PTHLP mRNA
expression and release of bioactive PTHLP in certain
PTHLP-producing tumors. The regulation of PTHLP
expression by female sex steroid hormones is still
unclear.
PTHLP is a downstream target for RAS and SRC, Kras mutation increases PTHLP expression while a
farnesyltransferase inhibitor known to inhibit RAS
function can decrease PTHLP expression. The von
Hippel-Lindau tumor suppressor protein also
negatively regulates PTHLP expression at the posttranscriptional level.
Atlas Genet Cytogenet Oncol Haematol. 2008;12(3)
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PTHLH (parathyroid hormone-like hormone)
Yeung SCJ
transcription. The promotion by PTHLP in cancer
growth and metastasis may be mediated by
upregulating integrin alpha6beta4 expression and
activating Akt.
PTHLP also interacts with beta-arrestin 1B, an
important component of MAPK signaling and Gprotein-coupled receptor desensitization, and this
interaction requires residues 122-141 of PTHLP.
Therefore, beta-arrestin 1 may mediate a novel
regulatory function of PTHLP in intracellular signaling.
PTHLP also play a major role in development of
several tissues and organs. PTHLP stimulates the
proliferation of chondrocytes and suppresses their
terminal differentiation. PTHLP (107-139) is a
substrate for secPHEX, and osteocalcin, pyrophosphate
and phosphate are inhibitors of secPHEX activity; thus
PHEX activity and PTHLP are part of a complex
network regulating bone mineralization. PTHLP plays
a central role in the physiological regulation of bone
formation, by promoting recruitment and survival of
osteoblasts, and probably plays a role in the
physiological regulation of bone resorption, by
enhancing osteoclast formation. Signaling by fibroblast
growth factor receptor 3 and PTHLP coordinate in
cartilage and bone development. PTHLP is also an
essential physiological regulator of adult bone mass.
PTHLP aids in normal mammary gland development
and lactation as well as placental transfer of calcium.
Mammary gland development depends upon a complex
interaction between epithelial and mesenchymal cells
that requires PTHLP. The calcium sensor (CaR)
regulates PTHLP production as well as transport of
calcium in the lactating mammary gland. In normal
animals, mammary epithelial cells secrete a lot of
PTHLP, which helps to adjust maternal metabolism to
meet the calcium demands of lactation. The mid-region
PTHLP peptide has also been shown to control the
normal maternal-to-fetal pumping of calcium across the
placenta.
PTHLP is secreted from smooth muscle in many
organs, usually in response to stretching. PTHLP
relaxes smooth muscle. Transgenic mice that express
PTHLP in vascular smooth muscle have hypotension,
being consistent with a vasodilating effect of PTHLP.
PTHLP is highly expressed in the skin. EGF and other
similar ligands can potentially activate PTHLP gene
expression in the epidermis. PTHLP can inhibit hair
growth and is required for tooth eruption as shown by
mouse models that manipulated the PTHLP gene.
syndrome is commonly encountered in advanced
cancer of epithelial origin, especially squamous cell
carcinoma of the lung. Studies of the 'humors' secreted
by cancer that causes hypercalcemia led to the
discovery of 3 classes of peptides: parathyroid-like
peptides, growth factor-like peptides, and boneresorbing factors. Then protein purification led to
molecular studies that cloned cDNAs for PTHLH. A
study suggested that the PTHLH may be responsible
for the abnormal calcium metabolism in HHM.
Prognosis
The median survival after the first occurrence of
hypercalcemia is 66 days in patients with serum
PTHLP inferior or equal to 21 pmol/L and 33 days in
patients with PTHLP superior to 21 pmol/L. In
hypercalcemia of malignancy, raised serum levels of
PTHLP indicate a more advanced tumor state and an
extremely poor prognosis.
Autocrine promotion of tumor
progression
Prognosis
In the absence of hypercalcemia, approximately 17% of
patients with gastroesophageal carcinoma have
elevated levels of PTHLP, and the increase in PTHLP
was associated with a poor prognosis.
Oncogenesis
mRNA for the PTH1R was detected many tumors
expressing PTHLP; thus the PTHLP produced by these
tumors may act in an autocrine or paracrine fashion.
PTHLP (1-34) treatment resulted in an increase in
proliferation in prostate cancer cells which may require
androgen in some cell lines. In breast cancer cells,
PTHLP regulates CDC2 and CDC25B via PTH1R in a
cAMP-independent manner, and PTHLP promotes cell
migration through induction of ITGA6, PAI-1, and
KISS-1, and promotes proliferation through induction
of KISS-1.
These pieces of evidence together suggest that PTHLP
and PTH1R together play an important role in the
autocrine/paracrine promotion of tumor proliferation in
some cancers.
Bone metastasis
Disease
Breast cancer
Oncogenesis
PTHLP is a mediator of the bone destruction associated
with osteolytic metastasis. Patients with PTHLPexpressing breast carcinoma are more likely to develop
bone metastasis, and bone metastasis expresses PTHLP
in more than 90% of cases as compared with less than
20% of cases of metastasis to other sites.
In breast cancer, osteolytic metastases are the most
common. PTHLP is a common osteolytic factor, and
other osteolytic factors include vascular endothelial
Implicated in
Humoral hypercalcemia of malignancy
Disease
Humoral hypercalcemia of malignancy (HHM) was
first described by Albright in 1941, and is a wellknown complication among cancer patients. This
Atlas Genet Cytogenet Oncol Haematol. 2008;12(3)
236
PTHLH (parathyroid hormone-like hormone)
Yeung SCJ
growth factor and interleukin 8 and interleukin 11.
Since osteoblasts are the main regulators of osteolytic
osteoclasts, stimulation of osteoblasts can paradoxically
increase osteoclast function. Simultaneous expression
of osteoblastic and osteolytic factors can produce
mixed metastases.
PTHLP expression by cancer cells may provide a
selective growth advantage in bone because PTHLP
stimulates osteoclastic bone resorption to release
growth factors such as TGF-beta from the bone matrix.
TGF-beta in turn will activate by osteoclastic bone
resorption and enhance PTHLP expression and tumor
cell growth, thus completing a vicious cycle (See
diagram). Taken together, PTHLP expression by breast
carcinoma cells enhance the development and
progression of breast carcinoma metastasis to bone.
Alternatively, cytokines such as IL-8 initiate the
process of osteoclastic bone resorption in the early
stages of breast cancer metastasis, and PTHLP
expression is induced to stimulate the vicious cycle of
osteolysis at a later stage.
Certain cancer treatments, especially sex steroid
hormone deprivation therapies, stimulate bone loss.
Bone resorption will result in the release of bone
growth factors, which may inadvertently facilitate bone
metastasis. Treatment with bisphosphonates will
prevent bone resorption and reduce the release of bone
growth factors.
hypercalcemia and proinflammatory cytokines. In a
rodent model, PTHLP induces a cachectic syndrome (in
addition to inducing hypercalcemia of malignancy) by
changing the mRNA levels of orexigenic and
anorexigenic peptides, except leptin and orexin.
Expression of cachexia-inducing cytokines such as
interleukin-6 and leukemia inhibitory factor is
increased by PTHLP. Animal data suggest that
humanized antibody against PTHLP may be effective
for patients with hypercalcemia and cachexia in
patients with humoral hypercalcemia of malignancy.
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239
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Gene Section
Mini Review
SOCS2 (suppressor of cytokine signaling 2)
Leandro Fernández-Pérez, Amilcar Flores-Morales
University of Las Palmas de GC, Faculty of Health Sciences, Molecular and Translational Endocrinology
Group, c/ Dr. Pasteur s/n - Campus San Cristobal, 35016 - Las Palmas, Spain, (LFP); Department of
Molecular Medicine and Surgery, Karolinska Institute, 17176 Stockholm, Sweden (AFM)
Published in Atlas Database: October 2007
Online updated version: http://AtlasGeneticsOncology.org/Genes/SOCS2ID44123ch12q21.html
DOI: 10.4267/2042/38528
This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence.
© 2008 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
Protein
Hugo: SOCS2
Other names: CIS-2, Cytokine-inducible SH2 protein
2; CIS2, STAT induced STAT inhibitor-2; Cish2,
STAT-induced STAT inhibitor 2; SOCS-2, suppressor
of cytokine signaling 2; SSI-2, suppressor of cytokine
signaling-2; SSI2; STATI2
Location: 12q21.33
Local order: By cytogenetic and radiation hybrid
mapping, SOCS-2 has been mapped to chromosome
12q21.3-q23 (Yandava et al., 1999).
Description
DNA/RNA
Localisation
22.2 kDa; 198 aa.
Expression
SOCS mRNA and protein levels are constitutively low
in unstimulated cells, but their expression is rapidly
induced upon cytokine stimulation, thereby creating a
negative feedback loop. Its expression is, in general,
induced by stimulation with different cytokines and
hormones (Rico-Bautista et al., 2006).
Intracellular, cytoplasm.
Description
Function
6,38 kb; 3 exons. Mouse SOCS2 gene is composed of 3
exons and 2 introns (Metcalf et al., 2000). Human
SOCS-2 is a functioning gene that comprises 3 exons
spanning roughly 6,38 kb of genomic DNA.
SOCS mechanisms of action rely on their ability to
bind tyrosine phosphorylated proteins through their
SH2 domains, but also to bind Elongin BC through
their SOCS box domains. SOCS family proteins form
part of a classical negative feedback system that
regulates cytokine signal transduction (Rico-Bautista et
al., 2006). SOCS2 appears to be a negative regulator in
the growth hormone/IGF1 signaling pathway (Metcalf
et al., 2000). SOCS2 appear to be involved in
regulating protein turnover, targeting proteins for
proteasome-mediated degradation (Rico-Bautista et al.,
2004).
