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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]
Staff
Sylvie Yau Chun Wan - Senon
Philippe Dessen is the Database Director, and Alain Bernheim the Chairman of the on-line version (Gustave Roussy
Institute – Villejuif – France).
The Atlas of Genetics and Cytogenetics in Oncology and Haematology is published 4 times a year by ARMGHM, a
non profit organisation.
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, 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]
Staff
Sylvie Yau Chun Wan - Senon
Philippe Dessen is the Database Director, and Alain Bernheim the Chairman of the on-line version (Gustave Roussy
Institute – Villejuif – France).
The Atlas of Genetics and Cytogenetics in Oncology and Haematology is published 4 times a year by ARMGHM, a
non profit organisation.
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
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Editor-in-Chief
Jean-Loup Huret
(Poitiers, France)
Editorial Board
Alessandro Beghini
Anne von Bergh
Vasantha Brito-Babapulle
Charles Buys
Anne Marie Capodano
Fei Chen
Antonio Cuneo
Paola Dal Cin
Louis Dallaire
François Desangles
Gordon Dewald
Richard Gatti
Oskar Haas
Anne Hagemeijer
Nyla Heerema
Jim Heighway
Sakari Knuutila
Lidia Larizza
Lisa Lee-Jones
Edmond Ma
Cristina Mecucci
Yasmin Mehraein
Fredrik Mertens
Konstantin Miller
Felix Mitelman
Hossain Mossafa
Florence Pedeutour
Susana Raimondi
Mariano Rocchi
Alain Sarasin
Albert Schinzel
Clelia Storlazzi
Sabine Strehl
Nancy Uhrhammer
Dan Van Dyke
Roberta Vanni
Franck Viguié
Thomas Wan
Bernhard Weber
(Milan, Italy)
(Rotterdam, The Netherlands)
(London, UK)
(Groningen, The Netherlands)
(Marseille, France)
(Morgantown, West Virginia)
(Ferrara, Italy)
(Boston, Massachussetts)
(Montreal, Canada)
(Paris, France)
(Rochester, Minnesota)
(Los Angeles, California)
(Vienna, Austria)
(Leuven, Belgium)
(Colombus, Ohio)
(Liverpool, UK)
(Helsinki, Finland)
(Milano, Italy)
(Newcastle, UK)
(Hong Kong, China)
(Perugia, Italy)
(Homburg, Germany)
(Lund, Sweden)
(Hannover, Germany)
(Lund, Sweden)
(Cergy Pontoise, France)
(Nice, France)
(Memphis, Tennesse)
(Bari, Italy)
(Villejuif, France)
(Schwerzenbach, Switzerland)
(Bari, Italy)
(Vienna, Austria)
(Clermont Ferrand, France)
(Rochester, Minnesota)
(Montserrato, Italy)
(Paris, France)
(Hong Kong, China)
(Würzburg, Germany)
Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1)
Genes Section
Genes / Leukemia Sections
Leukemia Section
Deep Insights Section
Solid Tumors Section
Genes / Deep Insights Sections
Leukemia Section
Genes / Solid Tumors Sections
Education Section
Leukemia / Solid Tumors Sections
Leukemia / Deep Insights Sections
Cancer-Prone Diseases / Deep Insights Sections
Genes / Leukemia Sections
Deep Insights Section
Leukemia Section
Genes / Deep Insights Sections
Deep Insights Section
Solid Tumors Section
Solid Tumors Section
Leukemia Section
Genes / Leukemia Sections
Cancer-Prone Diseases Section
Solid Tumors Section
Education Section
Deep Insights Section
Leukemia Section
Genes / Solid Tumors Sections
Genes / Leukemia Section
Genes Section
Cancer-Prone Diseases Section
Education Section
Genes Section
Genes / Leukemia Sections
Genes / Cancer-Prone Diseases Sections
Education Section
Solid Tumors Section
Leukemia Section
Genes / Leukemia Sections
Education Section
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
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Volume 8, Number 1, January - March 2004
Table of contents
Gene Section
DIRC2 (disrupted in renal carcinoma 2)
Anita Bonné, Danielle Bodmer, Marc Eleveld, Eric Schoenmakers, Ad Geurts van Kessel
1
DIRC3 (disrupted in renal carcinoma 3)
Anita Bonné, Danielle Bodmer, Marc Eleveld, Eric Schoenmakers, Ad Geurts van Kessel.
3
RAP1GDS1 (RAP1, GTP-GDP dissociation stimulator 1)
Franck Viguié
5
RET (REarranged during Transfection)
Patricia Niccoli-Sire
7
ZFHX3 (zinc finger homeobox 3)
Nadine Van Roy, Frank Speleman
9
LPHN2 (latrophilin 2)
Jim Heighway
11
MNX1 (motor neuron and pancreas homeobox 1)
Anne RM von Bergh, H Berna Beverloo
14
SYNPO2 (synaptopodin 2)
Jian-Hua Luo
16
Leukaemia Section
11p15 rearrangements in treatment related leukemia
Jean-Loup Huret
18
12p13 rearrangements in treatment related leukemia
Jean-Loup Huret
19
21q22 rearrangements in treatment related leukemia
Jean-Loup Huret
20
inv(16)(p13q22) in treatment related leukemia
Jean-Loup Huret
22
t(15;17)(q22;q21) in treatment related leukemia
Jean-Loup Huret
24
t(3;21)(q26;q22) in treatment related leukemia
Jean-Loup Huret
26
t(8;16)(p11;p13) in treatment related leukemia
Jean-Loup Huret
28
t(8;21)(q22;q22) in treatment related leukemia
Jean-Loup Huret
30
t(9;22)(q34;q11) in treatment related leukemia
Jean-Loup Huret
31
Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1)
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Acute megakaryoblastic leukemia (AMegL), M7 acute non lymphocytic leukemia (M7-ANLL)
Antonio Cuneo, Francesco Cavazzini, Gianluigi Castoldi
32
Refractory anemia (RA)
Antonio Cuneo, Gianluigi Castoldi
35
Refractory anemia with excess blasts (RAEB)
Antonio Cuneo, Gianluigi Castoldi
37
Refractory anemia with ringed sideroblasts (RARS)
Antonio Cuneo, Gianluigi Castoldi
39
Solid Tumour Section
Bladder: Urothelial carcinomas
Angela van Tilborg, Bas van Rhijn
41
Ovary: Sex cord-stromal tumors
Lisa Lee-Jones
48
Soft tissue tumors: Elastofibroma
Roberta Vanni
54
Testis: Spermatocytic seminoma
Ewa Rajpert-De Meyts
57
Cancer Prone Disease Section
Familial clear cell renal cancer
Anita Bonné, Danielle Bodmer, Marc Eleveld, Eric Schoenmakers, Ad Geurts van Kessel
Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1)
61
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Gene Section
Short Communication
DIRC2 (disrupted in renal carcinoma 2)
Anita Bonné, Danielle Bodmer, Marc Eleveld, Eric Schoenmakers, Ad Geurts van Kessel
Department of Human Genetics, University Medical Center Nijmegen, Nijmegen, the Netherlands (AB, DB,
ME, ES, AGVK)
Published in Atlas Database: October 2003
Online updated version : http://AtlasGeneticsOncology.org/Genes/DIRC2ID497.html
DOI: 10.4267/2042/38036
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2004 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
cells of the kidney), skeletal muscle, liver, lung,
placenta, brain and heart.
HGNC (Hugo): DIRC2
Location: 3q21
Function
DNA/RNA
Homology
See below, may be a transporter.
Computer predictions of the putative DIRC2 protein
showed significant homology to different members of
the major facilitator superfamily of transporters.
DIRC2 shares 43% similarity with the human homolog
of feline leukemia virus type C receptor (FLVXR),
which has been classified as a major facilitator
superfamily transporter, and over 85% homology with
Dirc2 from monkey, pig, dog, and mouse.
Description
The gene spans 73 kb, 9 exons. The first exon and 5prime UTR contain a CpG island. The gene contains 12
transmembrane segments. It contains a conserved
motif, shared with the major facilitator superfamily of
transporters, between membrane-spanning domains 2
and 3, and a proline-rich region between membranespanning domains 6 and 7. It also contains a putative
N-glycosylation
site
and
several
putative
phosphorylation sites.
Implicated in
t(2;3)(q35;q21) and hereditary renal cell
cancer
Protein
Disease
Familial renal cell cancer.
Cytogenetics
Disruption of the gene because of the t(2;3)
translocation.
Description
478 amino acids.
Expression
Expression in pancreas, kidney (proximal tubular
Probe(s) - Courtesy Mariano Rocchi, Resources for Molecular Cytogenetics.
Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1)
1
DIRC2
Bonné A et al.
Popescu NC, Kata G, Borowka A, Gronwald J, Lubinski J,
Huebner K. Characterization of a familial RCC-associated
t(2;3)(q33;q21) chromosome translocation. J Hum Genet.
2001;46(12):685-93
References
Bodmer D, Eleveld MJ, Ligtenberg MJ, Weterman MA,
Janssen BA, Smeets DF, de Wit PE, van den Berg A, van den
Berg E, Koolen MI, Geurts van Kessel A. An alternative route
for multistep tumorigenesis in a novel case of hereditary renal
cell cancer and a t(2;3)(q35;q21) chromosome translocation.
Am J Hum Genet. 1998 Jun;62(6):1475-83
Bodmer D, Eleveld M, Kater-Baats E, Janssen I, Janssen B,
Weterman M, Schoenmakers E, Nickerson M, Linehan M, Zbar
B, van Kessel AG. Disruption of a novel MFS transporter gene,
DIRC2, by a familial renal cell carcinoma-associated
t(2;3)(q35;q21). Hum Mol Genet. 2002 Mar 15;11(6):641-9
Koolen MI, van der Meyden AP, Bodmer D, Eleveld M, van der
Looij E, Brunner H, Smits A, van den Berg E, Smeets D,
Geurts van Kessel A. A familial case of renal cell carcinoma
and a t(2;3) chromosome translocation. Kidney Int. 1998
Feb;53(2):273-5
This article should be referenced as such:
Bonné A, Bodmer D, Eleveld M, Schoenmakers EFPMG,
Geurts van Kessel A. DIRC2 (disrupted in renal carcinoma 2).
Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1):1-2.
Podolski J, Byrski T, Zajaczek S, Druck T, Zimonjic DB,
Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1)
2
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
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Gene Section
Short Communication
DIRC3 (disrupted in renal carcinoma 3)
Anita Bonné, Danielle Bodmer, Marc Eleveld, Eric Schoenmakers, Ad Geurts van Kessel.
Department of Human Genetics, University Medical Center Nijmegen, Nijmegen, the Netherlands (AB, DB,
ME, ES, AGVK)
Published in Atlas Database: October 2003
Online updated version : http://AtlasGeneticsOncology.org/Genes/DIRC3ID498.html
DOI: 10.4267/2042/38037
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2004 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
Implicated in
HGNC (Hugo): DIRC3
Location: 2q35
t(2;3)(q35;q21) and hereditary renal cell
cancer
DNA/RNA
Disease
Familial renal cell cancer.
Cytogenetics
Disruption of the gene because of the t(2;3)
translocation.
Abnormal protein
DIRC3-HSPBAP1 is formed by replacing the first
coding exon of HSPBAP1 by the first two exons of
DIRC3. The fusion transcript most likely encodes a
truncated HSPBAP1 protein starting from a internal
initiation side embedded in a strong Kozak consensus
sequence.
Description
The gene spans 3071 bp and contains 12 exons. The
last exon contains a consensus polyadenylation site
sequence (AGTAA) at 20 nt upstream up the poly(a)
addition site. DIRC3 expression could be detected in
the placenta, but low expression was found in most
tissues and the gene may act as a non-coding RNA.
A schematic overview of the breakpoint regions on chromosome 2 and 3 in a family with a t(2;3) translocation with the breakpoint genes
DIRC2 and DIRC3, the fusion protein DIRC3-HSPBAP1 and their neighbouring genes. (TNS: tensin; SEMA5B: sema domain 5B).
Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1)
3
DIRC3 disrupted in renal carcinoma 3
Bonné A et al.
References
This article should be referenced as such:
Bonné A, Bodmer D, Eleveld M, Schoenmakers EFPMG,
Geurts van Kessel A. DIRC3 (disrupted in renal carcinoma 3).
Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1):3-4.
Bodmer D, Schepens M, Eleveld MJ, Schoenmakers EF,
Geurts van Kessel A. Disruption of a novel gene, DIRC3, and
expression of DIRC3-HSPBAP1 fusion transcripts in a case of
familial renal cell cancer and t(2;3)(q35;q21). Genes
Chromosomes Cancer. 2003 Oct;38(2):107-16
Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1)
4
Atlas of Genetics and Cytogenetics
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Gene Section
Short Communication
RAP1GDS1 (RAP1, GTP-GDP dissociation
stimulator 1)
Franck Viguié
Laboratoire de Cytogénétique - Service d'Hématologie Biologique, Hôpital Hôtel-Dieu, 75181 Paris Cedex
04, France (FV)
Published in Atlas Database: October 2003
Online updated version : http://AtlasGeneticsOncology.org/Genes/RAP1GDS1ID400.html
DOI: 10.4267/2042/38038
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2004 Atlas of Genetics and Cytogenetics in Oncology and Haematology
proliferation,
transformation.
Identity
Other names: RAP1; GTP-GDP
stimulator 1
HGNC (Hugo): RAP1GDS1
Location: 4q22.3
dissociation
and
oncogenic
Homology
With other mammalian rap1gds1 proteins.
Implicated in
DNA/RNA
t(4;11)(q21;p15)
Disease
T cell acute lymphocytic leukemia
Cytogenetics
Additional anomalies in 2/3 cases.
Hybrid/Mutated gene
Quasi totality of RAP1GDS1 fused with 5' part of
NUP98.
Abnormal protein
Chimeric protein 5' -NUP98 - RAP1GDS1 - 3'.
Description
181.2 kb - 15 exons.
Transcription
mRNA 2487 bases.
Protein
Description
rap1gds, also refered as smgGDS - 61.1 kDa, 558 aa.
Contains in major part an armadillo motif, which is
composed of tandemly repeated sequences of 43 amino
acid residues.
References
de Mazancourt P, Goldsmith PK, Weinstein LS. Inhibition of
adenylate cyclase activity by galanin in rat insulinoma cells is
mediated by the G-protein Gi3. Biochem J. 1994 Oct 15;303 (
Pt 2):369-75
Expression
Ubiquitary, high level of expression in central nervous
system.
Hussey DJ, Nicola M, Moore S, Peters GB, Dobrovic A. The
(4;11)(q21;p15) translocation fuses the NUP98 and
RAP1GDS1 genes and is recurrent in T-cell acute lymphocytic
leukemia. Blood. 1999 Sep 15;94(6):2072-9
Function
Acts as guanine nucleotide exchange factor (GEF).
Activates GDP/GTP exchange reaction on numerous
small proteins with GTPase activity (G proteins)
containing a C-terminal polybasic region (PBR),
including Ras and Rho family GTPases such as rap1a,
rap1b, K-ras, rac1, rac2, rhoA, ralB. These proteins
play a pivotal role in cell
Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1)
differentiation
Mecucci C, La Starza R, Negrini M, Sabbioni S, Crescenzi B,
Leoni P, Di Raimondo F, Krampera M, Cimino G, Tafuri A,
Cuneo A, Vitale A, Foà R. t(4;11)(q21;p15) translocation
involving NUP98 and RAP1GDS1 genes: characterization of a
new subset of T acute lymphoblastic leukaemia. Br J
Haematol. 2000 Jun;109(4):788-93
5
RAP1GDS1 (RAP1, GTP-GDP dissociation stimulator 1)
Viguié F
Vikis HG, Stewart S, Guan KL. SmgGDS displays differential
binding and exchange activity towards different Ras isoforms.
