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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, and clinical entities in cancer, and cancer-prone diseases.
It presents structured review articles (“cards”) on genes, leukaemias, solid tumours, cancer-prone diseases, and also
more traditional review articles (“deep insights”) on the above subjects and on surrounding topics.
It also present 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]
The Atlas of Genetics and Cytogenetics in Oncology and Haematology is published 4 times a year by ARMGHM, a
non profit organisation.
Philippe Dessen is the Database Director, and Alain Bernheim the Chairman of the on-line version (Gustave Roussy
Institute – Villejuif – France).
http://AtlasGeneticsOncology.org
© ATLAS - ISSN 1768-3262
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
National Center for Scientific Research (INIST-CNRS) since 2008.
The Atlas is hosted by INIST-CNRS (http://www.inist.fr)
http://AtlasGeneticsOncology.org
© ATLAS - ISSN 1768-3262
The PDF version of the Atlas of Genetics and Cytogenetics in Oncology and Haematology is a reissue of the original articles published in collaboration with the
Institute for Scientific and Technical Information (INstitut de l’Information Scientifique et Technique - INIST) of the French National Center for Scientific Research
(CNRS) on its electronic publishing platform I-Revues.
Online and PDF versions of the Atlas of Genetics and Cytogenetics in Oncology and Haematology are hosted by INIST-CNRS.
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Editor
Jean-Loup Huret
(Poitiers, France)
Volume 5, Number 2, April - June 2001
Table of contents
Gene Section
COL1A1 (collagen, type I, alpha 1)
Marie-Pierre Simon, Georges Maire, Florence Pedeutour
78
ERCC2 (Excision repair cross-complementing rodent repair deficiency,
complementation group 2)
Anne Stary, Alain Sarasin
83
ERCC3 (Excision repair cross-complementing rodent repair deficiency,
complementation group 3)
Anne Stary, Alain Sarasin
88
NF2 (neurofibromatosis type 2)
James F Gusella
91
PDGFB (platelet-derived growth factor beta polypeptide
(simian sarcoma viral (v-sis) oncogene homolog))
Marie-Pierre Simon, Georges Maire, Florence Pedeutour
93
POLH (polymerase (DNA direct), eta)
Anne Stary, Alain Sarasin
98
XPA (xeroderma pigmentosum, complementation group A)
Anne Stary, Alain Sarasin
100
XPC (xeroderma pigmentosum, complementation group C)
Anne Stary, Alain Sarasin
103
FBP17 (formin binding protein 17)
Uta Fuchs, Arndt Borkhardt
106
GHRL (ghrelin/obestatin prepropeptide)
Catherine Tomasetto
108
MAD2L1 (mitotic arrest deficient 2, yeast, human homolog like-1)
Elizabeth M Petty, Kenute Myrie
110
TFF3 (trefoil factor 3 (intestinal))
Catherine Tomasetto
114
WRN (Werner syndrome, RecQ helicase-like)
Mounira Amor-Guéret
116
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(2)
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Leukaemia Section
Classification of T-Cell disorders
Vasantha Brito-Babapulle, Estella Matutes, Daniel Catovsky
118
Burkitt's lymphoma (BL)
Antonio Cuneo, Gianluigi Castoldi
121
del(13q) in multiple myeloma
Franck Viguié
123
Follicular lymphoma (FL)
Antonio Cuneo, Gianluigi Castoldi
125
t(5;11)(q31;q23)
Stig E Bojesen
127
Solid Tumour Section
Testis: Germ cell tumors
Leendert HJ Looijenga
129
Cancer Prone Disease Section
Bruton's agammaglobulinemia
Niels B Atkin
139
Familial nervous system tumour syndromes
Anne-Marie Capodano
141
Multiple endocrine neoplasia type 2 (MEN2)
Sophie Giraud
142
Von Hippel-Lindau
Stéphane Richard
145
Neurofibromatosis type 2 (NF2)
James F Gusella
150
Deep Insight Section
Nucleotide excision repair
Leon HF Mullenders, Anne Stary, Alain Sarasin
152
Educational Items Section
Hardy-Weinberg model
Robert Kalmes, Jean-Loup Huret
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(2)
155
t(11;14)(q13;q32)
in multiple myeloma
Atlas
of Genetics
and Cytogenetics
in Oncology and Haematology
Huret JL, Laï JL
OPEN ACCESS JOURNAL AT INIST-CNRS
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(2)
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Gene Section
Review
COL1A1 (collagen, type I, alpha 1)
Marie-Pierre Simon, Georges Maire, Florence Pedeutour
Institute of Signalling, Developmental Biology and Cancer Research, CNRS UMR 6543, Centre AntoineLacassagne, 06189 Nice cedex 2, France (MPS); UF Recherche Clinique 952, Laboratoire de Génétique,
Université de Nice-Sophia Antipolis, CHU de Nice, 06202 Nice, France (GM, FP)
Published in Atlas Database: February 2001
Online updated version : http://AtlasGeneticsOncology.org/Genes/COL1A1ID186.html
DOI: 10.4267/2042/37719
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2001 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Transcription
Identity
Two RNA of 5,8 kb and 4,8 kb differing by their 3’
terminus non coding sequence and giving rise to a
single 140 kDa protein.
HGNC (Hugo): COL1A1
Location: 17q21.31-q22
Local order: Telomeric to MEOX1 (mesenchyme
homeo box 1), centromeric to MVWF (Modifier of von
Willebrand factor).
Protein
Description
1464 amino acids. The a1 (I) chains of the type I
collagen are synthesised as procollagen molecules
containing amino and carboxy-terminal propeptides,
wich are removed by site-specific endopeptidase. The
central triple helical domain is formed by 338 repeats
of a Gly-X-Y triplet where X and Y are often a proline.
Expression
Type I collagen is the most abundant protein in
vertebrates and a constituent of the extra cellular matrix
in connective tissue of bone, skin, tendon, ligament and
dentine. It is mostly produced and secreted by
fibroblasts and osteoblasts.
COL1A1 (17q21) - Courtesy Mariano Rocchi, Resources for
Molecular Cytogenetics.
DNA/RNA
Description
Localisation
The COL1A1 gene is 18 kb in size and is composed of
52 exons. Exons 6 to 49 encode the alpha helical
domain. Most of these exons were 45 bp, 54 bp or
multiple of 45 bp or 54 bp.
Extra-cellular matrix.
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(2)
78
COL1A1 (collagen, type I, alpha 1)
Simon MP et al.
-Darier Ferrand tumour or Darier-Hoffmann tumour.
-Giant cell fibrosarcoma (GCF) (juvenile form of DP).
- Bednar tumour (pigmented variant of DP).
Disease
Infiltrative skin tumours of intermediate malignancy.
Prognosis
The prognosis is usually favourable. These tumours are
locally aggressive and highly recurrent, but metastases
or tumour-related deaths are extremely rare.
Function
Two pro a1 (I) chain associate in trimers with one pro
a2 (I) chain to form the type I collagen fibrils after
proteolysis.
Homology
Member of the collagen family.
Implicated in
Dermatofibrosarcoma Protuberans (DP)
Also called:
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(2)
79
COL1A1 (collagen, type I, alpha 1)
Simon MP et al.
Cytogenetics
Dermatofibrosarcoma
Protuberans,
Giant
Cell
fibrosarcoma and Bednar tumours present specific
cytogenetic features such as reciprocal translocations
t(17;22)(q22;q13.1) (Fig A) or, more often,
supernumerary ring chromosomes derived from
t(17;22) (B). As shown by FISH analysis, the ring
chromosomes contain chromosome 22 centromere and
low-level amplification of 22cen-q13.1 and 17q22-qter
sequences. To note, in most cases, the derivative
chromosome 17 is not present. In contrast, several
copies of the derivative chromosome 22 are generally
observed.in addition to two apparently normal
chromosomes 17.
Hybrid/Mutated gene
Both rings and der(22) translocated chromosomes
present a same molecular rearrangement that fuses the
collagen type I alpha 1(COL1A1) and the plateletderived growth factor B chain (PDGFB) genes (C).
In all DP and GCF cases studied, the
t(17;22)translocation
results
in
chimerical
COL1A1/PDGFB mRNA production, in which the
PDGFB exon 1 is deleted and replaced by a variable
segment of COL1A1 mRNA sequence. In the 32 cases
tested the fusion mRNA was an in-frame fusion of one
of the COL1A1 exons (varying from exon 7 to exon
47) to PDGFB exon 2 (D).
A chimerical COL1A1/PDGFB cDNA sequence fusing COL1A1 exon 29 to PDGFB exon 2 was isolated from the DP T94796 tumour and
stably
transfected
in
the
Chinese
hamster
lung
fibroblastic
cell
line
PS200
(E).
The T94796 COL1A1/PDGFB chimerical protein sequence retained the COL1A1 N-terminus processing site encoded by the COL1A1
exon 6 and the N and C-terminus PDGFB processing sites encoded by the PDGFB exons 3 and 6 respectively (F).
Mutagenesis experiments and immunodetection with anti-PDGFBB and specific anti-COL1A1/PDGFB antibodies showed that
COL1A1/PDGFB expressing cells produced 116 kD chimerical COL1A1/PDGFB precursors chains, which formed dimers and were
processed to give active 30 kD PDGFB-like dimers (G).
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(2)
80
COL1A1 (collagen, type I, alpha 1)
Simon MP et al.
Abnormal protein
COL1A1 and PDGFB are both encoded as propeptides, which are processed by proteolytic cleavage
at N and C-terminus, to give mature proteins.
Sequences analyses of the chimerical COL1A1/PDGFB
fusion transcripts showed that the COL1A1/PDGFB
putative proteins displayed a pro-peptide structure,
which preserved the N-terminus COL1A1 pro-peptide
containing the signal peptide and the N and C-terminus
PDGFB maturation cleavage sites.
The functional and structural properties of the
COL1A1/PDGFB fusion protein were characterized by
generating stable fibroblastic cell lines that expressed
tumour-derived COL1A1/PDGFB chimerical genes.
The
diagram
herein
given
presents
the
COL1A1/PDGFB chimerical protein encoded by the
T94796 tumour-derived chimerical COL1A1/PDGFB
cDNA sequence.
Oncogenesis
Transfected cells lines expressing the chimerical
T94796-COL1A1/PDGFB
proteins
became
independent upon growth factors, including PDGFB,
and induced tumours formation in nude mice. In
addition, it was shown that the COL1A1/PDGFB stable
clones cells contained activated PDGF b-receptors and
that the conditioned media from COL1A1/PDGFB
transfected cells were able to stimulate fibroblastic
cells growth. Anti-PDGFBB antibodies neutralized this
effect.
These
results
strongly
suggest
that
the
COL1A1/PDGFB
chimerical
gene
expression
associated with DP, contributes to tumour formation
through ectopic production of mature PDGFB and the
formation of an autocrine loop.
Breakpoints
References
Byers PH. Brittle bones--fragile molecules: disorders of
collagen gene structure and expression. Trends Genet. 1990
Sep;6(9):293-300
Dalgleish R. The human type I collagen mutation database.
Nucleic Acids Res. 1997 Jan 1;25(1):181-7
Simon MP, Pedeutour F, Sirvent N, Grosgeorge J, Minoletti F,
Coindre JM, Terrier-Lacombe MJ, Mandahl N, Craver RD, Blin
N, Sozzi G, Turc-Carel C, O'Brien KP, Kedra D, Fransson I,
Guilbaud C, Dumanski JP. Deregulation of the platelet-derived
growth factor B-chain gene via fusion with collagen gene
COL1A1 in dermatofibrosarcoma protuberans and giant-cell
fibroblastoma. Nat Genet. 1997 Jan;15(1):95-8
Pedeutour F, Simon MP, Minoletti F, Sozzi G, Pierotti MA,
Hecht F, Turc-Carel C. Ring 22 chromosomes in
dermatofibrosarcoma protuberans are low-level amplifiers of
chromosome 17 and 22 sequences. Cancer Res. 1995 Jun
1;55(11):2400-3
Fish FS. Soft tissue sarcomas in dermatology. Dermatol Surg.
1996 Mar;22(3):268-73
Greco A, Fusetti L, Villa R, Sozzi G, Minoletti F, Mauri P,
Pierotti MA. Transforming activity of the chimeric sequence
formed by the fusion of collagen gene COL1A1 and the platelet
derived growth factor b-chain gene in dermatofibrosarcoma
protuberans. Oncogene. 1998 Sep 10;17(10):1313-9
Pedeutour F, Simon MP, Minoletti F, Barcelo G, TerrierLacombe MJ, Combemale P, Sozzi G, Ayraud N, Turc-Carel C.
Translocation, t(17;22)(q22;q13), in dermatofibrosarcoma
protuberans:
a
new
tumor-associated
chromosome
rearrangement. Cytogenet Cell Genet. 1996;72(2-3):171-4
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(2)
81
COL1A1 (collagen, type I, alpha 1)
Simon MP et al.
Mentzel T, Beham A, Katenkamp D, Dei Tos AP, Fletcher CD.
Fibrosarcomatous
("high-grade")
dermatofibrosarcoma
protuberans: clinicopathologic and immunohistochemical study
of a series of 41 cases with emphasis on prognostic
significance. Am J Surg Pathol. 1998 May;22(5):576-87
dermatofibrosarcoma protuberans by reverse transcriptionpolymerase chain reaction using archival formalin-fixed,
paraffin-embedded tissues. Diagn Mol Pathol. 1999
Sep;8(3):113-9
Nishio J, Iwasaki H, Ishiguro M, Ohjimi Y, Yo S, Isayama T,
Naito M, Kikuchi M. Supernumerary ring chromosome in a
Bednar tumor (pigmented dermatofibrosarcoma protuberans)
is composed of interspersed sequences from chromosomes 17
and 22: a fluorescence in situ hybridization and comparative
genomic hybridization analysis. Genes Chromosomes Cancer.
2001 Mar;30(3):305-9
Navarro M, Simon MP, Migeon C, Turc-Carel C, Pedeutour F.
COL1A1-PDGFB fusion in a ring chromosome 4 found in a
dermatofibrosarcoma protuberans. Genes Chromosomes
Cancer. 1998 Nov;23(3):263-6
O'Brien KP, Seroussi E, Dal Cin P, Sciot R, Mandahl N,
Fletcher JA, Turc-Carel C, Dumanski JP. Various regions
within the alpha-helical domain of the COL1A1 gene are fused
to the second exon of the PDGFB gene in
dermatofibrosarcomas and giant-cell fibroblastomas. Genes
Chromosomes Cancer. 1998 Oct;23(2):187-93
Simon MP, Navarro M, Roux D, Pouysségur J. Structural and
functional analysis of a chimeric protein COL1A1-PDGFB
generated by the translocation t(17;22)(q22;q13.1) in
Dermatofibrosarcoma protuberans (DP). Oncogene. 2001 May
24;20(23):2965-75
Shimizu A, O'Brien KP, Sjöblom T, Pietras K, Buchdunger E,
Collins VP, Heldin CH, Dumanski JP, Ostman A. The
dermatofibrosarcoma protuberans-associated collagen type
Ialpha1/platelet-derived growth factor (PDGF) B-chain fusion
gene generates a transforming protein that is processed to
functional PDGF-BB. Cancer Res. 1999 Aug 1;59(15):3719-23
This article should be referenced as such:
Simon MP, Maire G, Pedeutour F. COL1A1 (collagen, type I,
alpha 1). Atlas Genet Cytogenet Oncol Haematol. 2001;
5(2):78-82.
Wang J, Hisaoka M, Shimajiri S, Morimitsu Y, Hashimoto H.
Detection of COL1A1-PDGFB fusion transcripts in
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(2)
82
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Gene Section
Review
ERCC2 (Excision repair cross-complementing
rodent repair deficiency, complementation group
2)
Anne Stary, Alain Sarasin
Laboratory of Genetic Instability and Cancer, UPR2169 CNRS, Institut de Recherches sur le Cancer, 7, rue
guy Moquet, BP 8, 94801 Villejuif, France (AS, AS)
Published in Atlas Database: February 2001
Online updated version : http://AtlasGeneticsOncology.org/Genes/XPDID297.html
DOI: 10.4267/2042/37725
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2001 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Function
Identity
5'-3' ATP-dependent helicase activity involved in DNA
excision repair (NER) and as a subunit of the basal
transcription factor TFIIH.
The XPD gene product displayed 5'-3' helicase activity.
The XPD as the XPB protein are also found in the
transcription factor TFIIH, a large complex involved in
the initiation of transcription The striking discovery
that subunits of basal transcription factor TFIIH were
involved in Nucleotide Excision Repair (NER) sheds
light on a new aspect of NER : a close coupling to
transcription via common use of essential factors.
TFIIH fulfills a dual role in transcription initiation and
NER and the role of TFIIH in NER might closely
mimic its role in the transcription initiation process. In
transcription initiation TFIIH is thought to be involved
in unwinding of the promoter site and to allow
promoter clearance. In the NER process TFIIH causes
unwinding of the damage containing region that has
been localized by XPC-HR23B and XPA-RPA,
enabling the accumulation of NER proteins around the
damaged site. Contrarely to the XPB helicase, the
helicase activity of XPD is indispensable for NER but
not for transcription initiation. So, there is much more
XPD patients, and only two patients have been
described as XP and CS.
Other names: XPD
HGNC (Hugo): ERCC2
Location: 19q13.2
XPD (19q13) - Courtesy Mariano Rocchi, Resources for
Molecular Cytogenetics.
DNA/RNA
Description
54336 bp; 23 exons.
Transcription
2400b mRNA.
Protein
Description
760 amino acids.
Expression
Homology
Ubiquitous.
FLYBASE :Xpd ; MGI : Ercc2 (Nb 95413).
Localisation
Nuclear.
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(2)
83
ERCC2 (Excision repair cross-complementing rodent repair deficiency, complementation group 2)
Stary A, Sarasin A
Mutations
repair and in transcription by RNA polymerase II. Nature. 1994
Apr 21;368(6473):769-72
Germinal
Frederick GD, Amirkhan RH, Schultz RA, Friedberg EC.
Structural and mutational analysis of the xeroderma
pigmentosum group D (XPD) gene. Hum Mol Genet. 1994
Oct;3(10):1783-8
17 mutated sites associated with the xeroderma
pigmentosum group D syndrome (among them 3 are
also associated with the CockayneÕsyndrome) and 15
mutated sites associated with the trichothiodystrophy
syndrome.
Gözükara EM, Parris CN, Weber CA, Salazar EP, Seidman
MM, Watkins JF, Prakash L, Kraemer KH. The human DNA
repair gene, ERCC2 (XPD), corrects ultraviolet hypersensitivity
and ultraviolet hypermutability of a shuttle vector replicated in
xeroderma pigmentosum group D cells. Cancer Res. 1994 Jul
15;54(14):3837-44
Implicated in
Guzder SN, Qiu H, Sommers CH, Sung P, Prakash L, Prakash
S. DNA repair gene RAD3 of S. cerevisiae is essential for
transcription by RNA polymerase II. Nature. 1994 Jan
6;367(6458):91-4
Xeroderma pigmentosum (XP), XP
associated with Cockayne syndrome (CS), and
trichothiodystrophy (TTD)
Disease
Predisposition to skin cancer: early skin cancers (XPD).
Mental and stature abnormalities (XP/CS, and TTD).
Mezzina M, Eveno E, Chevallier-Lagente O, Benoit A, Carreau
M, Vermeulen W, Hoeijmakers JH, Stefanini M, Lehmann AR,
Weber CA. Correction by the ERCC2 gene of UV sensitivity
and repair deficiency phenotype in a subset of
trichothiodystrophy
cells.
Carcinogenesis.
1994
Aug;15(8):1493-8
References
Weber CA, Salazar EP, Stewart SA, Thompson LH. ERCC2:
cDNA cloning and molecular characterization of a human
nucleotide excision repair gene with high homology to yeast
RAD3. EMBO J. 1990 May;9(5):1437-47
Mondello C, Nardo T, Giliani S, Arrand JE, Weber CA,
Lehmann AR, Nuzzo F, Stefanini M. Molecular analysis of the
XP-D gene in Italian families with patients affected by
trichothiodystrophy and xeroderma pigmentosum group D.
Mutat Res. 1994 Mar;314(2):159-65
Flejter WL, McDaniel LD, Johns D, Friedberg EC, Schultz RA.
Correction of xeroderma pigmentosum complementation group
D mutant cell phenotypes by chromosome and gene transfer:
involvement of the human ERCC2 DNA repair gene. Proc Natl
Acad Sci U S A. 1992 Jan 1;89(1):261-5
Schaeffer L, Moncollin V, Roy R, Staub A, Mezzina M, Sarasin
A, Weeda G, Hoeijmakers JH, Egly JM. The ERCC2/DNA
repair protein is associated with the class II BTF2/TFIIH
transcription factor. EMBO J. 1994 May 15;13(10):2388-92
Wang Z, Svejstrup JQ, Feaver WJ, Wu X, Kornberg RD,
Friedberg EC. Transcription factor b (TFIIH) is required during
nucleotide-excision repair in yeast. Nature. 1994 Mar
3;368(6466):74-6
Mariani E, Facchini A, Honorati MC, Lalli E, Berardesca E,
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Jun;88(3):376-82
Weber CA, Kirchner JM, Salazar EP, Takayama K. Molecular
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mutants UV5 and UVL-13. Mutat Res. 1994 Aug;324(4):147-52
Stefanini M, Giliani S, Nardo T, Marinoni S, Nazzaro V, Rizzo
R, Trevisan G. DNA repair investigations in nine Italian patients
affected
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Mutat
Res.
1992
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Aboussekhra A, Biggerstaff M, Shivji MK, Vilpo JA, Moncollin
V, Podust VN, Protić M, Hübscher U, Egly JM, Wood RD.
Mammalian DNA nucleotide excision repair reconstituted with
purified protein components. Cell. 1995 Mar 24;80(6):859-68
Madzak C, Armier J, Stary A, Daya-Grosjean L, Sarasin A. UVinduced mutations in a shuttle vector replicated in repair
deficient trichothiodystrophy cells differ with those in
genetically-related cancer prone xeroderma pigmentosum.
Carcinogenesis. 1993 Jul;14(7):1255-60
Aboussekhra A, Wood RD. Detection of nucleotide excision
repair incisions in human fibroblasts by immunostaining for
PCNA. Exp Cell Res. 1995 Dec;221(2):326-32
Stefanini M, Lagomarsini P, Giliani S, Nardo T, Botta E,
Peserico A, Kleijer WJ, Lehmann AR, Sarasin A. Genetic
heterogeneity of the excision repair defect associated with
trichothiodystrophy. Carcinogenesis. 1993 Jun;14(6):1101-5
Broughton BC, Thompson AF, Harcourt SA, Vermeulen W,
Hoeijmakers JH, Botta E, Stefanini M, King MD, Weber CA,
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Stefanini M, Vermeulen W, Weeda G, Giliani S, Nardo T,
Mezzina M, Sarasin A, Harper JI, Arlett CF, Hoeijmakers JH. A
new nucleotide-excision-repair gene associated with the
disorder trichothiodystrophy. Am J Hum Genet. 1993
Oct;53(4):817-21
Carreau M, Quilliet X, Eveno E, Salvetti A, Danos O, Heard
JM, Mezzina M, Sarasin A. Functional retroviral vector for gene
therapy of xeroderma pigmentosum group D patients. Hum
Gene Ther. 1995 Oct;6(10):1307-15
Sung P, Bailly V, Weber C, Thompson LH, Prakash L, Prakash
S. Human xeroderma pigmentosum group D gene encodes a
DNA helicase. Nature. 1993 Oct 28;365(6449):852-5
Broughton BC, Steingrimsdottir H, Weber CA, Lehmann AR.
Mutations in the xeroderma pigmentosum group D DNA
repair/transcription gene in patients with trichothiodystrophy.
Nat Genet. 1994 Jun;7(2):189-94
Eveno E, Quilliet X, Chevallier-Lagente O, Daya-Grosjean L,
Stary A, Zeng L, Benoit A, Savini E, Ciarrocchi G, Kannouche
P. Stable SV40-transformation and characterisation of some
DNA repair properties of fibroblasts from a trichothiodystrophy
patient. Biochimie. 1995;77(11):906-12
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This article should be referenced as such:
Stary A, Sarasin A. ERCC2 (Excision repair crosscomplementing rodent repair deficiency, complementation
group 2). Atlas Genet Cytogenet Oncol Haematol. 2001;
5(2):83-87.
Lehmann AR. The xeroderma pigmentosum group D (XPD)
gene: one gene, two functions, three diseases. Genes Dev.
2001 Jan 1;15(1):15-23
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(2)
Stary A, Sarasin A
87
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Gene Section
Mini Review
ERCC3 (Excision repair cross-complementing
rodent repair deficiency, complementation group
3)
Anne Stary, Alain Sarasin
Laboratory of Genetic Instability and Cancer, UPR2169 CNRS, Institut de Recherches sur le Cancer, 7, rue
guy Moquet, BP 8, 94801 Villejuif, France (AS, AS)
Published in Atlas Database: February 2001
Online updated version : http://AtlasGeneticsOncology.org/Genes/XPBID296.html
DOI: 10.4267/2042/37723
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2001 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Expression
Identity
Ubiquitous.
Other names: ERCC-3 (Excision repair crosscomplementing
rodent
repair
deficiency,
complementation group 3); XPB; XPBC
HGNC (Hugo): ERCC3
Location: 2q21
Localisation
Nuclear.
Function
DNA excision repair protein. 3'-5' ATP-dependent
helicase activity involved in excision DNA repair and
initiation of basal transcription.
The XPB protein displays a 3'-5' helicase activity. This
protein is a subunit of the basal transcription factor
TFIIH involved in both Nucleotide Excision Repair
(NER) and the initiation of RNA polymerase II .
Indeed, TFIIH fulfills a dual role in transcription
initiation and NER and the role of TFIIH in NER might
closely mimic its role in the transcription initiation
process. In transcription initiation TFIIH is thought to
be involved in unwinding of the promoter site to
allowing promoter clearance. In the NER process
TFIIH causes unwinding of the lesion-containing
region that has been localized by XPC-HR23B and
XPA-RPA, enabling the accumulation of NER proteins
around the damaged site.
Among the Xeroderma pigmentosum (XP) patients,
XPB patients are extremely rare (only 3 patients known
in the world) due to the fact that the XPB gene product
is essential for transcription initiation and in all cases,
these patients show the double symptoms of
Xeroderma pigmentosum and Cockayne syndrome
(CS) (see below).
XPB (2q21) - Courtesy Mariano Rocchi, Resources for
Molecular Cytogenetics.
DNA/RNA
Description
2751 b mRNA.
Protein
Description
Homology
782 amino acids.
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(2)
Haywire gene (FLYBASE, hay); Ercc3 (MGI: 95414).
88
ERCC3 (Excision repair cross-complementing rodent repair deficiency, complementation group 3)
Stary A, Sarasin A
Ma L, Westbroek A, Jochemsen AG, Weeda G, Bosch A,
Bootsma D, Hoeijmakers JH, van der Eb AJ. Mutational
analysis of ERCC3, which is involved in DNA repair and
transcription initiation: identification of domains essential for
the DNA repair function. Mol Cell Biol. 1994 Jun;14(6):4126-34
Mutations
Germinal
F99S (T296C) is found in two XPB/CS patients; T119P
(A355C) is found in two TTD/XPB patients; FS740 is
found in one XPB/CS patient.
Schaeffer L, Moncollin V, Roy R, Staub A, Mezzina M, Sarasin
A, Weeda G, Hoeijmakers JH, Egly JM. The ERCC2/DNA
repair protein is associated with the class II BTF2/TFIIH
transcription factor. EMBO J. 1994 May 15;13(10):2388-92
Implicated in
van Vuuren AJ, Vermeulen W, Ma L, Weeda G, Appeldoorn E,
Jaspers NG, van der Eb AJ, Bootsma D, Hoeijmakers JH,
Humbert S. Correction of xeroderma pigmentosum repair
defect by basal transcription factor BTF2 (TFIIH). EMBO J.
1994 Apr 1;13(7):1645-53
ERCC3/XPB
Disease
Xeroderma pigmentosum and Cockayne syndrome in
the same patient or Trichothiodystrophy. Early skin
cancers.
Dabholkar MD, Berger MS, Vionnet JA, Overton L, Thompson
C, Bostick-Bruton F, Yu JJ, Silber JR, Reed E. Comparative
analyses of relative ERCC3 and ERCC6 mRNA levels in
gliomas and adjacent non-neoplastic brain. Mol Carcinog. 1996
Sep;17(1):1-7
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potentially interacts with the xeroderma pigmentosum group B
protein. Proc Natl Acad Sci U S A. 1999 Jan 5;96(1):203-7
Ribeiro DT, Machado CR, Costa RM, Praekelt UM, Van Sluys
MA, Menck CF. Cloning of a cDNA from Arabidopsis thaliana
homologous to the human XPB gene. Gene. 1998 Feb
27;208(2):207-13
Tirode F, Busso D, Coin F, Egly JM. Reconstitution of the
transcription factor TFIIH: assignment of functions for the three
enzymatic subunits, XPB, XPD, and cdk7. Mol Cell. 1999
Jan;3(1):87-95
Tantin D. RNA polymerase II elongation complexes containing
the Cockayne syndrome group B protein interact with a
molecular complex containing the transcription factor IIH
components xeroderma pigmentosum B and p62. J Biol Chem.
1998 Oct 23;273(43):27794-9
Butkiewicz D, Rusin M, Harris CC, Chorazy M. Identification of
four single nucleotide polymorphisms in DNA repair genes:
XPA and XPB (ERCC3) in Polish population. Hum Mutat. 2000
Jun;15(6):577-8
Coin F, Bergmann E, Tremeau-Bravard A, Egly JM. Mutations
in XPB and XPD helicases found in xeroderma pigmentosum
patients impair the transcription function of TFIIH. EMBO J.