Transcription
2210 bp mRNA. 1 protein (22.2 kDa; 198 aa).
Although constitutively expressed SOCS2 mRNA has
been detected in several tissues and cell types, its
expression is, in general, induced by stimulation with
different cytokines and hormones (Rico-Bautista et al.,
2006). SOCS2 promoter analysis indicates the presence
of AhR and STAT5 binding sites that confer
responsiveness to dioxin (Boverhof et al., 2004) and
GH (Vidal et al., 2006), respectively.
Atlas Genet Cytogenet Oncol Haematol. 2008;12(3)
240
SOCS2 (suppressor of cytokine signaling 2)
Fernández-Pérez L, Flores-Morales A
Diagram representing the structure of SOCS proteins. At least eight proteins belonging to the SOCS family of proteins are shown (upper
panel). They are characterized by the presence of an SH2 central domain and the SOCS box domain at the C-terminus. A small domain
called kinase inhibitory region (KIR), only found in SOCS1 and SOCS3, is shown as a small box at the N-terminal region. SOCS proteins
can interact with phosphotyrosine phosphorylated proteins through their SH2 domain and with Elongin BC through their SOCS box
domain. Other proteins containing a SOCS box domain but lacking a SH2 domain are also shown (lower panel). Adapted from Elliot and
Johnston (Elliott and Johnston, 2004) with modifications.
Mutations
differentiation of C2C12 mesenchymal cells into
myoblasts or osteoblasts (Ouyang et al., 2006).
Note: SNP: increasing the risk of type 2 diabetes.
Neural development
Implicated in
Note: SOCS2 plays a critical role in neuronal
development, growth, and stem cell differentiation
(Turnley et al., 2002).
Diabete
Cancer
Note: Susceptibility to type 2 diabetes (Kato et al.,
2006).
Note: SOCS2 has been associated with cancer such as
myeloid leukaemia, pulmonary adenocarcinoma, and
ovarian cancer, breast cancer, and anal cancer.
Metabolism
Note: SOCS2 null mice are giants but not obese
(Metcalf et al., 2000). SOCS2 deficient mice have
some metabolic characteristics that can be related to the
enhanced GH actions (Rico-Bautista et al., 2005).
References
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cytogenetic mapping of SOCS1 and SOCS2 to chromosomes
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Bone
Note: Analysis of SOCS2 null mice have revealed that
the absence of SOCS2 induces a reduction in the
trabecular and cortical volumetric bone mineral density
(Lorentzon et al., 2005). SOCS2 induces the
Atlas Genet Cytogenet Oncol Haematol. 2008;12(3)
Metcalf D, Greenhalgh CJ, Viney E, Willson TA, Starr R, Nicola
NA, Hilton DJ, Alexander WS. Gigantism in mice lacking
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Fernández-Pérez L, Flores-Morales A
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Fernández-Perez L, Flores-Morales A. Downregulation of the
growth hormone-induced Janus kinase 2/signal transducer and
activator of transcription 5 signaling pathway requires an intact
actin cytoskeleton. Exp Cell Res 2004;294:269-280.
Vidal OM, Merino R, Rico-Bautista E, Fernández-Perez L, Chia
DJ, Woelfle J, Ono M, Lenhard B, Norstedt G, Rotwein P,
Flores-Morales A. In vivo transcript profiling and phylogenetic
analysis identifies SOCS2 as a direct STAT5b target in liver.
Mol Endocrinol 2006;21(1):293-311.
Lorentzon M, Greenhalgh CJ, Mohan S, Alexander WS,
Ohlsson C. Reduced bone mineral density in SOCS-2-deficient
mice. Pediatr Res 2005;57:223-226.
Rico-Bautista E, Greenhalgh CJ, Tollet-Egnell P, Hilton DJ,
Alexander WS, Norstedt G, Flores-Morales A. Suppressor of
cytokine signaling-2 deficiency induces molecular and
metabolic changes that partially overlap with growth hormonedependent effects. Mol Endocrinol 2005;19:781-793.
This article should be referenced as such:
Fernández-Pérez L, Flores-Morales A. SOCS2 (suppressor of
cytokine signaling 2). Atlas Genet Cytogenet Oncol
Haematol.2008;12(3):240-242.
Kato H, Nomura K, Osabe D, Shinohara S, Mizumori O,
Katashima R, Iwasaki S, Nishimura K, Yoshino M, Kobori M,
Ichiishi E, Nakamura N, Yoshikawa T, Tanahashi T, Keshavarz
Atlas Genet Cytogenet Oncol Haematol. 2008;12(3)
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Leukaemia Section
Short Communication
del(11)(p12p13)
Pieter Van Vlierberghe, Jules PP Meijerink
ErasmusMC/Sophia Children’s Hospital, Pediatric Oncology/Hematology, Rotterdam, The Netherlands
Published in Atlas Database: July 2007
Online updated version: http://AtlasGeneticsOncology.org/Anomalies/del11p12p13ID1351.html
DOI: 10.4267/2042/38529
This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence.
© 2008 Atlas of Genetics and Cytogenetics in Oncology and Haematology
this transcription complex, LMO2 mediates the proteinprotein interactions by recruiting LDB1, whereas
TAL1, GATA1, and E2A regulate the binding to
specific DNA target sites. This complex regulates the
expression of several genes in various cellular
backgrounds including C-KIT, EKLF, and RALDH. In
normal T-cell development, LMO2 is expressed in
immature CD4/CD8 double-negative thymocytes, and
is down-regulated during T-cell maturation.
Clinics and pathology
Disease
T-cell acute lymphoblastic leukemia (T-ALL).
Epidemiology
About 5% of T-ALL patients.
Prognosis
Currenlty, no relation between the cryptic deletion,
del(11)(p12p13), and prognosis could be established.
This could be due to the limited patient numbers in the
study.
Results of the chromosomal
anomaly
Hybrid gene
Genetics
Note: Ectopic expression of the LMO2 oncogene due
to the removal of a negative regulatory element situated
upstream of the LMO2 gene, leading to activation of
the proximal LMO2 promoter.
In one T-ALL case, this recurrent deletion resulted in a
RAG2-LMO2 fusion gene, bringing the LMO2 gene
under the control of RAG2 promoter sequences.
However, it was shown that promoter substitution was
not the main activational mechanism as none of the
other del(11)(p12p13) positive cases showed a similar
RAG2-LMO2 fusion gene. In addition, RQ-PCR
analysis revealed that the expression of the RAG2LMO2 fusion is much lower than the wildtype LMO2
expression from the proximal LMO2 gene promoter.
Note: The cryptic deletion, del(11)(p12p13) was
identified using microarray-based comparative genome
hybridisation (array-CGH). The deleted region is about
3 Mb in size and the telomeric breakpoint of these
deletions is situated in or near the LMO2 oncogene.
Variances in the centromeric breakpoints is detected.
Cytogenetics
Variants
One of the T-ALL patients showed a cryptic deletion,
del(11)(p12p13), that did not target the LMO2
oncogene. Indeed, this case showed no ectopic LMO2
expression. Therefore, this genomic region could
potentially contain a tumor supressor gene that also
contributes to T-ALL pathogenesis.
References
Van Vlierberghe P, van Grotel M, Beverloo HB, Lee C,
Helgason T, Buijs-Gladdines J, Passier M, van Wering ER,
Veerman AJP, Kamps WA, Meijerink JPP, Pieters R. The
cryptic chromosomal deletion del(11)(p12p13) as a new
activation mechanism of LMO2 in pediatric T-cell acute
lymphoblastic leukemia. Blood 2006;108(10):3520-3529.
Genes involved and Proteins
RBTN2/LMO2
Location: 11p13
Protein
LMO2 encodes a protein that participates in the
transcription factor complex, which includes E2A,
TAL1, GATA1, and LDB1 in erythroid cells. Within
Atlas Genet Cytogenet Oncol Haematol. 2008;12(3)
This article should be referenced as such:
Van Vlierberghe P, Meijerink JPP. del(11)(p12p13). Atlas
Genet Cytogenet Oncol Haematol.2008;12(3):243.
243
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Leukaemia Section
Short Communication
t(3;5)(q26;q34)
Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France
Published in Atlas Database: July 2007
Online updated version: http://AtlasGeneticsOncology.org/Anomalies/t0305q26q34ID1278.html
DOI: 10.4267/2042/38530
This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence.
© 2008 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
t(3;5)(q26;q34) G-banding – Coutesy Melanie Zenger and Claudia Haferlach.
Protein
Transcrition factor; EVI1 targets include: GATA2,
ZBTB16/PLZF, ZFPM2/FOG2, JNK and the
PI3K/AKT pathway. Role in cell cycle progression,
likely to be cell-type dependant; antiapoptotic factor;
involved in neuronal development organogenesis; role
in hematopoietic differentiation.
Clinics and pathology
Disease
Acute myeloid leukaemia (AML)
Epidemiology
Only two cases to date, a 48-year-old female patient
and a male patient of unknown age, both with M2
AML.
References
Prognosis
Sendi HS, Elghezal H, Temmi H, Hichri H, Gribaa M, Elomri H,
Meddeb B, Ben Othmane T, Elloumi M, Saad A,. Cytogenetic
analysis in 139 Tunisian patients with de novo acute myeloid
leukemia. Ann Genet 2002;45:29-32.
No data.