Oncogene. 2002 Apr 4;21(15):2425-32
Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1)
This article should be referenced as such:
Viguié F. RAP1GDS1 (RAP1, GTP-GDP dissociation
stimulator 1). Atlas Genet Cytogenet Oncol Haematol. 2004;
8(1):5-6.
6
Atlas of Genetics and Cytogenetics
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Gene Section
Mini Review
RET (REarranged during Transfection)
Patricia Niccoli-Sire
Service d'Endocrinologie, Diabète et Maladies Métaboliques, Hôpital de la Timone, 254, rue St Pierre,
13385 Marseille cedex 05, France (PNS)
Published in Atlas Database: October 2003
Online updated version : http://AtlasGeneticsOncology.org/Genes/RETID76.html
DOI: 10.4267/2042/38039
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2004 Atlas of Genetics and Cytogenetics in Oncology and Haematology
neurotrophic factors of the glial-cell line derived
neurotrophic factor (GDNF) family, including GDNF,
neurturin, artemin and persefin. RET activation is
mediated via different glycosyl phosphatidylinositollinked GRF_ receptors.
Identity
HGNC (Hugo): RET
Location: 10q11.2
Note: proto-oncogene.
Homology
DNA/RNA
General structure is similar to other tyrosine kinase
receptors but RET differs by the presence of a cadherin
domain in its extracellular region.
Description
21 exons, 3415 pb.
Transcription
Mutations
3 mains alternative spliced mRNA in the 3' region.
Germinal
Protein
Germline RET mutations causes autosomal dominant
inherited multiple endocrine neoplasia type 2 (MEN2)
and familial medullary thyroid carcinoma only
(FMTC). All these mutations are missense activating
mutations. They are widely dispersed in 7/21 exons of
RET with phenotype-genotype relationships: mutations
in exon 11 are strongly associated with MEN2A
phenotype, mutations in exon 16 or exons 8, 10, 13, 14,
15, with NEM2B and FMTC (rarely NEM2A)
phenotypes respectively.
Germline RET mutations are associated to the
autosomal inherited Hirschprung's disease or colonic
aganglionosis (HSCR) which represents 15-20% of
HSCR cases. RET mutations are loss-of-function
mutations dispersed throughout the RET coding
sequence and include deletions, insertions, frameshift
missense and nonsense mutations.
Description
Several isoforms; 3 main isoforms detected in human:
Long isoform (RET51): 1114 amino acids ;
Middle isoform (RET 43): 1106 amino acids ;
Short isoform (RET 9): 1072 amino acids.
Expression
RET is mainly expressed in tumors of neural crest
origin:
medullary
thyroid
carcinoma,
pheochromocytoma, neuroblastoma.
In human embryos, RET is expressed in a cranial
population of neural crest cells, and in the developing
nervous and urogenital systems.
RET expression is found in several crest-derived cell
lines, spleen, thymus, lymph nodes, salivary glands,
spermatogonia, and recently in normal thyroid tissue,
thyroid adenoma and both papillary and follicular
thyroid cell neoplasias.
Somatic
Somatic RET mutations have been identified in
sporadic medullary thyroid carcinoma (MTC) and
pheochromocytoma, mostly located in exon 16 at
codon 918 (30-70% of sporadic MTC). Somatic
mutations in exons 15, codon 883 and in exon 13,
Function
RET is a tyrosine kinase receptor whose ligands are
Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1)
7
RET (REarranged during Transfection)
Niccoli-Sire P
codon 768 have been also detected in rare cases of
sporadic MTC.
Somatic rearranged forms of RET (RET/PTC) are
detected in human papillary thyroid carcinoma (PTC):
several activating genes rearrange with RET to form
RET/PTC by juxtaposing the genomic region coding
for the tyrosine kinase domain with the 5'-terminal
regions of several unrelated genes: H4: PTC1; RIa:
PTC2; ELE1: PTC3/4; RFG5: PTCT5; hTIF1: PTC6;
RFG7: PTC7, and ELKS.
RET rearrangement as RET/PTC1 is mostly detected in
typical sporadic papillary thyroid carcinoma,
RET/PTC3 occured at high frequency in chilhood
papillary thyroid carcinoma from areas contaminated
by the Chernobyl nuclear reactor accident.
Prognosis
The prognosis of MEN2 and FMTC is related to MTC:
it depends mainly on the histopathological stage of the
MTC disease.
References
Takahashi M, Buma Y, Iwamoto T, Inaguma Y, Ikeda H, Hiai
H. Cloning and expression of the ret proto-oncogene encoding
a tyrosine kinase with two potential transmembrane domains.
Oncogene. 1988 Nov;3(5):571-8
Ishizaka Y, Itoh F, Tahira T, Ikeda I, Sugimura T, Tucker J,
Fertitta A, Carrano AV, Nagao M. Human ret proto-oncogene
mapped to chromosome 10q11.2. Oncogene. 1989
Dec;4(12):1519-21
Mulligan LM, Kwok JB, Healey CS, Elsdon MJ, Eng C, Gardner
E, Love DR, Mole SE, Moore JK, Papi L. Germ-line mutations
of the RET proto-oncogene in multiple endocrine neoplasia
type 2A. Nature. 1993 Jun 3;363(6428):458-60
Implicated in
Multiple Endocrine Neoplasia type 2
(MEN2), Hirschprung's disease (HSCR).
Somatic rearranged forms of RET
(RET/PTC) are detected in human
papillary thyroid carcinoma.
Edery P, Lyonnet S, Mulligan LM, Pelet A, Dow E, Abel L,
Holder S, Nihoul-Fékété C, Ponder BA, Munnich A. Mutations
of the RET proto-oncogene in Hirschsprung's disease. Nature.
1994 Jan 27;367(6461):378-80
Hofstra RM, Landsvater RM, Ceccherini I, Stulp RP, Stelwagen
T, Luo Y, Pasini B, Höppener JW, van Amstel HK, Romeo G. A
mutation in the RET proto-oncogene associated with multiple
endocrine neoplasia type 2B and sporadic medullary thyroid
carcinoma. Nature. 1994 Jan 27;367(6461):375-6
Disease
MEN 2A (60% of MEN2) associates medullary thyroid
carcinoma (MTC) (100% of the cases) with
pheochromocytoma in 50% of cases and with primary
hyperparathyroidism (pHPT) in 5 to 20% of cases.
MEN 2B (5% of MEN2) is characterized by the
association of MTC (100% of the cases) with
pheochromocytoma (about 50% of the cases) as well as
a phenotype including skeletal abnormalities suggestive
of Marfan syndrome and the presence of multiple
mucosal neuroma; no pHPT is found in MEN 2B.
Familial MTC only (FMTC) represents 35% of MEN 2
and is characterized by the absence of other
associations throughout the entire follow up.
Hirschprung's disease or aganglionosis (HSCR) is a
frequent congenital intestinal malformation (1/5000
live births) characterized by the absence of neural crestderived parasympathetic neurons of the hindgut.
Typical sporadic papillary thyroid carcinoma and
chilhood papillary thyroid carcinoma linked to
radiation exposure are associated with somatic
RET/PTC rearrangements.
Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1)
Marsh DJ, Learoyd DL, Andrew SD, Krishnan L, Pojer R,
Richardson AL, Delbridge L, Eng C, Robinson BG. Somatic
mutations in the RET proto-oncogene in sporadic medullary
thyroid carcinoma. Clin Endocrinol (Oxf). 1996 Mar;44(3):24957
Bunone G, Uggeri M, Mondellini P, Pierotti MA, Bongarzone I.
RET receptor expression in thyroid follicular epithelial cellderived tumors. Cancer Res. 2000 Jun 1;60(11):2845-9
Jhiang SM. The RET proto-oncogene in human cancers.
Oncogene. 2000 Nov 20;19(49):5590-7
Manié S, Santoro M, Fusco A, Billaud M. The RET receptor:
function in development and dysfunction in congenital
malformation. Trends Genet. 2001 Oct;17(10):580-9
Takahashi M. The GDNF/RET signaling pathway and human
diseases. Cytokine Growth Factor Rev. 2001 Dec;12(4):361-73
This article should be referenced as such:
Niccoli-Sire P. RET (REarranged during Transfection). Atlas
Genet Cytogenet Oncol Haematol. 2004; 8(1):7-8.
8
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Gene Section
Mini Review
ZFHX3 (zinc finger homeobox 3)
Nadine Van Roy, Frank Speleman
Center for Medical Genetics, Ghent University Hospital, 1K5, De Pintelaan 185, B-9000 Gent, Belgium
(NV, FS)
Published in Atlas Database: October 2003
Online updated version : http://AtlasGeneticsOncology.org/Genes/ATBF1ID357.html
DOI: 10.4267/2042/38035
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2004 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Localisation
Identity
Nuclear.
Other names: AT motif-binding factor 1; Alphafetoprotein enhancer binding protein
HGNC (Hugo): ZFHX3
Location: 16q22.3-q23.1
Function
Transcription factor that binds to the AT-rich core
sequence of the enhancer element of the AFP gene and
downregulates AFP gene expression, possibly involved
in neuronal differentiation (ATBF1-A).
Homology
Mouse atbf1, drosophila zfh2 and C. Elegans ZC 123.3.
Mutations
Probe(s) - Courtesy Mariano Rocchi, Resources for Molecular
Cytogenetics.
Somatic
DNA/RNA
Two isoforms ATBF1-A and ATBF1-B, due to
alternative promotor usage combined with alternative
splicing, mRNA-size: 11893 bp.
Amplification, in one early neural crest derived cell
line SJNB-12 under the form of extrachromosomally
double minutes, non-syntenic co-amplification with
MYC.
Absence of ATBF1 expression in alpha-fetoprotein
expressing gastric cancer cell lines, lack of ATBF1
expression not due to mutation, deletion or
translocation but to strong repression at the
transcriptional level.
Protein
Implicated in
Description
Early neural crest derived cell line
(SJNB-12)
Description
10 exons, DNA size: 261.32 kb.
Transcription
3703 amino acids; 404 kDa; four homeodomains and
23 zinc fingers including 1 pseudo zinc finger motif,
one DEAD and one DEAH box, a RNA and an ATP
binding site, two large RS domains and multiple
phosphorylation sites.
Prognosis
Unknown.
Cytogenetics
Several structural and numerical chromosomal
aberrations and presence of extrachromosomally
double minutes and homogenously staining regions,
presence
of
a
reciprocal
unbalanced
t(8;16)(q24.3;q22.3).
Expression
Embryonic and neonatal brain.
Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1)
9
ZFHX3 (zinc finger homeobox 3)
Van Roy N, Speleman F
Kataoka H, Joh T, Miura Y, Tamaoki T, Senoo K, Ohara H,
Nomura T, Tada T, Asai K, Kato T, Itoh M. AT motif binding
factor 1-A (ATBF1-A) negatively regulates transcription of the
aminopeptidase N gene in the crypt-villus axis of small
intestine. Biochem Biophys Res Commun. 2000 Jan
7;267(1):91-5
Oncogenesis
Amplification in one neural crest derived cell line
(SJNB-12), non-syntenic co-amplification with MYC.
Alpha-fetoprotein producing gastric
cancer cell lines (GCIY and Ist-I)
Kaushik N, Malaspina A, de Belleroche J. Characterization of
trinucleotide- and tandem repeat-containing transcripts
obtained from human spinal cord cDNA library by high-density
filter hybridization. DNA Cell Biol. 2000 May;19(5):265-73
Prognosis
Poor (very malignant and highly metastatic cancer).
Oncogenesis
Alpha-fetoprotein producing cancer cell lines show
absence of ATBF1 expression, lack of ATBF1
expression not due to deletion mutation or translocation
but to strong repression at the transcriptional level.
Sawada Y, Miura Y, Umeki K, Tamaoki T, Fujinaga K, Ohtaki
S. Cloning and characterization of a novel RNA-binding protein
SRL300 with RS domains. Biochim Biophys Acta. 2000 Jun
21;1492(1):191-5
Berry FB, Miura Y, Mihara K, Kaspar P, Sakata N, HashimotoTamaoki T, Tamaoki T. Positive and negative regulation of
myogenic differentiation of C2C12 cells by isoforms of the
multiple homeodomain zinc finger transcription factor ATBF1. J
Biol Chem. 2001 Jul 6;276(27):25057-65
References
Morinaga T, Yasuda H, Hashimoto T, Higashio K, Tamaoki T.
A human alpha-fetoprotein enhancer-binding protein, ATBF1,
contains four homeodomains and seventeen zinc fingers. Mol
Cell Biol. 1991 Dec;11(12):6041-9
Kataoka H, Miura Y, Joh T, Seno K, Tada T, Tamaoki T,
Nakabayashi H, Kawaguchi M, Asai K, Kato T, Itoh M. Alphafetoprotein producing gastric cancer lacks transcription factor
ATBF1. Oncogene. 2001 Feb 15;20(7):869-73
Yasuda H, Mizuno A, Tamaoki T, Morinaga T. ATBF1, a
multiple-homeodomain zinc finger protein, selectively downregulates AT-rich elements of the human alpha-fetoprotein
gene. Mol Cell Biol. 1994 Feb;14(2):1395-401
Kawaguchi M, Miura Y, Ido A, Morinaga T, Sakata N, Oya T,
Hashimoto-Tamaoki T, Sasahara M, Koizumi F, Tamaoki T.
DNA/RNA-dependent ATPase activity is associated with
ATBF1, a multiple homeodomain-zinc finger protein. Biochim
Biophys Acta. 2001 Dec 17;1550(2):164-74
Miura Y, Tam T, Ido A, Morinaga T, Miki T, Hashimoto T,
Tamaoki T. Cloning and characterization of an ATBF1 isoform
that expresses in a neuronal differentiation-dependent manner.
J Biol Chem. 1995 Nov 10;270(45):26840-8
Van Roy N, Van Limbergen H, Vandesompele J, Van Gele M,
Poppe B, Salwen H, Laureys G, Manoel N, De Paepe A,
Speleman F. Combined M-FISH and CGH analysis allows
comprehensive description of genetic alterations in
neuroblastoma cell lines. Genes Chromosomes Cancer. 2001
Oct;32(2):126-35
Scheidl TM, Miura Y, Yee HA, Tamaoki T. Automated
fluorescent dye-terminator sequencing of G+C-rich tracts with
the aid of dimethyl sulfoxide. Biotechniques. 1995
Nov;19(5):691-4
Li H, Huang CJ, Choo KB. Expression of homeobox genes in
cervical cancer. Gynecol Oncol. 2002 Feb;84(2):216-21
Yamada K, Miura Y, Scheidl T, Yoshida MC, Tamaoki T.
Assignment of the human ATBF1 transcription factor gene to
chromosome
16q22.3-q23.1.
Genomics.
1995
Sep
20;29(2):552-3
Ninomiya T, Mihara K, Fushimi K, Hayashi Y, HashimotoTamaoki T, Tamaoki T. Regulation of the alpha-fetoprotein
gene by the isoforms of ATBF1 transcription factor in human
hepatoma. Hepatology. 2002 Jan;35(1):82-7
Tamaoki T, Hashimoto T. [ZFH/ATBF1 gene family:
transcription factors containing both homeo- and zinc fingerdomains].
Tanpakushitsu
Kakusan
Koso.