1999 Mar 1;18(5):1357-66
Douziech M, Coin F, Chipoulet JM, Arai Y, Ohkuma Y, Egly
JM, Coulombe B. Mechanism of promoter melting by the
xeroderma pigmentosum complementation group B helicase of
transcription factor IIH revealed by protein-DNA photo-crosslinking. Mol Cell Biol. 2000 Nov;20(21):8168-77
Maru Y, Kobayashi T, Tanaka K, Shibuya M. BCR binds to the
xeroderma pigmentosum group B protein. Biochem Biophys
Res Commun. 1999 Jul 5;260(2):309-12
Schultz P, Fribourg S, Poterszman A, Mallouh V, Moras D,
Egly JM. Molecular structure of human TFIIH. Cell. 2000 Sep
1;102(5):599-607
Moreland RJ, Tirode F, Yan Q, Conaway JW, Egly JM,
Conaway RC. A role for the TFIIH XPB DNA helicase in
promoter escape by RNA polymerase II. J Biol Chem. 1999
Aug 6;274(32):22127-30
This article should be referenced as such:
Stary A, Sarasin A. ERCC3 (Excision repair crosscomplementing rodent repair deficiency, complementation
group 3). Atlas Genet Cytogenet Oncol Haematol. 2001;
5(2):88-90.
Mounkes LC, Fuller MT. Molecular characterization of mutant
alleles of the DNA repair/basal transcription factor
haywire/ERCC3
in
Drosophila.
Genetics.
1999
May;152(1):291-7
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(2)
Stary A, Sarasin A
90
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Gene Section
Mini Review
NF2 (neurofibromatosis type 2)
James F Gusella
Molecular Neurogenetics Unit, Massachusetts General Hospital, Harvard Medical School, Charlestown,
Massachusetts 02129, USA (JFG)
Published in Atlas Database: February 2001
Online updated version : http://AtlasGeneticsOncology.org/Genes/NF2117.html
DOI: 10.4267/2042/37720
This article is an update of: Huret JL. NF2 (neurofibromatosis type 2). Atlas Genet Cytogenet Oncol Haematol.1998;2(2):39-40.
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2001 Atlas of Genetics and Cytogenetics in Oncology and Haematology
to be); role in the development of extraembryonic
structures before gastrulation; has characteristics of a
tumour suppressor, as has been found in sporadic as
well as neurofibromatosis type 2 induced schwannomas
and meningiomas.
Identity
Other names: SCH
HGNC (Hugo): NF2
Location: 22q12.1-12.2
Local order: 22q12.1-12.2 junction, incidentally not
far from EWS.
Homology
DNA/RNA
Ezrin, radixin, moesin, members of the erythrocytes
band 4.1 family, especially in the N-terminal FERM
domain.
Description
Mutations
Axons 17 exons (1-15, 17 constitutive, 16 alternatively
spliced); spans 120 kb; open reading frame: 1.8 kb.
Germinal
Inborn condition of neurofibromatosis type 2 patients:
protein truncations due to various frameshift deletions
or insertions or nonsense mutations; splice-site or
missense mutations are also found; phenotypegenotype correlations are observed (i.e. that severe
phenotype are found in cases with protein truncations
rather than those with amino acid substitution).
Transcription
Alternate splicing, in particular after exon 15.
Protein
Description
Called merlin, schwannomin, or SCH; isoform 1 595
amino acids, isoform 2 590 amino acids (due to
inclusion of exon 16 in transcript) ; 66 KDa; NH2 -FERM domain -- large a helix domain – COOH.
Somatic
Expression
Mutation and allele loss events in tumours in
neurofibromatosis type 2 and in sporadic schwannomas
and meningiomas are in accordance with the two-hit
model for neoplasia, as is found in retinoblastoma.
Wide: in lung, kidney, ovary, breast, placenta,
neuroblasts; high in fetal brain.
Implicated in
Localisation
Neurofibromatosis type 2
Membrane associated interacts with integral membrane
proteins and actin-cytoskeleton.
Disease
Autosomal
dominant
tumor
prone
disease;
neurofibromatosis type 2 (NF2: the same symbol is
used for the disease neurofibromatosis type 2 and the
gene) is an hamartoneoplastic syndrome.
Function
Membrane-cytoskeleton anchor (as APC also appears
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(2)
91
NF2 (neurofibromatosis type 2)
Gusella JF
JM, Hall BD, Propping P, Rouleau GA. Type of mutation in the
neurofibromatosis type 2 gene (NF2) frequently determines
severity of disease. Am J Hum Genet. 1996 Aug;59(2):331-42
Prognosis
Hamartomas have a potential towards neoplasia; those,
in NF2, are the tumors of NF2 are slow-growing benign
schwannomas which do not progress to malignancy and
meningiomas.
McClatchey AI, Saotome I, Ramesh V, Gusella JF, Jacks T.
The Nf2 tumor suppressor gene product is essential for
extraembryonic development immediately prior to gastrulation.
Genes Dev. 1997 May 15;11(10):1253-65
Sporadic meningioma
Sporadic schwannoma
Other tumours: ependymoma; mesothelioma
Deguen B, Mérel P, Goutebroze L, Giovannini M, Reggio H,
Arpin M, Thomas G. Impaired interaction of naturally occurring
mutant NF2 protein with actin-based cytoskeleton and
membrane. Hum Mol Genet. 1998 Feb;7(2):217-26
References
Gusella JF, Ramesh V, MacCollin M, Jacoby LB. Merlin: the
neurofibromatosis 2 tumor suppressor. Biochim Biophys Acta.
1999 Mar 25;1423(2):M29-36
Rouleau GA, Merel P, Lutchman M, Sanson M, Zucman J,
Marineau C, Hoang-Xuan K, Demczuk S, Desmaze C,
Plougastel B. Alteration in a new gene encoding a putative
membrane-organizing protein causes neuro-fibromatosis type
2. Nature. 1993 Jun 10;363(6429):515-21
Giovannini M, Robanus-Maandag E, van der Valk M, NiwaKawakita M, Abramowski V, Goutebroze L, Woodruff JM,
Berns A, Thomas G. Conditional biallelic Nf2 mutation in the
mouse promotes manifestations of human neurofibromatosis
type 2. Genes Dev. 2000 Jul 1;14(13):1617-30
Trofatter JA, MacCollin MM, Rutter JL, Murrell JR, Duyao MP,
Parry DM, Eldridge R, Kley N, Menon AG, Pulaski K. A novel
moesin-, ezrin-, radixin-like gene is a candidate for the
neurofibromatosis 2 tumor suppressor. Cell. 1993 Mar
12;72(5):791-800
Kluwe L, Mautner V, Parry DM, Jacoby LB, Baser M, Gusella
J, Davis K, Stavrou D, MacCollin M. The parental origin of new
mutations in neurofibromatosis 2. Neurogenetics. 2000
Sep;3(1):17-24
Parry DM, Eldridge R, Kaiser-Kupfer MI, Bouzas EA, Pikus A,
Patronas N. Neurofibromatosis 2 (NF2): clinical characteristics
of 63 affected individuals and clinical evidence for
heterogeneity. Am J Med Genet. 1994 Oct 1;52(4):450-61
Lim DJ, Rubenstein AE, Evans DG, Jacks T, Seizinger BG,
Baser ME, Beebe D, Brackmann DE, Chiocca EA, Fehon RG,
Giovannini M, Glazer R, Gusella JF, Gutmann DH, Korf B,
Lieberman F, Martuza R, McClatchey AI, Parry DM, Pulst SM,
Ramesh V, Ramsey WJ, Ratner N, Rutkowski JL, Ruttledge M,
Weinstein DE. Advances in neurofibromatosis 2 (NF2): a
workshop report. J Neurogenet. 2000 Jun;14(2):63-106
Parry DM, MacCollin MM, Kaiser-Kupfer MI, Pulaski K,
Nicholson HS, Bolesta M, Eldridge R, Gusella JF. Germ-line
mutations in the neurofibromatosis 2 gene: correlations with
disease severity and retinal abnormalities. Am J Hum Genet.
1996 Sep;59(3):529-39
This article should be referenced as such:
Gusella JF. NF2 (neurofibromatosis type 2). Atlas Genet
Cytogenet Oncol Haematol. 2001; 5(2):91-92.
Ruttledge MH, Andermann AA, Phelan CM, Claudio JO, Han
FY, Chretien N, Rangaratnam S, MacCollin M, Short P, Parry
D, Michels V, Riccardi VM, Weksberg R, Kitamura K, Bradburn
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(2)
92
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Gene Section
Review
PDGFB (platelet-derived growth factor beta
polypeptide (simian sarcoma viral (v-sis)
oncogene homolog))
Marie-Pierre Simon, Georges Maire, Florence Pedeutour
Institute of Signalling, Developmental Biology and Cancer Research, CNRS UMR 6543, Centre AntoineLacassagne, 06189 Nice cedex 2, France (MPS); UF Recherche Clinique 952, Laboratoire de Génétique,
Université de Nice-Sophia Antipolis, CHU de Nice, 06202 Nice, France (GM, FP)
Published in Atlas Database: February 2001
Online updated version : http://AtlasGeneticsOncology.org/Genes/PDGFBID155.html
DOI: 10.4267/2042/37721
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2001 Atlas of Genetics and Cytogenetics in Oncology and Haematology
growth factor (PDGF) B chain precursor and is the
cellular homologue of the v-sis oncogene. PDGFB gene
is 22 kb in size and is composed of 7 exons. The exon 7
and most part of the exon 1 are non coding sequences
(white boxes).
Identity
Other names: V-sis platelet-derived growth factor beta
(simian sarcoma viral oncogene homolog)
HGNC (Hugo): PDGFB
Location: 22q12.3-q13.1
Local order: Telomeric to TXN2 (thioredoxin,
mitochondrial), centromeric to DMC1 (dosage
suppressor of mck1, yeast homologue meiosis-specific
homologous recombination).
Transcription
The PDGFB chain precursor is usually translated from
a 3.5 kb transcript. The first exon contains the sequence
for the signal peptide preceeded by a 1 kb-long
untranslated sequence with potent translation inhibitory
activity. A 2.6 kb mRNA which initiates at an
alternative exon 1, exon 1A, was described in the
human choriocarcinoma cell line JEG-3. It initiates an
open reading frame that is continuous with the code for
the PDGF B chain precursor but lacks the code for the
signal peptide.
DNA/RNA
Description
The PDGFB gene encodes the human platelet-derived
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(2)
93
PDGFB (platelet-derived growth factor beta polypeptide (simian sarcoma viral (v-sis) oncogene homolog))
Disease
Infiltrative skin tumours of intermediate malignancy.
Prognosis
The prognosis is usually favourable. These tumours are
locally aggressive and highly recurrent, but metastases
or tumour-related deaths are extremely rare.
Cytogenetics
Dermatofibrosarcoma
Protuberans,
Giant
Cell
fibrosarcoma and Bednar tumours present specific
cytogenetic features such as reciprocal translocations
t(17;22)(q22;q13.1) ( Fig A) or, more often,
supernumerary ring chromosomes derived from
t(17;22) (B). As shown by FISH analysis, the ring
chromosomes contain chromosome 22 centromere and
low-level amplification of 22cen-q13.1 and 17q22-qter
sequences. To note, in most cases, the derivative
chromosome 17 is not present. In contrast, several
copies of the derivative chromosome 22 are generally
observed.in addition to two apparently normal
chromosomes 17.
Hybrid/Mutated gene
Both rings and der(22) translocated chromosomes
present a same molecular rearrangement that fuses the
collagen type I alpha 1(COL1A1) and the plateletderived growth factor B chain (PDGFB) genes (C).
In all DP and GCF cases studied, the
t(17;22)translocation
results
in
chimerical
COL1A1/PDGFB mRNA production, in which the
PDGFB exon 1 is deleted and replaced by a variable
segment of COL1A1 mRNA sequence. In the 32 cases
tested the fusion mRNA was an in-frame fusion of one
of the COL1A1 exons (varying from exon 7 to exon
47) to PDGFB exon 2 (D).
Protein
Description
The PDGFB chains are synthesised as 240 amino acids
precursors molecules containing amino and carboxyterminal propeptides, which are removed by sitespecific endopeptidases. Two PDGFB precursor chains
associate in dimers to form the mature PDGFBB after
proteolysis.
Expression
First isolated from human platelets, the PDGFBB is
synthesized by a variety of different cell lineages.
Localisation
Secreted in the extra-cellular medium.
Function
The homodimer PDGFBB is a potent growth factor that
acts as a mitogen and chemo-attractant for a variety of
cells from mesenchymal origin. It has various roles in
embryonic
development,
tissue
regeneration,
osteogenesis, fibrosis, atherosclerosis, and neoplasia.
Homology
Member of the PDGF/VEGF family.
Implicated in
Dermatofibrosarcoma Protuberans (DP)
Also called:
- Darier Ferrand tumour or Darier-Hoffmann tumour.
- Giant cell fibrosarcoma (GCF) (juvenile form of DP).
-Bednar tumour (pigmented variant of DP).
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(2)
Simon MP et al.
94
PDGFB (platelet-derived growth factor beta polypeptide (simian sarcoma viral (v-sis) oncogene homolog))
Abnormal protein
COL1A1 and PDGFB are both encoded as propeptides, which are processed by proteolytic cleavage
at N and C-terminus, to give mature proteins.
Sequences analyses of the chimerical COL1A1/PDGFB
fusion transcripts showed that the COL1A1/PDGFB
putative proteins displayed a pro-peptide structure,
which preserved the N-terminus COL1A1 pro-peptide
containing the signal peptide and the N and C-terminus
PDGFB maturation cleavage sites.
The functional and structural properties of the
COL1A1/PDGFB fusion protein were characterized by
generating stable fibroblastic cell lines that expressed
tumour-derived COL1A1/PDGFB chimerical genes.
The
diagram
herein
given
presents
the
COL1A1/PDGFB chimerical protein encoded by the
T94796 tumour-derived chimerical COL1A1/PDGFB
cDNA sequence.
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(2)
Simon MP et al.
Oncogenesis
Transfected cells lines expressing the chimerical
T94796-COL1A1/PDGFB
proteins
became
independent upon growth factors, including PDGFB,
and induced tumours formation in nude mice. In
addition, it was shown that the COL1A1/PDGFB stable
clones cells contained activated PDGF b-receptors and
that the conditioned media from COL1A1/PDGFB
transfected cells were able to stimulate fibroblastic
cells growth. Anti-PDGFBB antibodies neutralized this
effect.
These
results
strongly
suggest
that
the
COL1A1/PDGFB
chimerical
gene
expression
associated with DP, contributes to tumour formation
through ectopic production of mature PDGFB and the
formation of an autocrine loop.
95
PDGFB (platelet-derived growth factor beta polypeptide (simian sarcoma viral (v-sis) oncogene homolog))
Simon MP et al.
A chimerical COL1A1/PDGFB cDNA sequence fusing COL1A1 exon 29 to PDGFB exon 2 was isolated from the DP T94796 tumour and
stably
transfected
in
the
Chinese
hamster
lung
fibroblastic
cell
line
PS200
(E).
The T94796 COL1A1/PDGFB chimerical protein sequence retained the COL1A1 N-terminus processing site encoded by the COL1A1
exon 6 and the N and C-terminus PDGFB processing sites encoded by the PDGFB exons 3 and 6 respectively (F).
Mutagenesis experiments and immunodetection with anti-PDGFBB and specific anti-COL1A1/PDGFB antibodies showed that
COL1A1/PDGFB expressing cells produced 116 kD chimerical COL1A1/PDGFB precursors chains, which formed dimers and were
processed to give active 30 kD PDGFB-like dimers (G).
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(2)
96
PDGFB (platelet-derived growth factor beta polypeptide (simian sarcoma viral (v-sis) oncogene homolog))
Simon MP et al.
Breakpoints
References
of a series of 41 cases with emphasis on prognostic
significance. Am J Surg Pathol. 1998 May;22(5):576-87
Byers PH. Brittle bones--fragile molecules: disorders of
collagen gene structure and expression. Trends Genet. 1990
Sep;6(9):293-300
Navarro M, Simon MP, Migeon C, Turc-Carel C, Pedeutour F.
COL1A1-PDGFB fusion in a ring chromosome 4 found in a
dermatofibrosarcoma protuberans. Genes Chromosomes
Cancer. 1998 Nov;23(3):263-6
Westermark B and Sorg C. Biology of the platelet-derived
growth factor. Cytokines 1993, 5, Sorg C (ed): Karger S, Basel:
1-167.
O'Brien KP, Seroussi E, Dal Cin P, Sciot R, Mandahl N,
Fletcher JA, Turc-Carel C, Dumanski JP. Various regions
within the alpha-helical domain of the COL1A1 gene are fused
to the second exon of the PDGFB gene in
dermatofibrosarcomas and giant-cell fibroblastomas. Genes
Chromosomes Cancer. 1998 Oct;23(2):187-93
Pedeutour F, Simon MP, Minoletti F, Sozzi G, Pierotti MA,
Hecht F, Turc-Carel C. Ring 22 chromosomes in
dermatofibrosarcoma protuberans are low-level amplifiers of
chromosome 17 and 22 sequences. Cancer Res. 1995 Jun
1;55(11):2400-3
Shimizu A, O'Brien KP, Sjöblom T, Pietras K, Buchdunger E,
Collins VP, Heldin CH, Dumanski JP, Ostman A. The
dermatofibrosarcoma protuberans-associated collagen type
Ialpha1/platelet-derived growth factor (PDGF) B-chain fusion
gene generates a transforming protein that is processed to
functional PDGF-BB. Cancer Res. 1999 Aug 1;59(15):3719-23
Fish FS. Soft tissue sarcomas in dermatology. Dermatol Surg.
1996 Mar;22(3):268-73
Pedeutour F, Simon MP, Minoletti F, Barcelo G, TerrierLacombe MJ, Combemale P, Sozzi G, Ayraud N, Turc-Carel C.
Translocation, t(17;22)(q22;q13), in dermatofibrosarcoma
protuberans:
a
new
tumor-associated
chromosome
rearrangement. Cytogenet Cell Genet. 1996;72(2-3):171-4
Wang J, Hisaoka M, Shimajiri S, Morimitsu Y, Hashimoto H.
Detection of COL1A1-PDGFB fusion transcripts in
dermatofibrosarcoma protuberans by reverse transcriptionpolymerase chain reaction using archival formalin-fixed,
paraffin-embedded tissues. Diagn Mol Pathol. 1999
Sep;8(3):113-9
Dalgleish R. The human type I collagen mutation database.
Nucleic Acids Res. 1997 Jan 1;25(1):181-7
Simon MP, Pedeutour F, Sirvent N, Grosgeorge J, Minoletti F,
Coindre JM, Terrier-Lacombe MJ, Mandahl N, Craver RD, Blin
N, Sozzi G, Turc-Carel C, O'Brien KP, Kedra D, Fransson I,
Guilbaud C, Dumanski JP. Deregulation of the platelet-derived
growth factor B-chain gene via fusion with collagen gene
COL1A1 in dermatofibrosarcoma protuberans and giant-cell
fibroblastoma. Nat Genet. 1997 Jan;15(1):95-8
Nishio J, Iwasaki H, Ishiguro M, Ohjimi Y, Yo S, Isayama T,
Naito M, Kikuchi M. Supernumerary ring chromosome in a
Bednar tumor (pigmented dermatofibrosarcoma protuberans)
is composed of interspersed sequences from chromosomes 17
and 22: a fluorescence in situ hybridization and comparative
genomic hybridization analysis. Genes Chromosomes Cancer.
2001 Mar;30(3):305-9
Greco A, Fusetti L, Villa R, Sozzi G, Minoletti F, Mauri P,
Pierotti MA. Transforming activity of the chimeric sequence
formed by the fusion of collagen gene COL1A1 and the platelet
derived growth factor b-chain gene in dermatofibrosarcoma
protuberans. Oncogene. 1998 Sep 10;17(10):1313-9
Simon MP, Navarro M, Roux D, Pouysségur J. Structural and
functional analysis of a chimeric protein COL1A1-PDGFB
generated by the translocation t(17;22)(q22;q13.1) in
Dermatofibrosarcoma protuberans (DP). Oncogene. 2001 May
24;20(23):2965-75
Heldin CH, Ostman A, Rönnstrand L. Signal transduction via
platelet-derived growth factor receptors. Biochim Biophys Acta.
1998 Aug 19;1378(1):F79-113
This article should be referenced as such:
Simon MP, Maire G, Pedeutour F. PDGFB (platelet-derived
growth factor beta polypeptide (simian sarcoma viral (v-sis)
oncogene homolog)). Atlas Genet Cytogenet Oncol Haematol.
2001; 5(2):93-97.
Mentzel T, Beham A, Katenkamp D, Dei Tos AP, Fletcher CD.
Fibrosarcomatous
("high-grade")
dermatofibrosarcoma
protuberans: clinicopathologic and immunohistochemical study
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(2)
97
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Gene Section
Mini Review
POLH (polymerase (DNA direct), eta)
Anne Stary, Alain Sarasin
Laboratory of Genetic Instability and Cancer, UPR2169 CNRS, Institut de Recherches sur le Cancer, 7, rue
guy Moquet, BP 8, 94801 Villejuif, France (AS, AS)
Published in Atlas Database: February 2001
Online updated version : http://AtlasGeneticsOncology.org/Genes/XPVID303.html
DOI: 10.4267/2042/37726
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2001 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
Mutations
Other names: XP-V; RAD30A
HGNC (Hugo): POLH
Location: 6p21.1
Note: See also the deep insight on: Nucleotide Excision
Repair.
Germinal
DNA/RNA
Disease
Predisposition to skin cancer.
12 mutated sites involved in the XP variant syndrome.
Implicated in
Xeroderma pigmentosum, XP group V
Description
References
11 exons.
Of the 11 splice donor/acceptor sites, 10 contained
consensus GT/AG dinucleotides; only the splice donor
site in exon 11 (sequence CT) varied from the
consensus pattern.
The POLH gene lacked a TATA sequence in the region
upstream of the transcription-initiation site and the
upstream region was GC rich (76% in the sequence
between +1 and Ð270).
The first ATG codon for initiation of translation was
included in the second exon. Exon 11 contained the
termination codon followed by 661 bp of 3’untranslated sequence.
Lehmann AR, Kirk-Bell S, Arlett CF, Paterson MC, Lohman
PH, de Weerd-Kastelein EA, Bootsma D. Xeroderma
pigmentosum cells with normal levels of excision repair have a
defect in DNA synthesis after UV-irradiation. Proc Natl Acad
Sci U S A. 1975 Jan;72(1):219-23
D'Ambrosio SM, Setlow RB. Defective and enhanced
postreplication repair in classical and variant xeroderma
pigmentosum
cells
treated
with
N-acetoxy-2acetylaminofluorene. Cancer Res. 1978 Apr;38(4):1147-53
Lehmann AR. The relationship between pyrimidine dimers and
replicating DNA in UV-irradiated human fibroblasts. Nucleic
Acids Res. 1979 Dec 11;7(7):1901-12
Minka DF, Nath J. Cytological evidence for DNA chain
elongation after UV irradiation in the S phase. Biochem Genet.
1981 Apr;19(3-4):199-210
Protein
Function
Cordeiro-Stone M, Boyer JC, Smith BA, Kaufmann WK.
Xeroderma pigmentosum variant and normal fibroblasts show
the same response to the inhibition of DNA replication by
benzo[a]pyrene-diol-epoxide-I.
Carcinogenesis.
1986
Oct;7(10):1783-6
The POLH gene encodes DNA polymerase h, which
catalyzes the translesion synthesis past a cis-syn T-T
pyrimidine dimer, one of the major DNA
photoproducts induced by UV light.
McCormick JJ, Kateley-Kohler S, Watanabe M, Maher VM.
Abnormal sensitivity of human fibroblasts from xeroderma
pigmentosum variants to transformation to anchorage
independence by ultraviolet radiation. Cancer Res. 1986
Feb;46(2):489-92
Description
713 amino acids.
Homology
Boyer JC, Kaufmann WK, Brylawski BP, Cordeiro-Stone M.
Defective postreplication repair in xeroderma pigmentosum
variant fibroblasts. Cancer Res. 1990 May 1;50(9):2593-8
mXPV: 80.3% amino acids identity and 86.9%
similarity.
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(2)
98
POLH (polymerase (DNA direct), eta)
Stary A, Sarasin A
Griffiths TD, Ling SY. Effect of UV light on DNA chain growth
and replicon initiation in xeroderma pigmentosum variant cells.
Mutagenesis. 1991 Jul;6(4):247-51
Masutani C, Araki M, Yamada A, Kusumoto R, Nogimori T,
Maekawa T, Iwai S, Hanaoka F. Xeroderma pigmentosum
variant (XP-V) correcting protein from HeLa cells has a
thymine dimer bypass DNA polymerase activity. EMBO J. 1999
Jun 15;18(12):3491-501
Wang YC, Maher VM, McCormick JJ. Xeroderma
pigmentosum variant cells are less likely than normal cells to
incorporate dAMP opposite photoproducts during replication of
UV-irradiated plasmids. Proc Natl Acad Sci U S A. 1991 Sep
1;88(17):7810-4
Masutani C, Kusumoto R, Yamada A, Dohmae N, Yokoi M,
Yuasa M, Araki M, Iwai S, Takio K, Hanaoka F. The XPV
(xeroderma pigmentosum variant) gene encodes human DNA
polymerase. Nature. 1999 Jun 17;399(6737):700-4
Misra RR, Vos JM. Defective replication of psoralen adducts
detected at the gene-specific level in xeroderma pigmentosum
variant cells. Mol Cell Biol. 1993 Feb;13(2):1002-12
McGregor WG, Wei D, Maher VM, McCormick JJ. Abnormal,
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Ultraviolet hypermutability of a shuttle vector propagated in
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This article should be referenced as such:
Stary A, Sarasin A. POLH (polymerase (DNA direct), eta).
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(2):98-99.
Johnson RE, Kondratick CM, Prakash S, Prakash L. hRAD30
mutations in the variant form of xeroderma pigmentosum.
Science. 1999 Jul 9;285(5425):263-5
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(2)
99
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Gene Section
Review
XPA (xeroderma pigmentosum, complementation
group A)
Anne Stary, Alain Sarasin
Laboratory of Genetic Instability and Cancer, UPR2169 CNRS, Institut de Recherches sur le Cancer, 7, rue
guy Moquet, BP 8, 94801 Villejuif, France (AS, AS)
Published in Atlas Database: February 2001
Online updated version : http://AtlasGeneticsOncology.org/Genes/XPAID104.html
DOI: 10.4267/2042/37722
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2001 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Localisation
Identity
Other names: XPAC xeroderma
complementation group A
HGNC (Hugo) : XPA
Location : 9q22.3-9q22.3
Nuclear.
pigmentosum,
Function
Initiates DNA repair by binding to damaged sites with
various affinities, depending upon the chemical
structure of the lesion.
Two proteins have been identified and implicated in
(one of) the first steps of Nucleotide Excision Repair
(NER), i.e. the recognition of lesions in the DNA: the
XPA gene product and the XPC gene product. Cells
from XPA patients are extremely sensitive to UV and
have very low nucleotide excision repair activity. In
vitro the XPA protein binds preferentially to damaged
DNA compared to nondamaged DNA. The XPA
protein binds to replication protein A (RPA) which
enhances the affinity of XPA for damaged DNA and is
essential for NER. The XPA protein has been shown to
bind to ERCC1 and TFIIH. It is possible that the
complex XPA/RPA may tell to the repair machinery
which strand contained the damage and therefore
should be eliminated.
DNA/RNA
Description
Human xeroderma pigmentosum group A 25kbp, six
exons, 2 polyadenylation signals.
Transcription
1377 b mRNA; suggestion of 1 major transcript;
promoter G+C rich (73%); one CAAT box and no
TATA box.
Protein
Description
273 amino acids, 31 kDa. DNA excision repair protein.
The functional domain for damaged DNA recognition
contains a zinc-finger motif with 4 cysteine residues :
Cys-X2-Cys-X17-Cys-X2-Cys motif and a glutamic
acid cluster encoded by Exon 2. The nuclear
localization signal is located in Exon 1.
Homology
Xpac (FlyBase ID) ; Xpa (MGI).
Mutations
Germinal
Expression
13
nucleotide
substitutions
insertion/deletion in patients.
Ubiquitous.
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(2)
100
and
5
small
XPA (xeroderma pigmentosum, complementation group A)
Stary A, Sarasin A
Implicated in
protein XPA binds replication protein A (RPA). J Biol Chem.
1995 Feb 24;270(8):4152-7
Xeroderma pigmentosum XPA
Park CH, Mu D, Reardon JT, Sancar A. The general
transcription-repair factor TFIIH is recruited to the excision
repair complex by the XPA protein independent of the TFIIE
transcription factor. J Biol Chem. 1995 Mar 3;270(9):4896-902
Disease
Predisposition to skin cancer: early skin tumours (basal
cell carcinoma, squamous cell carcinoma and
melanoma); early internal tumours.
Satokata I, Uchiyama M, Tanaka K. Two novel splicing
mutations in the XPA gene in patients with group A xeroderma
pigmentosum. Hum Mol Genet. 1995 Oct;4(10):1993-4
References
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Saijo M, Kuraoka I, Masutani C, Hanaoka F, Tanaka K.
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Atlas Genet Cytogenet Oncol Haematol. 2001; 5(2)
This article should be referenced as such:
Stary A, Sarasin A. XPA (xeroderma pigmentosum,
complementation group A). Atlas Genet Cytogenet Oncol
Haematol. 2001; 5(2):100-102.
102
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Gene Section
Review
XPC (xeroderma pigmentosum, complementation
group C)
Anne Stary, Alain Sarasin
Laboratory of Genetic Instability and Cancer, UPR2169 CNRS, Institut de Recherches sur le Cancer, 7, rue
guy Moquet, BP 8, 94801 Villejuif, France (AS, AS)
Published in Atlas Database: February 2001
Online updated version : http://AtlasGeneticsOncology.org/Genes/XPCID122.html
DOI: 10.4267/2042/37724
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2001 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Repair (NER) repair capacity, but the residual repair
has been shown to occur specifically in transcribed
genes. It is very likely that the XPC-HR23B complex is
the principal damage recognition complex i.e. essential
for the recognition of DNA lesions in the genome.
Binding of XPC-HR23B to a DNA lesion causes local
unwinding, so that the XPA protein can bind and the
whole repair machinery can be loaded onto the
damaged site. The XPC-HR23B complex is only
required for global genome repair. In case of
transcription coupled repair when an RNA polymerase
is stalled at a lesion, the DNA is unwound by the
transcription complex and XPA can bind independently
of XPC-HR23B complex.