Cytogenetics
Poppe B, Dastugue N, Vandesompele J, Cauwelier B, De
Smet B, Yigit N, De Paepe A, Cervera J, Recher C, De Mas V,
Hagemeijer A, Speleman F. EVI1 is consistently expressed as
principal transcript in common and rare recurrent 3q26
rearrangements. Genes Chromosomes Cancer 2006;45:349356.
Cytogenetics morphological
Sole anomaly in both cases.
Genes involved and Proteins
Wieser R. The oncogene and developmental regulator EVI1:
expression, biochemical properties, and biological functions.
Gene 2007 Jul 15;396(2):346-57.
Note: The partner of EVI1 is yet unknown.
EVI1
Location: 3q26.2
This article should be referenced as such:
Huret JL. t(3;5)(q26;q34). Atlas Genet Cytogenet Oncol
Haematol.2008;12(3):244.
Atlas Genet Cytogenet Oncol Haematol. 2008;12(3)
244
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Leukaemia Section
Short Communication
t(3;9)(q26;p23)
Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France
Published in Atlas Database: July 2007
Online updated version: http://AtlasGeneticsOncology.org/Anomalies/t0309q26p23ID1279.html
DOI: 10.4267/2042/38531
This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence.
© 2008 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Protein
Transcrition factor; EVI1 targets include: GATA2,
ZBTB16 PLZF, ZFPM2/FOG2, JNK and the
PI3K/AKT pathway. Role in cell cycle progression,
likely to be cell-type dependant; antiapoptotic factor;
involved in neuronal development organogenesis; role
in hematopoietic differentiation.
Clinics and pathology
Disease
T-cell non Hodgkin lymphoma (T-cell NHL).
Note: This is one of the very rare cases of EVI1
involvement in lymphoid malignancies.
Epidemiology
References
Only one case to date, a 11-year-old boy.
Prognosis
Poppe B, Dastugue N, Vandesompele J, Cauwelier B, De
Smet B, Yigit N, De Paepe A, Cervera J, Recher C, De Mas V,
Hagemeijer A, Speleman F. EVI1 is consistently expressed as
principal transcript in common and rare recurrent 3q26
rearrangements. Genes Chromosomes Cancer 2006;45:349356.
No data.
Cytogenetics
Cytogenetics morphological
Sole anomaly.
Wieser R. The oncogene and developmental regulator EVI1:
expression, biochemical properties, and biological functions.
Gene 2007 396:346-357.
Genes involved and Proteins
This article should be referenced as such:
Note: The partner of EVI1 is yet unknown.
Huret JL. t(3;9)(q26;p23). Atlas Genet Cytogenet Oncol
Haematol.2008;12(3):245.
EVI1
Location: 3q26.2
Atlas Genet Cytogenet Oncol Haematol. 2008;12(3)
245
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Leukaemia Section
Short Communication
t(3;17)(q26;q22)
Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France
Published in Atlas Database: July 2007
Online updated version: http://AtlasGeneticsOncology.org/Anomalies/t0317q26q22ID1282.html
DOI: 10.4267/2042/38532
This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence.
© 2008 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
t(3;17)(q26;q22) G-banding – Coutesy Melanie Zenger and Claudia Haferlach.
Clinics and pathology
Genes involved and Proteins
Disease
Note: The partner of EVI1 is yet unknown.
Chronic myelogenous leukaemia with t(9;22)(q34;q11)
and blast crisis of CML (BC-CML) (4 cases
altogether), other myeloproliferative syndromes, Acute
myeloid leukaemia (AML) in 4 cases (one M1, 2
therapy related AML,one of which after breast cancer).
EVI1
Location: 3q26.2
Protein
Transcrition factor; EVI1 targets include: GATA2,
ZBTB16/PLZF, ZFPM2/FOG2, JNK and the
PI3K/AKT pathway. Role in cell cycle progression,
likely to be cell-type dependant; antiapoptotic factor;
involved in neuronal development organogenesis; role
in hematopoietic differentiation.
Epidemiology
At least 9 cases to date, aged 62 years (median, range:
49-78); sex ratio was 5M/3F.
Prognosis
No data.
References
Cytogenetics
Mecucci C, Michaux JL, Broeckaert-Van Orshoven A, Symann
M, Boogaerts M, Kulling G, Van den Berghe H. Translocation
t(3;17)(q26;q22):
a
marker
of
acute
disease
in
myeloproliferative disorders? Cancer Genet Cytogenet
1984;12:111-119.
Cytogenetics morphological
Sole anomaly in 3 cases, with t(9;22)(q34;q11) in 4
cases (one of which was a complex translocation), with
del(5q) (1 case), and with del(7q), and +21 in 1 case.
Atlas Genet Cytogenet Oncol Haematol. 2008;12(3)
Mugneret F, Solary E, Favre B, Caillot D, Sidaner I, Guy H.
New case of t(3;17)(q26;q22) as an additional change in a
Philadelphia-positive chronic myelogenous leukemia in
acceleration. Cancer Genet Cytogenet 1992;60:90-92.
246
t(3;17)(q26;q22)
Huret JL
Pedersen-Bjergaard J, Pedersen M, Roulston D, Philip P.
Different genetic pathways in leukemogenesis for patients
presenting with therapy-related myelodysplasia and therapyrelated acute myeloid leukemia. Blood 1995;86:3542-3552.
Poppe B, Dastugue N, Vandesompele J, Cauwelier B, De
Smet B, Yigit N, De Paepe A, Cervera J, Recher C, De Mas V,
Hagemeijer A, Speleman F. EVI1 is consistently expressed as
principal transcript in common and rare recurrent 3q26
rearrangements. Genes Chromosomes Cancer 2006;45:349356.
Charrin C, Belhabri A, Treille-Ritouet D, Theuil G, Magaud JP,
Fiere D, Thomas X. Structural rearrangements of chromosome
3 in 57 patients with acute myeloid leukemia: clinical,
hematological and cytogenetic features. Hematol J 2002;3:2131.
Wieser R. The oncogene and developmental regulator EVI1:
expression, biochemical properties, and biological functions.
Gene 2007;396:346-357.
Barjesteh van Waalwijk van Doorn-Khosrovani S, Erpelinck C,
van Putten WL, Valk PJ, van der Poel-van de Luytgaarde S,
Hack R, Slater R, Smit EM, Beverloo HB, Verhoef G, Verdonck
LF, Ossenkoppele GJ, Sonneveld P, de Greef GE, Löwenberg
B, Delwel R. High EVI1 expression predicts poor survival in
acute myeloid leukemia: a study of 319 de novo AML patients.
Blood 2003;101:837-845.
Atlas Genet Cytogenet Oncol Haematol. 2008;12(3)
This article should be referenced as such:
Huret JL. t(3;17)(q26;q22). Atlas Genet Cytogenet Oncol
Haematol.2008;12(3):246-247.
247
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Leukaemia Section
Mini Review
t(6;7)(q23;q34)
Emmanuelle Clappier, Jean Soulier
Genome Rearrangements and Cancer Group, Hematology Laboratory and U728 INSERM, Hopital SaintLouis and Paris 7 University, Paris, France
Published in Atlas Database: July 2007
Online updated version: http://AtlasGeneticsOncology.org/Anomalies/t0607q23q34ID1465.html
DOI: 10.4267/2042/38533
This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence.
© 2008 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Epidemiology
Identity
Less than 5% among a series of non selected adult and
pediatric T-ALLs (n = 3 out of 92). Six cases were
described, all of them children, and 5 out of 6 being
under 3 years old (1.1, 1.3, 1.8, 2.5, and 2.9 years old,
respectively), which is very young for T-cell leukemia.
The t(6;7) translocation could therefore be relatively
common in this very low range of age.
Cytology
Lymphoblasts.
Prognosis
R-band analysis. Partial karyotype showing t(6;7)(q23;q34).
The prognosis is yet to be evaluated.
Clinics and pathology
Cytogenetics
Disease
T cell acute lymphoblastic leukemia (T-ALL).
Cytogenetics morphological
Phenotype / cell stem origin
t(6;7)(q23;q34) may be barely
chromosome banding technics alone.
T cell precursor.
detectable
by
Left: Whole chromosome painting of chromosomes 6 (green) and 7 (red). Right: Locus-specific break-apart FISH using 6q23 probes
RP11-184J4 (red) and RP11-845K5 (green) showing translocation involving the 6q23 locus.
Atlas Genet Cytogenet Oncol Haematol. 2008;12(3)
248
t(6;7)(q23;q34)
Clappier E, Soulier J
Cytogenetics molecular
Fusion protein
Involvement of the TCRB locus and the MYB locus
can be demonstrated using flanking FISH probes.
Oncogenesis
C-MYB is a transcription factor involved in
hematopoiesis. In T-cell differentiation, discrete
threshold levels of MYB activity regulate transition
through distinct stages, suggesting that a deregulated
expression could disturb the maturation process and
play a role in oncogenesis.
A potential role of AHI1 deregulation as a cofactor has
to be evaluated.
Of note, the same locus at 6q23.3 is also involved in
short tandem duplications of a about 230 kb genomic
region which includes the C-MYB gene (about 10% TALL in children and adults). This somatic abnormality
can be detected by array-CGH, genomic Q-PCR or
fiber-FISH, but not or hardly by standard metaphasic or
interphasic FISH.
Genes involved and Proteins
TRB
Location: 7q34
Protein
T-cell receptor beta chain.
C-MYB
Location: 6q23.3
DNA / RNA
Spans over 38 kb, 15 exons (and additional alternative
exons), mRNA 3.3 kb.