1996
Sep;41(11):1550-9
Ishii Y, Kawaguchi M, Takagawa K, Oya T, Nogami S, Tamura
A, Miura Y, Ido A, Sakata N, Hashimoto-Tamaoki T, Kimura T,
Saito T, Tamaoki T, Sasahara M. ATBF1-A protein, but not
ATBF1-B, is preferentially expressed in developing rat brain. J
Comp Neurol. 2003 Oct 6;465(1):57-71
Watanabe M, Miura Y, Ido A, Sakai M, Nishi S, Inoue Y,
Hashimoto T, Tamaoki T. Developmental changes in
expression of the ATBF1 transcription factor gene. Brain Res
Mol Brain Res. 1996 Dec;42(2):344-9
This article should be referenced as such:
Chen H, Egan JO, Chiu JF. Regulation and activities of alphafetoprotein. Crit Rev Eukaryot Gene Expr. 1997;7(1-2):11-41
Van Roy N, Speleman F. ZFHX3 (zinc finger homeobox 3).
Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1):9-10.
Kaspar P, Dvoráková M, Králová J, Pajer P, Kozmik Z,
Dvorák M. Myb-interacting protein, ATBF1, represses
transcriptional activity of Myb oncoprotein. J Biol Chem. 1999
May 14;274(20):14422-8
Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1)
10
Atlas of Genetics and Cytogenetics
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Gene Section
Mini Review
LPHN2 (latrophilin 2)
Jim Heighway
Roy Castle International Centre for Lung Cancer Research, Liverpool, UK (JH)
Published in Atlas Database: November 2003
Online updated version : http://AtlasGeneticsOncology.org/Genes/LPHH1ID313.html
DOI: 10.4267/2042/38040
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2004 Atlas of Genetics and Cytogenetics in Oncology and Haematology
of the gene is not precisely defined with transcripts in
different tissues apparently initiating from specific
locations over an extensive region. The most distant
leader exon identified (foetal lung) lies approximately
390 kb from exon 1 which makes the total size of the
gene at least 550 kb.
Identity
Other names: LPHH1; LEC1; KIAA0786
HGNC (Hugo): LPHN2
Location: 1p31.1
Local order: --ELTD1---LPHH1----FLJ23033---PRKACB--
Transcription
Expression has been observed by RT-PCR in all normal
tissues and lines tested with the clear exception of
lymphocytes and lymphoblastoid cells. Strongest
expression was observed in foetal lung, normal adult
lung and thyroid. Alternative splicing to some degree in
at least one domain (minimally the carboxy-terminal
domain D) was seen in each tissue and line examined
with human brain showing a characteristic pattern and
additional variability in the other three coding sequence
domains.
DNA/RNA
Description
LPHH1 consists of 19 commonly used coding exons. A
further seven exons have been identified which may be
alternatively spliced into the core backbone with
variable frequencies and tissue specificities. At least a
number of these additional exons are highly conserved
in mammalian species. The core exons (ATG, exon 1 to
stop, exon 19) span a region of about 154 kb. However,
the 5'end
Pseudogene
No known pseudogene.
Probe(s) - Courtesy Mariano Rocchi, Resources for Molecular Cytogenetics.
Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1)
11
LPHN2 (latrophilin 2)
Heighway J
Representation of the genomic structure of LPHH1. Black blocks represent core exons which are present in the majority of gene
transcripts. The yellow blocks represent alternatively spliced coding exons which may be incorporated variably in transcripts derived from
different cell types/tissues or as a consequence of differing cellular states. The red boxes represent the presence of multiple, in some
cases tissue-specific, leader exons that have been identified for this gene, an observation consistent with the existence of multiple
dispersed promoter elements. The most variably spliced region of the coding sequence was the carboxy-terminal domain D.
Alternative splicing in domain D dramatically alters the structure of the carboxy-terminus of the encoded protein, latrophilin 2. Variable
splicing in this region occurs in all tissues and cell lines tested.
cells but that has not so far been confirmed. Human
brain-specific alternative splices alter the structure of
the extra-membrane, intra-cellular loop between TM
domains 5 and 6, a region thought to be critical for Gprotein/receptor interactions.
Protein
Description
LPHH1 encodes a putative seven-span transmembrane
receptor with atypically large extra membrane N
(predicted to be extra-cellular) and C termini. In
addition to the seven hydrophobic membrane spanning
domains, a putative lectin-like region is present near
the N-terminus.
Localisation
Likely to be plasma membrane.
Function
Expression
Likely role in coupling cell adhesion to cell signalling.
Protein likely to be ubiquitously expressed in adherent
Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1)
12
LPHN2 (latrophilin 2)
Heighway J
Note
None reported.
Strong expression in normal lung was reduced in 55%
(35/64) of matched primary non-small cell lung
carcinomas (NSCLC). Over-representation was not
scored in any tumour, nor in any lung cancer cell line
tested and transcript was undetectable by RT-PCR in
one line (1/15) and very low in a further two. Loss of
heterozygosity was scored in 8/16 informative NSCLC
lesions. Primary and SCLC lines showed a
characteristic pattern of alternative splicing.
Implicated in
References
Breast carcinoma
Hayflick JS. A family of heptahelical receptors with adhesionlike domains: a marriage between two super families. J Recept
Signal Transduct Res. 2000 May-Aug;20(2-3):119-31
Homology
Latrophilin 2 is part of a small sub-family of 7 TMs
which includes latrophilins 1 and 3. Latrophilin 1 is the
receptor for Black Widow spider toxin: -latrotoxin.
Mutations
Note
Analysis of breast cancer cell lines has demonstrated
dramatic differences in transcript levels between certain
lines. In one case, strong expression was allelically
imbalanced.
White GR, Varley JM, Heighway J. Genomic structure and
expression profile of LPHH1, a 7TM gene variably expressed
in breast cancer cell lines. Biochim Biophys Acta. 2000 Apr
25;1491(1-3):75-92
Lung carcinoma
This article should be referenced as such:
Note
Heighway J. LPHN2 (latrophilin 2). Atlas Genet Cytogenet
Oncol Haematol. 2004; 8(1):11-13.
Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1)
13
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Gene Section
Mini Review
MNX1 (motor neuron and pancreas homeobox 1)
Anne RM von Bergh, H Berna Beverloo
Department of Clinical Genetics, Erasmus MC, Dr. Molewaterplein 50, 3015 GE Rotterdam, The
Netherlands (ARMVB, HBB)
Published in Atlas Database: December 2003
Online updated version : http://AtlasGeneticsOncology.org/Genes/HLXB9ID393.html
DOI: 10.4267/2042/38041
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2004 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Function
Identity
Putative transcription factor.
Other names: HLXB9 (homeo box HB9); HB9;
HOXHB9; SCRA1; Mnr1
HGNC (Hugo): MNX1
Location: 7q36.3
Note: Telomeric to c7orf3 and SHH.
Homology
Related to Mnr2.
Mutations
Note
Mutations in HLXB9 cause an autosomal dominant
form of sacral agenesis, known as Currarino syndrome.
DNA/RNA
Description
Implicated in
3 exons stretched over an area of 5-6 kb.
Transcription
t(7;12)(q36;p13) – associated infant
acute myeloid leukemia (AML)
In a telomere to centromere direction; 2061 bp mRNA,
1206 bp open reading frame.
Prognosis
Prognosis probably poor: median survival is 13 months.
Cytogenetics
t(7;12)(q36;p13), but not always visible by
chromosome banding; may also be misdiagnosed as
del(12)(p13).
Hybrid/Mutated gene
5' HLXB9 _ 3' ETV6
Abnormal protein
N-term HLXB9, including its polyalanine repeat, is
fused to a large C-term part of the ETV6 protein
including its HLH domain and ETS domain; the
homeobox domain of HLXB9 is not retained in the
fusion protein; the reciprocal transcript is not
expressed.
Protein
Description
The homeobox gene HLXB9 encodes the nuclear
protein HB9. The protein contains a polyalanine repeat
region and a homeobox domain.
Expression
Expressed in lymphoid and pancreatic tissues. Highly
expressed in CD34+ bone marrow cells, down
regulated upon differentiation.
Localisation
Nuclear.
Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1)
14
MNX1 (homeo box HB9)
von Bergh ARM, Beverloo HB
Fig. 3. Schematic representation of the HLXB9 and ETV6 proteins and the putative HLXB9-ETV6 chimeric protein resulting from the
t(7;12)(q36;p13). Arrow, the observed breakpoints. nt numbers (cDNA level) are given above each protein, and amino acid numbers are
given in bold type below each protein.
Ross AJ, Ruiz-Perez V, Wang Y, Hagan DM, Scherer S, Lynch
SA, Lindsay S, Custard E, Belloni E, Wilson DI, Wadey R,
Goodman F, Orstavik KH, Monclair T, Robson S, Reardon W,
Burn J, Scambler P, Strachan T. A homeobox gene, HLXB9, is
the major locus for dominantly inherited sacral agenesis. Nat
Genet. 1998 Dec;20(4):358-61
To be noted
The t(7;12) is heterogeneous at the molecular level.
The formation of a fusion gene has only been described
in 2 cases and may not be the only mechanism by
which HLXB9 is involved in t(7;12) associated
leukaemias. Additional 7q36 genes may also be
involved.
Beverloo HB, Panagopoulos I, Isaksson M, van Wering E, van
Drunen E, de Klein A, Johansson B, Slater R. Fusion of the
homeobox gene HLXB9 and the ETV6 gene in infant acute
myeloid leukemias with the t(7;12)(q36;p13). Cancer Res.
2001 Jul 15;61(14):5374-7
References
This article should be referenced as such:
Harrison KA, Druey KM, Deguchi Y, Tuscano JM, Kehrl JH. A
novel human homeobox gene distantly related to
proboscipedia is expressed in lymphoid and pancreatic tissues.
J Biol Chem. 1994 Aug 5;269(31):19968-75
Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1)
von Bergh ARM, Beverloo HB. MNX1 (motor neuron and
pancreas homeobox 1). Atlas Genet Cytogenet Oncol
Haematol. 2004; 8(1):14-15.
15
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
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Gene Section
Mini Review
SYNPO2 (synaptopodin 2)
Jian-Hua Luo
Gene Array Laboratory, Univeristy of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA (JHL)
Published in Atlas Database: December 2003
Online updated version : http://AtlasGeneticsOncology.org/Genes/SYNPO2ID488.html
DOI: 10.4267/2042/38042
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2004 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Pseudogene
Identity
Unknown.
Other names: Myopodin; synaptopodin 2
HGNC (Hugo): SYNPO2
Location: 4q27
Note: Myopodin probably represents an alternative
splicing variant of synaptopodin 2. The predicted
synaptopodin 2 contains 1021 amino acid and
myopodin 698. The extra 323 amino acid in
synaptopodin 2 is located at the N-terminus.
Protein
Description
A nuclear localization signal is identified in N-terminus
region of myopodin. Myopodin also contains six
stretches of homologous sequences with synaptopodin
1.
Expression
DNA/RNA
Skeletal muscle, prostate, large and small intestine.
Description
Localisation
The genome sequence of myopodin contains 6.8 Kb,
while synaptopodin 2 38 kb.
Nucleus, cytoplasm.
Function
Transcription
Actin bundling.
A typical messenger RNA of myopodin is 4.2-4.4 kb,
and synaptopodin 2 6.7 kb.
Homology
Synaptopodin.
Genome structure of myopodin and synaptopodin 2. Green represents exons of myopodin, and orange synaptopodin 2. Introns are
indicated with lines.
Protein structure of myopodin and synaptopodin 2. Orange represents sequence unique to synaptopodin 2, Green myopodin. Black stripe
represents sequence homologous to synaptopodin 1.
Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1)
16
SYNPO2 (synaptopodin 2)
Luo JH
Mutations
References
Germinal
Lin F, Yu YP, Woods J, Cieply K, Gooding B, Finkelstein P,
Dhir R, Krill D, Becich MJ, Michalopoulos G, Finkelstein S, Luo
JH. Myopodin, a synaptopodin homologue, is frequently
deleted in invasive prostate cancers. Am J Pathol. 2001
Nov;159(5):1603-12
Not known.
Somatic
Deletion.
Weins A, Schwarz K, Faul C, Barisoni L, Linke WA, Mundel P.
Differentiation- and stress-dependent nuclear cytoplasmic
redistribution of myopodin, a novel actin-bundling protein. J
Cell Biol. 2001 Oct 29;155(3):393-404
Implicated in
Disease
Prostate cancer and urothelial cell carcinoma.
Prognosis
Deletion preferentially occurs in aggressive type of
prostate cancer. Loss of expression in nucleus in
urothelial cell carcinoma is predictive of poor clinical
outcome.
Cytogenetics
Not known.
Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1)
Sanchez-Carbayo M, Schwarz K, Charytonowicz E, CordonCardo C, Mundel P. Tumor suppressor role for myopodin in
bladder cancer: loss of nuclear expression of myopodin is cellcycle dependent and predicts clinical outcome. Oncogene.
2003 Aug 14;22(34):5298-305
This article should be referenced as such:
Luo JH. SYNPO2 (synaptopodin 2). Atlas Genet Cytogenet
Oncol Haematol. 2004; 8(1):16-17.
17
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
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Leukaemia Section
Short Communication
11p15 rearrangements
leukemia
in
treatment
related
Jean-Loup Huret
Genetics, Dept Medical Information, UMR 8125 CNRS, University of Poitiers, CHU Poitiers Hospital, F86021 Poitiers, France (JLH)
Published in Atlas Database: October 2003
Online updated version : http://AtlasGeneticsOncology.org/Anomalies/11p15TreatRelLeukID1299.html
DOI: 10.4267/2042/38043
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2004 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Prognosis
Identity
Median survival was 13 mths, with 56% of patients
surviving at 1 yr, and 33% at 2 yrs, a similar survival to
what is found in treatment related leukemias with a
21q22 rearrangement.
Note: This data is extracted from a very large study
from an International Workshop on treatment related
leukemias - restricted to balanced chromosome
aberrations (i.e.: -5/del(5q) and -7/del(7q) not taken
into account per see), published in Genes,
Chromosomes and Cancer in 2002.
Cytogenetics
Additional anomalies
Clinics and pathology
11p15 rearrangements included inv(11)(p15q23) in
35% of cases, t(7;11)(p15;p15) in 18%, or, more rarely:
t(1;11)(p32;p15), t(2;11)(q31;p15), t(4;11)(q22;p15),
t(10;11)(q22-23;p15),
t(11;17)(p15;q21),
or
t(11;20)(p15;q11); additional anomalies were: 7/del(7q) in 24%, and -5/del(5q) in 12 %. Complex
karyotypes were found in 18%.
Disease
Treatment related myelodysplasia (t-MDS) or acute
non lymphocytic leukaemias (t-ANLL).
Note
The study included 17 cases; t-MDS without
progression to ANLL accounted for 35%, t-MDS with
progression to ANLL for 18% and t-ANLL for the
remaining 47% (M2 or M4 mainly); no case of acute
lymphoblastic leukaemia.
Result of the chromosomal
anomaly
Epidemiology
Hybrid gene
11p15 rearrangements were found in 3% of t-MDS/tANLL and have been reported to be found in 5% of
childhood t-MDS/t-ANLL; sex ratio: 4M/13F.
Description
5' NUP98 -3' partner.
References
Clinics
Block AW, Carroll AJ, Hagemeijer A, Michaux L, van Lom K,
Olney HJ, Baer MR. Rare recurring balanced chromosome
abnormalities in therapy-related myelodysplastic syndromes
and acute leukemia: report from an international workshop.