Identity
Other names: XPCC xeroderma
complementation group C
HGNC (Hugo): XPC
Location : 3p25.1
pigmentosum,
DNA/RNA
Description
17703 bp; 16 exons.
Transcription
3558 b mRNA.
Homology
Protein
MGI : Xpc (Nb 103557).
Description
Mutations
939 amino acids.
Germinal
Expression
19 mutated sites involved in the XP group C syndrome
(XPC), 95% of these mutations (non sense, frameshift,
deletion or splice site mutations) give rise to truncated
proteins indicating that the XPC gene is not essential
for viability.
Ubiquitous.
Localisation
Nuclear.
Function
Implicated in
Involved in the early recognition of DNA damage
present in chromatine. Two proteins have been
identified and implicated in (one of) the first steps of
NER, i.e. the recognition of lesions in the DNA: the
XPA gene product and the XPC gene product in
complex with HR23B. This XPC-HR23B complex has
been implicated in DNA damage recognition,
especially the cyclobutane pyrimidine dimers induced
by UV-light. XPC cells have low Nucleotide Excision
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(2)
Xeroderma pigmentosum XPC
Disease
Predisposition to skin cancer: early skin tumours.
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103
XPC (xeroderma pigmentosum, complementation group C)
essential gene. Proc
Jun;83(11):3830-3
Natl
Acad
Sci
U
S
A.
Stary A, Sarasin A
1986
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Res. 1992 Mar;273(2):213-20
Cheo DL, Ruven HJ, Meira LB, Hammer RE, Burns DK, Tappe
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Characterization of defective nucleotide excision repair in XPC
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Evans MK, Taffe BG, Harris CC, Bohr VA. DNA strand bias in
the repair of the p53 gene in normal human and xeroderma
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Enomoto T, Takio K, Tanaka K, van der Spek PJ, Bootsma D.
Purification and cloning of a nucleotide excision repair complex
involving the xeroderma pigmentosum group C protein and a
human homologue of yeast RAD23. EMBO J. 1994 Apr
15;13(8):1831-43
Quilliet X, Chevallier-Lagente O, Zeng L, Calvayrac R, Mezzina
M, Sarasin A, Vuillaume M. Retroviral-mediated correction of
DNA repair defect in xeroderma pigmentosum cells is
associated with recovery of catalase activity. Mutat Res. 1997
Dec;385(3):235-42
van der Spek PJ, Smit EM, Beverloo HB, Sugasawa K,
Masutani C, Hanaoka F, Hoeijmakers JH, Hagemeijer A.
Chromosomal localization of three repair genes: the xeroderma
pigmentosum group C gene and two human homologs of yeast
RAD23. Genomics. 1994 Oct;23(3):651-8
Zeng L, Quilliet X, Chevallier-Lagente O, Eveno E, Sarasin A,
Mezzina M. Retrovirus-mediated gene transfer corrects DNA
repair defect of xeroderma pigmentosum cells of
complementation groups A, B and C. Gene Ther. 1997
Oct;4(10):1077-84
Yamaizumi M, Sugano T. U.v.-induced nuclear accumulation of
p53 is evoked through DNA damage of actively transcribed
genes independent of the cell cycle. Oncogene. 1994
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Baxter BK, Smerdon MJ. Nucleosome unfolding during DNA
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Carreau M, Eveno E, Quilliet X, Chevalier-Lagente O, Benoit
A, Tanganelli B, Stefanini M, Vermeulen W, Hoeijmakers JH,
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Berg RJ, Ruven HJ, Sands AT, de Gruijl FR, Mullenders LH.
Defective global genome repair in XPC mice is associated with
104
XPC (xeroderma pigmentosum, complementation group C)
Stary A, Sarasin A
skin cancer susceptibility but not with sensitivity to UVB
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families with xeroderma pigmentosum and consequences at
the cell, protein, and transcript levels. Cancer Res. 2000 Apr
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Sarasin A. p53 mutations in skin and internal tumors of
xeroderma pigmentosum patients belonging to the
complementation group C. Cancer Res. 1998 Oct
1;58(19):4402-9
Friedberg EC, Bond JP, Burns DK, Cheo DL, Greenblatt MS,
Meira LB, Nahari D, Reis AM. Defective nucleotide excision
repair in xpc mutant mice and its association with cancer
predisposition. Mutat Res. 2000 Mar 20;459(2):99-108
Garssen J, van Steeg H, de Gruijl F, de Boer J, van der Horst
GT, van Kranen H, van Loveren H, van Dijk M, Fluitman A,
Weeda G, Hoeijmakers JH. Transcription-coupled and global
genome repair differentially influence UV-B-induced acute skin
effects and systemic immunosuppression. J Immunol. 2000
Jun 15;164(12):6199-205
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transcription/DNA repair factor TFIIH and XP repair proteins
with DNA lesions in a cell-free repair assay. J Mol Biol. 1998
Aug 14;281(2):211-8
Sugasawa K, Ng JM, Masutani C, Iwai S, van der Spek PJ,
Eker AP, Hanaoka F, Bootsma D, Hoeijmakers JH. Xeroderma
pigmentosum group C protein complex is the initiator of global
genome nucleotide excision repair. Mol Cell. 1998
Aug;2(2):223-32
Khan SG, Metter EJ, Tarone RE, Bohr VA, Grossman L,
Hedayati M, Bale SJ, Emmert S, Kraemer KH. A new
xeroderma pigmentosum group C poly(AT) insertion/deletion
polymorphism. Carcinogenesis. 2000 Oct;21(10):1821-5
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Sands AT, Conti CJ. Persistence of p53 mutations and
resistance of keratinocytes to apoptosis are associated with
the increased susceptibility of mice lacking the XPC gene to
UV carcinogenesis. Oncogene. 1999 Dec 2;18(51):7395-8
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D, Friedberg EC. Genotype-specific Trp53 mutational analysis
in ultraviolet B radiation-induced skin cancers in Xpc and Xpc
Trp53 mutant mice. Cancer Res. 2000 Mar 15;60(6):1571-9
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Frumkin A, Busch DB, Albert RB, Kraemer KH. Clinical,
cellular, and molecular features of an Israeli xeroderma
pigmentosum family with a frameshift mutation in the XPC
gene: sun protection prolongs life. J Invest Dermatol. 2000
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Mutational inactivation of the xeroderma pigmentosum group C
gene confers predisposition to 2-acetylaminofluorene-induced
liver and lung cancer and to spontaneous testicular cancer in
Trp53-/- mice. Cancer Res. 1999 Feb 15;59(4):771-5
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mechanism of nucleotide excision repair. Genes Dev. 1999 Apr
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Horst GT, van Kranen HJ, Westerman A, van Zeeland AA,
Mullenders LH, de Gruijl FR. Differential role of transcriptioncoupled repair in UVB-induced G2 arrest and apoptosis in
mouse epidermis. Proc Natl Acad Sci U S A. 2000 Oct
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Differential behaviors toward ultraviolet A and B radiation of
fibroblasts and keratinocytes from normal and DNA-repairdeficient patients. Cancer Res. 1999 Mar 15;59(6):1212-8
Wijnhoven SW, Kool HJ, Mullenders LH, van Zeeland AA,
Friedberg EC, van der Horst GT, van Steeg H, Vrieling H. Agedependent spontaneous mutagenesis in Xpc mice defective in
nucleotide
excision
repair.
Oncogene.
2000
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12;19(43):5034-7
Wakasugi M, Sancar A. Order of assembly of human DNA
repair excision nuclease. J Biol Chem. 1999 Jun
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of human XPC complex to irradiated DNA confers strong
discrimination for damaged sites. J Mol Biol. 2000 Jul
7;300(2):275-90
Yokoi M, Masutani C, Maekawa T, Sugasawa K, Ohkuma Y,
Hanaoka F. The xeroderma pigmentosum group C protein
complex XPC-HR23B plays an important role in the
recruitment of transcription factor IIH to damaged DNA. J Biol
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Mullenders LH, van Vloten WA, de Gruijl FR. Impact of global
genome repair versus transcription-coupled repair on
ultraviolet carcinogenesis in hairless mice. Cancer Res. 2000
Jun 1;60(11):2858-63
This article should be referenced as such:
Stary A, Sarasin A. XPC (xeroderma pigmentosum,
complementation group C). Atlas Genet Cytogenet Oncol
Haematol. 2001; 5(2):103-105.
Chavanne F, Broughton BC, Pietra D, Nardo T, Browitt A,
Lehmann AR, Stefanini M. Mutations in the XPC gene in
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(2)
105
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Gene Section
Short Communication
FBP17 (formin binding protein 17)
Uta Fuchs, Arndt Borkhardt
Children's University Hospital Giessen, Hematology & Oncology, Feulgenstr. 12, 35392 Giessen, Germany
(UF, AB)
Published in Atlas Database: March 2001
Online updated version : http://AtlasGeneticsOncology.org/Genes/FBP17ID353.html
DOI: 10.4267/2042/37727
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2001 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Localisation
Identity
Exclusively cytoplasmatic.
Other names: FBP17 (Formin Binding Protein 17);
KIAA0554
HGNC (Hugo): FNBP1
Location: 9q34
Local order: centromeric of ABL
Function
Interacts with Sorting nexin 2 (SNX2) in vivo and in
vitro.
Mutations
DNA/RNA
Germinal
Description
Unknown.
At least 2042 bp.
Somatic
Transcription
Unknown.
Open reading frame of 679 amino acids.
Implicated in
Protein
t(9;11)(q34;q23) acute non lymphocytic
leukemia --> FBP17 - MLL
Description
Prognosis
Poor.
Hybrid/Mutated gene
5' MLL - 3' FBP17
Abnormal protein
MLL/FBP17
679 amino acids, 75 kDa.
Expression
Strong expression in epithelial cells from the
respiratory system, gastrointestinal tract, urinary, and
reproductive system.
FCH-domain: amino terminus; cdc15 homology region: aa 96-290; Rho-binding domain: aa 475-537; SH3-domain: aa 612-669
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(2)
106
FBP17 (formin binding protein 17)
Fuchs U, Borkhardt A
References
myelogeneous leukemia. Proc Natl Acad Sci U S A. 2001 Jul
17;98(15):8756-61
Fuchs U, Rehkamp G, Haas OA, Slany R, Kōnig M, Bojesen S,
Bohle RM, Damm-Welk C, Ludwig WD, Harbott J, Borkhardt A.
The human formin-binding protein 17 (FBP17) interacts with
sorting nexin, SNX2, and is an MLL-fusion partner in acute
This article should be referenced as such:
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(2)
Fuchs U, Borkhardt A. FBP17 (formin binding protein 17). Atlas
Genet Cytogenet Oncol Haematol. 2001; 5(2):106-107.
107
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Gene Section
Mini Review
GHRL (ghrelin/obestatin prepropeptide)
Catherine Tomasetto
I.G.B.M.C., BP 163, 1 rue Laurent Fries, 67404 Illkirch, France (CT)
Published in Atlas Database: March 2001
Online updated version : http://AtlasGeneticsOncology.org/Genes/GhrelinID327.html
DOI: 10.4267/2042/37728
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2001 Atlas of Genetics and Cytogenetics in Oncology and Haematology
signal peptide from residues 1to 23, the
ghrelin/MTLRP moity from residues 24 to 51, the
MTLRP-associated peptide moity from residues 52 to
117.
The 27 amino acids des-Gln14-Ghrelin/delta Gln 14
MTLRP is produced from a protein precursor of 116
residues identical to the 117 aa precursor excep that the
des-Gln14-Ghrelin/delta Gln14
MTLRP
moity
corresponds to residues 24 to 50 and accordingly the
MTLRP-associated peptide moity from resisues 51 to
116.
Identity
Other names: Motilin-related peptide (MTLRP)
HGNC (Hugo): GHRL
Location: 3p26-p25
Expression
Ghrelin/MTLRP is mainly expressed by the
enteroendocrine cells of the stomach; its expression
decreased gradually along the gastro-intestinal tract and
a faint expression was also detected in testis. By
Immnunochemistry Ghrelin-immuno reactive neurons
were found in the hypothalamic arcuate nucleus.
Probe(s) - Courtesy Mariano Rocchi, Resources for Molecular
Cytogenetics.
DNA/RNA
Localisation
Transcription
As a peptide hormone Ghrelin/MTLRP is secreted in
the blood.
600 bp, two mRNAs are encoded by the same genes,
they are identical except for the lack of one codon
(CAG) located at an exon intron boundary.
Function
As the endogenous ligand of the growth hormone
secretagogues (GHS) receptor, Ghrelin/MTLRP is
involved in the pulsatile secretion of Growth hormone.
In addition to this role Ghrelin/MTLRP is in the
regulation of feeding. In rodent In contrast to leptin,
Ghrelin/MTLRP promotes food intake and obesity. In
addition Ghrelin/MTLRP stimulates motricity of the
gastrointestinal tract and acid secretion.
Protein
Description
Two precursor s of 117 and 116 amino acids encoding
preproGhrelin/MTLRP and prepro-des-Gln14-Ghrelin/
delta Gln14 MTLRP, respectively. The 28 amino-acids
Ghrelin/MTLRP and the 27 amino-acids des-Gln14Ghrelin/delta Gln14 MTLRP are modified posttranslationally by the addition of a n-octanoic acid on
Serine 3.
The 28 amino acids Ghrelin/MTLRP is produced from
a protein precursor of 117 residues that contains a
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(2)
Homology
ppGhrelin/MTLRP share 47% of similarity with the
precursor of Motilin. In addition Ghrelin receptor
(GHS-R) and Motilin receptor (GPR38) share 52%
identity.
108
GHRL (ghrelin/obestatin prepropeptide)
Tomasetto C
References
motilin-related
peptide.
Aug;119(2):395-405
Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H,
Kangawa K. Ghrelin is a growth-hormone-releasing acylated
peptide from stomach. Nature. 1999 Dec 9;402(6762):656-60
Tschöp M, Smiley DL, Heiman ML. Ghrelin induces adiposity in
rodents. Nature. 2000 Oct 19;407(6806):908-13
2000
Wren AM, Small CJ, Ward HL, Murphy KG, Dakin CL, Taheri
S, Kennedy AR, Roberts GH, Morgan DG, Ghatei MA, Bloom
SR. The novel hypothalamic peptide ghrelin stimulates food
intake and growth hormone secretion. Endocrinology. 2000
Nov;141(11):4325-8
Hosoda H, Kojima M, Matsuo H, Kangawa K. Purification and
characterization of rat des-Gln14-Ghrelin, a second
endogenous ligand for the growth hormone secretagogue
receptor. J Biol Chem. 2000 Jul 21;275(29):21995-2000
Masuda Y, Tanaka T, Inomata N, Ohnuma N, Tanaka S, Itoh
Z, Hosoda H, Kojima M, Kangawa K. Ghrelin stimulates gastric
acid secretion and motility in rats. Biochem Biophys Res
Commun. 2000 Oct 5;276(3):905-8
Nakazato M, Murakami N, Date Y, Kojima M, Matsuo H,
Kangawa K, Matsukura S. A role for ghrelin in the central
regulation of feeding. Nature. 2001 Jan 11;409(6817):194-8
This article should be referenced as such:
Tomasetto C, Karam SM, Ribieras S, Masson R, Lefèbvre O,
Staub A, Alexander G, Chenard MP, Rio MC. Identification and
characterization of a novel gastric peptide hormone: the
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(2)
Gastroenterology.
Tomasetto C. GHRL (ghrelin/obestatin prepropeptide). Atlas
Genet Cytogenet Oncol Haematol. 2001; 5(2):108-109.
109
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Gene Section
Review
MAD2L1 (mitotic arrest deficient 2, yeast, human
homolog like-1)
Elizabeth M. Petty, Kenute Myrie
Division of Medical Genetics Departments of Human Genetics and Internal Medicine University of
Michigan Medical School 1150 West Medical Center Drive, 4301 MSRB III, Ann Arbor, Michigan 481090638, USA (EMP, KM)
Published in Atlas Database: March 2001
Online updated version : http://AtlasGeneticsOncology.org/Genes/MAD2L1ID304.html
DOI: 10.4267/2042/37729
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2001 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
Other names: HsMAD2; MAD2; MAD2A
HGNC (Hugo): MAD2L1
Location: 4q27
Local order: As noted on the GM99-GB4
Chromosome 4 map: Position: 548.24 (cR3000) Lod
score: 1.16 Reference Interval: D4S2945-D4S430
(115.1-125.1 cM) It is located within the NCBI BAC
genomic contig: NT_006302.2 which is part of the
homo sapiens chromosome 4 sequence segment.
Note: MAD2L1 was intially (and errounously) mapped
by fluorescence in situ hybridization (FISH) to 5q23q31. Subsequent comprehensive mapping studies using
somatic cell hybrid analysis, radiation hybrid (RH)
mapping, and FISH localized it to 4q27. This location
was susequently confrimed by RH analysis and through
the Human Genome Project Draft sequence assembly.
A related gene, MAD2L2, maps to to 1p36, and a
MAD2 pseudogene maps to to 14q21-q23. Other
related family members exist with similar names (eg.
MAD2L2, MAD1L1) highlighting the need for using
the MAD2L1 nomenclature to avoid confusion (A
MAD2L1 pseudogene maps to chromosome 14).
Shadded boxes (1-5) depict the 5 exons of MAD2L1. The black
triangle indicates a del A mutation that was found in the CAL51
breast cancer cell line. Open triangkes depict the locations of
identified sequence variants. Figure is not drawn to scale.
Transcription
MAD2L1 has 5 coding exons. No alternative splicing
has been described. Regulation of its transcription in
human cells is currently poorly understood.
Protein
Description
Called MAD2A (aliases MAD2-LIKE 1, MD2l,
HSMAD2); 205 amino acids; molecular weight:
23,509.95; theoretical pI: 5.02.
Expression
The MAD2L1 protein is widely expressed in all fetal
and adult and fetal tissues studied to date.
Localisation
Localizes to the nucleus and associates with unattached
kinetochores during after chromosome condensation.
DNA/RNA
Function
Description
Much of what we currently understand about MAD2L1
and its role in the mitotic spindle checkpoint stems
from early studies in non-mammalian cells. Several
genes have demonstrated critically important,
interrelated roles in appropriately responding to
The human MAD2L1 DNA sequence had an open
reading frame that was 60% identical to the yeast
MAD2 gene.
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(2)
110
MAD2L1 (mitotic arrest deficient 2, yeast, human homolog like-1)
Petty EM, Myrie K
established, that only the tetrameric form of MAD2A is
capable of inhibiting CDC20 activation of the APC. A
yeast 2-hybrid assay using cytoplasmic tails of several
a disintegrin and metalloproteinase domain (ADAM)
bait proteins, demonstrated that MAD2A interacts
strongly with TACE (ADAM17) but not with other
ADAMs tested, including ADAM9 which interacts
with another MAD family member, the MAD2L2
encoded protein MAD2B. A 35-amino acid stretch of
TACE that contains a proline-rich SH3-ligand domain
(PXPXXP) has been demonstrated as the interaction
site with MAD2A.
As noted above, MAD2A is a key protein that
functions as part of a larger protein complex that
regulates the highly conserved mitotic spindle
checkpoint. Appropriate chromosome segregation at
anaphase is regulated at least in part by this spindle
assembly checkpoint that monitors completion of
chromosome-microtubule
attachment
during
metaphase. To further determine the function of Mad2
during normal cell division, Mad2 knockout mice were
created and analyzed; day 5.5 embryonic cells lacking
Mad2, like mad2 deficient budding yeast cells, grew
normally but did not arrest in response to spindle
disruption. By d 6.5, the epiblast cells began rapid
division associated with widespread chromosome
missegregation and subsequent apoptosis. Interestingly,
postmitotic trophoblast giant cells survived, however,
without Mad2. It was concluded that Mad2 is critical
for the spindle assembly checkpoint and accurate
chromosome segregation in mitotic mouse cells as well
as for embryonic viability, even in the absence of any
mitotic spindle damage. Mad2 and the spindle
checkpoint in meiosis of S. cerevisiae were further
characterized by comparing wildtype and mad2 -/yeast that lacked normal checkpoint function. In the
mad2 deficient yeast cells, meiosis I missegregation
was noted to be significantly increased. These studies
suggested that mad2 and the spindle checkpoint in
budding yeast are critically important for normal
meiotic chromosome segregation, despite the fact that
normal mad2 function is largely dispensable in
wildtype mitosis of budding yeast.
aberrant spindle integrity or kinetochore damage by
arresting cell cycle progression including BUB
(budding uninhibited by benomyl), MAD (mitotic
arrest-deficient) genes, additional protein kinase genes,
and other cyclin related genes. In budding yeast the
mitotic arrest-deficient-2 (MAD2) gene was shown to
encode a protein that monitored accurate chromosome
segregation via the mitotic spindle checkpoint. The
mitotic spindle checkpoint helps regulate cell division
to ensure the creation of euploid daughter cells
following anaphase and cytokinesis. The checkpoint
acts to block cell cycle progression when the mitotic
spindle apparatus is not properly assembled or when
the kinetochore is not properly attached to the mitotic
spindle. The amphibian (Xenopus) homolog of MAD2
was identified and it was demonstrated that the MAD2
protein played a critical role in the normal spindle
checkpoint assembly as it associated only with
unattached kinetochores in prometaphase and in those
cells treated with a microtubule inhibitor, nocodazole.
MAD2 was absent from kinetochores in normal cells at
metaphase.
The human homolog of MAD2, MAD2L1, has been
isolated through identification of genes that reduced
sensitivity to a chemical mitotic spindle assembly
inhibiotor, thiabendazole, in yeast that were deficient
for a particular kinetochore element , CBF1. The
protein encoded by MAD2L1 monitors kinetochore
attachments to the mitotic spindle in human cells.
Interaction of MAD2L1 and additional checkpoint
components with kinetochores unattached to
chromosomes blocks the onset of anaphase, preventing
missegregation of chromosomes and aneuploidy in
resulting daughter cells.
The nuclear protein encoded by MAD2L1, MAD2A, is
a member of the MAD family of proteins that is a
critical component of the mitotic checkpoint. MAD2A
is required for proper execution of the mitotic
checkpoint. When kinetochore-spindle attachment is
not completed properly, anaphase is delayed via
activation of the mitotic spindle checkpoint. Anaphase
is prevented until all chromosomes are properly aligned
at the metaphase plate. Normally, the human MAD2A
protein localizes as part of a protein complex at
unattached
kinetochores
after
chromosome
condensation but not after metaphase. Similarly,
MAD2A localizes at the kinetochore upon activation of
the mitotic spindle checkpoint and mediates cell cycle
arrest by associating with CDC20/p55CDC and the
anaphase
promoting
complex
(APC)
when
chromosomes are not properly attached at the
kinetochore. Therefore, MAD2A may regulate the
activities of the WD40 protein CDC20 that is necessary
for progression through anaphase and exit from mitosis.
MAD2A reportedly exist in two states, a monomer and
a tetramer, both which are capable of binding CDC20.
In vitro studies have suggested, but not conclusively
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(2)
Homology
Homologous sequences: Mouse: Mm.43444 Mad2l1;
Mm.9648 ESTs, Highly similar to AF072933_1 Mad2like protein [H.sapiens]; Mm.28402 ESTs, Moderately
similar to KIAA0280 [H.sapiens]; Rat: Rn.27237
ESTs, Highly similar to AF072933_1 Mad2-like
protein; Rn.34733 ESTs, Weakly similar to mitotic
checkpoint
component
Mad2;
Drosophila:
Dm.LL.40677 CG2948 CG2948 gene product;
Dm.LL.38656 CG17498 CG17498 gene product;
Human: Hs.19400 MAD2L2.
Related Proteins: H. sapiens: MAD2L2 (27%); M.
musculus: MAD2L1 (95%); D. melanogaster:
111
MAD2L1 (mitotic arrest deficient 2, yeast, human homolog like-1)
Petty EM, Myrie K
attachment at the kinetochore, the mitotic checkpoint
genes regulate the cell cycle to ensure accurate
chromosome alignment and segregation at anaphase to
generate euploid daughter cells. Loss of appropriate
chromosome attachments at the kinetochore or defects
in the mitotic spindle lead to cell cycle arrest and a
block in the initiation of anaphase. Mad2 is just one
member of a handful of yeast genes, the budding
uninhibited by benomyl BUB and mitotic arrest
deficient (MAD) families of genes, that are important
regulators of this mitotic spindle checkpoint. Studies in
colorectal cell lines suggest that dominant negative
mutations in the human ortholog BUB1 may have a
role in CIN and aneuploidy led to speculation about the
potential role of MAD2L1 in human cancers. However,
no MAD2L1 mutations were identified in colon cancer
cells. Human breast tumor cell line T47D has reduced
MAD2 expression and it fails to arrest in mitosis after
nocodazole treatment. That loss of MAD2 function
might also lead to aberrant chromosome segregation in
mammalian cells was suggested. A truncation mutation
in MAD2L1 in breast cancer with altered protein
expression was subsequently reported but no functional
studies have yet demonstrated a functional role in
oncogenesis has been demonstrated. Studies of Brca2
deficient murine cells further supported a putative role
for these genes in cancer as Bub1 mutations were
demonstrated to potentiate growth and cellular
transformation (Lee et al., 1999).
Secondly, the studies of Mad2 knockout mice have
demonstrated that embryonic cells lacking Mad2 fail to
arrest in response to microtubule inhibitors and that
loss of the checkpoint results in chromosome
missegregation and apoptosis. It has subsequently been
reported that deletion of one allele results in a defective
mitotic checkpoint in both human cancer cells and
murine primary embryonic fibroblasts. Checkpointdefective cells show premature sister chromatid
separation in the presence of spindle inhibitors and an
elevated rate of chromosome missegregation events in
the absence of these agents. Furthermore, Mad2 +/mice develop lung tumors at high rates after long
latencies, implicating defects in the mitotic checkpoint
in tumorigenesis.
CG17498 (46%); C. elegans: MDF-2 (53%); S. pombe:
Mad2p (48%); Spac12d12.09p (26%); S. cerevisiae:
Mad2p (43%) [details]
Mutations
Note
No proven germline or somatic disease causing
mutations; one somatic frameshift mutation has been
identified , due to a 1 bp deletion, in one breast cancer
cell line, CAL51, that caused truncation of the resulting
protein product as assessed by in vitro transcription and
translation assays. The functional significance of this
alteration in relationship to cancer needs to be
determined.
Implicated in
Disease
Like other solid tumors, ovarian cancers, especially
those at later stages, demonstrate significant aneuploidy
and multiple regions of chromosome loss and
amplification. MAD2L1 maps to 4q27, an area that is
unstable in several cancers as revealed by loss of
heterozygosity and comparative genomic hybridization
studies. Interestingly, some of the malignant tumors in
individuals with BRCA1 germline mutations have
somatic loss of chromosome 4q, suggesting that
alterations of genes in this region may be associated
with breast cancer.
Cytogenetics
No cytogenetic translocations involving this gene,
however, have been reported or have been associated
with any disease, including cancer.
Hybrid/Mutated gene
None described.
Oncogenesis
Work by several groups have now suggested that
dysfunction of MAD2A may lead to malignancy or
degeneration of normal cells, but compelling evidence
that supports a role for MAD2L1 alterations in human
cancers are still lacking. Despite this lack of solid data,
there is increasing suggestive evidence to implicate
MAD2L1 alterations in association with the
development and/or progression of human cancer.
First, aneuploidy is a commonly observed phenotype in
many solid tumor malignancies, especially in later
stage tumors. Chromosomal instability (CIN) correlates
with aneuploidy and is thought to contribute to genetic
instability. Thus, it is widely hypothesized that
genomic instability which leads to aneuploidy may
accelerate malignant progression in many solid tumor
malignancies. Mutations in the genes controlling the
mitotic checkpoint, including MAD2L1, have therefore
been implicated to contribute to CIN in the
pathogenesis of solid tumor malignancies. By
monitoring proper microtubule assembly and
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(2)
References
Hoyt MA, Totis L, Roberts BT. S. cerevisiae genes required for
cell cycle arrest in response to loss of microtubule function.
Cell. 1991 Aug 9;66(3):507-17
Li R, Murray AW. Feedback control of mitosis in budding yeast.
Cell. 1991 Aug 9;66(3):519-31
Li X, Nicklas RB. Mitotic forces control a cell-cycle checkpoint.
Nature. 1995 Feb 16;373(6515):630-2
Chen RH, Waters JC, Salmon ED, Murray AW. Association of
spindle assembly checkpoint component XMAD2 with
unattached
kinetochores.
Science.
1996
Oct
11;274(5285):242-6
112
MAD2L1 (mitotic arrest deficient 2, yeast, human homolog like-1)
Petty EM, Myrie K
Li Y, Benezra R. Identification of a human mitotic checkpoint
gene: hsMAD2. Science. 1996 Oct 11;274(5285):246-8
Lee H, Trainer AH, Friedman LS, Thistlethwaite FC, Evans MJ,
Ponder BA, Venkitaraman AR. Mitotic checkpoint inactivation
fosters transformation in cells lacking the breast cancer
susceptibility gene, Brca2. Mol Cell. 1999 Jul;4(1):1-10
Tirkkonen M, Johannsson O, Agnarsson BA, Olsson H,
Ingvarsson S, Karhu R, Tanner M, Isola J, Barkardottir RB,
Borg A, Kallioniemi OP. Distinct somatic genetic changes
associated with tumor progression in carriers of BRCA1 and
BRCA2 germ-line mutations. Cancer Res. 1997 Apr
1;57(7):1222-7
Nelson KK, Schlöndorff J, Blobel CP. Evidence for an
interaction of the metalloprotease-disintegrin tumour necrosis
factor alpha convertase (TACE) with mitotic arrest deficient 2
(MAD2), and of the metalloprotease-disintegrin MDC9 with a
novel MAD2-related protein, MAD2beta. Biochem J. 1999 Nov
1;343 Pt 3:673-80
Xu L, Deng HX, Yang Y, Xia JH, Hung WY, Siddque T.
Assignment of mitotic arrest deficient protein 2 (MAD2L1) to
human chromosome band 5q23.3 by in situ hybridization.