Protein
v-myb myeloblastosis viral oncogene homolog.
Transcription factor: 640 amino acids.
References
Sinclair P, Harrison CJ, Jarosová M, Foroni L. Analysis of
balanced rearrangements of chromosome 6 in acute leukemia:
clustered breakpoints in q22-q23 and possible involvement of
c-MYB in a new recurrent translocation, t(6;7)(q23;q32 through
36). Haematologica 2005;90(5):602-611.
AHI-1
Location: 6q23.3
DNA / RNA
Spans over 214 kb, 28 exons (and additional alternative
exons), mRNA 5.5 kb.
Protein
Jouberin (Abelson helper integration site 1 protein
homolog) (AHI-1). 1196 amino acids including one
SH3 domain and WD repeats.
Clappier E, Cuccuini W, Kalota A, Crinquette A, Cayuela JM,
Dik WA, Langerak AW, Montpellier B, Nadel B, Walrafen P,
Delattre O, Aurias A, Leblanc T, Dombret H, Gewirtz AM,
Baruchel A, Sigaux F, Soulier J. The C-MYB locus is involved
in chromosomal translocation and genomic duplications in
human T-cell acute leukemia (T-ALL), the translocation
defining a new T-ALL subtype in very young children. Blood
2007; 110 (4):1251-1261.
Lahortiga I, De Keersmaecker K, Van Vlierberghe P, Graux C,
Cauwelier B, Lambert F, Mentens N, Beverloo HB, Pieters R,
Speleman F, Odero MD, Bauters M, Froyen G, Marynen P,
Vandenberghe P, Wlodarska I, Meijerink JP, Cools J.
Duplication of the MYB oncogene in T cell acute lymphoblastic
leukemia. Nat Genet 2007;39(5):593-595.
Results of the chromosomal
anomaly
Hybrid gene
This article should be referenced as such:
Note: No fusion gene
The t(6;7)(q23.3;q34) translocation results in
juxtaposition of TRB regulatory sequences to the
MYB-AHI1 locus. It results in deregulated expression
of C-MYB, as demonstrated by skewed allelic
expression.
Atlas Genet Cytogenet Oncol Haematol. 2008;12(3)
Clappier E, Soulier J. t(6;7)(q23;q34). Atlas Genet Cytogenet
Oncol Haematol.2008;12(3):248-249.
249
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in Oncology and Haematology
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Solid Tumour Section
Mini Review
Soft tissue tumors: Alveolar soft part sarcoma
Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France
Published in Atlas Database: Update -July 2007
Online updated version: http://AtlasGeneticsOncology.org/Tumors/AlveolSoftPartSID5125.html
DOI: 10.4267/2042/38534
This article is an update of: Huret JL. Soft tissue tumors: Alveolar soft part sarcoma. Atlas Genet Cytogenet Oncol
Haematol.2001;5(4):296-297.
This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence.
© 2008 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Pathology
Identity
Well circumscribed tumours with a multinodular
pattern, haemorrhagic and necrotic.
Microcopically, exhibits an alveolar structure, the
center of the alveolar space being formed by
detachment of necrotic cells, and with surronding
capillaries (there is a more solid pattern in children).
Cells are large, with abundant cytoplasm. Mitoses are
rare.
Secretory process with the formation of cytoplasmic
membrane-bound crystals (PAS+, diastase resistant)
can often be seen with electron microscopy, a feature of
great diagnostic value (they are pathognomic). These
granules contain monocarboxylate transporter 1
(MCT1) - CD147 complexes.
Immunochemistry: in general, alveolar soft part
sarcomas are negative for neuroendocrin and epithelial
markers, and often positive for vimentin, musclespecific actin, and desmin. The strong nuclear staining
of an anti C-term TFE3 can be used for diagnosis
(although cytogenetics and/or molecular genetics are
the most relevant tools for diagnosis).
To be noted is that a subset of renal cell carcinomas,
the primary renal ASPSCR1-TFE3 tumour, share some
morphological features with the alveolar soft part
sarcoma (it may be a differential diagnosis); they also
share a common genetic substratum.
Other
names:
Malignant
nonchromaffin
paraganglioma; Malignant organoid granular cell
myoblastoma
Clinics and pathology
Embryonic origin
The histogenesis of this tumour is still unknown,
despite immunohistochemistry studies and electron
microscopy. It may have a myogenic origin, and might
be a variant of rhabdomyosarcoma.
Epidemiology
Rare tumour: represents less than 1% of soft tissues
sarcomas of adults and 1-2% of soft tissues sarcomas in
children.
Occurs most often in the young adult, less frequently in
children.
Median age is 20 years in female patients, and 30 years
in male patients. More frequently, patients are females
(ratio M/F is 2/3).
Clinics
Involve the muscles and soft tissues, in particular those
of the lower extremities (buttocks, thighs and legs).
This represents more than half cases in the adults. It
may also arise in the upper extremities, in the head and
neck regions, especially in the child, but it can also
have extra muscular localizations, such as the female
genital tract, the trunk, the mediastinum, or the
retroperitoneum.
Metastases are frequent. They occur mainly in lungs,
bones, and brain.
Symptoms at diagnosis may be pain and/or swelling.
Diagnosis is often retarded.
Atlas Genet Cytogenet Oncol Haematol. 2008;12(3)
Treatment
Primary tumours: large surgical excision (a complete
resection is of great importance) and radiation.
Metastases: chemotherapy, with or without radiation or
surgery, depending on the number of metastases.
Evolution
Slow growing tumour, but highly angiogenic, which
favours metastases dissemination.
250
Soft tissue tumors: Alveolar soft part sarcoma
Huret JL
Metastases appear in more than half of the patients who
presented without metastases at diagnosis (up to 70% in
one study); however, there is a long disease-free
interval before appearence of metastases (median 6
years) in these patients.
Protein
Transcription factor; member of the basic helix-loophelix family (b-HLH) of transcription factors primarily
found to bind to the immunoglobulin enchancer muE3
motif.
Prognosis
ASPSCR1
Relatively indolent clinical course. In one study,
overall survival of adult patients without metastases
reached 87% at 5 years, but that of adult patients with
metastases at diagnosis was only 20% at 5 years, with a
median survival of 40 mths. Pediatric cases had a better
prognosis, with a 5 years survival of 80% for all cases
included, reaching 91% in cases without metastases.
Median survival in patients without metastases at
diagnosis was noted above 10 years in a large -but old
(period 1923-1986)- study, and it may be expected that
progress has been made. Due to the rarity of the disease
and its long course, survival data are outdated.
Location: 17q25
Protein
Contains an UBX domain, ASPSCR1 binds SLC2A4
(solute carrier family 2 (facilitated glucose transporter),
member 4, also called GLUT4) endocytosed from the
plasma membrane into vesicles. SLC2A4 is retained in
the cell by ASPSCR1 in the absence of insulin. Insulin
stimulates the release of retained SLC2A4 to
exocytosis, allowing the rapid mobilization of glucose
transporters to the cell surface.
Cytogenetics
Result of the chromosomal
anomaly
Cytogenetics morphological
Hybride Gene
t(X;17)(p11;q25) is found in all alveolar soft part
sarcomas so far studied, but also in primary renal
ASPSCR1-TFE3 tumours. In the case of alveolar soft
part sarcoma, the chromosome rearrangement is found
in an unbalanced form, as a der(17)t(X;17)(p11;q25), in
80% of cases;
the unbalanced form implicates:
1- the formation of a hybrid gene at the breakpoint, but
also,
2- gain in Xp11-pter sequences, and loss of
heterozygocity in
17q25-qter,
with
possible
implications, although no clinical (including
prognostic) nor pathological differences have so far
been noted between balanced and unbalanced cases...
but, again, the disease is rare, and cases with
cytogenetic studies even rarer (about 25 cases).
Note: the t(X;17)(p11;q25) in primary renal
ASPSCR1-TFE3 tumours is balanced in all known
cases.
Description
5' ASPSCR1 - 3' TFE3; the reciprocal 5' TFE3 - 3'
ASPSCR1 is most often absent. ASPSCR1 is fused in
frame either to TFE3 exon 3 or to exon 4 (type 1 and
type 2 fusions respectively).
Fusion protein
Description
234 NH2 term amino acids from ASPSCR1, fused to
the 280 or 315 C term amino acids from TFE3,
including the activation domain, the helix-loop-helix,
and the leucine zipper from TFE3.
References
Lieberman PH, Brennan MF, Kimmel M, Erlandson RA, GarinChesa P, Flehinger BY. Alveolar soft-part sarcoma. A clinicopathologic study of half a century. Cancer 1989;63:1-13.
Cullinane C, Thorner PS, Greenberg ML, Kwan Y, Kumar M,
Squire
J.
Molecular
genetic,
cytogenetic,
and
immunohistochemical characterization of alveolar soft-part
sarcoma.
Implications
for
cell
of
origin.
Cancer
1992;70(10):2444-2450.
Genes involved and Proteins
Note: Retention of heterozygocity in the tumours of
female patients (i.e. a normal maternal X and a normal
paternal X are present, in addition to the Xp11-pter
involved in the translocation) has been noted in all
(n=7) female cases studied, showing that the
translocation occurred in G2 phase.
van Echten J, van den Berg E, van Baarlen J, van Noort G,
Vermey A, Dam A, Molenaar WM. An important role for
chromosome 17, band q25, in the histogenesis of alveolar soft
part sarcoma. Cancer Genet Cytogenet 1995;82(1):57-61.
Heimann P, Devalck C, Debusscher C, Sariban E, Vamos E.