Genes Chromosomes Cancer. 2002 Apr;33(4):401-12
Age at diagnosis of the primary disease 45 yrs (range 270); age at diagnosis of the t-MDS/t-ANLL: 50 yrs
(range 4-75). Median interval was short: 54 mths
(range: 11-189). Primary disease was
a solid tumor in 47% of cases (in particular breast
cancer) and a hematologic malignancy in 53%,
treatment was chemotherapy (42%), or both
chemotherapy and radiotherapy (58%). Treatment
included topoisomerase II inhibitors in 71% of cases
and alkylating agents in 76%.
Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1)
This article should be referenced as such:
Huret JL. 11p15 rearrangements in treatment related
leukemia. Atlas Genet Cytogenet Oncol Haematol. 2004;
8(1):18.
18
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
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Leukaemia Section
Short Communication
12p13 rearrangements in treatment related
leukemia
Jean-Loup Huret
Genetics, Dept Medical Information, UMR 8125 CNRS, University of Poitiers, CHU Poitiers Hospital, F86021 Poitiers, France (JLH)
Published in Atlas Database: October 2003
Online updated version : http://AtlasGeneticsOncology.org/Anomalies/12p13TreatRelLeukID1301.html
DOI: 10.4267/2042/38044
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2004 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Prognosis
Identity
Median survival was very poor: 4 mths, with 15% of
patients surviving at 1 yr, and none at 2 yrs.
Note: This data is extracted from a very large study
from an International Workshop on treatment related
leukemias - restricted to balanced chromosome
aberrations (i.e.: -5/del(5q) and -7/del(7q) not taken
into account per see), published in Genes,
Chromosomes and Cancer in 2002.
Cytogenetics
Additional anomalies
12p13 rearrangements included:
t(1;12)(q21;p13), t(4;12)(q12;p13),
t(7;12)(p15;p13), t(8;12)(p12;p13),
t(12;20)p13;q11), and t(12;22)(p13;q11) and other
rearrangements. Complex karyotypes were found in 7
of 9 cases; -7/del(7q) and/or -5/del(5q) were found in 6
of 9 cases.
Clinics and pathology
Disease
Treatment related myelodysplasia (t-MDS) or acute
non lymphocytic leukaemias (t-ANLL).
Note
The study included 9 cases; t-MDS without progression
to ANLL accounted for 2 of 9 cases, t-MDS with
progression to ANLL for 1 case and t-ANLL for the
remaining 6 cases; no case of acute lymphoblastic
leukaemia.
Result of the chromosomal
anomaly
Hybrid gene
Description
5' ETV6 -3' partner where ETV6 is known to be
involved.
Epidemiology
12p13 rearrangements were found in 2% of t-MDS/tANLL; sex ratio: 5M/4F.
References
Clinics
Block AW, et al. Rare recurring balanced chromosome
abnormalities in therapy-related myelodysplastic syndromes
and acute leukemia: report from an international workshop.
Genes Chromosomes Cancer. 2002 Apr;33(4):401-12
Age at diagnosis of the primary disease 40 yrs (range
11-64); age at diagnosis of the t-MDS/t-ANLL: 48 yrs
(range 25-69). Median interval was relatively long: 81
mths (range: 18-223). Primary disease was a solid
tumor in only 2 of 9 cases, and a hematologic
malignancy in 7/9; treatment was chemotherapy (3/9),
or both (6/9). Treatment included topoisomerase II
inhibitors in 5 of 9 cases and alkylating agents in 8/9.
Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1)
This article should be referenced as such:
Huret JL. 12p13 rearrangements in treatment related leukemia.
Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1):19.
19
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Leukaemia Section
Mini Review
21q22 rearrangements
leukemia
in
treatment
related
Jean-Loup Huret
Genetics, Dept Medical Information, UMR 8125 CNRS, University of Poitiers, CHU Poitiers Hospital, F86021 Poitiers, France (JLH)
Published in Atlas Database: October 2003
Online updated version : http://AtlasGeneticsOncology.org/Anomalies/21q22TreatRelLeukID1296.html
DOI: 10.4267/2042/38045
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2004 Atlas of Genetics and Cytogenetics in Oncology and Haematology
ANLL was 51 yrs (11-77) and median interval was 39
mths (6-306). Primary disease was a solid tumor in
56% of cases (mainly: breast, lung, sarcoma/ PNET,
colon cancer) and an hematologic malignancy in 43%.
Treatment of the primary disease included radiotherapy
(in 6%), chemotherapy (46%) or both (48%). 75% of
patients with a 21q22 rearrangement had previously
received topoisomerase II inhibitors, a higher
proportion than other subgroups of treatment related
leukemia, except 11q23 patients, who were 84% to
have been exposed to topoisomerase II inhibitors;
alkylating agents exposure was higher than in patients
with t(15;17) or inv(16).
Identity
Note: This data is extracted from a very large study
from an International Workshop on treatment related
leukemias - restricted to balanced chromosome
aberrations (i.e.: -5/del(5q) and -7/del(7q) not taken
into account per see), published in Genes,
Chromosomes and Cancer in 2002.
Clinics and pathology
Disease
Treatment related myelodysplasia (t-MDS) or acute
non lymphocytic leukaemias (t-ANLL).
Note
The study included 79 cases; t-MDS without
progression to ANLL accounted for 15%, t-MDS
progressing to ANLL for 18%, t-ANLL for the
remaining 67%; there was no case of acute
lymphoblastic leukaemia.
Treatment
Patients who received bone marrow transplantation had
a higher median survival (31 mths).
Prognosis
Median survival was 14 mths, there was 58% of
patients surviving 1 yr, 33% 2 yrs, and 18% 5 yrs., a
better outcome than patients with 11q23 rearrangement,
3q21q26 rearrangement, 12p13 rearrangement, t(9;22),
or t(8;16) and a worse outcome than those with t(15;17)
or inv(16) treatment related leukemias. By th 21q22
group, patients with a t(8;21) had a better outcome, and
those with a t(3;21) had a worse outcome.
Phenotype/cell stem origin
MDS cases were frequently refractory anemia with
excess of blasts cases; 58% of ANLL cases were M2
ANLL.
Etiology
Frequent antracyclin exposure.
Cytogenetics
Epidemiology
Cytogenetics morphological
21q22 rearrangements were found in 15% of t-MDS/tANLL; 1M to 1F sex ratio
t(8;21)(q22;q22) (ETO / AML1) was found in 56% of
cases, t(3;21)(q26;q22) (MDS-EVI1 / AML1 in 20 %,
t(16;21)(q24;q22) (CBFA2T3 / AML1) in 5%. Rare
recurrent
anomalies
were:
t(1;21)(p36;q22),
Clinics
Age at diagnosis of the primary disease was 47 yrs
(range 2-75); age at diagnosis of the t-MDS/t-
Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1)
20
21q22 rearrangements in treatment related leukemia
Huret JL
t(9;21)(p22;q22), t(10;21)(p12;q22), t(15;21)(q2122;q22), t(17;21)(q12;q22), and t(20;21)(q11;q22).
Result of the chromosomal
anomaly
Additional anomalies
-7/del(7q) in 23% of cases (espacially in cases with
alkylating agents exposure), +8 in 11%, -5/del(5q)
rarely found; complex karyotypes in 28% of cases
(more frequently than in treatment related leukemias
with a 11q23 rearrangement or a t(15.17)).
Hybrid gene
Description
5' AML1 - 3' partner.
References
Genes involved and proteins
Slovak ML, Bedell V, Popplewell L, Arber DA, Schoch C, Slater
R. 21q22 balanced chromosome aberrations in therapy-related
hematopoietic disorders: report from an international
workshop. Genes Chromosomes Cancer. 2002 Apr;33(4):37994
AML1 partner
This article should be referenced as such:
Huret JL. 21q22 rearrangements in treatment related leukemia.
Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1):20-21.
Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1)
21
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Leukaemia Section
Mini Review
inv(16)(p13q22) in treatment related leukemia
Jean-Loup Huret
Genetics, Dept Medical Information, UMR 8125 CNRS, University of Poitiers, CHU Poitiers Hospital, F86021 Poitiers, France (JLH)
Published in Atlas Database: October 2003
Online updated version : http://AtlasGeneticsOncology.org/Anomalies/inv16p13q22TreatRelID1297.html
DOI: 10.4267/2042/38046
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2004 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Clinics
Identity
Age at diagnosis of the primary disease 43 yrs (range 675); age at diagnosis of the t-MDS/t-ANLL: 48 yrs
(range 13-77). Median interval was short: 22 mths
(range: 8-533). Primary disease was a solid tumor in
71% of cases (in particular breast cancer, sarcoma,
cancer of the ovary) and a hematologic malignancy in
27%, treatment was radiotherapy (21%, a relatively
high proportion compared to other groups),
chemotherapy (29%), or both (50%). Treatment
included topoisomerase II inhibitors in 60% of cases
and alkylating agents in 63%.
Note: This data is extracted from a very large study
from an International Workshop on treatment related
leukemias - restricted to balanced chromosome
aberrations (i.e.: -5/del(5q) and -7/del(7q) not taken
into account per see), published in Genes,
Chromosomes and Cancer in 2002.
Prognosis
Patients under 55 yrs of age had better outcome.
Median survival was 29 mths, with 45% of patients
surviving at 5 yrs, the best survival among subgroups
of treatment related leukemias with a balanced
chromosome aberration (patients with 11q23
rearrangement, 3q21q26 rearrangement, 12p13
rearrangement, t(9;22), t(8;16), or a 21q22
rearangement). Patients with t(15;17) had similar
median survival, but less long term survivors.
inv(16) diagram and FISH - Courtesy Hossein Mossafa; insert:
first row: inv(16)(p13q22) G-banding - Courtesy Diane H.
Norback, Eric B. Johnson, and Sara Morrison-Delap, UW
Cytogenetic Services; second row: R- banding - Courtesy
Hossein Mossafa.
Clinics and pathology
Disease
Cytogenetics
Treatment related myelodysplasia (t-MDS) or acute
non lymphocytic leukaemias (t-ANLL).
Note
The study included 48 cases; t-MDS without
progression to ANLL accounted for 8%, t-MDS with
progression to ANLL for 13% and t-ANLL for the
remaining 79% the ANLL subtype was M4eo in 83%,
M2 in 14%; no case of acute lymphoblastic leukaemia.
Additional anomalies
The inv(16) was found solely in 46% of cases;
additional anomalies were: +8 in 17% , +21 in 13%,
+22 in 8%, -7/del(7q) in 8%, +13 in 6%, or -5/del(5q).
Result of the chromosomal
anomaly
Epidemiology
Hybrid gene
inv(16)(p13q22) was found in 9% of t-MDS/t-ANLL;
sex ratio: 18M/30F.
Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1)
Description
5'CBFB -3' MYH11.
22
inv(16)(p13q22) in treatment related leukemia
Huret JL
References
an international workshop. Genes Chromosomes Cancer. 2002
Apr;33(4):395-400
Andersen MK, Larson RA, Mauritzson N, Schnittger S,
Jhanwar SC, Pedersen-Bjergaard J. Balanced chromosome
abnormalities inv(16) and t(15;17) in therapy-related
myelodysplastic syndromes and acute leukemia: report from
This article should be referenced as such:
Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1)
Huret JL. inv(16)(p13q22) in treatment related leukemia. Atlas
Genet Cytogenet Oncol Haematol. 2004; 8(1):22-23.
23
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Leukaemia Section
Mini Review
t(15;17)(q22;q21) in treatment related leukemia
Jean-Loup Huret
Genetics, Dept Medical Information, UMR 8125 CNRS, University of Poitiers, CHU Poitiers Hospital, F86021 Poitiers, France (JLH)
Published in Atlas Database: October 2003
Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t1517q22q21TreatRelID1298.html
DOI: 10.4267/2042/38051
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2004 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
Note: This data is extracted from a very large study from an International Workshop on treatment related leukemias restricted to balanced chromosome aberrations (i.e.: -5/del(5q) and -7/del(7q) not taken into account per see), published
in Genes, Chromosomes and Cancer in 2002.
t(15;17)(q22;q21) (or t(15;17)(q24;q21), since PML sits in 15q24, and RARA in 17q21) Top: G-banding - Courtesy Diane H. Norback,
Eric B. Johnson, and Sara Morrison-Delap, UW Cytogenetic Services; Bottom and right: R- banding and FISH - Courtesy Hossein
Mossafa.
Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1)
24
t(15;17)(q22;q21) in treatment related leukemia
Huret JL
Clinics and pathology
rearrangement, t(9;22), t(8;16), or a 21q22
rearangement) and similar, during the first 2 yrs to that
of the inv(16) treatment related leukemias.
Disease
Treatment related myelodysplasia (t-MDS) or acute
non lymphocytic leukaemias (t-ANLL).
Note
The study included 41 cases; t-MDS with progression
to ANLL accounted for 7% and t-ANLL for the
remaining 93% the ANLL subtype was M3 in all but
one case; no case of acute lymphoblastic leukaemia.
Cytogenetics
Additional anomalies
The t(15;17) was found solely in 59% of cases;
additional anomalies were: +8 in 12% , -5/del(5q) in
5%, or -7/del(7q).
Result of the chromosomal
anomaly
Epidemiology
t(15;17)(q22;q21) was found in 8% of t-MDS/t-ANLL;
sex ratio: 15M/26F.
Hybrid gene
Clinics
Description
5' PML -3' RARA.
Age at diagnosis of the primary disease 46 yrs (range
18-79); age at diagnosis of the t-MDS/t-ANLL: 49 yrs
(range 19-81). Median interval was 29 mths (range: 9175). Primary disease was a solid tumor in 71% of
cases (breast cancer in particular) and a hematologic
malignancy in 27%, treatment was radiotherapy (29%,
a high proportion compared to other groups),
chemotherapy (17%), or both (54%). Treatment
included topoisomerase II inhibitors in 49% of cases
and alkylating agents in 59%.
References
Andersen MK, Larson RA, Mauritzson N, Schnittger S,
Jhanwar SC, Pedersen-Bjergaard J. Balanced chromosome
abnormalities inv(16) and t(15;17) in therapy-related
myelodysplastic syndromes and acute leukemia: report from
an international workshop. Genes Chromosomes Cancer. 2002
Apr;33(4):395-400
Prognosis
This article should be referenced as such:
Median survival was 29 mths. Outcome was better than
the outcome of patients with 11q23
rearrangement, 3q21q26 rearrangement, 12p13
Huret JL. t(15;17)(q22;q21) in treatment related leukemia.
Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1):24-25.
Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1)
25
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Leukaemia Section
Short Communication
t(3;21)(q26;q22) in treatment related leukemia
Jean-Loup Huret
Genetics, Dept Medical Information, UMR 8125 CNRS, University of Poitiers, CHU Poitiers Hospital, F86021 Poitiers, France (JLH)
Published in Atlas Database: October 2003
Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t0321q26q22TreatRelID1294.html
DOI: 10.4267/2042/38047
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2004 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
Note: This data is extracted from a very large study from an International Workshop on treatment related leukemias restricted to balanced chromosome aberrations (i.e.: -5/del(5q) and -7/del(7q) not taken into account per see), published
in Genes, Chromosomes and Cancer in 2002.
t(3;21)(q26;q22) G- banding - Courtesy Melanie Zenger and Claudia Haferlach.
Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1)
26
t(3;21)(q26;q22) in treatment related leukemia
Huret JL
or inv(16) treatment related leukemias, and similar to
the outcome of patients with 11q23 rearrangement.
Clinics and pathology
Disease
Cytogenetics
Treatment related myelodysplasia (t-MDS) or acute
non lymphocytic leukaemias (t-ANLL).
Additional anomalies
The t(3;21) was found solely in 31% of cases;
additional anomaly was: -7/del(7q) in 31% of cases, +8
was not observed. A complex karyotype was found in
25% of cases.