Cytogenet Cell Genet. 1997;78(1):63-4
Dobles M, Liberal V, Scott ML, Benezra R, Sorger PK.
Chromosome missegregation and apoptosis in mice lacking
the mitotic checkpoint protein Mad2. Cell. 2000 Jun
9;101(6):635-45
Cahill DP, Lengauer C, Yu J, Riggins GJ, Willson JK,
Markowitz SD, Kinzler KW, Vogelstein B. Mutations of mitotic
checkpoint genes in human cancers. Nature. 1998 Mar
19;392(6673):300-3
Myrie KA, Percy MJ, Azim JN, Neeley CK, Petty EM. Mutation
and expression analysis of human BUB1 and BUB1B in
aneuploid breast cancer cell lines. Cancer Lett. 2000 May
1;152(2):193-9
Fang G, Yu H, Kirschner MW. The checkpoint protein MAD2
and the mitotic regulator CDC20 form a ternary complex with
the anaphase-promoting complex to control anaphase
initiation. Genes Dev. 1998 Jun 15;12(12):1871-83
Percy MJ, Myrie KA, Neeley CK, Azim JN, Ethier SP, Petty
EM. Expression and mutational analyses of the human
MAD2L1 gene in breast cancer cells. Genes Chromosomes
Cancer. 2000 Dec;29(4):356-62
Fang G, Yu H, Kirschner MW. Direct binding of CDC20 protein
family members activates the anaphase-promoting complex in
mitosis and G1. Mol Cell. 1998 Aug;2(2):163-71
Shonn MA, McCarroll R, Murray AW. Requirement of the
spindle checkpoint for proper chromosome segregation in
budding yeast meiosis. Science. 2000 Jul 14;289(5477):300-3
Jin DY, Spencer F, Jeang KT. Human T cell leukemia virus
type 1 oncoprotein Tax targets the human mitotic checkpoint
protein MAD1. Cell. 1998 Apr 3;93(1):81-91
Michel LS, Liberal V, Chatterjee A, Kirchwegger R, Pasche B,
Gerald W, Dobles M, Sorger PK, Murty VV, Benezra R. MAD2
haplo-insufficiency causes
premature anaphase and
chromosome instability in mammalian cells. Nature. 2001 Jan
18;409(6818):355-9
Krishnan R, Goodman B, Jin DY, Jeang KT, Collins C, Stetten
G, Spencer F. Map location and gene structure of the Homo
sapiens mitotic arrest deficient 2 (MAD2L1) gene at 4q27.
Genomics. 1998 May 1;49(3):475-8
This article should be referenced as such:
Cahill DP, da Costa LT, Carson-Walter EB, Kinzler KW,
Vogelstein B, Lengauer C. Characterization of MAD2B and
other mitotic spindle checkpoint genes. Genomics. 1999 Jun
1;58(2):181-7
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(2)
Petty EM, Myrie K. MAD2L1 (mitotic arrest deficient 2, yeast,
human homolog like-1). Atlas Genet Cytogenet Oncol
Haematol. 2001; 5(2):110-113.
113
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Gene Section
Mini Review
TFF3 (trefoil factor 3 (intestinal))
Catherine Tomasetto
I.G.B.M.C., BP 163, 1 rue Laurent Fries, 67404 Illkirch, France (CT)
Published in Atlas Database: March 2001
Online updated version : http://AtlasGeneticsOncology.org/Genes/TFF3ID265.html
DOI: 10.4267/2042/37730
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2001 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Function
Identity
Description
TFF3 promotes migration of epithelial cells in vitro and
enhance mucosal healing and epithelial restitutions in
vivo in the gastrointestinal mucosa. TFF3 deficient
mice aresuceptible to colonic injury induced by
standard agents and restitution is impaired. In addition
TFF3 deficient mice have an increase in colonocyte
apoptosis. The protective action of TFF3 involves
activation of both EGF-R and PI3K-Akt pathways. The
role of TFF3 in the brain is not clear yet.
3.3 kb gene, 3 exons.
Homology
Transcription
TFF3 belongs to the Trefoil peptide family (TFF) and
possesse one TFF1 motif homologous to the TFF motif
of TFF1 and TFF2. The TFF motif spans about 40
amino acids and is formed by 6 conserved cysteines
residues involved in specific disulfites bridges.
Other names: ITF (Intestinal Trefoil Factor)
HGNC (Hugo): TFF3
Location: 21q22.3
Local order: Belongs to the TFF cluster.
DNA/RNA
600 bp.
Protein
Description
Implicated in
precursor 74 amino acids, mature peptide 51
aminoacids, trefoil domain from aminoacids residues
24 to 67. The 74 aminoacids TFF3 protein precusor
contains a signal peptide. The mature secreted peptide
of 51 aminoacids contains one TFF (TreFoil Factor)
domain and one acidic C-terminal domain. The acidic
C-terminal domain contains a free cystein residue that
promotes homodimerization and heterodimerization.
Inflamatory bowel diseases, TFF3 is expressed in
cancer cells derived from the gastrointestinal tract, in
hepatocellular carcinoma cells and in small cell lung
carcinoma cells. Like TFF1, TFF3 is expressed in
oestrogen-responsive breast cancer cell line and is
expressed in breast cancer.
References
Expression
Hauser F, Poulsom R, Chinery R, Rogers LA, Hanby AM,
Wright NA, Hoffmann W. hP1.B, a human P-domain peptide
homologous with rat intestinal trefoil factor, is expressed also
in the ulcer-associated cell lineage and the uterus. Proc Natl
Acad Sci U S A. 1993 Aug 1;90(15):6961-5
Under normal conditions TFF3 is expressed by gobblet
cell of the intesine and the colon. TFF3 expression was
found in human respiratory tract, human conjunctival
goblet cells and in human salivarygland. In addition
TFF3 peptive was found in human hypothalamus.
Semenkovich CF, Coleman T, Goforth R. Physiologic
concentrations of glucose regulate fatty acid synthase activity
in HepG2 cells by mediating fatty acid synthase mRNA
stability. J Biol Chem. 1993 Apr 5;268(10):6961-70
Localisation
In secreterory epithelia TFF3 is expressed by mucinproducing cells. In the brain TFF3 is expressed by a
population of neurons of the human hypothamic
paraventricular and supraoptic nuclei.
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(2)
Chinery R, Bates PA, De A, Freemont PS. Characterisation of
the single copy trefoil peptides intestinal trefoil factor and pS2
114
TFF3 trefoil factor 3 (intestinal)
Tomasetto C
and their ability to form covalent dimers. FEBS Lett. 1995 Jan
2;357(1):50-4
human colon carcinoma cells. Proc Natl Acad Sci U S A. 1998
Mar 17;95(6):3122-7
Kindon H, Pothoulakis C, Thim L, Lynch-Devaney K, Podolsky
DK. Trefoil peptide protection of intestinal epithelial barrier
function: cooperative interaction with mucin glycoprotein.
Gastroenterology. 1995 Aug;109(2):516-23
Kanai M, Mullen C, Podolsky DK. Intestinal trefoil factor
induces inactivation of extracellular signal-regulated protein
kinase in intestinal epithelial cells. Proc Natl Acad Sci U S A.
1998 Jan 6;95(1):178-82
Babyatsky MW, deBeaumont M, Thim L, Podolsky DK. Oral
trefoil peptides protect against ethanol- and indomethacininduced gastric injury in rats. Gastroenterology. 1996
Feb;110(2):489-97
Langer G, Jagla W, Behrens-Baumann W, Walter S, Hoffmann
W. Secretory peptides TFF1 and TFF3 synthesized in human
conjunctival goblet cells. Invest Ophthalmol Vis Sci. 1999
Sep;40(10):2220-4
Mashimo H, Wu DC, Podolsky DK, Fishman MC. Impaired
defense of intestinal mucosa in mice lacking intestinal trefoil
factor. Science. 1996 Oct 11;274(5285):262-5
Wiede A, Jagla W, Welte T, Köhnlein T, Busk H, Hoffmann W.
Localization of TFF3, a new mucus-associated peptide of the
human respiratory tract. Am J Respir Crit Care Med. 1999
Apr;159(4 Pt 1):1330-5
Sands BE, Podolsky DK. The trefoil peptide family. Annu Rev
Physiol. 1996;58:253-73
Jagla W, Wiede A, Dietzmann K, Rutkowski K, Hoffmann W.
Co-localization of TFF3 peptide and oxytocin in the human
hypothalamus. FASEB J. 2000 Jun;14(9):1126-31
May FE, Westley BR. Expression of human intestinal trefoil
factor in malignant cells and its regulation by oestrogen in
breast cancer cells. J Pathol. 1997 Aug;182(4):404-13
Kinoshita K, Taupin DR, Itoh H, Podolsky DK. Distinct
pathways of cell migration and antiapoptotic response to
epithelial injury: structure-function analysis of human intestinal
trefoil factor. Mol Cell Biol. 2000 Jul;20(13):4680-90
Poulsom R, Hanby AM, Lalani EN, Hauser F, Hoffmann W,
Stamp GW. Intestinal trefoil factor (TFF 3) and pS2 (TFF 1),
but not spasmolytic polypeptide (TFF 2) mRNAs are coexpressed in normal, hyperplastic, and neoplastic human
breast epithelium. J Pathol. 1997 Sep;183(1):30-8
Podolsky DK. Mechanisms of regulatory peptide action in the
gastrointestinal tract: trefoil peptides. J Gastroenterol. 2000;35
Suppl 12:69-74
Seib T, Blin N, Hilgert K, Seifert M, Theisinger B, Engel M,
Dooley S, Zang KD, Welter C. The three human trefoil genes
TFF1, TFF2, and TFF3 are located within a region of 55 kb on
chromosome 21q22.3. Genomics. 1997 Feb 15;40(1):200-2
Taupin DR, Kinoshita K, Podolsky DK. Intestinal trefoil factor
confers colonic epithelial resistance to apoptosis. Proc Natl
Acad Sci U S A. 2000 Jan 18;97(2):799-804
Thim L. Trefoil peptides: from structure to function. Cell Mol
Life Sci. 1997 Dec;53(11-12):888-903
This article should be referenced as such:
Tomasetto C. TFF3 (trefoil factor 3 (intestinal)). Atlas Genet
Cytogenet Oncol Haematol. 2001; 5(2):114-115.
Efstathiou JA, Noda M, Rowan A, Dixon C, Chinery R, Jawhari
A, Hattori T, Wright NA, Bodmer WF, Pignatelli M. Intestinal
trefoil factor controls the expression of the adenomatous
polyposis coli-catenin and the E-cadherin-catenin complexes in
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(2)
115
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Gene Section
Mini Review
WRN (Werner syndrome, RecQ helicase-like)
Mounira Amor-Guéret
Institut Curie - Section de Recherche, UMR 2027 CNRS, Bâtiment 110, Centre Universitaire, F-91405 Orsay
Cedex, France (MAG)
Published in Atlas Database: March 2001
Online updated version : http://AtlasGeneticsOncology.org/Genes/WRNID284.html
DOI: 10.4267/2042/37731
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2001 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
identified human RecQL4, involved in the RothmundThomson syndrome, and RecQL5 proteins.
HGNC (Hugo): WRN
Location: 8p12
Mutations
Germinal
DNA/RNA
WRN mutations are located over the entire gene and
include stop codons, insertions/deletions and exon
deletions: not a single missense mutation has been
identified so far.
Transcription
4.4 kb mRNA.
Protein
Implicated in
Description
Werner syndrome
1432 amino acids; contains one ATP binding site, one
DExH helicase box, one exonuclease domain unique
among known RecQ helicases in the N-terminal region,
a nuclear localization signal in the C-terminus and a
direct repeat of 27 amino acids between the
exonuclease and helicase domains.
Disease
Uncommon autosomal recessive disorder characterized
by early onset of geriatric diseases, including
atherosclerosis, osteoporosis, diabetes mellitus,
juvenile cataract, graying of the hair and neoplasia, in
particular soft-tissue sarcomas, in approximately 10%
of WS patients.
Prognosis
WS patients die at mean age 46 +/- 11,6 years due to
malignant tumors or cardiovascular infarctions.
Cytogenetics
Reciprocal chromosomal translocations and extensive
genomic deletions.
Localisation
Nuclear, predominant nucleolar localization.
Function
3-5 DNA helicase; 3-5 exonuclease; functionally
interacts with DNA polymerase delta (POLD1) and
RPA which are required for DNA replication and DNA
repair, with Ku which is involved in double strand
DNA break repair by non-homologous DNA end
joining, and with p53.
References
Homology
Hoehn H, Bryant EM, Au K, Norwood TH, Boman H, Martin
GM. Variegated translocation mosaicism in human skin
fibroblast cultures. Cytogenet Cell Genet. 1975;15(5):282-98
Homologous to RecQ helicases, a subfamily of DExH
box-containing DNA and RNA helicases. In particular,
similarities with the four known human members in the
RecQ subfamily, human RecQL, human BLM, the
product of the Bloom syndrome gene, and the recently
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(2)
Fukuchi K, Martin GM, Monnat RJ Jr. Mutator phenotype of
Werner syndrome is characterized by extensive deletions. Proc
Natl Acad Sci U S A. 1989 Aug;86(15):5893-7
116
WRN Werner syndrome, RecQ helicase-like
Amor-Guéret M
Fukuchi K, Tanaka K, Kumahara Y, Marumo K, Pride MB,
Martin GM, Monnat RJ Jr. Increased frequency of 6thioguanine-resistant peripheral blood lymphocytes in Werner
syndrome patients. Hum Genet. 1990 Feb;84(3):249-52
Werner's syndrome
8;274(41):29463-9
protein.
J
Biol
Chem.
1999
Oct
Moser MJ, Oshima J, Monnat RJ Jr. WRN mutations in Werner
syndrome. Hum Mutat. 1999;13(4):271-9
Faragher RG, Kill IR, Hunter JA, Pope FM, Tannock C, Shall
S. The gene responsible for Werner syndrome may be a cell
division "counting" gene. Proc Natl Acad Sci U S A. 1993 Dec
15;90(24):12030-4
Blander G, Zalle N, Leal JF, Bar-Or RL, Yu CE, Oren M. The
Werner syndrome protein contributes to induction of p53 by
DNA damage. FASEB J. 2000 Nov;14(14):2138-40
Thweatt R, Goldstein S. Werner syndrome and biological
ageing: a molecular genetic hypothesis. Bioessays. 1993
Jun;15(6):421-6
Cooper MP, Machwe A, Orren DK, Brosh RM, Ramsden D,
Bohr VA. Ku complex interacts with and stimulates the Werner
protein. Genes Dev. 2000 Apr 15;14(8):907-12
Oshima J, Yu CE, Piussan C, Klein G, Jabkowski J, Balci S,
Miki T, Nakura J, Ogihara T, Ells J, Smith M, Melaragno MI,
Fraccaro M, Scappaticci S, Matthews J, Ouais S, Jarzebowicz
A, Schellenberg GD, Martin GM. Homozygous and compound
heterozygous mutations at the Werner syndrome locus. Hum
Mol Genet. 1996 Dec;5(12):1909-13
Kamath-Loeb AS, Johansson E, Burgers PM, Loeb LA.
Functional interaction between the Werner Syndrome protein
and DNA polymerase delta. Proc Natl Acad Sci U S A. 2000
Apr 25;97(9):4603-8
Li B, Comai L. Functional interaction between Ku and the
werner syndrome protein in DNA end processing. J Biol Chem.
2000 Sep 15;275(37):28349-52
Yu CE, Oshima J, Fu YH, Wijsman EM, Hisama F, Alisch R,
Matthews S, Nakura J, Miki T, Ouais S, Martin GM, Mulligan J,
Schellenberg GD. Positional cloning of the Werner's syndrome
gene. Science. 1996 Apr 12;272(5259):258-62
Ohsugi I, Tokutake Y, Suzuki N, Ide T, Sugimoto M, Furuichi Y.
Telomere repeat DNA forms a large non-covalent complex with
unique cohesive properties which is dissociated by Werner
syndrome DNA helicase in the presence of replication protein
A. Nucleic Acids Res. 2000 Sep 15;28(18):3642-8
Ogburn CE, Oshima J, Poot M, Chen R, Hunt KE, Gollahon
KA, Rabinovitch PS, Martin GM. An apoptosis-inducing
genotoxin differentiates heterozygotic carriers for Werner
helicase mutations from wild-type and homozygous mutants.
Hum Genet. 1997 Dec;101(2):121-5
Szekely AM, Chen YH, Zhang C, Oshima J, Weissman SM.
Werner protein recruits DNA polymerase delta to the
nucleolus. Proc Natl Acad Sci U S A. 2000 Oct
10;97(21):11365-70
Marciniak RA, Lombard DB, Johnson FB, Guarente L.
Nucleolar localization of the Werner syndrome protein in
human cells. Proc Natl Acad Sci U S A. 1998 Jun
9;95(12):6887-92
Wyllie FS, Jones CJ, Skinner JW, Haughton MF, Wallis C,
Wynford-Thomas D, Faragher RG, Kipling D. Telomerase
prevents the accelerated cell ageing of Werner syndrome
fibroblasts. Nat Genet. 2000 Jan;24(1):16-7
Yan H, Chen CY, Kobayashi R, Newport J. Replication focusforming activity 1 and the Werner syndrome gene product. Nat
Genet. 1998 Aug;19(4):375-8
This article should be referenced as such:
Amor-Guéret M. WRN (Werner syndrome, RecQ helicase-like).
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(2):116-117.
Blander G, Kipnis J, Leal JF, Yu CE, Schellenberg GD, Oren
M. Physical and functional interaction between p53 and the
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(2)
117
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Leukaemia Section
Mini Review
Classification of T-Cell disorders
Vasantha Brito-Babapulle, Estella Matutes, Daniel Catovsky
Academic Department of Haematology and Cytogenetics, The Royal Marsden NHS Trust, London, UK
(VBB, EM, DC)
Published in Atlas Database: February 2001
Online updated version : http://AtlasGeneticsOncology.org/Anomalies/TcellClassifID2079.html
DOI: 10.4267/2042/37736
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2001 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Phenotype/cell stem origin
TdT-, CD1a, CD3+, CD2+, CD8+ CD4-, CD57+,
CD16+/-Cytotoxic or suppressor activity.
Clinics
Indolent
Cytopenias, splenomegaly, lymphocytosis with
granular lymphocytes.
Cytogenetics
Clonal abnormalities. In some cases, but no consistent
specific abnormalities.
Genes
Clonality established by TCR rearrangements.
Identity
Note
T-cell lymphoid disorders include a variety of disease
entities which result from the clonal neoplastic
expansion of an uncommitted (thymic) or a committed
(post thymic) T-cell. Some of these diseases have
distinct cytogenetic/molecular genetic features which
allow to better define the various entities and
understand their pathogenesis.
Clinics and pathology
Disease
Disease
T-prolymphocytic leukemia (T-PLL)
Variants: small cell and cerebriform cell.
Phenotype/cell stem origin
TdT-, CD1a-, CD4+ CD8-, CD4- CD8+, CD4+ CD8+,
Clinics
Aggressive course
Splenomegaly, high WBC with prolymphocytes.
Cytogenetics
inv(14)(q11q32), t(14;14)(q11;q32)
Xq28 abnormalities
idic(8)(p11), t(8;8)(p11;q1-2)
11q22-23 abnormalities
12p abnormalities
13q14.3 deletions
Genes
ATM gene (11q22-23) mutated. TCL1 (14q32.1) or
MTCP1 (Xq28) activated.
Large granular lymphocyte leukemia (LGL) - NK type.
Phenotype/cell stem origin
TdT-, CD1a, CD2+, CD56+, CD16+, CD7+/-CD3-,
CD5-, TCR-Natural killer Activity.
Clinics
Aggressive or indolent
Lymphocytosis, splenomegaly, hepatomegaly.
Cytogenetics
del(6)(q21-25).
Genes
TCR chain genes in germ line.
Disease
Sezary syndrome (SS).
Phenotype/cell stem origin
TdT-, CD1a-, CD3+, CD4+, CD8-, Helper or no
functional activity.
Disease
Large granular lymphocyte leukemia (LGL) - T-cell
Type.
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(2)
118
Classification of T-Cell disorders
Brito-Babapulle V et al.
Clinics
Aggressive; advanced stages.
Cytogenetics
Variable.
Clinics
Variable clinical course with skin involvement and
cells with cerebriform nuclei.
Cytogenetics
Complex, clonal, oligoclonal or nonclonal with variable
ploidy.
Abnormal.2p,
Abnormal.6q,
i(17q),
del(13)(q14)
Genes
P53 gene deletion and protein expression in the absence
of gene mutation. Few cases express MDM2.
Disease
Angio immunoblastic T-cell lymphoma.
Phenotype/cell stem origin
TdT-, CD1a-, CD2+, CD5+, CD3+ CD4+ CD8-.
Clinics
Disproteinemia,
lymphadenopathy,
immune
abnormalities.
Cytogenetics
Complex with multiple related or unrelated clones.
+3 or i(3q), +5, del(6q). Progression from normal
karyotype to abnormal clone observed during transition
from hyperplasia to neoplasia.
Genes
Integrated EBV sequences present in both B-and Tcells and is unlikely to be the etiological agent.
Disease
Adult T-cell leukemia lymphoma (ATLL).
Phenotype/cell stem origin
TdT-, CD1a-, CD7- CD4+ CD8- CD25+, Suppressor
activity.
Clinics
Aggressive,
Hypercalcaemia,
lymphadenopathy,
Œflower cells', HTLV-1 Positive.
Cytogenetics
Complex and often oligoclonal.
Numerical abnormalities: 3, 7, X.
Structural abnormalities: 1q, 3q, 6q, 14q.
Genes
Oligoclonal/mono clonal integration of HTLV-1in host
DNA. Abnormalities of p53, p16 and p15 genes.
Disease
Angiocentric (nasal) T-cell lymphoma.
Phenotype/cell stem origin
TdT-, CD1a-, T-cell or NK phenotype.
Clinics
Prevalent in Asia and south America; extra nodal
involvement.
Cytogenetics
i(1q), del(6q), i(6p)
Genes
Majority have no TCR rearrangement; EBV clonally
integrated and plays a role in the etiology of the
disease.
Disease
T-NHL hepatosplenic lymphoma.
Phenotype/cell stem origin
TdT-, CD1a-, CD3+/- CD56+, CD7+, granzyme A+,
TCR g/d+
Clinics
Aggressive, Hepato splenomegaly
Cytogenetics
Abnormal.7q, i(7q)
Genes
TCR genes gamma/delta rearranged but alpha/beta not
rearranged.
Disease
Anaplastic (Ki 1+) large cell lymphoma.
Phenotype/cell stem origin
TdT-, CD1a-, CD3+/- CD30+ (Ki 1+), CD15-, CD25+,
HLA-Dr+, CD71+.
Clinics
Aggressive with skin nodes and extranodal
involvement.
Cytogenetics
t(2;5)(p23;q35)
Genes
Fusion
gene
NPM-ALK;
2p23
-Nucleolar
phosphoprotein- NPM; 5q35 -Anaplastic lymphoma
kinase- ALK.
Disease
Peripheral/post-thymic T-cell lymphoma (pleomorphic
and immunoblastic subtypes).
Phenotype/cell stem origin
TdT-, CD1a-, Variable expression of CD4 or CD8.
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(2)
119
Classification of T-Cell disorders
Brito-Babapulle V et al.
Schlegelberger B, Himmler A, Gödde E, Grote W, Feller AC,
Lennert K. Cytogenetic findings in peripheral T-cell lymphomas
as a basis for distinguishing low-grade and high-grade
lymphomas. Blood. 1994 Jan 15;83(2):505-11
Disease
Intestinal T-cell lymphoma.
Phenotype/cell stem origin
TdT, CD1a-, CD3+, CD8+, CD103+, CD4-, CD8-.
Clinics
Bone pain, coeliac disease, mesenteric nodes.
Genes
EBV genome present in mexican population but not in
the europeans.
Schlegelberger B, Zhang Y, Weber-Matthiesen K, Grote W.
Detection of aberrant clones in nearly all cases of
angioimmunoblastic lymphadenopathy with dysproteinemiatype T-cell lymphoma by combined interphase and metaphase
cytogenetics. Blood. 1994 Oct 15;84(8):2640-8
Wang CC, Tien HF, Lin MT, Su IJ, Wang CH, Chuang SM,
Shen MC, Liu CH. Consistent presence of isochromosome 7q
in hepatosplenic T gamma/delta lymphoma: a new cytogeneticclinicopathologic entity. Genes Chromosomes Cancer. 1995
Mar;12(3):161-4
Disease
Jaffe ES. Classification of natural killer (NK) cell and NK-like Tcell malignancies. Blood. 1996 Feb 15;87(4):1207-10
T-lymphoblastic Lymphoma/leukaemia (T-Lbly/TALL).
Phenotype/cell stem origin
TDT+, CD1a+, CD7+, cytCD3+ or +/-, other T-cell
antigens.Thymic uncommitted T-cell.
Clinics
Aggressive; course similar to ALL. Mediastinal mass,
high WBC.
Cytogenetics
del(6)(q21-q22)
t(11;14)(p13;q11)
t(1;14)(p34;q11); 1p34: tal-1gene; 14q11: TCR alpha.
Genes
TCR chain genes rearranged.
Mundle SD, Venugopal P, Cartlidge JD, Pandav DV, BroadyRobinson L, Gezer S, Robin EL, Rifkin SR, Klein M, Alston DE,
Hernandez BM, Rosi D, Alvi S, Shetty VT, Gregory SA, Raza
A. Indication of an involvement of interleukin-1 beta converting
enzyme-like protease in intramedullary apoptotic cell death in
the bone marrow of patients with myelodysplastic syndromes.
Blood. 1996 Oct 1;88(7):2640-7
Brito-Babapulle V, Maljaie SH, Matutes E, Hedges M, Yuille M,
Catovsky D. Relationship of T leukaemias with cerebriform
nuclei to T-prolymphocytic leukaemia: a cytogenetic analysis
with in situ hybridization. Br J Haematol. 1997 Mar;96(4):72432
Wong KF, Chan JK, Kwong YL. Identification of del(6)(q21q25)
as a recurring chromosomal abnormality in putative NK cell
lymphoma/leukaemia. Br J Haematol. 1997 Sep;98(4):922-6
Brito-Babapulle V, Hamoudi R, Matutes E, Watson S,
Kaczmarek P, Maljaie H, Catovsky D. p53 allele deletion and
protein accumulation occurs in the absence of p53 gene
mutation in T-prolymphocytic leukaemia and Sezary syndrome.
Br J Haematol. 2000 Jul;110(1):180-7
References
Mason DY, Bastard C, Rimokh R, Dastugue N, Huret JL,
Kristoffersson U, Magaud JP, Nezelof C, Tilly H, Vannier JP.
CD30-positive large cell lymphomas ('Ki-1 lymphoma') are
associated with a chromosomal translocation involving 5q35.
Br J Haematol. 1990 Feb;74(2):161-8
Matutes
E.
T-Cell
Lymphoproliferative
Disorders.
Classification, Clinical and Laboratory Aspects. Advances in
Blood Disorders 2000. Ed:.A.Polliak. Harwood Academic
Publishers
Kamada N, Sakurai M, Miyamoto K, Sanada I, Sadamori N,
Fukuhara S, Abe S, Shiraishi Y, Abe T, Kaneko Y.
Chromosome abnormalities in adult T-cell leukemia/lymphoma:
a karyotype review committee report. Cancer Res. 1992 Mar
15;52(6):1481-93
Loughran TP Jr. Clonal diseases of
lymphocytes. Blood. 1993 Jul 1;82(1):1-14
large
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(2)
This article should be referenced as such:
Brito-Babapulle V, Matutes E, Catovsky D. Classification of TCell disorders. Atlas Genet Cytogenet Oncol Haematol. 2001;
5(2):118-120.
granular
120
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in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Leukaemia Section
Mini Review
Burkitt's lymphoma (BL)
Antonio Cuneo, Gianluigi Castoldi
Hematology Section, Department of Biomedical Sciences, University of Ferrara, Corso Giovecca 203,
Ferrara, Italy (AC, GLC)
Published in Atlas Database: March 2001
Online updated version : http://AtlasGeneticsOncology.org/Anomalies/BurkittID2077.html
DOI: 10.4267/2042/37732
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2001 Atlas of Genetics and Cytogenetics in Oncology and Haematology
The related form “Burkitt-like” lymphoma shows
intermediate features between diffuse large cell
lymphoma and BL and probably includes different
disease entities. It was suggested by the WHO panel
that only those cases with c-MYC rearrangement
and/or a >99% proliferation fraction as demonstrated
by Ki-67 positivity should be classified as Burkitt-like
lymphoma.
Clinics and pathology
Phenotype/cell stem origin
Pan-B antigens positive; TdT-, CD10+; CD5-; sIgM+.
The cell of origin is a peripheral IgM+ memory B-cell
(presence of somatic hypermutation of the Ig gene).
Epidemiology
Treatment
Most common in children (1/3 of lymphomas). In adult
it accounts for 3-4% of all lymphomas in western
countries and it is frequently associated with
immunodeficiency.
Aggressive regimens specifically designed for this
lymphoma must be used.
Evolution
Clinics
Very rapid if untreated. Patients with limited disease
and favourable prognostic features at presentation may
rapidly show disease dissemination.
There is an endemic variant, affecting africans, which
primarily involves the jaws and other facial bones.
The non-endemic variant may be associated with
immunodeficiency states and usually presents with
abdominal involvement (distal ileum, ciecum,
mesentery). The disease is very aggressive and requires
prompt treatment with appropriate regimens.
Prognosis
If treated promptly with appropriate regimens the
majority of patients can be cured.
Cytogenetics
Cytology
The blast cells in the peripheral blood and bone marrow
display a basophilic cytoplasm with characteristic
vacuolization, a picture indisinguishable from acute
lymphoblastic leukemia (ALL) L3 of the FAB
classification, which represents the leukemic
counterpart of BL.
Cytogenetics morphological
The primary chromosome anomaly is the translocation
t(8;14)(q24;q32), found in 60-70% of the cases. Variant
translocations having in common an 8q24 break, i.e the
t(8;22)(q24;q11) and t(2;8)(p12;q24) occur in
approximately 10-15% and 2-5% of the cases,
respectively. A minority of cases may carry a
duplication of chromosome 1, involving the 1q21-25
segment as the only detectable chromosome lesion.