Alveolar soft-part sarcoma: further evidence by FISH for the
involvement
of
chromosome
band
17q25.
Genes
Chromosomes Cancer 1998;23(2):194-197.
Genes
TFE3
Ordóñez NG, Mackay B. Alveolar soft-part sarcoma: a review
of the pathology and histogenesis. Ultrastruct Pathol
1998;22:275-292.
Location: Xp11
DNA/RNA
8 exons.
Atlas Genet Cytogenet Oncol Haematol. 2008;12(3)
Joyama S, Ueda T, Shimizu K, Kudawara I, Mano M, Funai H,
Takemura K, Yoshikawa H. Chromosome rearrangement at
17q25 and xp11.2 in alveolar soft-part sarcoma: A case report
and review of the literature. Cancer 1999;86:1246-1250.
251
Soft tissue tumors: Alveolar soft part sarcoma
Huret JL
Ordóñez NG. Alveolar soft part sarcoma: a review and update.
Adv Anat Pathol 1999;6:125-139.
Sandberg A, Bridge J. Updates on the cytogenetics and
molecular genetics of bone and soft tissue tumors: alveolar soft
part sarcoma. Cancer Genet Cytogenet 2002;136(1):1-9.
Casanova M, Ferrari A, Bisogno G, Cecchetto G, Basso E, De
Bernardi B, Indolfi P, Fossati Bellani F, Carli M. Alveolar soft
part sarcoma in children and adolescents: A report from the
Soft-Tissue Sarcoma Italian Cooperative Group. Ann Oncol
2000;11:1445-1449.
Uppal S, Aviv H, Patterson F, Cohen S, Benevenia J, Aisner S,
Hameed M. Alveolar soft part sarcoma--reciprocal
translocation between chromosome 17q25 and Xp11. Report
of a case with metastases at presentation and review of the
literature. Acta Orthop Belg 2003;69(2):182-187.
Lasudry J, Heimann P. Cytogenetic analysis of rare orbital
tumors: further evidence for diagnostic implication. Orbit
2000;19(2):87-95.
Anderson ME, Hornicek FJ, Gebhardt MC, Raskin KA, Mankin
HJ. Alveolar soft part sarcoma: a rare and enigmatic entity.
Clin Orthop Relat Res 2005;438:144-148.
Argani P, Antonescu CR, Illei PB, Lui MY, Timmons CF,
Newbury R, Reuter VE, Garvin AJ, Perez-Atayde AR, Fletcher
JA, Beckwith JB, Bridge JA, Ladanyi M. Primary renal
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part sarcoma: a distinctive tumor entity previously included
among renal cell carcinomas of children and adolescents. Am
J Pathol 2001;159(1):179-192.
Huang HY, Lui MY, Ladanyi M. Nonrandom cell-cycle timing of
a somatic chromosomal translocation: The t(X;17) of alveolar
soft-part sarcoma occurs in G2. Genes Chromosomes Cancer
2005;44(2):170-176.
Folpe AL, Deyrup AT. Alveolar soft-part sarcoma: a review and
update. J Clin Pathol 2006;59(11):1127-1132.
Ladanyi M, Lui MY, Antonescu CR, Krause-Boehm A, Meindl
A, Argani P, Healey JH, Ueda T, Yoshikawa H, Meloni-Ehrig A,
Sorensen PHB, Mertens F, Mandahl N, van den Berghe H,
Sciot R, dal Cin P, Bridge J. The der(17)t(X.17)(p11;q25) of
human alveolar soft part sarcoma fuses the TFE3 transcription
factor gene to ASPL, a novel gene at 17q25. Oncogene
2001;20:48-57.
Kayton ML, Meyers P, Wexler LH, Gerald WL, LaQuaglia MP.
Clinical presentation, treatment, and outcome of alveolar soft
part sarcoma in children, adolescents, and young adults. J
Pediatr Surg 2006;41(1):187-193.
Tettamanzi MC, Yu C, Bogan JS, Hodsdon ME. Solution
structure and backbone dynamics of an N-terminal ubiquitinlike domain in the GLUT4-regulating protein, TUG. Protein Sci
2006;15(3):498-508.
Portera CA Jr, Ho V, Patel SR, Hunt KK, Feig BW, Respondek
PM, Yasko AW, Benjamin RS, Pollock RE, Pisters PW.
Alveolar soft part sarcoma: clinical course and patterns of
metastasis in 70 patients treated at a single institution. Cancer
2001;91:585-591.
Aulmann S, Longerich T, Schirmacher P, Mechtersheimer G,
Penzel R. Detection of the ASPSCR1-TFE3 gene fusion in
paraffin-embedded alveolar soft part sarcomas. Histopathology
2007;50(7):881-886.
Ladanyi M, Antonescu CR, Drobnjak M, Baren A, Lui MY,
Golde DW, Cordon-Cardo C. The precrystalline cytoplasmic
granules
of
alveolar
soft
part
sarcoma
contain
monocarboxylate transporter 1 and CD147. Am J Pathol
2002;160(4):1215-1221.
Zarrin-Khameh N, Kaye KS. Alveolar soft part sarcoma. Arch
Pathol Lab Med 2007;131(3):488-491.
This article should be referenced as such:
Huret JL. Soft tissue tumors: Alveolar soft part sarcoma. Atlas
Genet Cytogenet Oncol Haematol.2008;12(3):250-252.
van Ruth S, van Coevorden F, Peterse JL, Kroon BB. Alveolar
soft part sarcoma. a report of 15 cases. Eur J Cancer
2002;38(10):1324-1328.
Atlas Genet Cytogenet Oncol Haematol. 2008;12(3)
252
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Solid Tumour Section
Mini Review
Bone: Subungual exostosis with t(X;6)(q13;q22)
Clelia Tiziana Storlazzi, Fredrik Mertens
Department of Genetics and Microbiology, University of Bari, Bari, Italy (CTS); Department of Clinical
Genetics, Lund University Hospital, Lund, Sweden (FM)
Published in Atlas Database: July 2007
Online updated version: http://AtlasGeneticsOncology.org/Tumors/SubungExosttX6ID5526.html
DOI: 10.4267/2042/38535
This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence.
© 2008 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
Cytogenetics
Other names: Dupuytren's exostosis
Cytogenetics morphological
Classification
t(X;6)(q22;q13-14).
Note: Benign bone-producing neoplasm of unknown
cellular origin.
Clinics and pathology
Disease
Subungual exostosis.
Phenotype stem cell origin
Unknown.
Embryonic origin
Unknown.
Etiology
Unknown.
Epidemiology
Affects children and young adults.
Partial G-banding karyotype showing chromosomes 6 and X in
a case of subungual exostosis. The arrows indicate the
breakpoints.
Clinics
Cytogenetics molecular
Subungual exostosis usually presents as a slowly
growing, painful mass localized dorsomedially in the
distal phalanx, and in contrast to osteochondroma, there
is usually no continuity with the underlying cortex.
A Probe specific for COL12A1 (RP11-815E21)
identified the breakpoint in 6q14.1, as it showed
splitting signals on der(X) and der(6). On the same
chromosomes, these signals colocalized with the
signals of RP11-815E21, encompassing the COL4A5
and IRS4 genes in band Xq22.3.
Treatment
Surgical excision, but local recurrences are not
uncommon.
Probes
RP11-815E21 (COL4A5 and IRS4); RP11-1072D13
(COL12A1).
Prognosis
Excellent.
Variants
The breakpoint on chromosome 6 could be centromeric
to
COL4A5,
in
an
unknown
location.
Atlas Genet Cytogenet Oncol Haematol. 2008;12(3)
253
Bone: Subungual exostosis with t(X;6)(q13;q22)
Storlazzi CT, Mertens F
FISH experiment revealing the breakpoint regions on both chromosomes 6 and X on a case of subungual exostosis.
Genes involved and Proteins
To be noted
COL4A5 (alpha 5 type IV collagen)
To elucidate how the transcription of these genes is
affected by the translocation, further fresh or fresh
frozen samples need to be studied.
Location: Xq22.3
Note: It is currently unknown whether any of these two
genes is involved in the pathogenesis of subungual
exostosis.
DNA/RNA
Genomic (chrX:107,569,810-107,827,431). Three
transcript variants: isoform 1 (NM_000495), isoform 2
(NM_033380), isoform 3 (NM_03338).
Protein
Three proteins, respectively encoded by the isoform 1
(695 aa), isoform 2 (1691 aa), and isoform 3 (1688 aa).
References
Dal Cin P, Pauwels P, Poldermans LJ, Sciot R, Van den
Berghe H. Clonal chromosome abnormalities in a so-called
Dupuytren's subungual exostosis. Genes Chromosomes
Cancer 1999;24:162-164.
Murphey MD, Choi JJ, Kransdorf MJ, Flemming DJ, Gannon
FH. Imaging of osteochondroma: variants and complications
with
radiologic-pathologic
correlation.
Radiographics
2000;20:1407-1434. (Review).
Ilyas W, Geskin L, Joseph AK, Seraly MP. Subungual
exostosis of the third toe. J Am Acad Dermatol 2001;45:S200S201.
COL12A1 (collagen, type XII, alpha 1)
Location: 6q13
DNA/RNA
Genomic (chr6:75,850,762-75,972,343). Two transcript
variants, a long (NM_004370) and a short isoform
(NM_080645).
Protein
Two proteins: 1899 amino acids (aa) and 3063 aa,
respectively encoded by the short and long transcript
isoforms.