Note
The study included 16 cases; t-MDS without
progression to ANLL accounted for 38%, t-MDS
progressing to ANLL for 25%, t-ANLL for the
remaining 38% (to be compared with the 80% of tANLL in cases with t(8;21)); no case of acute
lymphoblastic leukaemia.
Result of the chromosomal
anomaly
Epidemiology
Hybrid gene
t(3;21)(q26;q22) was found in 3% of t-MDS/t-ANLL;
sex ratio: 5M/11F.
Description
5' AML1 - 3' MDS1-EVI1; breakpoint is most often in
the AML1 intron 6.
Clinics
Age at diagnosis of the primary disease 49 yrs (range
14-72); age at diagnosis of the t-MDS/t-ANLL: 53 yrs
range 19-73). Median interval was 36 mths, range: 17139). Primary disease was a solid tumor in 56% of
cases and a hematologic malignancy in 44%. Treatment
included topoisomerase II inhibitors in 81% of cases).
References
Slovak ML, Bedell V, Popplewell L, Arber DA, Schoch C, Slater
R. 21q22 balanced chromosome aberrations in therapy-related
hematopoietic disorders: report from an international
workshop. Genes Chromosomes Cancer. 2002 Apr;33(4):37994
Prognosis
This article should be referenced as such:
Median survival was 8 mths. Outcome was worse than
the outcome of patients with t(8;21)(q22;q22), t(15;17)
Huret JL. t(3;21)(q26;q22) in treatment related leukemia. Atlas
Genet Cytogenet Oncol Haematol. 2004; 8(1):26-27.
Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1)
27
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Leukaemia Section
Short Communication
t(8;16)(p11;p13) in treatment related leukemia
Jean-Loup Huret
Genetics, Dept Medical Information, UMR 8125 CNRS, University of Poitiers, CHU Poitiers Hospital, F86021 Poitiers, France (JLH)
Published in Atlas Database: October 2003
Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t0816p11p13TreatRelID1302.html
DOI: 10.4267/2042/38048
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© 2004 Atlas of Genetics and Cytogenetics in Oncology and Haematology
progression to ANLL accounted for 1 of 9 cases, and tANLL for the remaining 8 cases; no case of acute
lymphoblastic leukaemia.
Identity
Note: This data is extracted from a very large study
from an International Workshop on treatment related
leukemias - restricted to balanced chromosome
aberrations (i.e.: -5/del(5q) and -7/del(7q) not taken
into account per see), published in Genes,
Chromosomes and Cancer in 2002.
Epidemiology
t(8;16)(p11;p13) was found in 2% of t-MDS/t-ANLL;
sex ratio: 5M/4F.
Clinics
Age at diagnosis of the primary disease 33 yrs (range 670); age at diagnosis of the t-MDS/t-ANLL: 41 yrs
(range 7-71). Median interval was 17 mths (range: 13202). Primary disease was a solid tumor in 9 of 9 cases;
treatment was radiotherapy in 1 case, chemotherapy in
2 of 9 cases, or both (6/9). Treatment included
topoisomerase II inhibitors in 6 of 8 cases and
alkylating agents in 7/8.
Prognosis
Median survival was very poor: 5 mths, with 39% of
patients surviving at 1 yr, and none at 2 yrs.
Cytogenetics
Additional anomalies
Complex karyotypes were found in 4 of 9 cases.
t(8;16)(p11;p13) G- banding - Courtesy Melanie Zenger and
Claudia Haferlach.
Result of the chromosomal
anomaly
Clinics and pathology
Disease
Hybrid gene
Treatment related myelodysplasia (t-MDS) or acute
non lymphocytic leukaemias (t-ANLL).
Note
The study included 9 cases; t-MDS with
Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1)
Description
5' MOZ -3' CBP
28
t(8;16)(p11;p13) in treatment related leukemia
Huret JL
References
This article should be referenced as such:
Huret JL. t(8;16)(p11;p13) in treatment related leukemia. Atlas
Genet Cytogenet Oncol Haematol. 2004; 8(1):28-29.
Block AW, Carroll AJ, Hagemeijer A, Michaux L, van Lom K,
Olney HJ, Baer MR. Rare recurring balanced chromosome
abnormalities in therapy-related myelodysplastic syndromes
and acute leukemia: report from an international workshop.
Genes Chromosomes Cancer. 2002 Apr;33(4):401-12
Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1)
29
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Leukaemia Section
Short Communication
t(8;21)(q22;q22) in treatment related leukemia
Jean-Loup Huret
Genetics, Dept Medical Information, UMR 8125 CNRS, University of Poitiers, CHU Poitiers Hospital, F86021 Poitiers, France (JLH)
Published in Atlas Database: October 2003
Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t0821q22q22TreatRelID1293.html
DOI: 10.4267/2042/38049
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2004 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
Prognosis
Note: This data is extracted from a very large study
from an International Workshop on treatment related
leukemias - restricted to balanced chromosome
aberrations (i.e.: -5/del(5q) and -7/del(7q) not taken
into account per see), published in Genes,
Chromosomes and Cancer in 2002.
Median survival was 17 mths and 31 mths respectively
for patients without and with additionnal anomalies, but
the difference was not significant. Outcome was better
than the outcome of patients with 11q23 rearrangement,
3q21q26 rearrangement, 12p13 rearrangement, t(9;22),
t(8;16), or a t(3;21) and worse than the outcome of
patients with with t(15;17) or inv(16) treatment related
leukemias.
Clinics and pathology
Cytogenetics
Disease
Additional anomalies
Treatment related myelodysplasia (t-MDS) or acute
non lymphocytic leukaemias (t-ANLL).
Note
The study included 44 cases; t-MDS with or without
progression to ANLL accounted for 20% and t-ANLL
for the remaining 80%; no case of acute lymphoblastic
leukaemia.
The t(8;21) was found solely in 25% of cases;
additional anomalies were: -Y or -X in 25% of cases,
del(9q) in 18%, +8 in 9%, -7/del(7q) in 7%. A complex
karyotype was found in 32% of cases.
Epidemiology
Result of the chromosomal
anomaly
t(8;21)(q22;q22) was found in 9% of t-MDS/t-ANLL;
1M to 1F sex ratio.
Hybrid gene
Description
5' AML1 - 3' ETO; breakpoint is most often in the
AML1 intron 5.
Clinics
Age at diagnosis of the primary disease 45 yrs (range 275); age at diagnosis of the t-MDS/t-ANLL: 47 yrs for
patients with the t(8;21) solely and 50 yrs for patients
with an additional anomaly; range was(15-77). Median
interval was 39 mths for cases with t(8;21) solely, and
33 mths in other cases; (range: 6-306). Primary disease
was a solid tumor in 70% of cases (breast cancer in
particular) and a hematologic malignancy in 30%,
treated with radiotherapy (12%), chemotherapy (42%),
or both (46%).
References
Slovak ML, Bedell V, Popplewell L, Arber DA, Schoch C, Slater
R. 21q22 balanced chromosome aberrations in therapy-related
hematopoietic disorders: report from an international
workshop. Genes Chromosomes Cancer. 2002 Apr;33(4):37994
This article should be referenced as such:
Huret JL. t(8;21)(q22;q22) in treatment related leukemia. Atlas
Genet Cytogenet Oncol Haematol. 2004; 8(1):30.
Cytology
Cell morphology was similar to those of de novo
t(8;21).
Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1)
30
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
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Leukaemia Section
Short Communication
t(9;22)(q34;q11) in treatment related leukemia
Jean-Loup Huret
Genetics, Dept Medical Information, UMR 8125 CNRS, University of Poitiers, CHU Poitiers Hospital, F86021 Poitiers, France (JLH)
Published in Atlas Database: October 2003
Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t0922q34q11TreatRelID1300.html
DOI: 10.4267/2042/38050
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2004 Atlas of Genetics and Cytogenetics in Oncology and Haematology
breast cancer) and a hematologic malignancy in 20%;
treatment was radiotherapy in 1/10, chemotherapy
(6/10), or both (3/10). Treatment included
topoisomerase II inhibitors in 4 of 9 cases and
alkylating agents in 5/9.
Identity
Note: This data is extracted from a very large study
from an International Workshop on treatment related
leukemias - restricted to balanced chromosome
aberrations (i.e.: -5/del(5q) and -7/del(7q) not taken
into account per see), published in Genes,
Chromosomes and Cancer in 2002.
Prognosis
Median survival was very poor: 5 mths, with 14% of
patients surviving at 1 yr, and none at 2 yrs.
Clinics and pathology
Cytogenetics
Disease
Additional anomalies
Treatment related acute non lymphocytic leukaemias (tANLL) and lymphocytic leukemias (t-ALL).
Note
The study included 10 cases; t-ANLL and t-ALL
accounted for half cases each. Treatment related acute
lymphocytic leukemias (t-ALL) are extremely rare,
found in only 20 of 511 cases (4%) in this workshop: 5
cases of t(9;22), 12 cases of t(4;11)(q22;q23), 2 cases
of t(8;14)(q24;q32), and 1 case of t(11;19)(q23;p13.3).
Complex karyotypes were found in 6 of 10 cases.
Result of the chromosomal
anomaly
Hybrid gene
Description
5' BCR -3' ABL.
Epidemiology
References
t(9;22)(q34;q11) was found in 2% of treatment related
acute leukaemias; sex ratio: 2M/8F.
Block AW, Carroll AJ, Hagemeijer A, Michaux L, van Lom K,
Olney HJ, Baer MR. Rare recurring balanced chromosome
abnormalities in therapy-related myelodysplastic syndromes
and acute leukemia: report from an international workshop.
Genes Chromosomes Cancer. 2002 Apr;33(4):401-12
Clinics
Age at diagnosis of the primary disease 45 yrs (range 376); age at diagnosis of the t-MDS/t-ANLL: 64 yrs
(range 12-78). Median interval was long: 110 mths
(range: 25-310). Primary disease was a solid tumor in
70% of cases (in particular
Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1)
This article should be referenced as such:
Huret JL. t(9;22)(q34;q11) in treatment related leukemia. Atlas
Genet Cytogenet Oncol Haematol. 2004; 8(1):31.
31
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
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Leukaemia Section
Mini Review
Acute megakaryoblastic leukemia (AMegL)
M7 acute non lymphocytic leukemia (M7-ANLL)
Antonio Cuneo, Francesco Cavazzini, Gianluigi Castoldi
Hematology Section, Department of Biomedical Sciences, University of Ferrara, Corso Giovecca 203,
Ferrara, Italy (AC, FC)
Published in Atlas Database: November 2003
Online updated version : http://AtlasGeneticsOncology.org/Anomalies/M7ANLLID1100.html
DOI: 10.4267/2042/38052
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© 2004 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Clinics
Identity
The presentation is usually acute, though AMegL may
develop after myelodysplastic syndrome or chronic
myelogenous leukemia (CML).
In some cases acute myelofibrosis is the presentation
picture.
AMegL should be distinguished from AML with
megakaryoblastic involvement showing a minority of
megakaryoblasts.
In children there is an association with Down
syndrome.
Alias: AML-M7
Note: Sometimes presenting as "acute myelofibrosis"
Clinics and pathology
Phenotype/cell stem origin
This leukemia is thought to derive from the
transformation of a multipotent myeloid progenitor
cell. In the adult patient multilineage dysplasia is a
common finding and in some cases a minority of
myeloid blast cells is present.
The blast cells show one or more megakaryocytic
markers (i.e. Factor VIII, CD61, CD41, or CD42), they
test negative when using the anti-myeloperoxidase
monoclonal antibody and never show coordinated
expression of lymphoid markers, though isolated CD2
or CD7 positivity can be found on some occasions. The
CD34, CD13 and CD33 markers are positive in a
substantial fraction of cases, as is the case with the
CD36/thrombospondin receptor.
The myeloperoxidase stain is negative by light
microscopy, but ultrastructural peroxidase activity with
a specific peri-nuclear staining pattern can be detected
at the electron microscopy level.
Cytology
The blast cell morphology varies from case to case. In
some patients the blasts are undifferentiated and the
diagnosis requires immunophenotyping or electron
microscopy studies.
Dysmegakaryocytopoiesis is rather frequent. Other
patients may show bleb-forming blasts, but this feature
is
not
specific
for
megakaryoblasts.
Micromegakaryocytes can be frequently seen.
Pathology
The bone biopsy almost invariably shows fibrosis,
which can be extensive in up to 75% of the cases.
Spleen enlargement is frequently seen in children, less
frequently in adults.
Epidemiology
Treatment
The disease is rare and, due to difficulty in diagnosis,
its exact incidence is not known. Reasonably, it may
account for approximately 1-2% of all de novo acute
myeloid leukemias (AML) in the adult population, but
the incidence in the
pediatric age group is higher, partly due to an
association with Down syndrome.
Myeloablative treatment followed, whenever possible,
by allogeneic or autologous bone marrow transplant is
the treatment of choice.
Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1)
Prognosis
In general, the prognosis is severe. 30-to-50 % of the
adult patients achieve a complete morphologic
32
Acute megakaryoblastic leukemia (AMegL), M7 acute non lymphocytic leukemia (M7-ANLL)
remission, but the majority relapse within a few
months. Median duration of CR and survival in a study
was 10.6 months and 10.4 months, respectively. Some
children may fare better, with a 50% 3-year event free
survival in AML-M7 post Down Syndrome or with the
t(1;22) (see below). Prognosis is dismal in children
with other cytogenetic abnormalities.
Cuneo A et al.
Result of the chromosomal
anomaly
Hybrid gene
Note
The fusion gene OTT-MAL is on the der(22)
chromosome and contains almost all of the sequences
of each gene.
Cytogenetics
Cytogenetics morphological
References
a) Adults
There is no cytogenetic anomaly that is specific for
AML-M7. The karyotype is abnormal in the vast
majority of cases with complex aberrations (i.e. 3 or
more clonal aberrations) occurring more frequently
than in other AMLs. -5/5q- and/or -7/7q+ are found, as
a rule, in virtually all cases with complex karyotype,
which globally account for 70-80% of abnormal cases.
3q21 or q26 aberrations are found in 20-30% of the
cases; the t(9;22) is another recurrent chromosome
aberrations in de novo AML-M7.
Trisomy 19 and 21 may occur in de novo as well as in
secondary AML-M7. They are the most frequently
occurring chromosome gains and they may be
associated with any of the cytogenetic group listed
above.
b) Children
The t(1;22)(p13;q13) is specifically associated with
children AML-M7, being found in approximately half
of the cases. The remaining patients may show +21
(irrespective of the association with Down syndrome),
+19, +8. The karyotype may be normal in
approximately 10% of the cases.
Breton-Gorius J, Reyes F, Duhamel G, Najman A, Gorin NC.
Megakaryoblastic acute leukemia: identification by the
ultrastructural demonstration of platelet peroxidase. Blood.
1978 Jan;51(1):45-60
Zipursky A, Peeters M, Poon A. Megakaryoblastic leukemia
and Down's syndrome: a review. Pediatr Hematol Oncol.
1987;4(3):211-30
San Miguel JF, Gonzalez M, Cañizo MC, Ojeda E, Orfao A,
Caballero MD, Moro MJ, Fisac P, Lopez Borrasca A.
Leukemias with megakaryoblastic involvement: clinical,
hematologic, and immunologic characteristics. Blood. 1988
Aug;72(2):402-7
Cuneo A, Mecucci C, Kerim S, Vandenberghe E, Dal Cin P,
Van Orshoven A, Rodhain J, Bosly A, Michaux JL, Martiat P.
Multipotent stem cell involvement in megakaryoblastic
leukemia: cytologic and cytogenetic evidence in 15 patients.