In the Burkitt-like form there are at least 3 cytogenetic
categories: one with an 8q24/c-MYC translocation, one
with an 8q24 and 18q21/ BCL2 translocation and
another
with
“miscellaneous”
rearrangements,
frequently including an 18q21 break.
Pathology
The lymphoma consists of a monomorphic infiltrate of
the lymph node by medium-sized cells showing round
nuclei with several nucleoli and basophilic cytoplasm.
Numerous benign macrophages confer a histologic
pattern referred to as “starry sky”. Involvement of the
peripheral blood and bone marrow may occur.
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(2)
121
Burkitt's lymphoma (BL)
Cuneo A, Castoldi GL
the c-MYC transactivation domain less susceptible to
modulation.
Probes
Conventional karyotyping is the method of choice for
the detection of the 8q24 translocations occurring in
BL.
There is variability in the location of the breakpoint at
band 8q24, making the detection of c-MYC
rearrangement (see below) difficult by molecular
genetics. Southern blotting is the preferred method. In
the endemic form the breakpoint in the Ig locus is
usually located in the Ig heavy chain variable region,
whereas in the nonendemic form the breakpoint falls in
the Ig switch region.
Fluorescence in situ hybridization is of value in
detecting the the t(8;14) in interphase cells. Dual color
FISH detection of the t(8;14) in interphase cells is
possible by using cosmid clones spanning the c-MYC
locus at 8q24 and a differently labelled IgH probe.
References
Kornblau SM, Goodacre A, Cabanillas F. Chromosomal
abnormalities in adult non-endemic Burkitt's lymphoma and
leukemia: 22 new reports and a review of 148 cases from the
literature. Hematol Oncol. 1991 Mar-Apr;9(2):63-78
Harris NL, Jaffe ES, Stein H, Banks PM, Chan JK, Cleary ML,
Delsol G, De Wolf-Peeters C, Falini B, Gatter KC. A revised
European-American classification of lymphoid neoplasms: a
proposal from the International Lymphoma Study Group.
Blood. 1994 Sep 1;84(5):1361-92
Mitelmam F ed. Catalogue of chromosome aberrations in
cancer (5th edition). Wiley Liss, New York. 1994.
Polito P, Cilia AM, Gloghini A, Cozzi M, Perin T, De Paoli P,
Gaidano G, Carbone A. High frequency of EBV association
with non-random abnormalities of the chromosome region
1q21-25 in AIDS-related Burkitt's lymphoma-derived cell lines.
Int J Cancer. 1995 May 4;61(3):370-4
Additional anomalies
Recurrent chromosome aberrations associated with the
8q24 translocations include 1q21-25 duplications,
deletions of 6q11-14, 17p deletions and trisomy 12, +7,
+8 and +18.
Gaidano G. Molecular genetics of malignant lymphoma. In:
Fo?¬˙ R (ed): Reviews in clinical and experimental
hematology. Forum Service Editore, Genova and Martin
Dunitz, London,. 1997.
Genes involved and proteins
Magrath I. Small noncleaved cell lymphomas (Burkitt's and
Burkitt-like lymphomas). In: Magrath I (ed): The non Hodgkin's
lymphomas. Pp781-811. Arnold, London 1997.
Note
The t(8,14) and the variant t(8;22) and t(2;8) juxtapose
IgH sequences and the c-MYC oncogene, bringing
about its constitutional expression.
The 17p deletion may have a correlation with p53 loss
of function, determined by deletion of one allele and
inactivating mutation of the remaining allele.
Siebert R, Matthiesen P, Harder S, Zhang Y, Borowski A,
Zühlke-Jenisch R, Metzke S, Joos S, Weber-Matthiesen K,
Grote W, Schlegelberger B. Application of interphase
fluorescence in situ Hybridization for the detection of the Burkitt
translocation t(8;14)(q24;q32) in B-cell lymphomas. Blood.
1998 Feb 1;91(3):984-90
Harris NL, Jaffe ES, Diebold J, Flandrin G, Muller-Hermelink
HK, Vardiman J, Lister TA, Bloomfield CD. World Health
Organization classification of neoplastic diseases of the
hematopoietic and lymphoid tissues: report of the Clinical
Advisory Committee meeting-Airlie House, Virginia, November
1997. J Clin Oncol. 1999 Dec;17(12):3835-49
Result of the chromosomal
anomaly
Macpherson N, Lesack D, Klasa R, Horsman D, Connors JM,
Barnett M, Gascoyne RD. Small noncleaved, non-Burkitt's
(Burkit-Like) lymphoma: cytogenetics predict outcome and
reflect
clinical
presentation.
J
Clin
Oncol.
1999
May;17(5):1558-67
Fusion protein
Oncogenesis
Constitutive expression of c-MYC is crucial for the
pathogenesis of BL, this protein being a key
transcriptional regulator, controlling cell proliferation,
differentiation and death. The deregulated expression
of c-MYC, caused by the 8q24 translocations, is
achieved
through
multiple
mechanisms:
a)
juxtaposition to regulatory elements of the Ig loci, b)
mutations in the c-MYC 5' regulatory regions and, c)
aminoacid substitutions occurring in exon 2, making
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(2)
Schlegelberger B, Zwingers T, Harder L, Nowotny H, Siebert
R, Vesely M, Bartels H, Sonnen R, Hopfinger G, Nader A, Ott
G, Müller-Hermelink K, Feller A, Heinz R. Clinicopathogenetic
significance of chromosomal abnormalities in patients with
blastic peripheral B-cell lymphoma. Kiel-Wien-Lymphoma
Study Group. Blood. 1999 Nov 1;94(9):3114-20
This article should be referenced as such:
Cuneo A, Castoldi GL. Burkitt's lymphoma (BL). Atlas Genet
Cytogenet Oncol Haematol. 2001; 5(2):121-122.
122
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Leukaemia Section
Short Communication
del(13q) in multiple myeloma
Franck Viguié
Laboratoire de Cytogénétique - Service d'Hématologie Biologique, Hôpital Hôtel-Dieu, 75181 Paris Cedex
04, France (FV)
Published in Atlas Database: March 2001
Online updated version : http://AtlasGeneticsOncology.org/Anomalies/del13qMMyeloID2094.html
DOI: 10.4267/2042/37733
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2001 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Epidemiology
Identity
del(13q) is detected in 15-20% of MM patients by
conventional karyotype and in 33-52% of cases by
FISH analysis.
Prognosis
-13/del(13q) appears as one of the main prognostic
factors with ?2-microglobulin serum level and the
percentage of bone marrow plasma cells. Patients with
del(13q) have a significantly lower event-free survival,
overall survival and complete remission duration, either
in standard-dose or in high dose therapy protocols.
Cytogenetics
del(13q) G- banding - Courtesy Melanie Zenger and Claudia
Haferlach.
Cytogenetics morphological
del(13q) is a frequent occurrence in chronic
lymphoproliferative diseases and in non Hodgkin
lymphoma.
del(13q) in MM is rarely observed as a sole anomaly;
detected both in hyperdiploid and hypodiploid
karyotypes, but with a higher incidence in hypodiploi
forms; consequently, according to some authors, the
prognostic value of del(13q) should have to be related
to the ploidy.
It is considered as a secondary event, however
occurring early in the evolution of MM because it is
observed in patients with MGUS.
The minimal common region of deletion is in band
13q14.3, the same as in chronic lymphocytic leukemia.
Del(13q) is clearly underscored by karyotyping because
a number of deletions are submicroscopic or only
detected in interphase nuclei. It involves rb-1, and loci
D13S319 and D13S272 which are approximately
100kb distal from rb-1.
rb-1 deletion / mutation would be a key event in MM
evolution; however other gene(s) would be involved at
Clinics and pathology
Disease
Multiple myeloma (MM) is a monoclonal B-cell
malignancy, which originates theoretically in lymph
node germinal centers but locates and expands in bone
marrow. It represents 10% of all the hematopoietic
cancers, with a great variability in clinical presentation,
response to therapy and survival duration. In more than
1/3 of cases, MM can be preceded by a phase of
monoclonal gammopathy of uncertain significance
(MGUS). At the extreme it can evolve in plasma blast
acute leukemia.
Phenotype/cell stem origin
Malignant myeloma cells are long-lived cells with
morphological features varying from normal to
dystrophic considering size of the cells, presence of
nucleolar structures and aspect of the chromatin.
Immunophenotype includes inconstant expression of
CD56, CD38, CD40 and CD138.
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(2)
123
del(13q) in multiple myeloma
Viguié F
Königsberg R, Ackermann J, Kaufmann H, Zojer N, Urbauer E,
Krömer E, Jäger U, Gisslinger H, Schreiber S, Heinz R, Ludwig
H, Huber H, Drach J. Deletions of chromosome 13q in
monoclonal gammopathy of undetermined significance.
Leukemia. 2000 Nov;14(11):1975-9
13q14.3 because rb-1 and D13S319 deletions are
dissociated in some cases.
References
Shaughnessy J, Tian E, Sawyer J, Bumm K, Landes R, Badros
A, Morris C, Tricot G, Epstein J, Barlogie B. High incidence of
chromosome 13 deletion in multiple myeloma detected by
multiprobe interphase FISH. Blood. 2000 Aug 15;96(4):150511
Avet-Loiseau H, Facon T, Daviet A, Godon C, Rapp MJ,
Harousseau JL, Grosbois B, Bataille R. 14q32 translocations
and monosomy 13 observed in monoclonal gammopathy of
undetermined significance delineate a multistep process for the
oncogenesis of multiple myeloma. Intergroupe Francophone
du Myélome. Cancer Res. 1999 Sep 15;59(18):4546-50
Zojer N, Königsberg R, Ackermann J, Fritz E, Dallinger S,
Krömer E, Kaufmann H, Riedl L, Gisslinger H, Schreiber S,
Heinz R, Ludwig H, Huber H, Drach J. Deletion of 13q14
remains an independent adverse prognostic variable in
multiple myeloma despite its frequent detection by interphase
fluorescence in situ hybridization. Blood. 2000 Mar
15;95(6):1925-30
Chang H, Bouman D, Boerkoel CF, Stewart AK, Squire JA.
Frequent monoallelic loss of D13S319 in multiple myeloma
patients shown by interphase fluorescence in situ hybridization.
Leukemia. 1999 Jan;13(1):105-9
Desikan R, Barlogie B, Sawyer J, Ayers D, Tricot G, Badros A,
Zangari M, Munshi NC, Anaissie E, Spoon D, Siegel D,
Jagannath S, Vesole D, Epstein J, Shaughnessy J, Fassas A,
Lim S, Roberson P, Crowley J. Results of high-dose therapy
for 1000 patients with multiple myeloma: durable complete
remissions and superior survival in the absence of
chromosome
13
abnormalities.
Blood.
2000
Jun
15;95(12):4008-10
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(2)
This article should be referenced as such:
Viguié F. del(13q) in multiple myeloma. Atlas Genet Cytogenet
Oncol Haematol. 2001; 5(2):123-124.
124
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Leukaemia Section
Mini Review
Follicular lymphoma (FL)
Antonio Cuneo, Gianluigi Castoldi
Hematology Section, Department of Biomedical Sciences, University of Ferrara, Corso Giovecca 203,
Ferrara, Italy (AC, GC)
Published in Atlas Database: March 2001
Online updated version : http://AtlasGeneticsOncology.org/Anomalies/FollLymphomID2075.html
DOI: 10.4267/2042/37734
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2001 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Clinics and pathology
antibody has an important role in combination with
chemotherapy.
Phenotype/cell stem origin
Evolution
Pan-B antigens test positive. The immunophenotypic
profile is CD10+, CD5-, sIg+ and the cell of origin is a
germinal centre B-cell that has encountered the antigen.
The majority of patients cannot be cured by
chemotherapy and eventually relapse. Histologic switch
into high grade lymphoma may occur.
Epidemiology
Prognosis
This lymphoma accounts for 30-40% of all lymphomas
occurring in the adult population in western countries.
Its peak incidence is in the fifth and sixth decade.
Approximately 60% of the patients presenting with
limited disease are alive at 10 years. Patients in stages
III and IV were reported to have a median survival in
the 8-12 years range.
Clinics
The patients most often present widespead disease at
diagnosis, with nodal and extranodal (bone marrow)
involvement. Peripheral blood involvement is
detectable by light microscopy in approximately 10%
of the cases, but the majority of cases can be shown to
have circulating malignant cells by sensitive molecular
genetic methods.
The disease usually runs an indolent course. Grade 3
FL may be characterized by earlier relapse, especially
if treated with regimens not including an anthracycline
drug.
Cytogenetics
Cytogenetics morphological
Seventy-80% of the cases carry the t(14;18)(q32;q21)
as the primary chromosome anomaly. Rare variant
translocation t(2;18)(p11;q21) and t(18;22)(q21;q11)
were described. Approximately 15% of the cases show
a 3q27 break, half of which include the
t(3;14)(q27;q32) and the variant translocations
t(3;22)(q27;q11) and t(2;3)(p11;q27).
Cytogenetics molecular
Pathology
The incidence of 6q21 deletion and 17p13/p53 deletion
(see below) by interphase FISH analysis may be around
60% and 20%, respectively.
The lymphoma is composed of a mixture of centrocytes
and centroblasts with a follicular and diffuse pattern.
Lymphoma grading by the number of large
cells/centroblasts is recommended: three grades are
recognized with incresing number of centroblasts.
Additional anomalies
Secondary chromosome changes are both numerical
and structural. Trisomy 7, +8; +12, +3, +18, +X each
occur in 10-20% of the cases. There is an association
between +7 and the presence of a large cell component,
but no numerical anomaly has an independent impact
on prognosis.
Treatment
Depending on age and stage at presentation it may vary
from a "watch and wait" policy in initial stages to
multiagent chemotherapy in advanced stages.
Immunotherapy using chimeric anti-CD20 monoclonal
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(2)
125
Follicular lymphoma (FL)
Cuneo A, Castoldi G
histology, immunophenotype, karyotype, and clinical outcome
in 217 patients. Blood. 1994 May 1;83(9):2423-7
Deletions of 6q23-26 occur at a 25-30% incidence; 17p
anomalies are present in approximately 10% of the
cases. The presence of these anomalies may have a
correlation with disease transfornation and it was
associated with an inferior prognosis.
Rarely, histologic switch into a high grade lymphoma
may be associated with the development of an
additional t(8;14)(q24;q32).
Other anomalies include 1p36 deletion in 10-12% of
the cases, probably centered around the p73 gene;
10q22-24 deletions in 10-13% of the cases and 9p21
deletions/p16 deletions, associated with histologic
transformation.
Harris NL, Jaffe ES, Stein H, Banks PM, Chan JK, Cleary ML,
Delsol G, De Wolf-Peeters C, Falini B, Gatter KC. A revised
European-American classification of lymphoid neoplasms: a
proposal from the International Lymphoma Study Group.
Blood. 1994 Sep 1;84(5):1361-92
Tilly H, Rossi A, Stamatoullas A, Lenormand B, Bigorgne C,
Kunlin A, Monconduit M, Bastard C. Prognostic value of
chromosomal abnormalities in follicular lymphoma. Blood.
1994 Aug 15;84(4):1043-9
Zhang Y, Weber-Matthiesen K, Siebert R, Matthiesen P,
Schlegelberger B. Frequent deletions of 6q23-24 in B-cell nonHodgkin's lymphomas detected by fluorescence in situ
hybridization.
Genes
Chromosomes
Cancer.
1997
Apr;18(4):310-3
Result of the chromosomal
anomaly
Bernell P, Jacobsson B, Liliemark J, Hjalmar V, Arvidsson I,
Hast R. Gain of chromosome 7 marks the progression from
indolent to aggressive follicle centre lymphoma and is a
common finding in patients with diffuse large B-cell lymphoma:
a study by FISH. Br J Haematol. 1998 Jun;101(3):487-91
Fusion protein
Description
No fusion protein. The t(14;18) brings about the
juxtaposition of BCL-2 with the Ig heavy chain joining
segment, with consequent marked overexpression of
the BCL2 protein product. The majority of breakpoints
on 18q22 fall into two regions: the major breakpoint
region (60-70% of the cases) and the minor cluster
region (20-25% of the cases).
Oncogenesis
BCL-2 overexpression prevents cell to die by apoptosis
(Gaidano, 1997). BCL-2 forms heterodimers with BAX
and the relative proportion of BCL-2 to BAX
determines the functional activity of BCL-2. In vitro,
BCL-2 constitutive expression has a definite role in
sustaining cell growth, whereas in vivo, BCL-2
transgenes induce a pattern of polyclonal proliferation
of mature B-cells.
Elenitoba-Johnson KS, Gascoyne RD, Lim MS, Chhanabai M,
Jaffe ES, Raffeld M. Homozygous deletions at chromosome
9p21 involving p16 and p15 are associated with histologic
progression in follicle center lymphoma. Blood. 1998 Jun
15;91(12):4677-85
Butler MP, Wang SI, Chaganti RS, Parsons R, Dalla-Favera R.
Analysis of PTEN mutations and deletions in B-cell nonHodgkin's lymphomas. Genes Chromosomes Cancer. 1999
Apr;24(4):322-7
Dave BJ, Hess MM, Pickering DL, Zaleski DH, Pfeifer AL,
Weisenburger DD, Armitage JO, Sanger WG. Rearrangements
of chromosome band 1p36 in non-Hodgkin's lymphoma. Clin
Cancer Res. 1999 Jun;5(6):1401-9
Harris NL, Jaffe ES, Diebold J, Flandrin G, Muller-Hermelink
HK, Vardiman J, Lister TA, Bloomfield CD. World Health
Organization classification of neoplastic diseases of the
hematopoietic and lymphoid tissues: report of the Clinical
Advisory Committee meeting-Airlie House, Virginia, November
1997. J Clin Oncol. 1999 Dec;17(12):3835-49
References
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Cuneo A, Castoldi G. Follicular lymphoma (FL). Atlas
Genet Cytogenet Oncol Haematol. 2001; 5(2):125-126.
Bastard C, Deweindt C, Kerckaert JP, Lenormand B, Rossi A,
Pezzella F, Fruchart C, Duval C, Monconduit M, Tilly H. LAZ3
rearrangements in non-Hodgkin's lymphoma: correlation with
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(2)
126
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Leukaemia Section
Short Communication
t(5;11)(q31;q23)
Stig E Bojesen
Department of Clinical Biochemistry, Herlev University Hospital, Herlev Ringvej 75, Herlev DK-2730,
Denmark (SEB)
Published in Atlas Database: March 2001
Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t0511ID1192.html
DOI: 10.4267/2042/37735
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2001 Atlas of Genetics and Cytogenetics in Oncology and Haematology
MLL (Mixed Lineage Leukemia)
Clinics and pathology
Location: 11q23
Phenotype/cell stem origin
Result of the chromosomal
anomaly
1 case of chronic myelogenous leukemia (CML), one
JMML evolving towards a M4-M5 type acute non
lymphocytic leukemia (ANLL), two M5-ANLL, one
treatment related ANLL (t-ANLL), and one L2 acute
lymphoblastic leukemia (ALL).
Hybrid gene
Description
5' MLL-Inverted MLL-GRAF 3'
Epidemiology
6 cases known in the litterature; two infants, one 18
months old baby, and three adults (?, 55, 60 years); sex
ration 4M/1F.
Fusion protein
Description
Hybrid transcript MLL-GRAF contains the code for the
following domains: AT-hook+DNA methyltransferase
(from MLL) + SH3 (from GRAF).
Clinics
WBC: 20-420 X 109/l
Pathology
References
In at least 2 infant cases, cutane infiltrations were
noticed.
Hoyle CF, de Bastos M, Wheatley K, Sherrington PD, Fischer
PJ, Rees JK, Gray R, Hayhoe FG. AML associated with
previous cytotoxic therapy, MDS or myeloproliferative
disorders: results from the MRC's 9th AML trial. Br J Haematol.
1989 May;72(1):45-53
Prognosis
Survival (mths) was: 8+, 17, 17+, 48+ and 65+.
Cytogenetics
Kearney L, Bower M, Gibbons B, Das S, Chaplin T, Nacheva
E, Chessells JM, Reeves B, Riley JH, Lister TA. Chromosome
11q23 translocations in both infant and adult acute leukemias
are detected by in situ hybridization with a yeast artificial
chromosome. Blood. 1992 Oct 1;80(7):1659-65
Probes
YAC, 13HH4.
Additional anomalies
Sole anomaly in 5 of 6 cases; acompanied with +8 in
one case.
Bower M, Chaplin T, Das S, Kearney L, Gibbons B, Riley JH,
Lister TA, Young BD. The isolation of a yeast artificial
chromosome which spans the chromosome 11q23 region
involved in a number of translocations in acute leukaemias.
Leukemia. 1993 Aug;7 Suppl 2:S34-9
Genes involved and proteins
Harrison CJ, Cuneo A, Clark R, Johansson B, LafagePochitaloff M, Mugneret F, Moorman AV, Secker-Walker LM.
Ten novel 11q23 chromosomal partner sites. European 11q23
Workshop participants. Leukemia. 1998 May;12(5):811-22
GRAF (GTPase regulator associated
with FAK)
Location: 5q31
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(2)
127
t(5;11)(q31;q23)
Bojesen SE
Fernandez MC, Weiss B, Atwater S, Shannon K, Matthay KK.
Congenital leukemia: successful treatment of a newborn with
t(5;11)(q31;q23). J Pediatr Hematol Oncol. 1999 MarApr;21(2):152-7
human GRAF gene is fused to MLL in a unique
t(5;11)(q31;q23) and both alleles are disrupted in three cases
of myelodysplastic syndrome/acute myeloid leukemia with a
deletion 5q. Proc Natl Acad Sci U S A. 2000 Aug
1;97(16):9168-73
Itoh M, Okazaki T, Tashima M, Sawada H, Uchiyama T. Acute
myeloid leukemia with t(5;11): two case reports. Leuk Res.
1999 Jul;23(7):677-80
This article should be referenced as such:
Bojesen SE. t(5;11)(q31;q23). Atlas Genet Cytogenet Oncol
Haematol. 2001; 5(2):127-128.
Borkhardt A, Bojesen S, Haas OA, Fuchs U, Bartelheimer D,
Loncarevic IF, Bohle RM, Harbott J, Repp R, Jaeger U,
Viehmann S, Henn T, Korth P, Scharr D, Lampert F. The
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(2)
128
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Solid Tumour Section
Review
Testis: Germ cell tumors
Leendert HJ Looijenga
Pathology/Lab. Exp. Patho-Oncology, Erasmus Medical Center/Daniel, Josephine Nefkens Institute,
Building Be, room 430b, P.O. Box 1738, 3000 DR Rotterdam, Dr. Molewaterplein 50, 3015 GE Rotterdam,
The Netherlands (LHJL)
Published in Atlas Database: February 2001
Online updated version : http://AtlasGeneticsOncology.org/Tumors/malegermID5005.html
DOI: 10.4267/2042/37737
This article is an update of: Desangles F, Camparo P. Testis: Germ cell tumors. Atlas Genet Cytogenet Oncol Haematol.1998;2(4):151152.
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2001 Atlas of Genetics and Cytogenetics in Oncology and Haematology
These groups are defined by epidemiological
characteristics,
histological
composition
and
chromosomal constitution (Table 1). Designation of
tumours to these groups is clinically relevant because
they require different strategies for treatment.
Identity
Alias
Testicular cancer
Classification
Clinics and pathology
Germ cell tumours comprise a heterogeneous group of
neoplasms, which can be found at different, although
restricted anatomical locations. In the testis three
groups of germ cell-derived tumours are distinguished:
I- teratomas and yolk sac tumours of infants;
II- seminomas and nonseminomas of adolescents and
adults;
III- spermatocytic seminomas of the elderly.
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(2)
Disease
Testicular germ cell tumours, teratomas and yolk sac
tumours, seminomas and nonseminomas, carcinoma in
situ (CIS), intratubular germ cell neoplasia
undifferentiated (IGCNU) , testicular intratubular
neoplasia (TIN) , spermatocytic seminomas.
129
Testis: Germ cell tumors
Looijenga LHJ
and spermatocytic seminomas are clinically manifest
during or after puberty, therefore likely related to
sexual maturation. Spermatocytic seminomas are
predominantly found in patients of 50 years and older.
While most patients with a seminoma present in their
4th decade of life, this is in the 3rd decade for patients
with a nonseminoma. An increasing incidence (in
between 6-11/100.000) has been reported both for
seminomas and nonseminomas during the last decades
in white populations throughout the world, with an
annual increase of 3-6%. Although in general rare,
accounting for 1-2% of all malignancies in males,
seminomas and nonseminomas are the most common
cancer in young Caucasian males. In some European
countries, i.e., Denmark and Switzerland, the life time
risk for seminoma or nonseminoma is up to 1%.
However, the increase seems to stabilise to date. In
contrast to whites, blacks have a significantly lower,
not
increasing,
incidence
for
seminomas/nonseminomas, although histology and
age-distribution are the same. No significantly
increasing incidence has been reported for teratomas
and yolk sac tumours of infants and spermatocytic
seminomas.
The incidence of CIS, the precursor of both seminomas
and nonseminomas, in the general population is similar
to
the
life
time
risk
to
develop
a
seminoma/nonseminoma. This indicates that CIS will
always progress to invasiveness. About 5% of patients
with a unilateral seminoma or nonseminoma have
contralateral CIS.
Embryonic origin
That the different types of germ cell tumours of the
testis are derived from cells belonging to the germ cell
lineage, is established, although the actual nonmalignant counterparts are still a matter of debate. It is
likely that the teratomas and yolk sac tumours of
infants originate from an embryonic germ cell, while
this is a spermatogonial/spermatocyte-type of cell for
spermatocytic seminomas. In contrast, it is established
that the precursor of seminomas and nonseminomas is
carcinoma in situ (CIS), also referred to as intratubular
germ cell neoplasia undifferentiated (IGCNU) or
testicular intratubular neoplasia (TIN). CIS is
composed of tumour cells located on the basal
membrane at the inner side of the seminiferous tubules,
under the tight junction, where normally the
spermatogonia reside. It has been suggested that the
normal counterpart of CIS, i.e., a primordial germ
cell/gonocyte is present within the gonad around the
7th to 10th week gestational age. This is supported by
the epidemiological finding that the incidence of
seminomas and nonseminomas show a lower incidence
in cohorts of men born during the period of the second
word war in Denmark, Norway and Sweden. An
alternative model has been proposed, in which the cell
of origin is a pachytene spermatocyte.
Epidemiology
During the first few years of life, the only types of
germ cell tumours diagnosed in the testis are teratomas
and yolk sac tumours. They are evidently unrelated to
puberty. In contrast, the seminomas, nonseminomas,
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(2)
130
Testis: Germ cell tumors
Looijenga LHJ
Figure 1. Representative example of the precursor cells of both seminoma and nonseminoma of the adult testis, known as carcinoma in
situ (CIS), intratubular germ cell neoplasia undifferentiated (IGCNU), and testicular intratubular neoplasia (TIN). The cells are identified by
detection of alkaline phosphatase reactivity on a frozen tissue section of testicular parenchyma adjacent to an invasive seminoma. Note
the presence of the alkaline phosphatase positive IGCNU cells at the inner basal membrane of the seminiferous tubules (indicted by an
arrow), under the tight junctions present between the Sertoli cells (indicated by 'S'). Micro-invasive seminoma cells (indicated by an
arrow-head) are also detectable, as well as IGCNU cells in the lumen of the seminiferous tubules (within the squares).
Figure 2. Representative example of a seminoma, stained for placental/germ cell specific alkaline phosphatase. Note the presence of
lymphocytic infiltrations.
Figure 3. Representative example of an embryonal carcinoma, stained for CD30.
Figure 4. Representative example of a teratoma, stained for cytokeratin.
Figure 5. Representative example of a yolk sac tumor, stained for AFP.
Figure 6. Representative example of a choriocarcinona, stained for hCG.
Figure 7. Representative example of a spermatocytic seminoma, stained with hematoxylin and eosin.
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(2)
131
Testis: Germ cell tumors
Looijenga LHJ
is the precursor for seminoma and nonseminoma, the
relationship(s) between these histological elements is
still a matter of debate. It has been shown, especially
using cell lines derived from nonseminomas, that
embryonal carcinoma is the undifferentiated stem cell
of all differentiated nonseminomatous components. So
far, no cell lines for seminoma or CIS are available.
Nonseminomas mimick embryonal development to a
certain level. However, it is unproven so far whether
seminomas may also progress into nonseminoma,
although various observations, both biological and
clinical, may support this model. It has been suggested
that CIS present in the adjacent parenchyma of an
invasive seminoma or nonseminoma is only one step
behind in the progression of the cancer, which is
supported by molecular findings.
Pathology
CIS cells show similarities to embryonic germ cells,
like their positivity for alkaline phosphatase, the stem
cell factor receptor (c-KIT), and their glycogen content.
These cells are frequently found in the adjacent
parenchyma of an invasive seminoma and
nonseminoma, of which a representative example is
given
in
Figure
1.
Histologically
and
immunohistochemically, seminoma cells mimick CIS.
Lymphocytic infiltrations in the supportive stroma are a
consistent feature of these tumors (Figure 2). So far, no
differences have been found between CIS and
seminoma cell, except the invasive growth of the latter.
In contrast to the homogeneity of CIS and seminomas,
nonseminomas can be composed of different elements,
including embryonal carcinoma (the undifferentiated,
stem cell, component), teratoma (the somatically
differentiated component), yolk sac tumour and
choriocarcinoma (the components of extra-embryonal
differentiation) (see Figure 3-6). These different
histological elements can be identified using
immunohistochemistry for different markers, like
CD30 for embryonal carcinoma, alpha fetoprotein
(AFP) for yolk sac tumour, and human chorionic
gonadotropin (hCG) for choriocarcinoma (see
illustrations). Most nonseminomas are mixtures of
these different elements. About 50% of germ cell
tumors of adolescents and adults are pure seminomas,
and 40% pure or mixed nonseminomas. Tumours
containing both a seminoma and a nonseminoma
component are classified as combined tumours
according to the British Classification system, and as
nonseminomas according to the World Health
Organisation (WHO) classification. These tumours
present at an age in between that of pure seminoma and
nonseminoma.