Zambrano E, Nosé V, Perez-Atayde AR, Gebhardt M, Hresko
MT, Kleinman P, Richkind KE, Kozakewich HP. Distinct
chromosomal rearrangements in subungual (Dupuytren)
exostosis and bizarre parosteal osteochondromatous
proliferation (Nora lesion). Am J Surg Pathol 2004;28:10331039.
Storlazzi CT, Wozniak A, Panagopoulos I, Sciot R, Mandahl N,
Mertens F, Debiec-Rychter M. Rearrangement of the
COL12A1 and COL4A5 genes in subungual exostosis:
molecular cytogenetic delineation of the tumor-specific
translocation t(X;6)(q13-14;q22). Int J Cancer 2006;118:19721976.
Result of the chromosomal
anomaly
This article should be referenced as such:
Storlazzi CT, Mertens F. Bone: Subungual exostosis with
t(X;6)(q13;q22).
Atlas
Genet
Cytogenet
Oncol
Haematol.2008;12(3):253-254.
Hybride Gene
Note: No detected fusion gene.
Atlas Genet Cytogenet Oncol Haematol. 2008;12(3)
254
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Cancer Prone Disease Section
Mini Review
Glomuvenous malformation (GVM)
Virginie Aerts, Pascal Brouillard, Laurence M Boon, Miikka Vikkula
Human Molecular Genetics (GEHU) de Duve Institute, Universite catholique de Louvain, Avenue
Hippocrate 74(+5), bp. 75.39, B-1200 Brussels, Belgium
Published in Atlas Database: July 2007
Online updated version: http://AtlasGeneticsOncology.org/Kprones/GlomuvenousID10120.html
DOI: 10.4267/2042/38536
This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence.
© 2008 Atlas of Genetics and Cytogenetics in Oncology and Haematology
(3) Localization: lesions are more often located on the
extremities, although they can be found all over the
body;
(4) Appearance: lesions are usually nodular and
multifocal, raised with a cobblestone-like appearance,
except for the rare plaque-like variant. They are often
hyperkeratotic;
(5) The lesions are not compressible;
(6) The lesions are painful on palpation;
(7) New lesions can appear with time, likely after
trauma.
Identity
Other names: Venous malformation with glomus cells
(VMGLOM); Glomangioma; Multiple glomus tumor.
Note: Glomuvenous malformation (GVM) is a
localized bluish-purple cutaneous vascular lesion,
histologically consisting of distended venous channels
with flattened endothelium surrounded by variable
number of maldifferentiated smooth muscle-like
“glomus cells” in the wall. GVM account for 5% of
venous anomalies referred to centers for vascular
anomalies. Previously, these lesions have been called
“multiple glomus tumors” or “glomangioma”.
Inheritance: GVM is often, if not always, hereditary
(64%), and transmitted as an autosomal dominant
disorder. Expressivity varies, as does penetrance, which
is age dependent and maximal (93%) by 20 years of
age.
Clinics
Phenotype and clinics
There is a wide phenotypic variation between GVM
patients, even within the same family (with the same
germline mutation). An individual can have an
extensive lesion, affecting for example a whole
extremity or most of the trunk, while others have
minor, scattered papulonodular lesions of a few
millimetres in diameter. The lesions are often multiple,
and they can affect any body part.
Seven features characterize GVM lesions :
(1) Colour: GVMs can be pink in infants, the most are
bluish-purple;
(2) Affected tissues: the lesions are localized to the skin
and subcutis, and they are rarely mucosal and never
extend deeply into muscles;
Atlas Genet Cytogenet Oncol Haematol. 2008;12(3)
Examples of GVMs: (A) Extended GVM on leg. (B) Small GVM
on knee.
255
Glomuvenous malformation (GVM)
Aerts V, et al.
At the histological level, the mural glomus cells are
positive for smooth muscle alpha-actin and vimentin,
but negative for desmin, Von Willebrand factor and S100. Under electron microscopy, glomus cells show
smooth muscle myofibrils and “dense bodies”,
characteristics of vascular smooth muscle cells
(vSMCs). Thus, these cells are most likely
incompletely or improperly differentiated vSMCs.
Localisation: Glomulin is likely an intracellular protein.
Function: The exact function of glomulin is unknown.
Glomulin has been described to interact with FKBP12,
an immunophilin that binds the immunosuppressive
drugs FK506 and rapamycin. FKBP12 interacts with
the TGFbeta type I receptor, and prevents its
phosphorylation. Thus, FKBP12 safeguards against the
ligand-independent activation of this pathway.
Glomulin, through its interaction with FKBP12, could
act as a repressor of this inhibition.
Glomulin has also been described to interact with cMET. Glomulin interacts with the inactive, non
phosphorylated form of c-MET. When c-MET is
activated by HGF, glomulin is released in a
phosphorylated form. This leads to p70 S6 protein
kinase (p70S6K) phosphorylation. It is not known
whether glomulin activates p70S6K directly or
indirectly. The p70S6K is a key regulator of protein
synthesis. Glomulin could thereby control cellular
events such as migration and cell division.
The third reported glomulin partner is Cul7. This places
glomulin in an SCF-like complex, which is implicated
in protein ubiquitination and degradation.
Mutations
There is no phenotype-genotype correlation in GVM.
Germinal: To date, 29 different inherited mutations
(deletions, insertions and nonsense substitutions) have
been identified. The most 5' mutation are located in the
first coding exon. The majority of them cause
premature truncation of the protein and likely result in
loss-of-function. One mutation deletes 3 nucleotides
resulting in the deletion of an asparagine at position
394 of the protein.
More than 70% of GVMs are caused by eight different
mutations in glomulin: 157delAAGAA (40,7%), 108C
to A (9,3%), 1179delCAA (8,1%), 421insT and
738insT (4,65% each), 554delA+556delCCT (3,5%),
107insG and IVS5-1(G to A) (2,3% each).
Somatic: The phenotypic variability observed in GVM
could be explained by the need of a somatic second-hit
mutation. Such a mechanism was discovered in one
GVM (somatic mutation 980delCAGAA), suggesting
that the lesion is due to a complete localized loss-offunction of glomulin. This concept can explain why
some patients have bigger lesions than others, why new
lesions appear, and why they are multifocal. This could
also explain, why some mutation carriers are
unaffected.
Neoplastic risk
GVM has no neoplastic histological characteristics and
never becomes malignant.
Treatment
The gold-standard treatment for GVM consists of
surgical resection, as lesions are superficial and rarely
affect deeply the underlying muscle, and sometimes
sclerotherapy. In contrast to venous malformations, the
use of elastic compressive garments often aggravate
pain and should thus be avoided.
Evolution
GVM is a developmental lesion that grows
proportionally with the child. After partial resection,
recurrence is frequent. New small lesions can appear
with time. The red plaque-like lesions of the young
darken with age.
Cytogenetics
No cytogenetic abnormally has been reported for
GVM.
Genes involved and Proteins
Glomulin
Location: 1p22.1
DNA/RNA
Description: The glomulin gene spans about 55 kbp and
contains 19 exons coding for 1785 bp.
Transcription: 2 kb transcript.
Protein
Glomulin was identified by reverse genetics, and its
function is currently unknown.
Description: Glomulin gene encodes a protein of 594
amino acids (68 kDa).
Expression: The high level of glomulin expression in
the murine vasculature indicates that glomulin may
have an important role in blood vessel development
and/or maintenance.
Atlas Genet Cytogenet Oncol Haematol. 2008;12(3)
256
Glomuvenous malformation (GVM)
Aerts V, et al.
Schematic representation of glomulin : The two stars indicate the start and the stop codons, in exon 2 and 19 respectively. All known
mutations are shown. Somatic second hit is in blue.
References
Arai T, Kasper JS, Skaar JR, Ali SH, Takahashi C, DeCaprio
JA. Targeted disruption of P185/Cul7 gene results in abnormal
vascular morphogenesis. Proc Natl Acad Sci USA
2003;100(17):9855-9860.
Goodman TF, Abele DC. Multiple glomus tumors. A clinical
and
electron
microscopic
study.
Arch
Dermatol
1971;103(1):11-23.
Boon LM, Mulliken JB, Enjolras O, Vikkula M. Glomuvenous
malformations (glomangioma) and Venous malformations,
Distinct clinicopathologic and genetic entities. Arch Dermatol
2004;140:971-976.
Chambraud B, Radanyi C, Camonis JH, Shazand K, Rajkowski
K, Baulieu EE. FAP48, a new protein that forms specific
complexes with both immunophilins FKBP59 and FKBP12.
Prevention by the immunosuppressant drugs FK506 and
rapamycin. J biol Chem 1996;271(51):32923-32929.
McIntyre BA, Brouillard P, Aerts V, Gutierrez-Roelens I,
Vikkula M. Glomulin is predominantly expressed in vascular
smooth muscle cells in the embryonic and adult mouse. Gene
Expr Patterns 2004;4(3):351-358.
Chen YG, Liu F, Massagué J. TGFbeta receptor inhibition by
FKBP12. EMBO J 1997;16(13):3866-3876.
Boon LM, Brouillard P, Irrthum A, Karttunen L, Warman ML,
Rudolph R, Mulliken JB, Olsen BR, Vikkula M. A gene for
inherited cutaneous venous anomalies ('glomangiomas')
localizes to chromosome 1p21-22. Am J Hum Genet
1999;65(1):125-133.
Brouillard P, Ghassibe M, Penington A, Boon LM, Dompmartin
a, Temple IK, Cordisco M, Adams D, Piette F, Harper JI, Syed
S, Boralevi F, Taieb A, Danda S, Baselga E, Enjolras O,
Mulliken JB, Vikkula M. Four common glomulin mutation cause
two thirds of glomuvenous malformations ('familial
glomangiomas') : evidence for a founder effect. J Med Genet
2005;42(2):e13.