Blood. 1989 Oct;74(5):1781-90
Tallman MS, Neuberg D, Bennett JM, Francois CJ, Paietta E,
Wiernik PH, Dewald G, Cassileth PA, Oken MM, Rowe JM.
Acute megakaryocytic leukemia: the Eastern Cooperative
Oncology Group experience. Blood. 2000 Oct 1;96(7):2405-11
Alvarez S, MacGrogan D, Calasanz MJ, Nimer SD, Jhanwar
SC. Frequent gain of chromosome 19 in megakaryoblastic
leukemias detected by comparative genomic hybridization.
Genes Chromosomes Cancer. 2001 Nov;32(3):285-93
Cytogenetics molecular
Ma Z, Morris SW, Valentine V, Li M, Herbrick JA, Cui X,
Bouman D, Li Y, Mehta PK, Nizetic D, Kaneko Y, Chan GC,
Chan LC, Squire J, Scherer SW, Hitzler JK. Fusion of two
novel genes, RBM15 and MKL1, in the t(1;22)(p13;q13) of
acute megakaryoblastic leukemia. Nat Genet. 2001
Jul;28(3):220-1
Partial trisomy 19, involving the q13 band, can be
shown to occur at a 20-30% incidence by comparative
genomic hybridization.
The t(1;22)(p13;q13) fuses the OTT (RBM15) gene on
1p13 to the MAL (MLK1) gene on chromosome 22,
leading to the OTT-MAL fusion gene on the derivative
22.
Mercher T, Coniat MB, Monni R, Mauchauffe M, Nguyen Khac
F, Gressin L, Mugneret F, Leblanc T, Dastugue N, Berger R,
Bernard OA. Involvement of a human gene related to the
Drosophila spen gene in the recurrent t(1;22) translocation of
acute megakaryocytic leukemia. Proc Natl Acad Sci U S A.
2001 May 8;98(10):5776-9
Genes involved and proteins
Dastugue N, Lafage-Pochitaloff M, Pagès MP, Radford I,
Bastard C, Talmant P, Mozziconacci MJ, Léonard C, BilhouNabéra C, Cabrol C, Capodano AM, Cornillet-Lefebvre P,
Lessard M, Mugneret F, Pérot C, Taviaux S, Fenneteaux O,
Duchayne E, Berger R. Cytogenetic profile
OTT (one twenty-two) or RBM15 (Rnabinding motif protein 15)
Location
1p13
of childhood and adult megakaryoblastic leukemia (M7): a
study of the Groupe Français de Cytogénétique
Hématologique (GFCH). Blood. 2002 Jul 15;100(2):618-26
MAL (Megakaryocytic acute leukemia)
or MLK1 (megakaryoblastic leukemia-1)
Dastugue N, Lafage-Pochitaloff M, Pagès MP, Radford I,
Bastard C, Talmant P, Mozziconacci MJ, Léonard C, BilhouNabéra C, Cabrol C, Capodano AM, Cornillet-Lefebvre P,
Location
22q13
Lessard M, Mugneret F, Pérot C, Taviaux S, Fenneteaux O,
Duchayne E, Berger R. Cytogenetic profile of childhood and
Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1)
33
Acute megakaryoblastic leukemia (AMegL), M7 acute non lymphocytic leukemia (M7-ANLL)
adult megakaryoblastic leukemia (M7): a study of the Groupe
Français de Cytogénétique Hématologique (GFCH). Blood.
2002 Jul 15;100(2):618-26
and childhood cases by the Groupe Français d'Hématologie
Cellulaire (GFHC). Leuk Lymphoma. 2003 Jan;44(1):49-58
This article should be referenced as such:
Nimer SD, MacGrogan D, Jhanwar S, Alvarez S. Chromosome
19 abnormalities are commonly seen in AML, M7. Blood. 2002
Nov 15;100(10):3838; author reply 3838-9
Cuneo A, Cavazzini F, Castoldi GL. Acute megakaryoblastic
leukemia (AMegL), M7 acute non lymphocytic leukemia (M7ANLL). Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1):3234.
Duchayne E, Fenneteau O, Pages MP, Sainty D, Arnoulet C,
Dastugue N, Garand R, Flandrin G. Acute megakaryoblastic
leukaemia: a national clinical and biological study of 53 adult
Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1)
Cuneo A et al.
34
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Leukaemia Section
Mini Review
Refractory anemia (RA)
Antonio Cuneo, Gianluigi Castoldi
Hematology Section, Department of Biomedical Sciences, University of Ferrara, Corso Giovecca 203,
Ferrara, Italy (AC, GC)
Published in Atlas Database: November 2003
Online updated version : http://AtlasGeneticsOncology.org/Anomalies/RAID1104.html
DOI: 10.4267/2042/38054
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2004 Atlas of Genetics and Cytogenetics in Oncology and Haematology
In the WHO classification RA shows anemia, no or rare
blasts in the peripheral blood, isolated erythroid
dysplasia with <5% blasts and <15% ringed
sideroblasts in the BM. RCMD shows cytopenias
(bicytopenia or pancytopenia) in the peripheral blood
plus dysplasia in more than 10% of the cells in 2 or
more myeloid lineages.
Identity
Note: This disorder is part of the heterogeneous
category of myelodysplastic syndrome (MDS).
According to the FAB classification of MDS, RA
includes those patients with refractory cytopenia with
multilineage dysplasia (RCMD), the latter category
having been recognised as a distinct entity by the WHO
classification (vide infra). Also, the 5q- syndrome is
part of the RA in the FAB classification.
In this card, the FAB classification will be used,
because the majority of available data on cytogenetic
anomalies was derived from studies published before
WHO classification.
Cytology
Clinics and pathology
Pathology
Phenotype/cell stem origin
The bone biopsy may be useful in some cases of MDS
with BM fibrosis and allows for the demonstration of
the so called "abnormal localization of immature
precursors" (ALIP) which may represent a prognostic
factor.
Criteria for the recognition of dysplastic features of BM
cells were published by the FAB group.
Dyserythropoiesis includes megaloblastoid changes of
erythroid
precursors,
multinuclearity,
nuclear
fragmentation, unstained area in the cytoplasm
(dysemoglobinization).
RA is a clonal disorder originating from a totipotent
stem cell or from a multipotent myeloid progenitor cell,
characterized by ineffective hemopoiesis and
diserythropoiesis.
Treatment
Epidemiology
Treatment of this condition is largely supportive,
including blood transfusion in patients with
symptomatic anemia. Anemic patients with low serum
erythropoietin (EPO) levels may benefit of the
administration of rHu-EPO.
There are few data on the epidemiology of RA, which
may account for 30-40% of all MDS cases. MDS is
predominantly diagnosed in the elderly population. The
global incidence of all MDS was comprised between
3,5 and 12,6 new cases / year / per 100,000 in some
studies. The incidence may rise from 0,5 MDS cases
per year in the 40 years age-group to 89 cases per year
in the >80 age-group.
Evolution
This is a preleukemic condition, carrying a 10-20%
probability of evolving into leukemia. The probability
of RA to transform into AML may be lower when
including the 5q- syndrome and excluding RCMD, but
prospective studies are lacking. In a study 25% of the
patient developed acute myeloid leukemia (AML)
within 5 years.
Clinics
RA usually presents with hypercellular bone marrow
(BM) and anemia. There may be leukopenia and/or and
thrombocytopenia, but these features do not represent a
diagnostic requirement.
Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1)
35
Refractory anemia (RA)
Cuneo A, Castoldi GL
Prognosis
References
Median survival of RA may fall in the 27-50 month
range. As noted above, heterogeneity of patient
population may account for inter-study variability in
median survival. The best outcome is usually observed
in RA with isolated 5q- (5q- syndrome of the WHO
classification) and in those patients without
multilineage dysplasia, corresponding to the RA
category in the WHO classification.
Chromosomal
abnormalities
have
independent
prognostic significance and are to be included in risk
assessment at diagnosis. Favourable cytogenetic
features are normal karyotype, 5q- or 20q- isolated;
unfavourable features are complex karyotype (i.e. 3 or
more clonal anomalies) and abnormalities of
chromosome 7q; other abnormalities identify patients
in the intermediate cytogenetic-risk group.
Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA,
Gralnick HR, Sultan C. Proposals for the classification of the
myelodysplastic syndromes. Br J
Haematol. 1982
Jun;51(2):189-99
Gattermann N, Aul C, Schneider W. Two types of acquired
idiopathic sideroblastic anaemia (AISA) Br J Haematol. 1990
Jan;74(1):45-52
Goasguen JE, Garand R, Bizet M, Bremond JL, Gardais J,
Callat MP, Accard F, Chaperon J. Prognostic factors of
myelodysplastic syndromes--a simplified 3-D scoring system.
Leuk Res. 1990;14(3):255-62
Toyama K, Ohyashiki K, Yoshida Y, Abe T, Asano S, Hirai H,
Hirashima K, Hotta T, Kuramoto A, Kuriya S. Clinical
implications of chromosomal abnormalities in 401 patients with
myelodysplastic syndromes: a multicentric study in Japan.
Leukemia. 1993 Apr;7(4):499-508
Maschek H, Gutzmer R, Choritz H, Georgii A. Life expectancy
in primary myelodysplastic syndromes: a prognostic score
based upon histopathology from bone marrow biopsies of 569
patients. Eur J Haematol. 1994 Nov;53(5):280-7
Cytogenetics
Cytogenetics morphological
Greenberg P, Cox C, LeBeau MM, Fenaux P, Morel P, Sanz
G, Sanz M, Vallespi T, Hamblin T, Oscier D, Ohyashiki K,
Toyama K, Aul C, Mufti G, Bennett J. International scoring
system for evaluating prognosis in myelodysplastic syndromes.
Blood. 1997 Mar 15;89(6):2079-88
There is no specific chromosome marker for patients
with RA, 70 to 80% of whom may show a normal
karyotype. More sensitive techniques such as
fluorescence in situ hybridization (FISH) failed to
increase the percentage of abnormal cases in this
category of MDS.
The 5q- chromosome may be found in as many as 70%
of RA with a clonal aberrations. Usually, but not
invariably, the breakpoints involve the bands q13 and
q33. When the 5q- is the sole change and it is
associated with hypolobated megakaryocytes in the
BM, with macrocytic anemia, with normal or increased
platelet count then the patient should be diagnosed as
having the "5q- syndrome". The 5q- can be present in
other subsets of MDS.
A chromosome 20q deletion if found in 5% of all MDS
and in 10-15% of RA with abnormal karyotype.
Other chromosome aberrations in RA include trisomy 8
in 10% of cytogenetically abnormal cases -7/7q- or
11q- in < 5% of the abnormal cases.
A number of very rare chromosome aberrations were
described in single reports.
Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1)
Alessandrino EP, Amadori S, Cazzola M, Locatelli F, Mecucci
C, Morra E, Saglio G, Visani G, Tura S. Myelodysplastic
syndromes:
recent
advances.
Haematologica.
2001
Nov;86(11):1124-57
Rigolin GM, Bigoni R, Milani R, Cavazzini F, Roberti MG, Bardi
A, Agostini P, Della Porta M, Tieghi A, Piva N, Cuneo A,
Castoldi G. Clinical importance of interphase cytogenetics
detecting occult chromosome lesions in myelodysplastic
syndromes with normal karyotype. Leukemia. 2001
Dec;15(12):1841-7
Vardiman JW, Harris NL, Brunning RD. The World Health
Organization (WHO) classification of the myeloid neoplasms.
Blood. 2002 Oct 1;100(7):2292-302
This article should be referenced as such:
Cuneo A, Castoldi GL. Refractory anemia (RA). Atlas Genet
Cytogenet Oncol Haematol. 2004; 8(1):35-36.
36
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Leukaemia Section
Mini Review
Refractory anemia with excess blasts (RAEB)
Antonio Cuneo, Gianluigi Castoldi
Hematology Section, Department of Biomedical Sciences, University of Ferrara, Corso Giovecca 203,
Ferrara, Italy (AC, GC)
Published in Atlas Database: November 2003
Online updated version : http://AtlasGeneticsOncology.org/Anomalies/RAEBID1105.html
DOI: 10.4267/2042/38053
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2004 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Clinics
Identity
RAEB usually presents with hypercellular bone
marrow (BM) with 5-20% blasts (5-9% in RAEB-1 and
10-19% in RAEB-2) and cytopenias of various degree.
Blast cells (<20%) can be present in the peripheral
blood.
The patient may be asymptomatic or, alternatively
he/she may suffer from BM failure-related symptoms.
Alias: RAEB-1 and RAEB-2
Note: This disorder is part of the heterogeneous
category of myelodysplastic syndrome (MDS).
According to the FAB classification of MDS, RAEB
includes those patients with 5-20% blasts in the bone
marrow (BM). Because the severity of the disease
largely depends on the percentage of blasts in the BM,
two categories of RAEB were recognised by the WHO
classification, i.e. RAEB-1 and RAEB-2, with 5-9%
and 10-19% blasts, respectively.
In this card, the FAB classification will be used,
because the majority of available data on cytogenetic
anomalies was derived from studies published before
WHO classification.
Cytology
Criteria for the recognition of dysplastic features of BM
cells were published by the FAB group.
Dyserythropoiesis includes megaloblastoid changes of
erythroid
precursors,
multinuclearity,
nuclear
fragmentation, unstained area in the cytoplasm
(dysemoglobinization). Dysgranulocytopoiesis include
hypogranular neutrophils, the pseudo-Pelger anomaly
of
neutrophils.
Micromegakaryocytes,
large
mononuclear forms and multiple separated nuclei are
major signs of dysmegakaryocytopoiesis.
Clinics and pathology
Phenotype/cell stem origin
RAEB is a clonal disorder originating from a totipotent
stem cell or from a multipotent myeloid progenitor cell,
characterized by ineffective hemopoiesis and
diserythropoiesis. The blast cells present in the BM are
usually CD34+ and express myeloid markers (i.e.
CD33 and/or CD13).
Pathology
Epidemiology
Treatment
There are few data on the epidemiology of RAEB,
which may account for 20-30% of all MDS cases. MDS
is predominantly diagnosed in the elderly population.
The global incidence of all MDS was comprised
between 3,5 and 12,6 new cases / year / per 100,000 in
some studies. The incidence may rise from 0,5 MDS
cases per year in the 40 years
age-group to 89 cases per year in the >80 age-group.
Treatment of this condition in the elderly patient is
largely supportive, including blood transfusion in
patients with symptomatic anemia. Anemic patients
with low serum erythropoietin (EPO) levels may
benefit of the administration of rHu-EPO. Low dose
cytarabine can be used to reduce the burden of blasts.
Myeloablative regimens including anthracyclines and
cytarabine in conventional or high doses can be used in
Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1)
The bone biopsy may be useful in some cases of MDS
with BM fibrosis and allows for the demonstration of
the so called "abnormal localization of immature
precursors" (ALIP) which may represent a prognostic
factor.
37
Refractory anemia with excess blasts (RAEB)
Cuneo A, Castoldi GL
recurrent structural anomalies which can also be found
in acute myeloid leukemia include: t(6;9)(p23;q34);
t(3;5)(q25;q35); t(1;3)(p36;q21); t(3;21)(q26;q22);
inv(3)(q21q26); t(7;11)(p15;p15). Trisomies are
represented in <1% of the cases by +4; +11; +13; +21.
high-risk patients under 60 years. Allogeneic bone
marrow transplantation may offer a chance of cure in
young patients.
Evolution
This is an oligoblastic leukemia, carrying a 20-40%
probability of evolving into leukemia. In a study
approximately 25% of the patients developed acute
myeloid leukemia (AML) within 18 months.