The spermatocytic seminomas are histologically
uniform and composed of three cell types, small,
intermediate and large cells, that are evenly distributed
(Figure 7). The immunohistochemical markers for
CIS/seminoma are overall negative in spermatocytic
seminomas. So far, no specific markers have been
reported for spermatocytic seminomas, Histologically
and immunohistochemically, the teratoma and yolk sac
tumour components found in the infantile testis are
indistinguishable from those elements found in
nonseminomas of the adult testis. However, they differ
in chromosomal constitution (see Table 1 and below),
and the first lack CIS in the adjacent parenchyma.
Prognosis
The teratomas of infants, and the spermatocytic
seminomas are generally benign. Therefore,
orchidectomy alone is mostly curative. However,
spermatocytic seminomas may progress to sarcoma, a
highly malignant tumour. When the yolk sac tumour
component of infants is metastatic, it can be cured in
the majority of patients using chemotherapy.
Seminomas are highly sensitive to irradiation, while
nonseminomas are overall highly sensitive to cisplatinbased chemotherapy, with cure rates of up to 90%.
Criteria have been developed to distinguish
nonseminoma patients with a good, intermediate and
poor response (Table 2). Although these parameters are
not informative on an individual basis, they separate
the three groups as a whole. Seminoma patients always
fall in the good and intermediate prognostic group.
Stage I disease might be treated by orchidectomy
followed by a "wait and see" strategy. Alternatively,
retroperitoneal lymph node dissection (nerve sparing)
and/or irradiation (in case of pure seminoma) can be
performed. Moreover, a single dose cisplatin-based
chemotherapy is tested in an experimental set up. These
issues are of interest, because the risk of occult
metastases in clinically stage I nonseminomas is about
30%. Established factors predicting metastastic disease
are lymphovascular space invasion and percentage of
embryonal carcinoma. For nonseminomas there is no
consensus on the best method to define the risk of
occult metastases and on how the information can be
used for the clinical management of patients. In
clinically stage I seminoma patients occult metastases
are predicted by vascular invasion and tumor size.
More recently, the mean nuclear volume has been
reported to be an informative parameter.
Evolution
In spite of the fact that it is generally accepted that CIS
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(2)
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Testis: Germ cell tumors
Looijenga LHJ
Obviously these parameters could serve to define a
group of patients that could benefit from surveillance.
Patients with refractory disease might benefit from
high-dose chemotherapy.
Because CIS is formed during intra-uterine growth, and
the treatable cancer in most cases becomes clinically
manifest after puberty, methods for early diagnosis and
treatment might prevent progression of CIS to an
invasive seminoma or nonseminoma, thereby
preventing possible progression to refractory disease. A
number of putative parameters have been reported,
although none of them have been tested in a clinical
setting thus far. Moreover, it has been shown that CIS
can be effectively eradicated using local irradiation,
with limited side effects.
The presence of CIS in the contralateral testis in 5% of
patients with a seminoma or nonseminomas has led to
the routine of a contralateral biopsy in some countries.
However, in most countries the clinicians prefer a
closely "wait and see" strategy. Patients with
cryptorchidism, atrophic testis, or prior infertility have
a higher risk of CIS in the contralateral testis. The exact
numbers are unknown, but it is estimated that high-risk
patients comprise 40-50% of the population with CIS.
Altogether about 50-60% of patients with a unilateral
testis tumor will have no other risk factors for CIS.
studies indicated linkage to chromosome 18. The latter
study found linkage to the short arm of chromosome 2,
and the telomeric region of 3q. A telomeric region of
the long arm of chromosome 12 showed linkage when
the results of both studies were combined, while no
linkage was found in the separate studies. An other
finding of interest is the fact that bilateral occurrence of
the tumor is more frequent in familial than in sporadic
cases (15 versus 5%). Indeed, most recently linkage to
Xq27 has been found for cryptorchidism and bilateral
germ cell tumors, although the gene involved is still
unknown.
Cytogenetics
Cytogenetics Morphological
The three groups of germ cell tumours of the testis
show characteristic chromosomal anomalies, which
favor the model of separate pathogeneses. The
chromosomal data on germ cell tumors of the infantile
testis and spermatocytic seminomas are scarse.
While no aberrations are found so far in teratomas of
the infantile testis, the yolk sac tumours show recurrent
loss of part of 6q, and gain of parts of 1q, 20q, and 22.
In addition, these yolk sac tumours are all found to be
aneuploid.
One study reports the analysis of spermatocytic
seminomas by karyotyping and comparative genomic
hybridization, showing gain of chromosome 9 as the
only recurrent and characteristic chromosomal
abnormality.
Seminomas, nonseminomas as well as CIS are
consistently aneuploid with a characteristic pattern of
chromosomal gains and losses. The cells of seminoma
and CIS are hypertriploid, while those of
nonseminoma, irrespective of histological composition,
are hypotriploid. Using karyotyping, more recently
supported by in situ and comparative genomic
hybridization, a complex, but similar pattern of overand underrepresentation of (parts of) chromosomes has
been identified in seminomas and nonseminomas.
Genetics
Note
Familial predisposition About 2% of the patients with a
seminoma or nonseminoma have an affected family
member, indicating a genetic component in the
development of this cancer. So far, two genome-wide
linkage analyses have been performed. The first
showed linkage to regions of chromosome 1, 4, 5, 14
and 18, while the second found no evidence for linkage
to chromosome 1, and a weaker indication for
involvement of region 2 of chromosome 4 (4cen-q13).
For the other region on chromosome 4 (p14-p13), and
for chromosome 5, similar results were obtained. Both
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(2)
133
Testis: Germ cell tumors
Looijenga LHJ
Representative example of: actual G-banding and schematic of a normal chromosome 12 (left within panel) and an isochromosome 12p
(i(12p)) (right within panel); the fluorescent in situ hybridization pattern with a probe specific for the centromeric region of chromosome 12
(red) and the p-arm (green). Note the presence of three normal chromosomes 12 (paired green and red signal), and two
isochromosomes (one red and two green signals).
be a tool to identify the gene(s) on 12p. So far, these
data suggest that is relates to a gene that suppresses
induction of apoptosis upon invasive growth of the
tumour cells.
Proto-oncogenes Several studies deal with the possible
role of activation of proto-oncogenes in the
development of seminomas and nonseminomas. RAS
genes are rarely found to be mutated One study
reported the presence of mutations in c-KIT in some
cases. Overexpression of c-MYC has been found in less
than 10% of nonseminomas, and amplification of
MDM2 in also less than 10% of the tumors. Cyclin D2
has been suggested as the candidate gene on 12p.
However, this gene maps outside the amplified region
found in some seminomas and nonseminomas. In
conclusion, the role of activation of proto-oncogenes in
the genesis of seminomas and nonseminomas is not
illucidated so far.
Tumor suppressor genes Studies of loss of
heterozygosity (LOH), a hallmark of the involvement
of tumor suppressor genes, have given rather
inconsistent results in seminomas and nonseminomas,
which might be related to their aneuploidy. Several
studies have been performed on chromosomes 1, 5, 11,
12 and 18. Recurrent loss has been observed on 1p, in
particular bands p13, p22, p31.3-p32, and 1q; in
particular bands q32. Several regions on chromosome 5
show LOH, including p15.1-p15.2, q11, q14, q21, and
q34-qter. Chromosome 12 contains two regions of
interest, i.e., q13 and q22. In spite of the identification
of homozygous deletions at 12q22, no candidate genes
have been identified so far. Homozygous deletions
have also been identified on the long arm of
chromosome 18. Although DCC (deleted in colorectal
cancer) might be a candidate, it has been indicated that
loss of this gene is likely progression-related. More
recently, inactivating mutations of SMAD4, also
mapped to 18q, have been reported in a limited number
of seminomas. LOH analysis on microdissected tumor
cells of different histologies, including CIS, revealed
Overall, the chromosomes 4, 5, 11, 13, 18 and Y are
underrepresented, while the chromosomes 7, 8, 12 and
X are overrepresented. In spite of the highly similar
pattern of gains and losses in seminomas and
nonseminomas, some differences were observed, like
overrepresentation of chromosome 15 in seminomas
compared to nonseminomas, which might explain the
ploidy difference between these two histological
groups.
The recurrent pattern of chromosomal gains and losses
suggests that both activation of proto-oncogenes, and
inactivation of tumor suppressor genes is involved in
the development of this cancer.
Gain of 12p The isochromosome 12p can be used as a
diagnostic molecular marker for seminomas and
nonseminomas: the most consistent chromosomal
anomaly in seminomas and nonseminomas, besides
their aneuploidy, is gain of the short arm of
chromosome 12. In fact, about 80% of the invasive
tumors have extra copies of 12p due to the formation of
an isochromosome (i(12p)) (Figure). The 20% i((12p)
negative tumors also show gain of 12p, due to other
chromosomal changes. These data strongly indicate
that the short arm of chromosome 12 contains a gene or
genes of which extra copies are required for the
development of the invasive tumor. Analysis of LOH
on the long arm of chromosome 12 showed that
polyploidisation occurs prior to i(12p) formation. In
addition, it was demonstrated that i(12p) results from
sister chromatin exchange. In contrast, non-sister
cromatin exchange has also been suggested. Most
recently, it was shown that the presence of extra copies
of the short arm of chromosome 12 is related to
invasive growth of the tumor, i.e., no gain of 12p is
observed in CIS. This suggests that addition copies of
one or more genes on 12p is relevant for the
progression of CIS to an invasive tumor. Analysis of
seminomas and nonseminomas containing a high level
amplification of a restricted region of 12p, i.e., band
p11.2-12.1, cyclin D2 being outside this region, might
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(2)
134
Testis: Germ cell tumors
Looijenga LHJ
tumors of the testis. Pathogenetic and clinical relevance. Lab
Invest. 1989 Jan;60(1):14-21
recurrent LOH at 3q27-q28, 5q31, 5q34-q35, 9p21-p22
and 12q22. These anomalies were also found in the
adjacent CIS cells. Interestingly, loss of 3q27-q28 was
only but consistently detected in the embryonal
carcinoma components. The other targets investigated
with overall negative findings are: NME1 and 2, APC,
MCC, RB, WT1, and P53. However, hypermethylation
of exon 1 of p16 was found in about 50% of the
tumors, which was related to no, or a low level of
expression.
In summary, although interesting observations have
been made, no convincing data based on studies on
LOH, mutations and expression so far, indicate a
significant involvement of one of the studied tumor
suppressor genes in the development of testicular
seminomas and nonseminomas. Moreover, no
candidate genes have been identified for the teratomas
and yolk sac tumors of the infantile testis, as well as for
spermatocytic seminomas.
Oosterhuis JW, Castedo SM, de Jong B, Cornelisse CJ, Dam
A, Sleijfer DT, Schraffordt Koops H. Ploidy of primary germ cell
tumors of the testis. Pathogenetic and clinical relevance. Lab
Invest. 1989 Jan;60(1):14-21
Giwercman A, Müller J, Skakkebaek NE. Prevalence of
carcinoma in situ and other histopathological abnormalities in
testes from 399 men who died suddenly and unexpectedly. J
Urol. 1991 Jan;145(1):77-80
Mukherjee AB, Murty VV, Rodriguez E, Reuter VE, Bosl GJ,
Chaganti RS. Detection and analysis of origin of i(12p), a
diagnostic marker of human male germ cell tumors, by
fluorescence in situ hybridization. Genes Chromosomes
Cancer. 1991 Jul;3(4):300-7
de Graaff WE, Oosterhuis JW, de Jong B, Dam A, van Putten
WL, Castedo SM, Sleijfer DT, Schraffordt Koops H. Ploidy of
testicular carcinoma in situ. Lab Invest. 1992 Feb;66(2):166-8
el-Naggar AK, Ro JY, McLemore D, Ayala AG, Batsakis JG.
DNA ploidy in testicular germ cell neoplasms. Histogenetic and
clinical implications. Am J Surg Pathol. 1992 Jun;16(6):611-8
Cytogenetics Molecular
Moul JW, Theune SM, Chang EH. Detection of RAS mutations
in archival testicular germ cell tumors by polymerase chain
reaction
and
oligonucleotide
hybridization.
Genes
Chromosomes Cancer. 1992 Sep;5(2):109-18
The isochromosome 12p can be identified on
interphase nuclei by fluorescent in situ hybridization,
using simultaneously a probe specific for the
centromeric region and the short am of chromosome
12. The use of the centromeric probe only was not
found to be informative.
Burke AP, Mostofi FK. Spermatocytic seminoma. A
clinicopathologic study of 79 cases. J Urol Path. 1993;1:21-32.
Giwercman A, Skakkebaek NE. Carcinoma in situ of the testis:
biology, screening and management. Eur Urol. 1993;23 Suppl
2:19-21
Genes involved and proteins
Looijenga LH, Gillis AJ, Van Putten WL, Oosterhuis JW. In situ
numeric analysis of centromeric regions of chromosomes 1,
12, and 15 of seminomas, nonseminomatous germ cell tumors,
and carcinoma in situ of human testis. Lab Invest. 1993
Feb;68(2):211-9
Note
In spite of several suggestions about a possible role of a
number of genes in the development of teratomas and
yolk sac tumours of the infantile testis, the seminomas
and nonseminomas and the spermatocytic seminomas,
actual prove for their involvement is missing so far.
Looijenga LH, Gillis AJ, Van Putten WL, Oosterhuis JW. In situ
numeric analysis of centromeric regions of chromosomes 1,
12, and 15 of seminomas, nonseminomatous germ cell tumors,
and carcinoma in situ of human testis. Lab Invest. 1993
Feb;68(2):211-9
To be noted
Lothe RA, Hastie N, Heimdal K, Fosså SD, Stenwig AE,
Børresen AL. Frequent loss of 11p13 and 11p15 loci in male
germ cell tumours. Genes Chromosomes Cancer. 1993
Jun;7(2):96-101
Note
Gain of 12p is restricted to invasive seminomas and
nonseminomas, and is not found in CIS. Therefore
additional copies of the gene(s) on 12p is not involved
in the early development of this cancer.
Oosterhuis JW, Looijenga LH. The biology of human germ cell
tumours: retrospective speculations and new prospectives. Eur
Urol. 1993;23(1):245-50
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Testis: Germ cell tumors
tumor 1 gene.
Mar;9(3):153-60
Genes
Looijenga LHJ
Chromosomes
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T, du Manoir S, Geurts van Kessel A, Harstrick A, Seeber S,
Becher R. Detection of chromosomal DNA gains and losses in
testicular germ cell tumors by comparative genomic
hybridization.
Genes
Chromosomes
Cancer.
1996
Oct;17(2):78-87
Mathew S, Murty VV, Bosl GJ, Chaganti RS. Loss of
heterozygosity identifies multiple sites of allelic deletions on
chromosome 1 in human male germ cell tumors. Cancer Res.
1994 Dec 1;54(23):6265-9
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Detection and enrichment of carcinoma-in-situ cells in semen
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Hoffman KJ. Testicular cancer in blacks. A multicenter
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HJ, van Zoelen EJ, Oosterhuis JW. Aberrant platelet-derived
growth factor alpha-receptor transcript as a diagnostic marker
for early human germ cell tumors of the adult testis. Proc Natl
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Murty VV, Bosl GJ, Houldsworth J, Meyers M, Mukherjee AB,
Reuter V, Chaganti RS. Allelic loss and somatic differentiation
in human male germ cell tumors. Oncogene. 1994
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region of 12p over-representation in testicular germ cell tumors
of adolescents and adults. Oncogene. 1998 May;16(20):261727
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Echten-Arends J, de Jong B, Mostert M, Wolter Oosterhuis J.
Comparative genomic hybridization of microdissected samples
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Looijenga LHJ
Roelofs H, Mostert MC, Pompe K, Zafarana G, van Oorschot
M, van Gurp RJ, Gillis AJ, Stoop H, Beverloo B, Oosterhuis
JW, Bokemeyer C, Looijenga LH. Restricted 12p amplification
and RAS mutation in human germ cell tumors of the adult
testis. Am J Pathol. 2000 Oct;157(4):1155-66
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testicular seminomas and nonseminomas. Oncogene. 2000
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This article should be referenced as such:
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(2)
Looijenga LHJ. Testis: Germ cell tumors. Atlas Genet
Cytogenet Oncol Haematol. 2001; 5(2):129-138.
138
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in Oncology and Haematology
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Cancer Prone Disease Section
Mini Review
Bruton's agammaglobulinemia
Niels B Atkin
Department of Cancer Research, Mount Vernon Hospital, Northwood, Middlesex, UK (NBA)
Published in Atlas Database: January 2001
Online updated version : http://AtlasGeneticsOncology.org/Kprones/BrutonAgammaID10023.html
DOI: 10.4267/2042/37738
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© 2001 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
Other findings
Alias
X-linked agammaglobulinemia (XLA)
Inheritance
X-linked disorder occurring in males; frequency of
XLA is about 0.3-0.6/105.
Note
Absence of plasma cells in bone marrow and lymph
nodes (the latter lack germinal centres) resulting in an
almost complete lack of humoral immunity due to a
failure of early B-lymphocyte development; normal
myeloid and T-cell function: extremely deficient
production of antibodies to all antigens.
Clinics
Phenotype and clinics
Genes involved and proteins
Immunological deficiency, first described in 1952,
manifest from late infancy and typically resulting in
frequent bacterial infections commencing in the second
half of the first year of life: tonsils and lymph nodes are
very
small;
marked
decrease
of
serum
immunoglobulins of all isotypes (maternal IgG gives
some protection in early infancy);
BTK (Bruton's tyrosine kinase)
Location: Xq21.3-Xq22
DNA/RNA
Description: Encoded in 19 exons spanning 37 kb.
Protein
Description: Btk is a 659 amino-acid cytoplasmic
tyrosine kinase.
Expression: Is expressed at all except the terminally
differentiated plasma cell stage of B-cell development.
Function: It is a member of a small family of srcrelated hematopoietic kinases and, like them, has
several interaction domains that allow it to bind to
other components of signal-transduction pathways;
unlike other src family members, Btk family members
have a pleckstrin homology (PH) domain which is
followed by a proline rich region that binds to the SH3
region of several src family members.
Mutations
Germinal: Over 300 different mutations in Btk have
been identified; only about 50% of patients with the
clinical and laboratory findings of XLA have a family
history of immunodeficiency; most of the remaining
patients are the first manifestation of a new mutation in
Neoplastic risk
Probably slight; in a 1963 paper, two patients with
lymphoma were reported and reference was made to
two adults with hypoglobulinemia who also had
lymphomas; recent surveys of XLA patients do not
reveal any cases of lymphoma; however, long-term
vigilance needs to be maintained; at least seven cases
of adenocarcinoma of the gastrointestinal tract in young
adults with XLA have been reported; other
malignancies have also been reported, but it is not clear
whether they occur with an increased frequency;
Treatment
Vigorous antibiotic therapy and regular injections of
immunoglobulin.
Prognosis
Good, on survival into early adulthood.
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(2)
139
Bruton's agammaglobulinemia
Atkin NB
Tsuge I, Yamadori T, Kunikata T, Arai S, Yoshizaki K,
Taniguchi N, Kishimoto T. Identification of Bruton's tyrosine
kinase (Btk) gene mutations and characterization of the
derived proteins in 35 X-linked agammaglobulinemia families:
a nationwide study of Btk deficiency in Japan. Blood. 1996 Jul
15;88(2):561-73
Btk; most mutations are single base-pair substitutions
that result in premature stop codons, splice defects, or
amino-acid substitutions. 5-10% of patients with XLA
have gross alterations in the BTK gene (usually
deletions) detectable by Southern-blot analysis; most
amino-acid substitutions in Btk render the protein
unstable and markedly reduced or absent.
Rawlings DJ, Scharenberg AM, Park H, Wahl MI, Lin S, Kato
RM, Fluckiger AC, Witte ON, Kinet JP. Activation of BTK by a
phosphorylation mechanism initiated by SRC family kinases.
Science. 1996 Feb 9;271(5250):822-5
References
1952
Tsukada S. Symposium on gene abnormalities in medical
diseases.
1.
Immunological
diseases:
Bruton's
agammaglobulinemia. Intern Med. 1997 Feb;36(2):148-50
PAGE AR, HANSEN AE, GOOD RA. Occurrence of leukemia
and lymphoma in patients with agammaglobulinemia. Blood.
1963 Feb;21:197-206
Conley
ME,
Rohrer
J,
Minegishi
Y.
X-linked
agammaglobulinemia. Clin Rev Allergy Immunol. 2000
Oct;19(2):183-204
BRUTON OC.
Jun;9(6):722-8
Agammaglobulinemia.
Pediatrics.
Good RA, Peterson RDA, Perey DY, Finstad J, Cooper MD.
The immunological deficiency diseases of man: consideration
of some questions asked by these patients with an attempt at
classification. Birth Defects 1968;4:17-39.
This article should be referenced as such:
Atkin NB. Bruton's agammaglobulinemia. Atlas
Cytogenet Oncol Haematol. 2001; 5(2):139-140.
Hashimoto S, Tsukada S, Matsushita M, Miyawaki T, Niida Y,
Yachie A, Kobayashi S, Iwata T, Hayakawa H, Matsuoka H,
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(2)
140
Genet
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Cancer Prone Disease Section
Mini Review
Familial nervous system tumour syndromes
Anne-Marie Capodano
Laboratoire de Cytogénétique Oncologique, Hôpital de la Timone, 264 rue Saint Pierre, 13005 Marseille,
France (AMC)
Published in Atlas Database: January 2001
Online updated version : http://AtlasGeneticsOncology.org/Kprones/FamilNervousCanID10067.html
DOI: 10.4267/2042/37739
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2001 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Renal hamartomatous tumors, Cysts of the lung and
kidney.
Genes TSC1 and TSC2 located in 9q34 and 16p13
respectively
Turcot syndrome:
Nervous
System
Tumors
Medulloblastomas,
Glioblastomas
Other tumors Colorectal polyps
Genes APC, hMLh1 and hPMS2 located in 5q21,
3p21, and 7p22 respectively
Von Hippel-Lindau syndrome:
Nervous System Tumors Hemangioblastomas
Other tumors Retinal hemangioblastomas, Renal cell
carcinoma, Pheochromocytoma
Genes VHL located in 3p25
Li-Fraumeni syndrome:
Nervous System Tumors Astrocytomas, PNET
Other tumors Breast carcinoma, Bone and soft tissues
sarcomas, Adenocortical carcinoma, leukaemia
Genes TP53 located in 17p13
Gorlin syndrome:
Nervous System Tumors Medulloblastomas
Other tumors Multiple basal cell carcinomas, Ovarian
fibromas.
Genes PTCH located in 9q31
Cowden syndrome:
Nervous System Tumors Dysplastic gangliocytoma of
the cerebellum
Other tumors Hamartomatous polyps of the colon,
Thyroid neoplasms, Breast carcinoma
Genes PTEN located in 10q23
Identity
Inheritance
Eight genetic syndromes are associated with nervous
system tumours; these are:
Neufibromatosis 1 (NF1),
Neufibromatosis 2 (NF2),
Tuberous sclerosis,
Turcot syndrome,
Von Hippel-Lindau syndrome,
Li-Fraumeni syndrome,
Gorlin syndrome,
Cowden syndrome,
Clinics
Neoplastic risk
Neufibromatosis 1 (NF1):
Nervous
System
Tumors
Neurofibromas,
Astrocytomas, Optic nerve gliomas
Other tumors Pheochromocytoma , Osseous lesions,
Iris hamartomas
Genes NF1 located in 17q11
Neufibromatosis 2 (NF2):
Nervous System Tumors Schwanomas, Meningiomas,
Spinal ependymomas, Astrocytomas
Other tumors Retinal hamartoma
Genes NF2 located in 22q12
Tuberous sclerosis:
Nervous
System
Tumors
Astrocytomas,
Subependymal giant cell tumors
Other tumors Cutaneous angio-fibroma, Cardiac
rhabdomyomas, Adenomatous polyps of duodenum,
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(2)
This article should be referenced as such:
Capodano AM. Familial nervous system tumour syndromes.
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(2):141.
141
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
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Cancer Prone Disease Section
Mini Review
Multiple endocrine neoplasia type 2 (MEN2)
Sophie Giraud
Laboratoire de Génétique, Hôpital E. Herriot, 69437 Lyon cedex 03, France (SG)
Published in Atlas Database: January 2001
Online updated version : http://AtlasGeneticsOncology.org/Kprones/MEN2ID10009.html
DOI: 10.4267/2042/37740
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2001 Atlas of Genetics and Cytogenetics in Oncology and Haematology
the later course of the disease. There is no obvious
syndrome of calcitonin overproduction.
Pheochromocytoma
secrete
adrenaline
and
noradrenaline which are responsible of hypertension
but could be undetected and lead to fatal hypertensive
episodes.
Parathyroid hyperplasia or adenoma lead to
hyperparathyroidism; they are often clinically silent but
could be revealed by symptomatic hypercalcemia or
renal stones.
Identity
Alias
Sipple syndrome
Gorlin syndrome (not to be confused with the GorlinGoltz/naevoid basal cell carcinoma syndrome ).
Note
Multiple Endocrine Neoplasia type 2 (MEN2) is
defined by the association of C-cell tumors of the
thyroid ( medullar thyroid carcinoma), tumors of the
adrenal medulla ( pheochromocytoma) and parathyroid
hyperplasia or adenoma in a single patient or in close
relatives.
Inheritance
MEN2 is an autosomal dominant disorder with a high
penetrance. Expressivity is variable but phenotypegenotype correlations have been described. Incidence is
estimated at 0.1/105/year. It is generally assumed that
20 to 25% of medullar thyroid carcinomas (MTC) are
heritable.
Neoplastic risk
MTC is a malignant tumor, metastasizing at first
locally within the neck and then to distant sites. Usually
pheochromocytoma is non malignant; parathyroid
hyperplasia or adenoma are benign.
Treatment
Total thyroidectomy with bilateral radical lymph node
dissection is the treatment of MTC. Thyroidectomy is
recommended for carriers of mutations, in the first
years of life in MEN2A and MEN2B families, as soon
as elevation CT during pentagastrin test in FMTC
families.
Pheochromocytoma, hyperplasic parathyroid or
adenoma should be surgically removed.
Clinics
Phenotype and clinics
Three subtypes have been described:
MEN2A (Sipple syndrome) is the most frequent form,
characterized by MTC in 95% of cases,
phaeochromocytoma in 50% and parathyroid
hperplasia or adenoma in 25%.
In familial MTC (FMTC), MTC is the only clinical
manifestation.
MEN2B (Gorlin syndrome) is the least frequent variant
defined
by
predisposition
to
MTC
and
phaechromocytoma and marfanoid habitus, mucosal
neuromas
and
ganglioneuromatosis
of
the
gastrointestinal tract.
C-cells secrete the hormon calcitonin which is a
valuable marker for early diagnosis and for following
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(2)
Prognosis
Pheochromocytoma could be letal by hypertension
episodes but prognosis is essentially dependant from
MTC.
Genes involved and proteins
RET
Location : 10q11.2
DNA/RNA
Description: 21 exons; genomic sequence of 55kb.
142
Multiple endocrine neoplasia type 2 (MEN2)
Giraud S
Schuchardt A, D'Agati V, Larsson-Blomberg L, Costantini F,
Pachnis V. Defects in the kidney and enteric nervous system of
mice lacking the tyrosine kinase receptor Ret. Nature. 1994
Jan 27;367(6461):380-3
Protein
Description: Three main 3' alternatively spliced forms
of 1072 to 1114 aminoacids. There is a cleavable signal
sequence of 28 aminoacids, a glycosylated extracellular
domain formed of a region of cadherin homology and
another cystein-rich region, a transmembrane domain
and an intracellular tyrosine kinase domain.
Expression: RET is expressed predominantly in the
developing central and peripheral nervous system, the
excretory system and the migratory neural-crest cells
during embryogenesis.
Function: Receptor tyrosine kinase.
Mutations
Germinal: In MEN2A and FMTC, mutations are
located in the sequence encoding the juxtamembrane
cystein-rich domain and involved aminoacids C609,
C611, C618, C620, C630, D631 and C634. Most of
these mutations result in the substitution of the cystein
for a different amino acid. MEN2A is predominantly
associated with a mutation of C634, highly predictive
for the development of pheochromocytoma and
hyperparathyroidism. Until today three duplications in
the cystein-rich domain have been published.
MEN2B is caused by germline mutations of the tyrosin
kinase domain: substitution M918T in more than 95%
of cases, A883F in less than 4% of those. Rare
mutations at aminoacids 912, 922 and an association of
V804M/Y806C have been described.
Other mutations of the tyrosin kinase domain have been
identified in FMTC families and unusually in MEN2A
patients: E768D, L790F, Y791F, V804M, V804L and
S891A.
Some families with MEN2 and Hirschsprung disease
have been described: each of them has a mutation in
either C618 or C620. Families with Hirschsprung
disease alone have mutations overspread in all the
coding region of RET.
Schuffenecker I, Billaud M, Calender A, Chambe B, Ginet N,
Calmettes C, Modigliani E, Lenoir GM. RET proto-oncogene
mutations in French MEN 2A and FMTC families. Hum Mol
Genet. 1994 Nov;3(11):1939-43
van Heyningen V. Genetics. One gene--four syndromes.
Nature. 1994 Jan 27;367(6461):319-20
Pacini F, Romei C, Miccoli P, Elisei R, Molinaro E, Mancusi F,
Iacconi P, Basolo F, Martino E, Pinchera A. Early treatment of
hereditary medullary thyroid carcinoma after attribution of
multiple endocrine neoplasia type 2 gene carrier status by
screening for ret gene mutations. Surgery. 1995
Dec;118(6):1031-5
Santoro M, Carlomagno F, Romano A, Bottaro DP, Dathan NA,
Grieco M, Fusco A, Vecchio G, Matoskova B, Kraus MH.