Brouillard P, Olsen BR, Vikkula M. High-resolution physical
and transcript map of the locus for venous malformations with
glomus cells (VMGLOM) on chromosome 1p21-p22. Genomics
2000;67(1):96-101.
Boon LM, Vanwijck R. Medical and surgical treatment of
venous malformations. Ann Chir Plast Esthet 2006;51(45):403-411.
Grisendi S, Chambraud B, Gout I, Comoglio PM, Crepaldi T.
Ligand-regulated binding of FAP68 to the hepatocyte growth
factor receptor. J Biol Chem 2001;276(49):46632-46638.
Mallory SB, Enjolras O, Boon LM, Rogers E, Berk DR, Blei F,
Baselga E, Ros AM, Vikkula M. Congenital plaque-type
glomuvenous malformations presenting in childhood. Arch
Dermatol 2006;142(7):892-896.
Irrthum A, Brouillard P, Enjolras O, Gibbs NF, Eichenfield LF,
Olsen BR, Mulliken JB, Boon LM, Vikkula M. Linkage
disequilibrium narrows locus for venous malformation with
glomus cells (VMGLOM) to a single 1.48 Mbp YAC. Eur J Hum
Genet 2001;9(1):34-38.
Brouillard P, Enjolras O, Boon LM, Vikkula M. GLMN and
Glomuvenous Malformation. Inborn Errors of Development 2e,
edited by Charles Epstein, Robert Erickson and Anthony
Wynshaw-Boris, Oxford University Press, Inc.
Brouillard P, Boon LM, Mulliken JB, Enjolras O, Ghassibé M,
Matthew L, Warman O, Tan T, Olsen BR, Vikkula M. Mutations
in a novel factor, Glomulin, are responsible for glomuvenous
malformations ('Glomangiomas'). Am J Hum Genet
2002;70:866-874.
Atlas Genet Cytogenet Oncol Haematol. 2008;12(3)
This article should be referenced as such:
Aerts V, Brouillard P, Boon LM, Vikkula M. Glomuvenous
malformation (GVM). Atlas Genet Cytogenet Oncol
Haematol.2008;12(3):255-257.
257
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Case Report Section
Paper co-edited with the European LeukemiaNet
Translocation t(1;6)(p35;p25) in B-cell
lymphoproliferative disorder with evolution to
Diffuse Large B-cell Lymphoma
Elvira D Rodrigues Pereira Velloso, Cristina Ratis, Sérgio AB Brasil, João Carlos Guerra, Nydia
S Bacal, Cristóvão LP Mangueira
Clinical Laboratory, Hospital Israelita Albert Einstein, São Paulo, Brazil (EDRPV, CAR, NSB, CLPM);
Centro de Hematologia São Paulo, São Paulo, Brazil (SABB, JCG)
Published in Atlas Database: July 2007
Online updated version: http://AtlasGeneticsOncology.org/Reports/0106RodriguesID100030.html
DOI: 10.4267/2042/38537
This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence.
© 2008 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Rituximab and Fludarabine was started. The PB counts
showed: Hb: 13g/dl, WBC: 69,6 x 109/l, lymphocytes:
62 x 109/l, platelets: 145 x 109/l. Inguinal lymph node
biopsy showed diffuse large B-cell Lymphoma, Ki-67:
70%, cyclin D1 -, CD20 +, BCL2 +. From December,
2005 to April, 2006, 6 cycles of R-CHOP showed no
response. From October, 2006 to May, 2007, regression
of lymph nodes and clinical improvement was done
with 6 cycles of MiCEP. At this time, cytogenetics and
immunophenotyping studies of bone marrow were
performed.
Clinics
Age and sex: 75 years old female patient.
Organomegaly:
- hepatomegaly;
- splenomegaly;
- enlarged lymph nodes;
- no central nervous system involvement.
Previous history:
- B-cell Lymphoproliferative disorder for 8 years;
- A 75-years-old female with an 8 years diagnosis of
mature B-cell proliferation disorder. At August, 1999 a
CBC showed high WBC, and physical examination
showed enlarged lymph nodes (cervical and axillaries).
Peripheral blood revealed Hb: 14,8g/dl, WBC: 21,8 x
109/l, lymphocytes 16 x 109/l, platelets 241 x 109/l and
bone marrow trephine showed interstitial infiltration
with small lymphocytes consistent with CLL stage A
(Binet). In April, 2000 there was a significant increase
in the lymph nodes and night sweats. PB
immunophenotyping study showed a CD19/CD5
positive population consisted with B-CLL (Matutes'
score 4). The patient was treated with 6 cycles of COP,
with evolution to pulmonary nodules and axillae bulky
in 2001. From 2001 to 2004, a few cycles of
Chlorambucil and 7 cycles of R-COP produced a good
response. In April, 2005, the PB morphology and
immunophenotype were consistent to atypical B-CLL
(CD19, CD20, CD23, CD25, HLA-DR, IgM, IgD,
CD79b, CD38, and sKappa,positive and CD5
negative), and PB karyotype showed no clonal
abnormalities in 20 metaphases. In August, 2005, there
was an increased in the number of lymph nodes and
Atlas Genet Cytogenet Oncol Haematol. 2008;12(3)
Blood
WBC: 5,4 x 109/l; Hb: 13,6 g/dl; platelets: 169 x 109/l;
blasts: 3,35 x 109/l (lymphoid cells)%.
Bone marrow: 28% of lymphoid mature cells.
Cytopathology classification
Cytology: B-cell Lymphoproliferative disorder
(Atypical CLL) with evolution to diffuse large B-cell
Lymphoma. Atypical CLL.
Immunophenotype: 25% of total bone marrow cells are
positive : CD20++, CD22+, CD25+, CD38, CD79b++,
HLA-DR, sIgM, sIgD e sKappa ++.
Rearranged Ig or Tcr: not done.
Pathology: Inguinal Lymph node biopsy (August,
2005): Diffuse large B-cell Lymphoma, Ki-67: 70%,
ciclina D1 -, CD20 +, BCL2 +.
Electron microscopy: not done.
Precise diagnosis: B-cell Lymphoproliferative disorder
(Atypical CLL) with evolution to diffuse large B-cell
Lymphoma.
258
Translocation t(1;6)(p35;p25) in B-cell lymphoproliferative disorder
with evolution to Diffuse Large B-cell Lymphoma
Rodrigues Pereira Velloso ED, et al.
Survival
Comments
Date of diagnosis: 07-2007.
Treatment: wide previous history (long previous history
of chemotherapy), no chemotherapy after July, 2007.
Complete remission: not applied.
Treatment related death: Relapse: Status: Alive 09-2007.
Survival: 2 months.
In 2005, the Belgian group described the
t(1;6)(p35.3;p25.2) in 8 patients with unmutated BCLL. As in this case, this rare cytogenetic entity has
been described in typical or atypical CLL (8/8 cases),
with evolution to diffuse large B-cell Lymphoma (3/8
cases); trisomy 12 been a common additional
abnormality (3/8 cases).
References
Karyotype
Michaux L, Wlodarska I, Rack K, Stul M, Criel A, Maerevoet M,
Marichal S, Demuynck H, Mineur P, Kargar Samani K, Van
Hoof A, Ferrant A, Marynen P, Hagemeijer A. Translocation
t(1;6)(p35.3;p25.2): a new recurrent aberration in 'unmutated'
B-CLL. Leukemia 2005;19:77-82.
Sample: bone marrow cells; culture time: 72 hours with
and without TPA (o-tetradecanoyl phorbol-13-acetate);
banding: G; results: 47, XX, t(1;6)(p35;p25),
+12[13]/46,XX[7].
Karyotype at relapse: not done.
Other molecular cytogenetic techniques: not done.
This article should be referenced as such:
Rodrigues Pereira Velloso ED, Ratis CA, Brasil SAB, Guerra
JC, Bacal NS, Mangueira LM Pitangueira CP. Translocation
t(1;6)(p35;p25) in B-cell lymphoproliferative disorder with
evolution to Diffuse Large B-cell Lymphoma. Atlas Genet
Cytogenet Oncol Haematol.2008;12(3):258-259.
Other molecular studies
Technics: not done
Partial karyotype, G-band.
Atlas Genet Cytogenet Oncol Haematol. 2008;12(3)
259
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Educational Item Section
Oral presentation at the 6th European Cytogenetic Conference (ECC), Istanbul, July
2007, organized by the European Cytogeneticists Association.
How human chromosome aberrations are formed
Albert Schinzel
Institute of Medical Genetics, Schorenstr. 16, CH-8603 Schwerzenbach, Switzerland
Published in Atlas Database: July 2007
Online updated version: http://AtlasGeneticsOncology.org/Educ/ChromAberFormedID30065ES.html
DOI: 10.4267/2042/38538
This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence.