The probability of RAEB to transform into AML is
lower in the RAEB-1 group (approximately 50% of the
patients develop acute leukemia within 6 years) than in
the RAEB-2 group (approximately 50% at 18 months
with overt leukemia).
References
Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA,
Gralnick HR, Sultan C. Proposals for the classification of the
myelodysplastic syndromes. Br J
Haematol. 1982
Jun;51(2):189-99
Goasguen JE, Garand R, Bizet M, Bremond JL, Gardais J,
Callat MP, Accard F, Chaperon J. Prognostic factors of
myelodysplastic syndromes--a simplified 3-D scoring system.
Leuk Res. 1990;14(3):255-62
Prognosis
Toyama K, Ohyashiki K, Yoshida Y, Abe T, Asano S, Hirai H,
Hirashima K, Hotta T, Kuramoto A, Kuriya S. Clinical
implications of chromosomal abnormalities in 401 patients with
myelodysplastic syndromes: a multicentric study in Japan.
Leukemia. 1993 Apr;7(4):499-508
Median survival of RAEB falls in the 1-2 year range.
The best outcome is usually observed in RAEB-1.
Chromosomal
abnormalities
have
independent
prognostic significance and are to be included in risk
assessment at diagnosis. Favourable cytogenetic
features are normal karyotype, 5q- or 20q- isolated;
unfavourable features are complex karyotype (i.e. 3 or
more clonal anomalies) and abnormalities of
chromosome 7q; other abnormalities identify patients
in the intermediate cytogenetic-risk group.
Maschek H, Gutzmer R, Choritz H, Georgii A. Life expectancy
in primary myelodysplastic syndromes: a prognostic score
based upon histopathology from bone marrow biopsies of 569
patients. Eur J Haematol. 1994 Nov;53(5):280-7
Cytogenetics
Lai JL, Preudhomme C, Zandecki M, Flactif M, Vanrumbeke M,
Lepelley P, Wattel E, Fenaux P. Myelodysplastic syndromes
and acute myeloid leukemia with 17p deletion. An entity
characterized by specific dysgranulopoïesis and a high
incidence of P53 mutations. Leukemia. 1995 Mar;9(3):370-81
Cytogenetics morphological
Fenaux P, Morel P, Lai JL. Cytogenetics of myelodysplastic
syndromes. Semin Hematol. 1996 Apr;33(2):127-38
There is no specific chromosome marker for patients
with RAEB, up to 60% of whom may show an
abnormal karyotype. More sensitive techniques such as
fluorescence in situ hybridization (FISH) found that a
minority of patients with apparently normal karyotype
can be shown to carry an occult chromosome defect.
The 5q- chromosome may be found in up to 40% of the
cases, usually in association with additional
chromosome aberrations. Approximately 20% of the
cases may carry a -7/7q- or trisomy 8. A chromosome
12p deletion or 11q deletion can be found in 5% of
cytogenetically abnormal cases.
Those patients with a 17p deletion may display
distinctive
hematologic
features,
including
dysgranulopoiesis with the pseudo-Pelger anomaly and
small vacuoles in the cytoplasm of the neutrophils, p53
mutation and poor outcome.
A number of very rare chromosome aberrations were
described in some reports. Recurrent deletions are
represented by del(3)(p14p21), del(6)(p21),
del(9)(q13q22), del(12)(p13), del(18)(p11). Monosomy
Y may occur more frequently in elderly males. Rare
Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1)
Greenberg P, Cox C, LeBeau MM, Fenaux P, Morel P, Sanz
G, Sanz M, Vallespi T, Hamblin T, Oscier D, Ohyashiki K,
Toyama K, Aul C, Mufti G, Bennett J. International scoring
system for evaluating prognosis in myelodysplastic syndromes.
Blood. 1997 Mar 15;89(6):2079-88
Alessandrino EP, Amadori S, Cazzola M, Locatelli F, Mecucci
C, Morra E, Saglio G, Visani G, Tura S. Myelodysplastic
syndromes:
recent
advances.
Haematologica.
2001
Nov;86(11):1124-57
Rigolin GM, Bigoni R, Milani R, Cavazzini F, Roberti MG, Bardi
A, Agostini P, Della Porta M, Tieghi A, Piva N, Cuneo A,
Castoldi G. Clinical importance of interphase cytogenetics
detecting occult chromosome lesions in myelodysplastic
syndromes with normal karyotype. Leukemia. 2001
Dec;15(12):1841-7
Vardiman JW, Harris NL, Brunning RD. The World Health
Organization (WHO) classification of the myeloid neoplasms.
Blood. 2002 Oct 1;100(7):2292-302
This article should be referenced as such:
Cuneo A, Castoldi GL. Refractory anemia with excess blasts
(RAEB). Atlas Genet Cytogenet Oncol Haematol. 2004;
8(1):37-38.
38
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Leukaemia Section
Mini Review
Refractory
(RARS)
anemia
with
ringed
sideroblasts
Antonio Cuneo, Gianluigi Castoldi
Hematology Section, Department of Biomedical Sciences, University of Ferrara, Corso Giovecca 203,
Ferrara, Italy (AC, GC)
Published in Atlas Database: November 2003
Online updated version : http://AtlasGeneticsOncology.org/Anomalies/RARSID1106.html
DOI: 10.4267/2042/38055
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2004 Atlas of Genetics and Cytogenetics in Oncology and Haematology
thrombocytopenia, but these features do not represent a
diagnostic requirement.
According to the WHO classification RARS shows
anemia, no blasts in the peripheral blood, isolated
erythroid dysplasia with 15% ringed sideroblasts in the
BM. RCMD-RS shows cytopenias (bicytopenia or
pancytopenia) in the peripheral blood plus dysplasia in
more than 10% of the cells in 2 or more myeloid
lineages and no Auer rods.
Identity
Note: This disorder is part of the heterogeneous
category of myelodysplastic syndrome (MDS).
According to the FAB classification of MDS, RARS
includes those patients with refractory cytopenia with
multilineage dysplasia and ringed sideroblasts (RCMDRS), the latter category having been recognised as a
distinct entity by the WHO classification (vide infra).
In this card, the FAB classification will be used,
because the majority of available data on cytogenetic
anomalies was derived from studies published before
WHO classification.
Cytology
RARS is a clonal disorder originating from a totipotent
stem cell or from a multipotent myeloid progenitor cell,
characterized by ineffective hemopoiesis and
diserythropoiesis.
Criteria for the recognition of dysplastic features of BM
cells were published by the FAB group. Typically,
more than 15% of the erythroid cells are ringed
sideroblasts showing iron laden mitochondria around
the nucleus. These cells appear as erythroblast with
Prussian Blue-positive granules which form an arc
extending around at least 30% of the nucleus. There is
evidence that mutations occurring in the mitochondrial
DNA may have a role in generating deranged
mitochondrial iron metabolism with consequent
accumulation of the ferric form (Fe3+) in the matrix.
Epidemiology
Pathology
There are few data on the epidemiology of RARS,
which may account for 5-15% of all MDS cases. MDS
is predominantly diagnosed in the elderly population.
The global incidence of all MDS was comprised
between 3,5 and 12,6 new cases / year / per 100,000 in
some studies. The incidence may rise from 0,5 MDS
cases per year in the 40 years age-group to 89 cases per
year in the >80 age-group.
The bone biopsy may be useful in some cases of MDS
with BM fibrosis and allows for the demonstration of
the so called "abnormal localization of immature
precursors" (ALIP) which may represent a prognostic
factor.
Clinics and pathology
Phenotype/cell stem origin
Treatment
Treatment of this condition is largely supportive,
including blood transfusion in patients with
symptomatic anemia. Anemic patients with low serum
erythropoietin (EPO) levels may benefit of the
administration of rHu-EPO.
Clinics
RARS usually presents with hypercellular bone marrow
(BM) and anemia. There may be leukopenia and/or and
Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1)
39
Refractory anemia with ringed sideroblasts (RARS)
Cuneo A, Castoldi GL
Gattermann N, Aul C, Schneider W. Two types of acquired
idiopathic sideroblastic anaemia (AISA) Br J Haematol. 1990
Jan;74(1):45-52
Evolution
This is a preleukemic condition, carrying a 10-20%
probability of evolving into leukemia. The probability
of RARS to transform into AML may be lower when
excluding RCMD, but prospective studies are lacking.
In a study 25% of the patient developed acute myeloid
leukemia (AML) in approximately 10 years.
Goasguen JE, Garand R, Bizet M, Bremond JL, Gardais J,
Callat MP, Accard F, Chaperon J. Prognostic factors of
myelodysplastic syndromes--a simplified 3-D scoring system.
Leuk Res. 1990;14(3):255-62
Toyama K, Ohyashiki K, Yoshida Y, Abe T, Asano S, Hirai H,
Hirashima K, Hotta T, Kuramoto A, Kuriya S. Clinical
implications of chromosomal abnormalities in 401 patients with
myelodysplastic syndromes: a multicentric study in Japan.
Leukemia. 1993 Apr;7(4):499-508
Prognosis
Median survival of RARS may fall in the 40-50 month
range.
Chromosomal
abnormalities
have
independent
prognostic significance and are to be included in risk
assessment at diagnosis. Favourable cytogenetic
features are normal karyotype, 5q- syndrome or 20qisolated; unfavourable features are complex karyotype
(i.e. 3 or more clonal anomalies) and abnormalities of
chromosome 7q; other abnormalities identify patients
in the intermediate cytogenetic-risk group.
Wattel E, Laï JL, Hebbar M, Preudhomme C, Grahek D, Morel
P, Bauters F, Fenaux P. De novo myelodysplastic syndrome
(MDS) with deletion of the long arm of chromosome 20: a
subtype of MDS with distinct hematological and prognostic
features? Leuk Res. 1993 Nov;17(11):921-6
Maschek H, Gutzmer R, Choritz H, Georgii A. Life expectancy
in primary myelodysplastic syndromes: a prognostic score
based upon histopathology from bone marrow biopsies of 569
patients. Eur J Haematol. 1994 Nov;53(5):280-7
Fenaux P, Morel P, Lai JL. Cytogenetics of myelodysplastic
syndromes. Semin Hematol. 1996 Apr;33(2):127-38
Cytogenetics
Greenberg P, Cox C, LeBeau MM, Fenaux P, Morel P, Sanz
G, Sanz M, Vallespi T, Hamblin T, Oscier D, Ohyashiki K,
Toyama K, Aul C, Mufti G, Bennett J. International scoring
system for evaluating prognosis in myelodysplastic syndromes.
Blood. 1997 Mar 15;89(6):2079-88
Cytogenetics morphological
There is no specific chromosome marker for patients
with RARS, 70 to 80% of whom may show a normal
karyotype. More sensitive techniques such as
fluorescence in situ hybridization (FISH) failed to
increase the percentage of abnormal cases in this
category of MDS.
The 5q- chromosome may be found in 20% of RARS
with clonal aberrations. A chromosome 11q deletion
may be found in as many as 20% of the cases. A
chromosome 20q deletion can be found in 5% of all
MDS and in 10-15% of RARS with abnormal
karyotype.
Other chromosome aberrations in RARS include
trisomy 8 in 20% of cytogenetically abnormal cases 7/7q- or 11q- in < 5% of the abnormal cases.
A number of rare chromosome aberrations were
described in single reports.
Alessandrino EP, Amadori S, Cazzola M, Locatelli F, Mecucci
C, Morra E, Saglio G, Visani G, Tura S. Myelodysplastic
syndromes:
recent
advances.
Haematologica.
2001
Nov;86(11):1124-57
Rigolin GM, Bigoni R, Milani R, Cavazzini F, Roberti MG, Bardi
A, Agostini P, Della Porta M, Tieghi A, Piva N, Cuneo A,
Castoldi G. Clinical importance of interphase cytogenetics
detecting occult chromosome lesions in myelodysplastic
syndromes with normal karyotype. Leukemia. 2001
Dec;15(12):1841-7
Greenberg P, Young N, Gattermann N. Myelodysplastic
syndromes. ASH Education Program Book. Philadelphia,
Pennsylvania. December 6-10, 2002
Vardiman JW, Harris NL, Brunning RD. The World Health
Organization (WHO) classification of the myeloid neoplasms.
Blood. 2002 Oct 1;100(7):2292-302
References
This article should be referenced as such:
Cuneo A, Castoldi GL. Refractory anemia with ringed
sideroblasts (RARS). Atlas Genet Cytogenet Oncol Haematol.
2004; 8(1):39-40.
Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA,
Gralnick HR, Sultan C. Proposals for the classification of the
myelodysplastic syndromes. Br J
Haematol. 1982
Jun;51(2):189-99
Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1)
40
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Solid Tumour Section
Review
Bladder: Urothelial carcinomas
Angela van Tilborg, Bas van Rhijn
Department of Pathology, Josephine Nefkens Institute, Erasmus University, 3000 DR Rotterdam, The
Netherlands (AVT, BVR)
Published in Atlas Database: October 2003
Online updated version : http://AtlasGeneticsOncology.org/Tumors/blad5001.html
DOI: 10.4267/2042/38056
This article is an update of: Huret JL, Léonard C. Bladder: Transitional cell carcinoma. Atlas Genet Cytogenet Oncol
Haematol.2000;4(4):212-217.
Huret JL, Léonard C. Bladder: Transitional cell carcinoma. Atlas Genet Cytogenet Oncol Haematol.1999;3(4):205-206.
Huret JL, Léonard C. Bladder cancer. Atlas Genet Cytogenet Oncol Haematol.1997;1(1):32-33.
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2004 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
Bladder cancer : gross pathology : the bladder wall is massively infiltered by an ulcerated and hemorragic tumor. Courtesy Pierre
Bedossa.
Classification
Clinics and pathology
Histologic types:
Urothelial carcinoma of the bladder, herein described,
Squamous cell carcinoma,
Adenocarcinoma (2%), rare,
Poorly differenciated carcinoma/small cell carcinoma,
exceptional.
Disease
Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1)
Cancer of the urothelium.
Epidemiology
Urothelial carcinoma of the transitional epithelium is
the most frequent bladder cancer in Europe and in the
USA, representing 90-95 % of cases, while
41
Bladder: Urothelial carcinomas
van Tilborg AA, van Rhijn BW
Staging – Editor.
squamous cell carcinoma represents only 5% in these
countries, but up to 70-80% of cases in the Middle
East; annual incidence: 250/106, 2% of cancers, the
fourth cancer in males, the seventh in females, 3M/1F;
occurs mainly in the 6th-8th decades of life; risk
factors: cigarette smoking and occupational exposure
(aniline, benzidine, naphtylamine); 20 to 30 yrs latency
after exposure.
soon/often does it come back), progression and (disease
specific) survival are of importance. Patients with
superficial bladder cancer (pTa and pTis) are frequently
evaluated by cystoscopy to allow early detection of a
possible recurrence and to prevent disease progression
to invasive, potentially lethal, bladder cancer.
According to mutational status of FGFR3 and TP53;
tumors with an FGFR3 mutation have a lower
recurrence
rate,
tumors
with
elevated
immunohistochemical expression of p53 and MIB-1
have the highest recurrence rate: and the highest
propensity for progression and death of disease (see
figure below).
Clinics
Hematuria, irritation.
Pathology
Grading and staging: tumours are:
graded by the degree of cellular atypia (G1->G3), and
staged:
- Papilloma,
- Papillary tumor of low malignant potential (PTLMP),
- Papillary urothelial carcinomas low grade,
- Papillary urothelial carcinomas high grade.