Activation of RET as a dominant transforming gene by
germline mutations of MEN2A and MEN2B. Science. 1995 Jan
20;267(5196):381-3
Eng C, Clayton D, Schuffenecker I, Lenoir G, Cote G, Gagel
RF, van Amstel HK, Lips CJ, Nishisho I, Takai SI, Marsh DJ,
Robinson BG, Frank-Raue K, Raue F, Xue F, Noll WW, Romei
C, Pacini F, Fink M, Niederle B, Zedenius J, Nordenskjöld M,
Komminoth P, Hendy GN, Mulligan LM. The relationship
between specific RET proto-oncogene mutations and disease
phenotype in multiple endocrine neoplasia type 2. International
RET mutation consortium analysis. JAMA. 1996 Nov
20;276(19):1575-9
Eng C, Mulligan LM. Mutations of the RET proto-oncogene in
the multiple endocrine neoplasia type 2 syndromes, related
sporadic tumours, and hirschsprung disease. Hum Mutat.
1997;9(2):97-109
Ito S, Iwashita T, Asai N, Murakami H, Iwata Y, Sobue G,
Takahashi M. Biological properties of Ret with cysteine
mutations correlate with multiple endocrine neoplasia type 2A,
familial medullary thyroid carcinoma, and Hirschsprung's
disease phenotype. Cancer Res. 1997 Jul 15;57(14):2870-2
Michiels FM, Chappuis S, Caillou B, Pasini A, Talbot M, Monier
R, Lenoir GM, Feunteun J, Billaud M. Development of
medullary thyroid carcinoma in transgenic mice expressing the
RET protooncogene altered by a multiple endocrine neoplasia
type 2A mutation. Proc Natl Acad Sci U S A. 1997 Apr
1;94(7):3330-5
References
Block MA, Jackson CE, Greenawald KA, Yott JB, Tashjian AH
Jr. Clinical characteristics distinguishing hereditary from
sporadic medullary thyroid carcinoma. Treatment implications.
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Höppner W, Dralle H, Brabant G. Duplication of 9 base pairs in
the critical cysteine-rich domain of the RET proto-oncogene
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1998;Suppl 1:S128-30
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Kidd JR, Jackson CE, Duncan AM, Farrer LA, Brasch
Assignment of multiple endocrine neoplasia type 2A
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S,
K.
to
6-
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Mechanisms of development of multiple endocrine neoplasia
type 2 and Hirschsprung's disease by ret mutations. Recent
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A novel 9-base pair duplication in RET exon 8 in familial
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carcinoma. Nature. 1994 Jan 27;367(6461):375-6
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This article should be referenced as such:
Giraud S. Multiple endocrine neoplasia type 2 (MEN2). Atlas
Genet Cytogenet Oncol Haematol. 2001; 5(2):142-144.
Iwashita T, Murakami H, Kurokawa K, Kawai K, Miyauchi A,
Futami H, Qiao S, Ichihara M, Takahashi M. A two-hit model
for development of multiple endocrine neoplasia type 2B by
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(2)
144
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Cancer Prone Disease Section
Review
Von Hippel-Lindau
Stéphane Richard
Génétique Oncologique EPHE, Faculté de Médecine Paris-Sud, 63 av Gabriel Péri, 94276 Le KremlinBicêtre, France (SR)
Published in Atlas Database: January 2001
Online updated version : http://AtlasGeneticsOncology.org/Kprones/VHLKpr10010.html
DOI: 10.4267/2042/37741
This article is an update of: Capodano AM. Von Hippel-Lindau. Atlas Genet Cytogenet Oncol Haematol.1998;2(4):155-156.
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2001 Atlas of Genetics and Cytogenetics in Oncology and Haematology
hemangioblastomas occur peripherally but optic disc
(papillary or juxtapapillary) locations are encountered
in almost 15% of cases.
Renal cell carcinomas occur in up to 75% of cases.
They are mostly multifocal and bilateral. Tumors have
a classical solid or a more specific mixed cystic/solid
appearance and are always of clear cell subtype.
Multiple benign cysts are also observed.
Pheochromocytomas, often bilateral, are mostly found
in a subset of families, where it can be the only sign of
VHL. Extraadrenal paragangliomas are sometimes
encountered.
Pancreas manifestations occur in up to 77% of patients:
isolated or multiple cysts and serous cystadenomas are
the most frequent lesions, neuroendocrine tumours
occur in about 10-15 % of cases.
Endolymphatic sac tumours, only recently recognised
as a manifestation of VHL disease, occur in up to 11%
of cases.
Epididymal cysts, often bilateral, occur in about 54% of
men.
Cystadenomas of the broad ligament ("adnexal
papillary tumour of probable mesonephric origin") are
extremely rare but highly specific.
There are two main clinical types of VHL according to
the absence (type 1) or presence of pheochromocytoma
(type 2). The type 2 is subdivised in three subtypes, 2A
(with low risk of renal cancer and pancreatic tumors);
2B (the full multi-tissues subtype), and 2C
(pheochromocytomas only, recently individualised by
molecular genetics).
Identity
Note
Von Hippel-Lindau (VHL) disease is a hereditary
devastating cancer syndrome, predisposing to the
development of various benign and malignant tumours
(Central Nervous System [CNS] and retinal
hemangioblastomas, endolymphatic sac tumours, renal
cell carcinoma (RCC) and/or renal cysts,
pheochromocytomas,
pancreatic
cysts
and
neuroendocrine tumours, endolymphatic sac tumours,
epididymal and broad ligament cystadenomas). VHL
disease is the first cause of hereditary kidney cancer.
Inheritance
An autosomal dominant disorder with high penetrance
(increasing with age: 97% by age 60 years) but variable
expressivity (with phenotype/genotype correlations);
frequency is estimated at about 2.5/105; neomutations
represent about 20% of cases.
Clinics
Phenotype and clinics
Onset of the disease usually occurs between 18 and 30
yrs, often with retinal or cerebellar hemangioblastomas,
but can also manifests in children, especially by retinal
hemangioblastomas and pheochromocytoma.
Central nervous system (CNS) hemangioblastomas
occur in 60-80% of patients (infratentorial localisation
in 60 % of cases, intraspinal in 30-40%; supratentorial
in
1%).
Multiple
tumours
are
frequent
(hemangioblastomatosis).
Retinal hemangioblastomas, often multiple and
bilateral, occur in about 50% of patients. Most retinal
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(2)
Neoplastic risk
Central nervous system (CNS) hemangioblastomas
may cause life-threatening complications in spite of
145
Von Hippel-Lindau
Richard S
Pancreatic cysts and serous cystadenomas do not
require resection but sometimes a percutaneous
drainage or endoscopic implantation of a biliary stent is
indicated in cases of compression.
Surgery is indicated for broad ligament cystadenomas
and for symptomatic epididymal cystadenomas.
Medical perspectives: several clinical studies are ongoing with specific drugs that block VEGF in the hope
of causing stabilisation or recession of CNS and retinal
hemangioblastomas. Such clinical trials are in
processing in France, England and Poland.
their benign nature and classic slow-growing course
and remain a major cause of morbidity and mortality in
VHL disease.
Retinal hemangioblastomas may cause retinal
detachment, haemorrhage, glaucoma and cataract,
leading to blindness, in absence of early detection and
treatment.
Renal cell carcinomas is becoming the main cause of
death in the disease, because of secondary
dissemination mainly due to delay in diagnosis.
Pheochromocytomas are malignant in about 5-10% of
cases.
Neuroendocrine pancreatic tumours tend to be slow
growing but have the potential of a truly malignant
course with locoregional dissemination.
Endolymphatic sac tumours is a low grade papillary
adenocarcinoma resulting in progressive hearing loss. It
can grow to the pontocerebelline angle and/or the
middle ear, then destroying the temporal bone.
Epididymal cysts and cystadenomas of the broad
ligament are benign tumors.
Prognosis
According to the severity of the disease in a given
patient, and to the quality of a regular follow up. Mean
age at death is about 50 yrs and renal cell carcinomas
and CNS hemangioblastomas are the major causes of
death. As treatment of VHL manifestations in first
stages will improve significantly the clinical outcome
and the quality of life of patients, early and
unambiguous diagnosis is mandatory. Thus, DNA
testing is emerging as a major progress in this
consideration, pawing the way to an effective
presymptomatic diagnosis.
Treatment
Regular clinical follow-up of patients and gene-carriers
is imperative in order to detect manifestations early and
to avoid complications;
Treatment of symptomatic CNS hemangioblastoma
remains mainly neurosurgical, often in emergency, but
stereotactic radiosurgery is emerging as an alternative
therapeutic procedure in patients with multifocal solid
hemangioblastomas.
Retinal hemangioblastoma are treated by cryotherapy
or laser depending on the location, size and number of
tumours.
Endolymphatic sac tumours require surgical treatment
with the help of ENT specialists as soon as possible in
order to prevent definitive hearing loss. Preoperative
embolisation is sometimes performed to avoid
bleeding.
Renal cell carcinomas have to be treated when their
size is about 3 cm in diameter. Nephron sparing surgery
is the choice method and may delay bilateral
nephrectomy and dialysis. When binephrectomy is
inevitable, renal transplantation can be discussed after a
2 year period without metastasis.
Pheochromocytomas have to be surgically removed,
preferentially with the use of laparoscopy. When
possible, partial adrenalectomy appears to be a safe
method of preserving adrenocortical function and
quality of life.
Pancreatic neuroendocrine tumours require surgical
removal at a 2-3 cm size in order to avoid metastatic
dissemination.
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(2)
Genes involved and proteins
VHL
Location: 3p25-26
DNA/RNA
Description: 3 exons.
Protein
Description: 213 amino acids.
Expression: Wide.
Function: Tumour-suppressor gene. pVHL interacts
with elongins B and C and cullin 2 through a complex
exhibiting ubiquitine ligase activity. Its main function
is to negatively regulate VEGF mRNAs (and
angiogenesis as a result) by targeting hypoxia inducible
transcription factors HIF for degradation by the
proteasome. pVHL has also major functions in extra
cellular matrix formation and cell cycle control.
Mutations
Germinal: Causes VHL disease.
More than 400 mutations have been identified,
comprising for more than 150 independent intragenic
mutational events; virtually 100% of mutations are
detectable. The majority of mutations are represented
by point mutations including missense, nonsense
mutations, splicing, microinsertions or microdeletions.
In about 25 % of cases, a large deletion of the VHL
gene is observed.
146
Von Hippel-Lindau
Richard S
Functional domains of pVHL and distribution of germline point mutations.
Latif F, Tory K, Gnarra J, Yao M, Duh FM, Orcutt ML,
Stackhouse T, Kuzmin I, Modi W, Geil L. Identification of the
von Hippel-Lindau disease tumor suppressor gene. Science.
1993 May 28;260(5112):1317-20
Mutations resulting in a truncated protein are mostly
associated with type 1 VHL. In type 2, mutations are
generally missense mutations affecting preferentially
the critical contact region between pVHL and elongin
C (residues 157-171) with an hot-spot at codon 167. In
type 2A there is a founder effect for a specific missense
mutation at codon 98. In type 2C, mutations occur in
regions potentially involved in critical function
exclusive to the adrenals (as codon 188). Last, patients
with identical VHL germline mutations may display
different phenotypes, indicating that the issue of
genotype-phenotype correlations is complex in VHL.
Evidence was recently provided that unknown modifier
genes and environmental influences could play an
additional role in the clinical expression of the disease.
Somatic: Somatic VHL gene inactivation is frequent in
sporadic hemangioblastomas and moreover in sporadic
renal cell carcinoma, representing a significant event in
the development of these tumors. Different mutational
mechanisms lead to the inactivation of the VHL gene
including loss of heterozygosity, small intragenic
mutations or hypermethylation of the promoter.
Brauch H, Kishida T, Glavac D, Chen F, Pausch F, Höfler H,
Latif F, Lerman MI, Zbar B, Neumann HP. Von Hippel-Lindau
(VHL) disease with pheochromocytoma in the Black Forest
region of Germany: evidence for a founder effect. Hum Genet.
1995 May;95(5):551-6
Linehan WM, Lerman MI, Zbar B. Identification of the von
Hippel-Lindau (VHL) gene. Its role in renal cancer. JAMA. 1995
Feb 15;273(7):564-70
Neumann HP, Lips CJ, Hsia YE, Zbar B. Von Hippel-Lindau
syndrome. Brain Pathol. 1995 Apr;5(2):181-93
Chauveau D, Duvic C, Chrétien Y, Paraf F, Droz D, Melki P,
Hélénon O, Richard S, Grünfeld JP. Renal involvement in von
Hippel-Lindau disease. Kidney Int. 1996 Sep;50(3):944-51
Maddock IR, Moran A, Maher ER, Teare MD, Norman A,
Payne SJ, Whitehouse R, Dodd C, Lavin M, Hartley N, Super
M, Evans DG. A genetic register for von Hippel-Lindau
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Zbar B, Kishida T, Chen F, Schmidt L, Maher ER, Richards
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Gläsker S, Bender BU, Apel TW, Natt E, van Velthoven V,
Scheremet R, Zentner J, Neumann HP. The impact of
molecular genetic analysis of the VHL gene in patients with
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(2)
148
Von Hippel-Lindau
Richard S
Levy M, Richard S. Attitudes of von Hippel-Lindau disease
patients towards presymptomatic genetic diagnosis in children
and prenatal diagnosis. J Med Genet. 2000 Jun;37(6):476-8
Tanimoto K, Makino Y, Pereira T, Poellinger L. Mechanism of
regulation of the hypoxia-inducible factor-1 alpha by the von
Hippel-Lindau tumor suppressor protein. EMBO J. 2000 Aug
15;19(16):4298-309
Richard S, David P, Marsot-Dupuch K, Giraud S, Béroud C,
Resche F. Central nervous system hemangioblastomas,
endolymphatic sac tumors, and von Hippel-Lindau disease.
Neurosurg Rev. 2000 Mar;23(1):1-22; discussion 23-4
Woodward ER, Buchberger A, Clifford SC, Hurst LD, Affara
NA, Maher ER. Comparative sequence analysis of the VHL
tumor suppressor gene. Genomics. 2000 May 1;65(3):253-65
Sgambati MT, Stolle C, Choyke PL, Walther MM, Zbar B,
Linehan WM, Glenn GM. Mosaicism in von Hippel-Lindau
disease: lessons from kindreds with germline mutations
identified in offspring with mosaic parents. Am J Hum Genet.
2000 Jan;66(1):84-91
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(2)
This article should be referenced as such:
Richard S. Von Hippel-Lindau. Atlas Genet Cytogenet Oncol
Haematol. 2001; 5(2):145-149.
149
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OPEN ACCESS JOURNAL AT INIST-CNRS
Cancer Prone Disease Section
Mini Review
Neurofibromatosis type 2 (NF2)
James F Gusella
Molecular Neurogenetics Unit, Massachusetts General Hospital, Harvard Medical School, Charlestown,
Massachusetts 02129, USA (JFG)
Published in Atlas Database: February 2001
Online updated version : http://AtlasGeneticsOncology.org/Kprones/NF2Kpr10007.html
DOI: 10.4267/2042/37742
This article is an update of:
Huret JL. Neurofibromatosis type 2 (NF2). Atlas Genet Cytogenet Oncol Haematol.1998;2(3):109-110.
Huret JL. Neurofibromatosis type 2 (NF2). Atlas Genet Cytogenet Oncol Haematol.1997;1(1):38-39.
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2001 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Neoplastic risk
Identity
NF2 cases represent about 5 % of schwannomas and
meningiomas (i.e. risk increased by 2000), appearing at
the age of 20, while they are found in the general
population at the age of 50 and over.
Alias
Central neurofibromatosis
Bilateral acoustic neurofibromatosis
Bilateral acoustic neurinoma
Bilateral acoustic schwannomas
Inheritance
Autosomal dominant with almost complete penetrance;
frequency is 3/105 newborns; neomutation represent
50% of cases; variable expressivity from mild disease
through life (Gardner type) to severe condition at
young age (Wishart type: with more than 3 tumours).
Prognosis
These tumours are usually benign, but their location
within the central nervous system gives them a grave
prognosis; patients with the Wishart severe form
usually do not survive past 50 yrs.
Cytogenetics
Clinics
Inborn conditions
Note
NF2 is an hamartoneoplastic syndrome; hamartomas
are localized tissue proliferations with faulty
differenciation and mixture of component tissues; they
are heritable malformations that have a potential
towards neoplasia.
Cytogenetics of cancer
Phenotype and clinics
NF2 (neurofibromatosis 2)
Bilateral vestibular (8th cranial pair) schwannomas;
other central or peripheral nerve schwannomas;
meningiomas; ependymomas.
Hearing loss (average age 20 yrs), tinnitus, imbalance,
headache, cataract in 50%, facial paralysis.
Café-au-lait spots and cutaneous and peripheral
neurofibromas may be present, but far less extensively
than in neurofibromatosis type 1.
Location: 22q12
DNA/RNA
Description: 17 exons (1-15, 17 constitutive, 16
alternatively spliced).
Protein
Description: Isoform 1 595 amino acids, isoform 2 590
amino acids (due to inclusion of exon 16 in transcript);
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(2)
Normal.
Chromosome 22 loss is very frequent both in sporadic
and in NF2 schwannomas and meningiomas.
Genes involved and proteins
150
Neurofibromatosis type 2 (NF2)
Gusella JF
disease severity and retinal abnormalities. Am J Hum Genet.
1996 Sep;59(3):529-39
contains a FERM domain and a large a helix domain.
Expression: Wide.
Function: Membrane-cytoskeleton anchor; tumour
suppressor.
Homology: Band 4.1 family , ezrin, radixin, moesin.
Mutations
Germinal: Germ-line mutations in NF2 patients lead to
protein truncation; splice-site or missense mutations are
also found; phenotype-genotype correlations are
observed (i.e. that severe phenotype are found in cases
with protein truncations rather than those with amino
acid substitution).
Somatic: Mutation and allele loss events in tumours in
neurofibromatosis type 2 and in sporadic schwannomas
and meningiomas are in accordance with the two-hit
model for neoplasia.
Ruttledge MH, Andermann AA, Phelan CM, Claudio JO, Han
FY, Chretien N, Rangaratnam S, MacCollin M, Short P, Parry
D, Michels V, Riccardi VM, Weksberg R, Kitamura K, Bradburn
JM, Hall BD, Propping P, Rouleau GA. Type of mutation in the
neurofibromatosis type 2 gene (NF2) frequently determines
severity of disease. Am J Hum Genet. 1996 Aug;59(2):331-42
McClatchey AI, Saotome I, Ramesh V, Gusella JF, Jacks T.
The Nf2 tumor suppressor gene product is essential for
extraembryonic development immediately prior to gastrulation.
Genes Dev. 1997 May 15;11(10):1253-65
Deguen B, Mérel P, Goutebroze L, Giovannini M, Reggio H,
Arpin M, Thomas G. Impaired interaction of naturally occurring
mutant NF2 protein with actin-based cytoskeleton and
membrane. Hum Mol Genet. 1998 Feb;7(2):217-26
Gusella JF, Ramesh V, MacCollin M, Jacoby LB. Merlin: the
neurofibromatosis 2 tumor suppressor. Biochim Biophys Acta.
1999 Mar 25;1423(2):M29-36
References
Giovannini M, Robanus-Maandag E, van der Valk M, NiwaKawakita M, Abramowski V, Goutebroze L, Woodruff JM,
Berns A, Thomas G. Conditional biallelic Nf2 mutation in the
mouse promotes manifestations of human neurofibromatosis
type 2. Genes Dev. 2000 Jul 1;14(13):1617-30
Rouleau GA, Merel P, Lutchman M, Sanson M, Zucman J,
Marineau C, Hoang-Xuan K, Demczuk S, Desmaze C,
Plougastel B. Alteration in a new gene encoding a putative
membrane-organizing protein causes neuro-fibromatosis type
2. Nature. 1993 Jun 10;363(6429):515-21
Kluwe L, Mautner V, Parry DM, Jacoby LB, Baser M, Gusella
J, Davis K, Stavrou D, MacCollin M. The parental origin of new
mutations in neurofibromatosis 2. Neurogenetics. 2000
Sep;3(1):17-24
Trofatter JA, MacCollin MM, Rutter JL, Murrell JR, Duyao MP,
Parry DM, Eldridge R, Kley N, Menon AG, Pulaski K. A novel
moesin-, ezrin-, radixin-like gene is a candidate for the
neurofibromatosis 2 tumor suppressor. Cell. 1993 Mar
12;72(5):791-800
Lim DJ, Rubenstein AE, Evans DG, Jacks T, Seizinger BG,
Baser ME, Beebe D, Brackmann DE, Chiocca EA, Fehon RG,
Giovannini M, Glazer R, Gusella JF, Gutmann DH, Korf B,
Lieberman F, Martuza R, McClatchey AI, Parry DM, Pulst SM,
Ramesh V, Ramsey WJ, Ratner N, Rutkowski JL, Ruttledge M,
Weinstein DE. Advances in neurofibromatosis 2 (NF2): a
workshop report. J Neurogenet. 2000 Jun;14(2):63-106
Parry DM, Eldridge R, Kaiser-Kupfer MI, Bouzas EA, Pikus A,
Patronas N. Neurofibromatosis 2 (NF2): clinical characteristics
of 63 affected individuals and clinical evidence for
heterogeneity. Am J Med Genet. 1994 Oct 1;52(4):450-61
Evans DG, Bourn D, Wallace A, Ramsden RT, Mitchell JD,
Strachan T. Diagnostic issues in a family with late onset type 2
neurofibromatosis. J Med Genet. 1995 Jun;32(6):470-4
This article should be referenced as such:
Gusella JF. Neurofibromatosis type 2 (NF2). Atlas Genet
Cytogenet Oncol Haematol. 2001; 5(2):150-151.
Parry DM, MacCollin MM, Kaiser-Kupfer MI, Pulaski K,
Nicholson HS, Bolesta M, Eldridge R, Gusella JF. Germ-line
mutations in the neurofibromatosis 2 gene: correlations with
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(2)
151
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Deep Insight Section
Nucleotide excision repair
Leon HF Mullenders, Anne Stary, Alain Sarasin
Department of Radiation Genetics and Chemical Mutagenesis, MGC Leiden University Medical Center,
P.O.Box 9503, 2300 RA Leiden and J.A. Cohen Institute, Interuniversity Research Institute for
Radiopathology and Radiation Protection, Leiden, The Netherlands (LHFM); Laboratory of Genetic
Instability and Cancer, UPR2169 CNRS, Institut de Recherches sur le Cancer, 7 rue guy Moquet, BP 8,
94801 Villejuif, France (AS, AS)
Published in Atlas Database: February 2001
Online updated version : http://AtlasGeneticsOncology.org/Deep/ExcisRepairID20014.html
DOI: 10.4267/2042/37743
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2001 Atlas of Genetics and Cytogenetics in Oncology and Haematology
and hypersensitivity to UV. The XP variant cells are
proficient in NER but deficient in lesion bypass when
the replication fork encountered a bulky adduct.
Normally, the translesion synthesis is carried out by the
polymerase eta, which is mutated in the XP variant.
XP-V patients are more UV-sensitive than normal
individuals but less than classical XP. They develop
skin cancers around the age of 20-30 and exhibit less
neurological abnormalities.
In addition to XP, other UV sensitive syndromes exist.
Cockayne' syndrome (CS) is a rare disorder that is
associated with a wide variety of clinical symptoms.
Beside other symptoms, the patients generally show
dwarfism, mental retardation and photosensitivity. In
contrast to XP, CS is not associated with an enhanced
incidence of skin cancer. Cells from CS patients are
hypersensitive to the cytotoxic effects of UV and are
characterized by the inability to resume UV inhibited
DNA and RNA synthesis. Two CS complementation
groups (A and B) have been established. A third group
encompasses patients exhibiting both XP and CS
symptoms, they belong to XP groups B, D or G. The
progressive neurological abnormalities associated with
CS may be due to the inability of CS cells to repair
oxidatice DNA lesions (LePage et al., 2000).
PIBIDS
is
a
photosensitive
variant
of
Trichothiodystrophy (TTD) and the third syndrome that
can be associated with NER defects (PIBIDS is the
acronym of the characteristic clinical symptoms of the
patients for Photosensitivity, Ichthyosis, Brittle hair,
Impaired intelligence, Decreased
All living organisms are equipped with DNA repair
systems that can cope with a wide variety of DNA
lesions. Among these repair pathways, nucleotide
excision repair (NER) is a versatile repair pathway,
involved in the removal of a variety of bulky DNA
lesions such as UV induced cyclobutane pyrimidine
dimers (CPD) and pyrimidine 6-4 pyrimidone
photoproducts (6-4PP). NER is a complex process in
which basically the following steps can be
distinguished:
• (i) recognition of a DNA lesion;
• (ii) separation of the double helix at the DNA
lesion site;
• (iii) single strand incision at both sides of the
lesion;
• (iv) excision of the lesion-containing single
stranded DNA fragment;
• (v) DNA repair synthesis to replace the gap and
• (vi) ligation of the remaining single stranded nick.
The importance of NER for human health is illustrated
by the occurrence of rare autosomal recessive disorder
xeroderma
pigmentosum
(XP).
Patients
characteristically show severe photosensitivity and
abnormal pigmentation, often accompanied by mental
retardation, and they usually develop skin cancer at
very young age (Bootsma et al., 1998) . Cells from
these patients are also extremely sensitive to UV light
and have a defect in NER. Complementation studies
revealed that eight genes are involved in XP: XPA
through XPG and XPV (XP-Variant). Mutations in the
XP genes (except XP-variant) lead to defective NER
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(2)
152
Nucleotide excision repair
Mullenders LHF et al.
NER proteins and their functions
to nondamaged DNA. The XPA protein binds to
replication protein A (RPA) which enhances the
affinity of XPA for damaged DNA and is essential for
NER. The other complex that has been implicated in
DNA damage recognition is XPC-HR23B. XPC cells
have low NER repair capacity, but the residual repair
has been shown to occur specifically in transcribed
genes. It is very likely that the XPC-HR23B complex is
the principal damage recognition complex i.e. essential
for the recognition of DNA lesions in the genome
(Sugasawa et al, 1998). Binding of XPC-HR23B to a
DNA lesion causes local unwinding, so that the XPA
protein can bind and the whole repair machinery can be
loaded onto the damaged site. This would imply that
the XPA protein has binding affinity for other repair
proteins. Indeed, the XPA protein has been shown to
bind to ERCC1 and TFIIH. The XPC-HR23B complex
is only required for global genome repair. In case of
transcription coupled repair when an RNA polymerase
is stalled at a lesion, the DNA is unwound by the
transcription complex and XPA can bind independently
of XPC- HR23B complex.
XPE patients show mild dermatological symptoms and
cells from these patients have a relatively high repair
capacity. The function of the gene product is not
completely clarified yet. Band shift assays suggested
that the XPE gene product acts as a damaged DNA
binding protein (DDB), with high affinity to UVinduced 6-4PP. However, defective DDB binding
activity is not a common feature of XPE mutant cell
lines and in fact two (or even more) proteins may be
involved in the binding activity: p48 and p125. In cells
from several XPE patient mutations in p48 have been
found but so far no mutations have been found in the
p125 gene. XPE cells are not necessarily defective in
repair: p125 is proposed to play a role in opening up
chromatin to make CPD accessible to the NER
machinery, but is not required for repair of 6-4PP.
Interestingly, cell lines and primary tissues from
rodents are fully deficient in the expression of the p48
protein (Tang et al., 2000). This explains the absence of
GGR of CPD in these cells. Exogenous expression of
p48 in hamster cells confers enhanced removal of CPD
from genomic DNA and nontranscribed strand of active
genes.
DNA damage recognition
Damage demarcation
Two proteins have been identified and implicated in
(one of) the first steps of NER, i.e. the recognition of
lesions in the DNA: the XPA gene product and the
XPC gene product in complex with HR23B. In
addition, the XPE protein has been shown to have a
high affinity for damaged DNA, but whether it is
required for the damage recognition step of NER
remains unclear. Cells from XPA patients are
extremely sensitive to UV and have very low
nucleotide excision repair activity. In vitro the XPA
protein binds preferentially to damaged DNA compared
The striking discovery that subunits of basal
transcription factor TFIIH were involved in NER sheds
light on a new aspect of NER : a close coupling to
transcription via common use of essential factors. Two
repair proteins, encoded by XPB and XPD genes,
appeared to be identical to components of the basal
transcription factor TFIIH, a large complex involved in
the initiation of transcription.The XPB and XPD
proteins displayed 3'-5' and 5'-3' helicase activity
respectively (Schaeffer et al., 1994). TFIIH fulfills a
dual role in transcription initiation and NER and the
role of TFIIH in NER might closely mimic its role in
Name
when
cloned
Usual
Name
Other
Alias
Location
Disease
XPA
XPA
XPAC
9q22.3 �
9q22.3
XP
ERCC3
XPB
XPBC
2q21 � 2q 21
XP ;CS;
TTD
XPC
XPC
XPCC
3p25.1 �
3p25.1
XP
ERCC2
XPD
XPDC
19q13.2 19q13.3
XP; XP/
CS; TTD
p48; p125
XPE
XPEC
DDB1,
DDB2
p48 = 11p12 p11
p125 =11q12 q13
XP
ERCC4
XPF
XPFC
19q13.3 19q13.3
XP
ERCC5
XPG
XPGC
13q32 � 13q
32
XP; XP/
CS
ERCC8
CSA
(5pter � 5 qter)
unapprouved
CS
ERCC6
CSB
10q11 � 10 q
21
CS
Pol eta
XPV
6p21.1 � 6p12
XP variant
fertility and Short stature) (Itin et al., 2000). Certain
mutations in the XPB and XPD genes have been shown
to cause the PIBIDS phenotype, but not in combination
with the specific XP characteristics like cancer
proneness.
It has been shown that NER can operate via two
subpathways. The first pathway is global genome repair
(GGR) and involves repair activity that acts on DNA
lesions across the genome. Although the efficiency of
this pathway can be influenced by various parameters,
it is not actively targeted to specific regions of the
genome. A second NER pathway is coupled to active
transcription and is called transcription coupled repair.
This pathway involves repair activity that is directed to
the transcribed strand of active genes.
The cloning of the XP genes and the isolation of the
encoded proteins has lead to the elucidation of the core
NER reactions and ultimately to the reconstitution of
the process in vitro (Aboussekhra et al., 1995; Mu et
al., 1995).