© 2008 Atlas of Genetics and Cytogenetics in Oncology and Haematology
IIIIIIIVVVIVIIVIIIIXXXIXIIXIIIXIVXVXVIXVIIXVIII-
Introduction
Origin and mechanisms of formation of chromosome aberrations
Chromosome aberrations, classification
Modes of determination of the mechanisms of formation of chromosome aberrations
Microsatellite marker analysis
Summary of parental origin of chromosome aberrations
Origin of Ullrich-Turner syndrome 45,X
Origin of recurrent free trisomy 21
Interchromosal effect (ICE)
Origin of mosaic trisomy
Origin of interstitial (micro-)deletions, interchromosomal versus intrachromosomal
Frequent interstitial microdeletions (15q12, 7q11.23, 22q11.2)
Origin of mosaic duplications (de novo)
Origin of additional isochromosomes and isodicentric chromosomes
Chaotic chromosome aberrations
Origin of multipe structural chromosome aberrations
Primary and secondary chromosome aberrations
Conclusion
I- Introduction
Formation:
- Nondisjunction: meiotic, pre-meiotic, post-meiotic
- Rearrangement: meiotic, pre-meiotic, post-meiotic
Any combination:
Incorporation of 2 sperms or of a polar body into the
oocyte.
Characteristics of the species homo sapiens:
- Many!
- Among others: excessively high incidence of
reproductive failure and chromosome aberrations.
- Determination of origin and mechanisms of
formation of chromosome aberrations: Each newly
developed technique, from Q banding over FISH and
microsatellite marker analysis to CGH, has brought
additional information as to the origin of
chromosomal imbalance in man.
III- Chromosome aberrations,
classification
Numerical aberrations:
- Monosomy (X/Y)
- Trisomy
- Sex chromosome aneuploidy
- Double/triple aneuploidy
- Uniparental disomy
Ploidy aberrations:
- Haploidy
- Triploidy
II- Origin and mechanisms of formation of
chromosome aberrations
Origin may be:
- maternal
- paternal
- combined
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How human chromosome aberrations are formed
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IV- Modes of determination of the
mechanisms of formation of chromosome
aberrations
- Tetraploidy
Structural aberrations:
- Deletions
- Rings
- Duplications
- Balanced rearrangements
- Combined duplication-deletion
- Complex rearrangements
Mosaic and chimeras
Combinations:
- Numerical and structural
- Numerical and ploidy, etc...
1. Aberration per se:
- free trisomy: nondisjunction
- mosaicism: either postzygotic origin or two steps
- triploidy
2. Cytogenetic markers.
3. Molecular marker analysis in proband and parents.
4. Molecular marker analysis in grandparents of proband.
5. CGH.
Legend: Paternal (P) and maternal (M) chromosomes 14, the free 14 and the 14/21 translocation from the Down's offspring, Q-banded.
The free 14 is of paternal origin, therefore the 14/21 is of maternal origin (from Chamberlin 1980; Hum Genet 53: 343).
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V- Microsatellite marker analysis
- Structural,
terminal
deletions
and
rings:
predominantly pat.
- Structural,
extra
rearranged
chromosomes
isochromosomes,
inv
dup
chromosomes:
predominantly mat from initial nondisjunction.
- Structural , intrachromosomal rearrangements: equal
distribution.
- Structural, interchromosomal rearrangements: idem.
- Uniparental disomy:
o Heterodisomy: predominantly mat from
initial trisomy.
o Isodisomy: predominantly pat.
- Mosaics: mostly starting with maternal trisomy
o Triploidy:
o predominantly (80%) mat, incorporation
of a polar body into the oocyte;
o rarer (20%) fertilization of the oocyte by
2 different sperms.
- Almost always able to determine the origin of
deletions.
- Often not successful for duplications, especially
direct or inverted duplications stemming from
chromatid interchanges (no third allele, often no
clear intensity differences).
VII- Origin of Ullrich-Turner syndrome 45,X
Xg studies: predominant maternal origin of the
remaining X-chromosome.
Expected distribution (as 45,Y is none-viable) if mat =
pat: 66 vs 33%.
Distribution found: 80 vs 20% (statistically
significant).
Parental Xg information about 306 females with 45,X
Ullrich-Turner syndrome (Sanger et al., 1971).
Xg groups of
Father Mother
+
+
+
+
+
+
+
+
-
T
+
+
+
Total
Source of normal
X
unknown
maternal
paternal
maternal
maternal
unknown
unknown
Number
150
31
5
10
60
35
15
306
+ = Xg(a+); - = Xg(a-)
VIII- Origin of recurrent free trisomy 21
Results of molecular marker studies:
- 1. In siblings:
- 60% by chance
- 40% parental gonadal mosaicism
- 2. In more remote relatives:
- 100% by chance
VI- Summary of parental origin of
chromosome aberrations
- Numerical, autosomes: predominantly mat.
- Numerical, X chromosomes: idem.
- Numerical, X and Y: overwhelming paternal origin.
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How human chromosome aberrations are formed
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IX- Interchromosal effect (ICE)
- Definition:
A balanced chromosome aberration increases the risk
of non-disjunction for other chromosomes.
- Consequence:
Prenatal cytogenetic diagnosis is indicated if one parent
carries a balanced rearrangement even if unbalanced
segregation cannot lead to viable offspring.
- Evidence for ICE:
More familial balanced translocations found in Down
syndrome patients than expected by chance.
- Evidence against an ICE:
In haploid sperms of male carriers of balanced
translocations there is no increase of disomies over
controls.
Origin of the
Number
supernumerary 21
of
families
mat
pat
mat.
2
2
0
rearrangement
pat.
11
11
0
rearrangement
Result:
- Switch from grandpaternal to grandmaternal
origin on either side:
- interchromosomal rearrangement.
- meiotic origin.
- low recurrence risk.
- No switch, markers on either side from
grandparent:
- intrachromosomal rearrangement (between 2
chromatids).
- meiotic or pre- or post-meiotic origin.
- not necessarily low recurrence risk.
X- Origin of mosaic trisomy
- Mostly first trisomy: secondary somatic loss of the
third homologue.
- Not infrequently: mosaicism between (maternal)
trisomy and (maternal) uniparental disomy.
XI- Origin of interstitial (micro-)deletions,
interchromosomal versus
intrachromosomal
Principle
Investigation of grandparents of the side of origin with
markers flanking the deleted segment.
Williams-Beuren syndrome:
- Deletion of 7q11.22 including the Elastin locus.
- Supravalvular aortic stenosis.
- Peripheral pulmonary stenosis.
- Growth retardation.
- Moderate mental retardation.
- Outgoing pleasant personality.
- Full lips, cheeks and lids.
- Deep voice
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How human chromosome aberrations are formed
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Representative examples of microsatellite analysis at 7q11.2 carried out. The deleted region of chromosome 7 is indicated with a black
bar beside the chromosome 7 ideogram. Marker D7S1870, located within the deleted region, illustrates the maternal origin of the
deletion. Grandparental origin of the regions flanking the deletion are shown with markers D7S672 (proximal region) and D7S524 (distal
region).
XII- Frequent interstitial microdeletions
(15q12, 7q11.23, 22q11.2)
- Reason for their high incidence: similar short tandem
repeats.
- Frequent paracentric inversions of this segment.
- Tend to pair at meiosis.
- Cutting out of the segment forming an inversion
loop.
XIII- Origin of mosaic duplications (de
novo)
Not infrequently:
- First trisomy;
- Second rearrangement;
- Third uniparental disomy.
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How human chromosome aberrations are formed
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- Meiotic: M1: proximal heterozygosity / M2 : vice
versa.
- Results: mostly M2 maternal.
Mechanism:
- first meiotic nondisjunction,
- second isochromosome formation.
Examples: i(8p), i(9p), i(12p), i(18p).
XV- Chaotic chromosome aberrations
XIV- Origin of additional isochromosomes
and isodicentric chromosomes
- Found especially at investigation of early
spontaneous abortions.
- Multiple deletions, combined deletions and
duplications, etc...
Molecular marker analysis:
- Postmeiotic: one normal, one strong allele.
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How human chromosome aberrations are formed
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- Complex balanced and unbalanced aberrations often
following irradiation.
XVII- Primary and secondary chromosome
aberrations
XVIOrigin
of
multipe
chromosome aberrations
Secondary aberrations may enable survival of an
otherwise lethal unbalanced product.
Examples:
- Additional isochromosomes deriving from a
trisomy.
- Correction of trisomy through uniparental disomy.
- Secondary structural aberrations with loss of a
chromosomal segment following a trisomy.
- Reduction of a complex rearrangement with multiple
breaks to a simpler one through recombination balanced and unbalanced.
structural
CGH
re-investigations
of
visible
structural
chromosome aberrations not infrequently detect further
submicroscopic imbalances, mostly small deletions,
rarer duplications. These point towards a much more
complex mechanism of origin of structural aberrations
than seen on the first glance and parallels the complex
origin of mosaics, especially for structural and
combined numerical - structural chromosome
aberrations.
XVIII- Conclusion
A distinct feature of homo sapiens is the excessively
high incidence of unbalanced chromosome aberrations,
especially trisomy and triploidy.
Nature has an incredible phantasy and many different
mechanisms to correct such unbalanced aberrations.
This may happen because of a high proneness to early
postzygotic numerical and structural aberrations
combined with a high selection pressure.
It is unknown whether primary aberrations may lead
with preference to secondary imbalance.
Anyway, these visible aberrations constitute the tip of
an iceberg, and under the water surface are the many
spontaneous miscarriages due to chromosomal
imbalance.
Acknowledgements
IMG Zurich:
Alessandra Baumer and Collaborators.
Mariluce Riegel and Collaborators.
Europe:
Collegues from many countries, especially Turkey
(Seher Basaran), Poland, Hungary, Ukraine, Spain,
and the ECARUCA project .
This article should be referenced as such:
Schinzel A. How human chromosome aberrations are formed.
Atlas Genet Cytogenet Oncol Haematol.2008;12(3):260-266.
Atlas Genet Cytogenet Oncol Haematol. 2008;12(3)
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