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(2)
153
Nucleotide excision repair
Mullenders LHF et al.
the transcription initiation process. In transcription
initiation TFIIH is thought to be involved in unwinding
of the promoter site and to allow promoter clearance. In
the NER process TFIIH causes unwinding of the
damage containing region that has been localized by
XPC-HR23B
and
XPA-RPA,
enabling
the
accumulation of NER proteins around the damaged
site.
Among the XP patients, XPB patients are extremely
rare (only 3 patients known in the world) due to the fact
that the XPB gene product is essential for transcription
initiation and in all cases, these patients show the
double symptoms of XP and CS. The helicase activity
of XPD is indispensable for NER but not for
transcription initiation. So, there is much more XPD
patients, and only two patients have been described as
XP and CS.
Global genome repair (GGR)
GGR acts on DNA lesions throughout the genome, but
the kinetics of repair can be influenced by a number of
parameters related to DNA lesion structure and
chromatin configuration. It is conceivable that the
damage recognition step is a rate-limiting step in the
repair process and that more efficient recognition of
DNA lesions will lead to more rapid repair. The lesion
recognition and binding potency of proteins that are
involved in damage recognition, depends on the
chemical structure of the DNA lesion itself or the way
it interferes with the DNA helical structure. Some
lesions such as ultraviolet light induced 6-4PP and
CPD, are large bulky lesions located in the minor
groove of the DNA helix and are recognized by NER
proteins as being abnormal structures in the DNA.
DNA is thought to be a dynamic molecule subject to an
extremely rapid process of bending, twisting,
unwinding and rewinding ('breathing'). Lesions that
interfere with these dynamic properties of the DNA
may be recognized by repair proteins. Lesions that have
been shown to be a good substrate for NER often cause
local unwinding of a few DNA bases around the
damaged site. UV-induced CPD as well as cisplatinuminduced intrastrand crosslinks are a better substrate for
in vitro NER when they are superimposed on a
mismatch than in normally base paired DNA. The
unwinding of a few basepairs energetically favours
bending of the DNA and this may facilitate further
unwinding by NER enzymes. Repair of DNA lesions
that are substrates for NER by themselves, is strongly
stimulated by disruption of base pairing at the site of
the lesion. The role of chromatin structure in governing
the repair efficiency is indicated by the notion that
repair in the nontranscribed strand of active genes or
chromatin poissed for transcription, is faster than in
inactive X- chromosomal genes (Venema et al., 1992).
The latter are known to consist of heavily methylated
DNA sequences and their chromatin structure is
relatively inaccessible to molecular probes such as
DNAse1.
Thus, the efficiency of repair might be influenced by
accessibility of DNA lesions to repair proteins. Indeed,
when repair was investigated at the nucleotide level,
profound differences in repair rate were found due to
protein binding in promotor regions.
Incision
The XPF protein and the ERCC1 protein form a
complex that exhibits structure specific endonuclease
activity that is responsible for the 5' incision during the
NER reaction. XPF-ERCC1 also binds to XPA
(through ERCC1) and to RPA (through XPF) but not
preferentially to damaged DNA. The XPG protein has
DNA endonuclease activity without preference for
damaged DNA and is responsible for the 3' incision
made during NER. At the site of a lesion NER proteins
create a DNA bubble structure over a length of
approximately 25 nucleotides and the XPG protein
incises the damaged DNA strand 0-2 nucleotides 3' to
the ssDNA-dsDNA junction. In most studies the 3'incision made by the XPG protein appeared to be made
prior to and independently of the 5'-incision by XPFERCC1.
Patients
belonging
to
the
XP-G
complementation
group
clinically
exhibit
heterogeneous symptoms, from mild to very severe,
sometimes associated with CS. XP-G cells are almost
completely repair-deficient and as UV-sensitive as XPA cells. About half of the described XPG patients
exhibit also CS symptoms. In contrast to XPG, XP-F
patients have a relatively mild XP phenotype without
neurological abnormalities. Cells from XP-F patients
are slightly UV-sensitive and exhibit low levels of
repair initially after UV-irradiation.
Repair patch synthesis and ligation
Proliferating Cell Nuclear Antigen (PCNA) is required
for DNA synthesis by DNA polymerases delta and
epsilon. PCNA has also been shown to be required for
NER in vitro i.e. for the DNA resynthesis step,
suggesting that DNA polymerase delta or epsilon is
involved in NER. Biochemical analysis and
fluorescence microscopy revealed that in quiescent
cells upon UV-irradiation PCNA (that usually resides
in the cytoplasm) becomes rapidly bound to chromatin.
The enzymes involved in these pathways are normal in
DNA repair-deficient cells.
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(2)
Transcription-coupled repair
The NER subpathway transcription-coupled repair
(TCR) first described by Mellon and Hanawalt for
cultured mammalian cells (Mellon et al., 1987),
specifically removes DNA lesions from the transcribed
strand of an active gene. Subsequently, TCR was
shown to operate in a variety of organisms including
bacteria and yeast. All data indicate that TCR is
directly coupled to active transcription and it is
generally assumed that a stalled transcript provides a
strong signal to attract the repair machinery. All
154
Nucleotide excision repair
Mullenders LHF et al.
of repair of cyclobutane pyrimidine dimers in the human
adenosine deaminase gene. J Biol Chem. 1992 May
5;267(13):8852-6
classical XP cells are deficient in TCR except the group
C that is fully deficient in GGR but proficient in TCR
(Van Hoffen et al., 1995).However, until now it is not
clear how repair is coupled to transcription. A major
obstacle that prevents a major breakthrough, is the lack
of a cell free system capable to perform TCR.
Genetic analysis has put some light on specific factors
that play a role in TCR. In an E. coli mdf- mutant strain
a protein has been identified called transcription-repair
coupling factor (TRCF, the mdf gene product), that
actively couples repair to a stalled RNA polymerase at
the site of a DNA lesion (Selby and Sancar, 1993). In
mammalian cells such factor has not been found yet,
but it was suggested that the proteins mutated in the
Cockayne' syndrome might fulfill such a function.
Similarly to the mdf bacteria strain, Cockayne
syndrome cells are unable to perform transcriptioncoupled repair, whereas the global repair pathway is
functioning normally. The defect in transcriptioncoupled repair has been related to the inability of CS
cells to restore UV-inhibited RNA synthesis (Mayne
and Lehmann 1982). Slow removal of DNA lesions
from transcription templates would prevent efficient
transcription and this could lead to cell death if
essential genes are involved. Moreover, by analogy to
bacteria such a factor could attract NER proteins.
Indeed, several investigators showed that CSB can be
copurified with RNA polymerase II but could not
detect interaction of CSB with any other tested NER
component. In cells that have been treated with UV, a
small fraction of RNA polymerase II becomes
ubiquitinated within 15 minutes after treatment and this
fraction persists for about 8 hours (Bregman et al.,
1996). However, neither in CS-A nor in CS-B cells this
specific response was observed. One explanation
favoured by several studies, is that the polymerase
could be ubiquitinated as a signal for degradation of the
protein so that the lesion becomes accessible for repair
enzymes. In this model, CS proteins would be required
to make lesions (at stalled transcripts) repairable.
Selby CP, Sancar A. Molecular mechanism of transcriptionrepair coupling. Science. 1993 Apr 2;260(5104):53-8
Schaeffer L, Moncollin V, Roy R, Staub A, Mezzina M, Sarasin
A, Weeda G, Hoeijmakers JH, Egly JM. The ERCC2/DNA
repair protein is associated with the class II BTF2/TFIIH
transcription factor. EMBO J. 1994 May 15;13(10):2388-92
Aboussekhra A, Biggerstaff M, Shivji MK, Vilpo JA, Moncollin
V, Podust VN, Protić M, Hübscher U, Egly JM, Wood RD.
Mammalian DNA nucleotide excision repair reconstituted with
purified protein components. Cell. 1995 Mar 24;80(6):859-68
Mu D, Park CH, Matsunaga T, Hsu DS, Reardon JT, Sancar A.
Reconstitution of human DNA repair excision nuclease in a
highly defined system. J Biol Chem. 1995 Feb 10;270(6):24158
van Hoffen A, Venema J, Meschini R, van Zeeland AA,
Mullenders LH. Transcription-coupled repair removes both
cyclobutane pyrimidine dimers and 6-4 photoproducts with
equal efficiency and in a sequential way from transcribed DNA
in xeroderma pigmentosum group C fibroblasts. EMBO J. 1995
Jan 16;14(2):360-7
Bregman DB, Halaban R, van Gool AJ, Henning KA, Friedberg
EC, Warren SL. UV-induced ubiquitination of RNA polymerase
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Le Page F, Kwoh EE, Avrutskaya A, Gentil A, Leadon SA,
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implications for Cockayne syndrome. Cell. 2000 Apr
14;101(2):159-71
Tang JY, Hwang BJ, Ford JM, Hanawalt PC, Chu G.
Xeroderma pigmentosum p48 gene enhances global genomic
repair and suppresses UV-induced mutagenesis. Mol Cell.
2000 Apr;5(4):737-44
References
Itin PH, Sarasin A, Pittelkow MR. Trichothiodystrophy: update
on the sulfur-deficient brittle hair syndromes. J Am Acad
Dermatol. 2001 Jun;44(6):891-920; quiz 921-4
Mayne LV, Lehmann AR. Failure of RNA synthesis to recover
after UV irradiation: an early defect in cells from individuals
with Cockayne's syndrome and xeroderma pigmentosum.
Cancer Res. 1982 Apr;42(4):1473-8
This article should be referenced as such:
Mellon I, Spivak G, Hanawalt PC. Selective removal of
transcription-blocking DNA damage from the transcribed strand
of the mammalian DHFR gene. Cell. 1987 Oct 23;51(2):241-9
Mullenders LHF, Stary A, Sarasin A. Nucleotide excision
repair. Atlas Genet Cytogenet Oncol Haematol. 2001;
5(2):152-155.
Venema J, Bartosová Z, Natarajan AT, van Zeeland AA,
Mullenders LH. Transcription affects the rate but not the extent
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(2)
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Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Educational Item Section
Hardy-Weinberg model
Robert Kalmes, Jean-Loup Huret
Institut de Recherche sur la Biologie de l'Insecte, IRBI - CNRS - ESA 6035, Av. Monge, F-37200 Tours,
France (RK); Genetics, Dept Medical Information, UMR 8125 CNRS, University of Poitiers, CHU Poitiers
Hospital, F-86021 Poitiers, France (JLH)
Published in Atlas Database: February 2001
Online updated version : http://AtlasGeneticsOncology.org/Educ/HardyEng.html
DOI: 10.4267/2042/37744
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2001 Atlas of Genetics and Cytogenetics in Oncology and Haematology
I THE INTUITIVE APPROACH
II THE HARDY-WEINBERG EQUILIBRIUM
II-1 FOR AN AUTOSOMAL, DIALLELE, CO-DOMINANT GENE EXERCISE
III THE HW LAW
III-1 DEMONSTRATION OF THE LAW
III-2 EXERCISES
III-3 CONSEQUENCES OF THE LAW
III-3.1 WHAT IS THE ALLELE FREQUECY IN THE n+ 1 GENERATION?
III-3.2 WHAT IS THE GENOTYPE FREQUENCY IN THE n+ 1 GENERATION?
III-3.3 EXAMPLE
IV
EXTENSION OF HW TO OTHER GENE SITUATIONS
IV-1 TO AN AUTOSOMAL, TRIALLELE, CO-DOMINANT GENE
IV-2 TO AN AUTOSOMAL, DIALLELE, NON CO-DOMINANT GENE
IV-3 TO AN AUTOSOMAL, TRIALLELE, NON CO-DOMINANT GENE
IV-3.1 BERNSTEIN's EQUATION
IV-4 TO A HETEROSOMAL (= gonosomic) GENE
IV-4.1 Y CHROMOSOME
IV-4.2 X CHROMOSOME
V SUMMARY- CONSEQUENCES OF HW's LAW
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I- THE INTUITIVE APPROACH
The Hardy-Weinberg law can be used under some circumstances to calculate genotype frequencies from allele
frequences.
Let A1 and A2 be two alleles at the same locus,
p is the frequency of allele A1
0 =< p =< 1
q is the frequency of allele A2
0 =< q =< 1 and p + q = 1
Where the distribution of allele frequencies is the same in men and women, i.e.:
Men (p,q) Women (p,q)
If they procreate : (p + q)2 = p2 + 2pq + q2 = 1
where:
p2 = frequency of the A1 A1 genotype ← HOMOZYGOTE
2pq = frequency of the A1 A2 genotype ← HETEROZYGOTE
q2 = frequency of the A2 A2 genotyp
← HOMOZYGOTE
These frequencies remain constant in successive generations.
Example : Autosomal recessive inheritance with alleles A and a, and allele frequencies p and q:
→ frequency of the genotypes: AA = p2 and the phenotypes [ ]: [A] = p2 + 2pq
Aa = 2pq
[a] = q2
2
aa = q
Example : Phenylketonuria (recessive autosomal), of which the deleterious gene has a frequency of 1/100: → q = 1/100
therefore, the frequency of this disease is q2 = 1/10 000,
and the frequency of heterozygotes is 2pq = 2 x 99/100 x 1/100 = 2/100;
Note that there are a lot of heterozygotes: 1/50, two hundred times more than there are individuals suffering from the
condition. .
For a rare disease, p is very little different from 1, and the frequency of the heterozygotes = 2q.
We use these equations implicitly, in formal genetics and in the genetics of pooled populations, usually without
considering whether, and under what conditions, they are applicable.
II- THE HARDY-WEINBERG EQUILIBRIUM
The Hardy-Weinberg equilibium, which is also known as the panmictic equilibrium, was discovered at the beginning of
the 20th century by several researchers, notably by Hardy, a mathematician and Weinberg, and physician.
The Hardy-Weinberg equilibrium is the central theoretical model in population genetics. The concept of equilibrium in
the Hardy-Weinberg model is subject to the following hypotheses/conditions:
1.
2.
3.
4.
The population is panmictic (couples form randomly (panmixia), and their gametes encounter each other
randomly (pangamy))
The population is "infinite" (very large: to minimize differences due to sampling).
There must be no selection, mutation, migration (no allele loss /gain).
Successive generations are discrete (no crosses between different generations).
Under these circumstances, the genetic diversity of the population is maintained and must tend towards a stable
equilibrium of the distribution of the genotype.
II-1. FOR AN AUTOSOMAL, DIALLELE, CO-DOMINANT GENE (Alleles A1 and A2)
Let:
The frequencies of genotypes F(G) be called D, H, and R with 0 =< [D,H,R] = < 1 and D + H + R = 1
The frequencies of alleles F(A) be called p, and q with 0 =< [p,q] =< 1 and p+q = 1
Génotypes
Number of subjects
Frequencies F(G)
A1A1 A1A2 A2A2
DN
HN RN
D
H
R
Allele frequencies F(A):
of A1 D + H/2 = p
of A2 R + H/2 = q with p+q=1
(total number N)
with (D+H+R) = 1
Nucleotide excision repair
Mullenders LHF et al.
NOTES
The genotype frequencies F(G) can always be used to calculate the allele frequencies F(A)
F(A) contains less information than F(G)
if p = 0: allele is lost; if p = 1: allele is fixed..
First demonstration that p = D + H/2, by counting the alleles:
•
•
•
•
size of the population = N -> number of alleles = 2N
p = nb A1 / nb total = (2DN + HN) / 2N = D + H/2
p = nb A1 / nb total = (2DN + HN) / 2N = D + H/2 similarly for A2
q = nb A2 / nb total = (2RN + HN) / 2N = R + H/2 (note the symmetry between p and q)
Second demonstration, by calculating the probabilities:
proba of drawing A1 = drawing A1A1: : D x 1 then drawing A1 into A1A1
or
drawing A1A2: H x 1/2 then drawing A1 amongst A1A2
sum:
→ → P(A1) = D + H/2
similarly for A2 ...;
EXERCISE
Let:
Phenotypes
Genotypes
Number of subjects
[A1]
A1A1
167
[A1A2]
A1A2
280
[A2]
A2A2
109
total N : 556
calculate the following frequencies: F(P: phenotypes), F(G: genotypes), F(A: alleles), F (gametes):
F(A) = F(gam), because there is 1 allele (of each gene) per gamete
In addition, here F(p) = F(G), because these are co-dominant alleles.
F(P) = F(G)
Where :
167/556
D=0.300
280/556
H=0.504
109/556
R=0.196
F(A) = F(gam.)
p = D+H/2 = (167+280/2)/ 556 or 0.300+0.504/2 = 0.552
q = R+H/2 = (109+280/2)/ 556 or 0.196 + 0.504/2 = 0.448
confirm: Σ(D,H,R)=2
confirm:Σ(p,q)=1
III- THE HW LAW
In a population consisting of an infinite number of individuals (i.e. a very large population), which is panmictic
(mariages occur randomly), and in the absence of mutation and selection, the frequency of the genotypes will be the
development of (p+q)2, p and q being the allele frequencies.
The figure shows the correspondence between the allele frequency q of a and the genotype frequencies in the case of
two alleles in a panmictic system. The highest frequency of heterozygotes, H, is then reached when p = q and H = 2pq =
0.50. In contrast, when one of the alleles is rare (i.e. q is very small), virtually all the subjects who have this allele are
heterozygotes.
III-1. DEMONSTRATION OF THE LAW
Let A be an autosomal gene that is found in a population in two allele forms, A1 and A2 (with the same frequencies in
both sexes of course). As there is codominance, 3 genotypes can be distinguished. According to the
hypotheses/conditions of Hardy-Weinberg (HW), the individuals of the n + 1 generation will be assumed to be the
descendants of the random union of a male gamete and a femal gamete.
Consequently, if, by generation n, the probability of drawing an A1 allele is p, then that of producing an A1A1 zygote
after fertilization is p x p = p2 and similarly for A2, that of producing an A2A2 zygote is q x q = q2. The probability of
producing a heterozygote is pq + pq = 2pq. Finally, p2 + 2pq + q2 = (p+q)2 = 1
A1A1
D = p2
A1A2
H=2pq
A2A2
R = q2
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(2)
← only under HW
158
Nucleotide excision repair
Table of gametes
A1
(p)
A1
(p)
A1A1 (p2)
A2
(q)
A1A2 (pq)
Mullenders LHF et al.
A2
(q)
A1A2 (pq)
A2A2 (q2)
(The allele frequencies can only be used to calculate the genotype frequencies if they are subject to HW).
The allele frequencies remain the same from one generation to another.
The genotype frequencies remain the same from one generation
to another.
III-2. EXERCICES
Exercise
Show that, in the absence of panmixia, two populations with
similar allele frequencies can have different genotype
frequencies (by doing this, you show that there is a loss of
information between genotype and allele frequencies):
Example:
for p = q = 0,5
Answer
if H = 0−>
0.5
if H = 1−>
p = D + H/2 = 0.5
→ D = 0.5
H=0
R=
D=R=0
→D=0
H=1
R=0
Exercise
Calculation of the genotype and allele frequencies, calculation
of the numbers predicted by HW (theoretical numbers of individuals), and confirmation that we are indeed in a situation
subject to HW :
AA
1787
DN
AB
3039
HN
BB
1303
RN
N=6129
Answer:
F(A) = (1787 + 3039/2) / 6129 = 0.54 = p
F(B) = (1303 + 3039/2) / 6129 = 0.46 = q
… and Σ(p,q)=1
Genotype frequencies predicted by HW genotype frequencies predicted by HW
AA :
p2 = (0.54)2
= 0.2916
AB : 2pq = 2x 0.54 x 0.46 = 0.4968
BB :
q2 = (0.46)2
= 0.2116
Numbers predicted by HW
AA : p2N = 0.2916 x 6129 = 1787.2
AB : 2pqN = 0.4968 x 6129 = 3044.9
BB : q2N = 0.2116 x 6129 = 1296.9
Confirmation:
(1787 - 1787.2)2 + (3039 - 3044.9)2 + (1303 - 1296.9)2
Σ (0i - Ci)2
=
= NS
1787.2
3044.9
1296.9
Ci
→ We are in a situation subject to HW
χ2
=
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(2)
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Mullenders LHF et al.
III-3. CONSEQUENCES OF THE LAW
Change in HW across the generations (demonstration that the frequencies are invariable). In a population subject to
HW, an equilibrium involving the distribution of the genotype frequencies is reached after a single reproductive cycle.
Is a population in the n generation.
III-3.1. WHAT WILL THE ALLELE FREQUENCY BE IN THE n+1 GENERATION?
A1A1 A1A2 A2A2
p2
n
q2
2pq
n + 1 F(A1) = D + H/2 = p2 +1/2 (2pq) = p (p+q) = p
F(A2) = R + H/2 = q2 +1/2 (2pq) = q (p+q) = q
→ No change in allele frequencies:
in the n generation, we have p and q
in the n+1 generation, we have p and q
III-3.2. WHAT WILL THE GENOTYPE FREQUENCY BE IN THE n+1 GENERATION ?
male
female
p2
2pq
q2
A1A1
A1A2
A2A2
A1A1
A1A1
no A1A1
p2
A1A1
2pq
A1A2
1/2A1A1 1/4A1A1
no A1A1
q2
A2A2
no A1A1 no A1A1
no A1A1
Generation n+1
Frequency of (A1A1) in the generation n+1 = (p2)2 + 1/2 (2 pq.p2) + 1/2 (p2.2pq) + 1/4 (2pq)2
= p4 + p3q + p3q + p2q2 = p2 (p2 + 2pq + q2) = p2
The frequency of the (A1A1) genotype does not change between generation n and generation n+1 (same demonstration
for the (A2A2 ) and (A1A2) genotypes). The genotype structure no longer undergoes any further changes once the
population reaches the Hardy Weinberg equilibrium.
In very many examples, the frequencies seen in natural populations are consistent with those predicted by the HardyWeinberg law.
III-3.3. EXAMPLE
The MN human blood groups.
Group
Number:
MM
1787
MN
3039
NN
1303
Frequency of M = (1787 + 3039/2)/ 6129
Frequency of N = (1303 + 3039/2)/6129
Total, N = 6129
= 0.540 = p
= 0.460 = q
Predicted proportion of MM = p2 = (0.540)2
= 0,2916
Predicted proportion of MN = 2pq = 2(0.540)(0.460) = 0.4968
Predicted proportion of NN = q2 = (0.460)2
= 0.2116
Numbers predicted by Hardy-Weinberg :
For MM = p2N = 0,2916 x 6129 = 1787.2
For MN = 2pqN = 0,4968 x 6129 = 3044.9
For NN = q2N = 0,2116 x 6129 = 1296.9
In the present situation, there is no need to do χ2 test to see that the actual numbers are not statistically different from
those predicted.
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IV- EXTENSION OF HW TO OTHER GENE SITUATIONS
IV-1.TO AN AUTOSOMAL, TRIALLELE, CO-DOMINANT GENE
3 alleles
with frequencies
A1, A2, A3
F(A1) = p, F(A2) = q, F(A3) = r
there will be 6 genotypes
A1A1
Genotype frequencies according to HW
p
q
r
A1
A2
A3
p
p
q
r
A1
A2
A3
pq
q2
qr
pr
qr
r2
2
p
pq
pr
2
A1A2
2pq
A1A3
2pr
A2A2
q
2
A2A3
A3A3
2qr
r2
IV-2. TO AN AUTOSOMAL, DIALLELE, NON CO-DOMINANT GENE
A is dominant over a, which is recessive; in this case the genotypes (AA) and (Aa) cannot be distinguished within the
population. Only the individuals with the phenotype [A], who number N1, will be distinguishable from the individuals
with the phenotype [a], who number N2.
Genotypes
Phenotypes
Number
Frequency of genotype
AA
Aa
[A]
N1
1-q2
aa
[a]
N2
q2
N
with q2 = N2/N = N2 / (N1 + N2)
and the frequency of the allele a = F(a) =(q2)1/2 = (N2/(N1 + N2))1/2
This is a method commonly used in human genetics to calculate the frequency of rare, recessive genes.
Frequencies of homozygotes and heterozygotes for rare recessive human genes.
Gene
Incidence in population q2
Albinism
1/22 500
Phenylketonuria
1/10 000
Mucopolysaccharidosis
11/90 000
Frequency of allele q Frequency of heterozygotes 2pq
1/150
1/75
1/100
1/50
1/300
1/150
IV-3. TO AN AUTOSOMAL, TRIALLELE, NON CO-DOMINANT GENE
Example: the ABO blood group system. Although the human (ABO) blood group system is often taken to be a simple
example of polyallelism, it is in fact a relatively complex situation combining the codominance of A and B, the presence
of a nul O allele and the dominance of A and B over O.
If we take
p to designate the frequency of allele A
q to designate the frequency of allele B
(p + q + r = 1)
Rdiffering genotype and phenotype frequencies are found by applying the Hardy-Weinberg law.
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(2)
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Phenotype
[A]
Mullenders LHF et al.
Genotype
(AA)
Genotype frequency
p2
Phenotype frequency
(AO)
2pr
p2+2pr
(BB)
q2
(BO)
2qr
q2+2qr
(AB)
(OO)
2pq
r2
2pq
r2
[B]
[AB]
[O]
Using::
p2 +2pr +r2 = (p+r)2
q2 +2qr +r2 = (q+r)2
Where
F[A] + F[O] = (p+r)2
F[B] + F[O] = (q+r)2 et F[O] = r2
IV-3.1. BERNSTEIN's EQUATION (1930)
Bernstein's equation (1930) simplifies the calculations:
p = 1 - (F[B] + F[O])1/2
q = 1 - (F[A] + F[O])1/2
r = (F[O])1/2
Then, if p+q+r # 1, correction by the deviation D = 1 - (p + q + r) →
p'= p (1 + D/2) q'= q (1 + D/2) r'= (r + D/2) (1 + D/2)
Example:
Group
Number
Frequency
A
9123
0.4323
B
2987
0.1415
O
7725
0.3660
AB
1269
0.601
p = 1 - (0.3660+0.1415)1/2 = 0.2876
q = 1 - (0.3660+0.4323)1/2 = 0.1065
r = = 0.6050
p+q+r = 0.9991 ... --> p'= 0.2877, q'= 0.1065, r'= 0.6057.
IV-4. TO A HETEROSOMAL (= gonosomic) GENE
IV-4.1. Y CHROMOSOME
Frequency p and q in subjects XY; transmission to male descendants.
IV-4.2. X CHROMOSOME
Female
XA1XA1
XA1XA2
XA2XA2
2
2pq
q2
XA1/Y
XA2/Y
p
Male
p
q
i.e. the frequency of the q allele, is qx in men, and qxx in women:
The X chromosome of the boys (in generation n) has been transmitted from the mothers (generation n-1) → qx(n) =
qxx(n-1) qx(n) = qxx(n-1)
The X chromosome carrying the q allele in the daughters has:
1/2 chance of coming from their father,
1/2 chance of coming from their mother,
→ qxx(n) = ( qx(n-1) + qxx(n-1))/2
The frequency of the allele in men = the frequency in women in the previous generation.
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Mullenders LHF et al.
The frequency of the allele in women = mean of the frequencies in the 2 sexes in the previous generation.
* calculation of the difference in allele frequencies between the 2 sexes:
qx(n) - qxx(n) = qxx(n-1) - (qxx(n-1))/2 - (qxx(n-1)) /2 = - 1/2 (qx(n-1) - qxx(n-1))
→ qx(n) - qxx(n) = (- 1/2)n (qx(0) - qxx(0)) : tends towards zero in 8 to 10 generations
* mean frequency q: :
1/3 of the X chromosomes belong to men, 2/3 to women: q = 1/3 qx(n) + 2/3 qxx(n)
The mean frequency is invariable (develop q1 into q0 ...... --> q1 = q0)
At equilibrium, q(e) est : qx(e) = qxx(e) = q(e)
Exercise: For generation G0, consisting of 100% of normal men and 100% of color-blind women, calculate the
frequencies of the gene up to G6:
Answer
G0: XNY
XDXD
G0 : qx(0) = 0.00
qxx(0) = 1.00
G1 : qx(1) = 1.00
qxx(1) = 0.50
G2 : qx(2) = 0.50
qxx(2) = 0.75
G3 : qx(3) = 0.75
qxx(3) = 0.63
G4 : qx(4) = 0.63
qxx(4) = 0.69
G5 : qx(5) = 0.69
qxx(5) = 0.66
G6 : qx(6) = 0.66
qxx(6) = 0.60
Therefore:
For a sex-linked locus, the Hardy Weinberg equilibrium is
reached asymptotically after 8-10 generations, whereas it is
reached after 1 generation for an autosomal locus.
V- CONSEQUENCES OF THE HW LAW
Regardless of whether we are in a situation subject to HW or
not, the genotype frequencies (D, H, R) can be used to calculate
the allele frequencies (p,q), from : p = D + H/2, q = R + H/2.
Whereas, if and only if we are subject to HW, the genotype frequencies can be calculated from the allele frequencies,
from D = p2, H = 2pq, R = q2.
The dominance relationships between alleles have no effect on the change in allele frequencies (although they do affect
how difficult the exercises are!)
The allele frequencies remain stable over time; and so do the genotype frequencies.
The random mendelian segregation of the chromosomes preserves the genetic variability of populations.
Since "evolution" is defined as a change in allele frequencies, an ideal diploid population would not evolve.
It is only violations of the properties of an ideal population that allow the evolutionary process to take place.
The practical approach to a problem is always the same:
1. The Numbers Observed → the (Observed) Genotype Frequencies;
2. Calculate the Allele Frequencies: p=D/2 + S Hi/2 , q = ...
3. If we are subject to HW (hypothetically), then D=p2, H= 2pq, etc ... : we calculate the Theoretical Genotype
Frequencies according to HW.
4. The Calculated Genotype Frequencies --> the Calculated Numbers;
5. Comparison of Observed Numbers - Calculated Numbers: : χ2 = Σ (Oi - Ci)2/Ci
6. If χ2 is significant: we are not in accordance with HW; this
→ Consanguinity?
→ Selection?
→ Mutations ?
This article should be referenced as such:
Kalmes R, Huret JL. Hardy-Weinberg model. Atlas Genet
Cytogenet Oncol Haematol. 2001; 5(2):155-163.
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(2)
163
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Atlas Genet Cytogenet Oncol Haematol. 2001; 5(2)
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
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