Cytogenetics
Cytogenetics Morphological
Karyotype
Urothelial carcinomas exhibit pseudo diploid
karyotypes with only a few anomalies in early stages,
evolving towards pseudo-tetraploides complexes
karyotypes. Partial or complete monosomy 9 (-9) is an
early event, found in half cases. Deletion (11p) or -11 is
found in 20-50% of cases, more often in high grade and
invasive tumours. Del(13q) is found in 25% of cases
and correlated with high grade/stage; tumours with Rb
alterations are invasive. Del(17p) is a late event, found
in 40% of cases; TP53 alterations are correlated with
grade and stage, tumour progression, and a worse
prognosis. Del(1p), i(5q), +7, and many other
rearrangements - more often deletions than duplications
- are frequently found. These losses of heterozygocity
point to a multistep complex process involving tumor
suppressor genes.
Amplifications
Chromosome 1: P73 (1p36) is often over-expressed.
Chromosome 8: C-MYC (8q24) is rarely amplified.
Treatment
Resection (more or less extensive: electrofulguration -> cystectomy); chemo and/or radiotherapy, BCGtherapy.
Evolution
Recurrence is highly frequent.
Prognosis
According to the stage and the grade; pTa is of good
prognosis (> 90% are cured); prognosis is uncertain in
pT1 and G2 tumours. 20% survival at 1 yr (stable at 3
yrs) is found in T4 cases; however, identification of
individual patient's prognosis is often difficult,
although of major concern for treatment decision and
for follow up.
Multiple endpoints may be identified in bladder cancer.
Recurrence (does it come back), recurrence rate (how
Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1)
42
Bladder: Urothelial carcinomas
van Tilborg AA, van Rhijn BW
LOH
LOH analysis in bladder cancer has so far not led to the
identification of tumor suppressor genes. LOH appears
to be numerous within a given chromosome (e.g. on
chromosome 9 five regions, 9p21, 9q22,
9q31-32, 9q33 and 9q34, and on chromosome 5 four
regions, 5q13.3-q22, 5q22-q31.1, 5q31.1-q32, and
5q34, and on chromosome 3 frequent LOH has been
found in three regions, 3p12-14, 3p21.3-22 and 3p24.225), but loci remain to be precised, as reports are
controversial. Due to the unique possibility to study
multiple recurrent tumors from the same patient, it is
now becoming apparent that loss of heterozygosity
(LOH) on chromosome 9 is almost never the
characteristic first step in tumor development. LOH can
be detected in up to 67% of markers tested. The regions
of loss are multiple and variable in different tumours
from the same patient and expand in subsequent
tumours. Moreover, the regions of loss on chromosome
9 vary from patient to patient. To explain the type and
extent of genetic damage in combination with the low
stage and grade of these tumors, it was hypothesized
that in bladder cancer pathogenesis an increased rate of
mitotic recombination is acquired early in the
tumorigenic process.
Chromosome 11: cyclin D1 is often over-expressed.
Amplifications 10q13-14, 13q21-31 and 17q22-23 have
been noted.
Losses
Chromosome 8: loss of 8p12-22.
The potential target is the FEZ1/LZTS1 gene, which is
downregulated in high-grade carcinomas.
Chromosome 9: Allelic loss on chromosome 9q is a
very frequent event in bladder carcinogenesis.
Monosomy 9 or deletions of chromosome 9 are found
in about 50% of cases; at times found as the sole
anomaly, demonstrating that it is an early event, found
equally in pTa stage and in more advanced stages; not
associated with a given grade, and not correlated with
p53 expression. Efforts have been directed towards
identifying the postulated tumour suppressor genes on
this chromosome arm by deletion mapping and
mutation analysis. However, no convincing candidate
genes have been identified. Homozygous deletions of
CDKN2A/MTS1/P16 (9p21) have been documented;
LOH + mutation on the second allele of CDKN2A are
rare, but of significance; CDKN2A is implicated in pTa
stage but not in pTIS, where p53 is found mutated;
CDKN2B/INK4B/P15 (9p21) is also implicated in a
small subset of cases. LOH + mutation on the second
allele of TSC1 (9q33-34) has been described.
Homozygous deletion and methylational silencing of a
candidate gene DBCCR1 (9q32-33) has been reported.
Chromosome 10: PTEN (10q23), appears to be
implicated in a very few percentage of cases
(homozygote
deletion
has
been
found);
Fas/APO1/CD95 (10q24): loss of one allele and
mutation in the second allele has been reported; a hotspot of mutations has been determined.
Chromosome 11: HRAS1 (11p15.5) is mutated in 15%
of cases.
Chromosome 13: an altered Rb (13q14) is expressed in
30 to 40% of tumours; these are high stage, invasive,
and indicate a short survival; 90% of tumours
expressing Rb are invasives; disregulation of the
normal P16-Rb interactions have been documented,
with hyper expression of Rb and loss of function of
P16.
Chromosome 17: P53 (17p13) alterations are correlated
with grade and stage (often PT3), and tumour
progression; P53 is mutated in more than 50% of high
grade/stage tumours, and in most PTIS; P53 is a
prognostic factor: by high grade/stage tumours, those
expressing P53 are of a worse prognosis; by low
grade/stage, those not expressing P53 are of better
outcome; there is usually LOH + mutation on the
second allele of P53; ERBB2 (HER2/Neu) (17q21) is
expressed in high grade/stages tumours, in metastases,
and is associated with relapses; NF1 (17q11)
expression may be very low in tumours.
Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1)
Cytogenetics Molecular
(Matrix) CGH
Array-based comparative genomic hybridization
detected high-level amplification of 6p22.3 (E2F3),
8p12 (FGFR1), 8q22.2 (CMYC), 11q13 (CCND1,
EMS1, INT2), and 19q13.1 (CCNE) and homozygous
deletion of 6p22 (TRAF6), 9p21.3 (CDKN2A/p16) and
8p23.1.
Genes involved and proteins
FGFR3
Note
The expression of a constitutively activated FGFR3 in a
large proportion of bladder cancers is the first evidence
of an oncogenic role for FGFR3 in these carcinomas.
FGFR3 currently appears to be the most frequently
mutated oncogene in bladder cancer: it is mutated in
more than 30% of cases. FGFR3 seems to mediate
opposite signals, acting as a negative regulator of
growth in bone and as an oncogene in several tumour
types. Complete elucidation of the role of FGFR3 in
normal and malignant tissues requires further
investigation. Missense mutations were observed
identical to those in thanatophoric dysplasia (R248C,
S249C, G372C, and K652E), achondroplasia and
SADDAN (G380/382R and K650/652M, respectively)
and Crouzon Syndrome with Acanthosis Nigricans
(A393E). Furthermore, a K650/652T mutation was
found not previously identified in carcinomas or
43
Bladder: Urothelial carcinomas
van Tilborg AA, van Rhijn BW
gains in bladder cancer detected by fluorescence in situ
hybridization. Am J Pathol. 1995 May;146(5):1131-9
thanatophoric dysplasia. In urothelial papilloma,
generally considered a benign lesion, 9/12 (75%)
mutations were found. Another novel finding was the
occurrence of two simultaneous FGFR3 mutations in
four tumours.
Sauter G, Moch H, Carroll P, Kerschmann R, Mihatsch MJ,
Waldman FM. Chromosome-9 loss detected by fluorescence in
situ hybridization in bladder cancer. Int J Cancer. 1995 Apr
21;64(2):99-103
TP53
Sauter G, Moch H, Wagner U, Novotna H, Gasser TC,
Mattarelli G, Mihatsch MJ, Waldman FM. Y chromosome loss
detected by FISH in bladder cancer. Cancer Genet Cytogenet.
1995 Jul 15;82(2):163-9
Note
The TP53 gene in bladder cancer is mainly an indicator
of progression and recurrence rate. Interestingly,
mutations in FGFR3 and TP53 are mutually exclusive
in bladder cancer.
Shackney SE, Berg G, Simon SR, Cohen J, Amina S,
Pommersheim W, Yakulis R, Wang S, Uhl M, Smith CA.
Origins and clinical implications of aneuploidy in early bladder
cancer. Cytometry. 1995 Dec 15;22(4):307-16
HRAS
Note
HRAS mutations are found in approximately 15% of
cases.
Tanaka M, Müllauer L, Ogiso Y, Fujita H, Moriya S, Furuuchi K,
Harabayashi T, Shinohara N, Koyanagi T, Kuzumaki N.
Gelsolin: a candidate for suppressor of human bladder cancer.
Cancer Res. 1995 Aug 1;55(15):3228-32
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van Tilborg AA, van Rhijn BW. Bladder: Urothelial carcinomas.
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Sanchez-Carbayo M, Socci ND, Lozano JJ, Li W,
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47
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Solid Tumour Section
Review
Ovary: Sex cord-stromal tumors
Lisa Lee-Jones
Tumour Molecular Genetics Group, Institute of Medical Genetics, University of Wales College of Medicine,
Heath Park, Cardiff, CF14 4XN, UK (LLJ)
Published in Atlas Database: November 2003
Online updated version : http://AtlasGeneticsOncology.org/Tumors/OvarSexCordStromID5223.html
DOI: 10.4267/2042/38058
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2004 Atlas of Genetics and Cytogenetics in Oncology and Haematology
There have also been clinical reports of several other
types of sex cord-stromal tumours being less frequently
associated with PJS including:
- oxyphilic Sertoli cell tumour;
- Sertoli cell tumour (lipid-rich);
- malignant Sertoli-Leydig cell tumour and
- ovarian fibroma.
10% of patients with lipid cell tumours have Cushing
Syndrome.
Fibromas are associated with Meigs Syndrome. The
phenotype of Meigs syndrome is a benign ovarian
tumour (fibroma), with ascites and pleural effusion that
resolve within several weeks to months following
surgical resection without any recurrence. Thus it
imitates a malignant tumour, but has a very good
prognosis. Indeed, following resection, life expectancy
is similar to the general population.
Ovarian fibromas occur in 75% of female patients with
Gorlin syndrome (also known as Nevoid basal cell
carcinoma syndrome). Gorlin syndrome is an
autosomal dominant disorder that predisposes to basal
cell carcinomas of the skin, ovarian fibroma and
medulloblastoma.
2 theories account for the aetiology of sex cord-stromal
tumours hypothesising that they develop either from:
(1) mesenchyme of the developing genital
ridge, or
(2) precursors of the mesonephric and
coelmic epithelium.
No definite aetiologies have been established for
granulosa cell tumours, although chromosomal
abnormalities and abnormal autocrine and endocrine
signalling have been suggested.
Identity
Note: Sex cord-stromal tumours develop from the
gonadal stroma, and are a type of ovarian tumour. They
account for 5-10 % of all ovarian neoplasms.
Classification
Ovarian sex cord-stromal tumours are subdivided into
the following clinicopathological entities:
- Granulosa cell tumour,
- Theca cell tumour,
- Thecoma,
- Fibroma,
- Sertoli-Leydig cell tumour,
- Sex cord tumour with annular tubules,
- Lipid cell tumour,
- Gynandroblastoma.
Clinics and pathology
Etiology
There appear to be several established clinical
syndromes associated with several subtypes of sex
cord-stromal tumours.
30% of patients with sex cord tumours with annular
tubules have Peutz-Jeghers syndrome (PJS), an
autosomal dominant disorder characterised by multiple
gastrointestinal hamartomatous polyps, increased risk
of various neoplasms, and melanocytic macules of the
lips, buccal mucosa, and digits. Peutz-Jegher females
are also susceptible to granulosa cell tumours. When
associated with this syndrome, the tumour is usually
small, benign and bilateral. Meanwhile in the absence
of this syndrome, it is usually large and unilateral, and
malignant in 20% of cases.
Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1)
Epidemiology
The frequency of sex cord-stromal tumours is similar
48
Ovary: Sex cord-stromal tumors
Lee-Jones L
throughout the world. There does not appear to a racial
predisposition, in contrast to epithelial ovarian cancers.
Every year, 15-20,000 new cases of sex cord-stromal
tumours are diagnosed in the USA. Sex cord-stromal
tumours appear in any age group but usually in the 4th
and 5th decades. Fibromas are usually detected in the
fifth decade of life. The mean age of presentation of
Leydig cell tumours is 50. The median age of diagnosis
of adult granulosa cell tumours is 52, and is 53-years
for theca cell tumours. Theca cell tumours account for
1 % of ovarian neoplasms, and are rarely diagnosed in
women under 30-years of age, unless they have
luteinized thecoma which is more apparent in younger
women. However, Sertoli-Leydig cell tumours tend to
present at a younger age, usually in the third decade of
life.
Adult and Juvenile Granulosa cell tumour
Adult granulosa cell tumours contain granulosa cells in
the presence or absence of theca cells. Granulosa theca
cell tumours are composed of at least 25% theca cells
in addition to the granulosa cells. Varying histologies
have been reported in adult granulosa cell tumours,
including well-differentiated histologies such as
microfollicular, macrofollicular, trabecular and insular,
and less well diffentiated subtypes including diffuse
and watered-silk (gyriform). Call-Exner bodies are
pathognomonic of granulosa cell tumour, and are found
in the microfollicular pattern, the most common
histological subtype. Call-Exner bodies consist of small
rings of granulosa cells surrounding eosinophilic fluid
and
basement
membrane
material
(http://www.emedicine.com/med/topic928.htm#target1
). Macrofollicular granulosa cell tumours contain one
or more large cysts lined with granulosa cells.
Granulosa cells are organised into nests and bands in
the trabecular and insular histologies, with an
intervening fibrothecomatous stroma present in the
trabecular type. The diffuse subtype contains sheets of
cells
arranged
in
no
pattern
(http://www.emedicine.com/med/topic928.htm#target2
), and the watered-silk entity contains cells arranged in
single
file
in
lines
(http://www.emedicine.com/med/topic928.htm#target4
). Both the well-differentiated and the less welldifferentiated adult granulosa cell tumours contain
large, pale, ovoid or angular nuclei with nuclear
grooves.
Few mitotic figures, mild nuclear atypia and little
cytoplasm are usually found, however luteinization can
sometimes be evident.
The gross appearance of juvenile granulosa cell
tumours is similar to the adult counterparts-both
comprise a mixture of solid and cystic components with
many haemorrhagic areas. However the similarity
ceases at the gross level, as morphologically both types
differ greatly. Juvenile granulosa cell tumours contain
round hyperchromatic nuclei, nuclear grooves are
usually absent, severe nuclear atypia, contain more
mitotic figures, more cytoplasm (which is dense).
Fibromas
Fibromas are benign and are classified as such if they
contain <3 mitoses per high-power field. Malignant
fibromas are called fibrosarcomas, and are classified as
such if they have > 4 mitoses per high-power field.
Less than 5% of fibromas are malignant.
Thecomas
Thecomas or theca cell tumours contain exclusively
theca cells. Thecomas are solid, tan or yellow-orange
tumours. They are highly similar to fibromas, except
that thecomas secrete excess oestrogen. Thecomas are
usually benign, and are characterised by <3 mitoses per
high-power field. Malignant thecomas have >3 mitoses
Clinics
Granulosa cell tumours usually follow a nonaggressive
clinical course. However, they may become malignant
or recur (up to 30 years after the initial diagnosis). 65%
of granulosa cell tumours occur in postmenopausal
females. Juvenile and adult granulosa cell tumours,
fibromas, and Sertoli-Leydig cell tumours are usually
unilateral. Granulosa-theca cell tumours are usually
large and benign, with cystic degeneration
(http://chorus.rad.mcw.edu/doc/00506).
Intraabdominal bleeding following rupture is often the
presenting symptom of patients with granulosa cell
tumour. Both adult and juvenile granulosa cell tumours
are indolent. Approximately 10% of granulosa cell
tumours occur in pregnant patients, and should be
surgically removed at 16-18 weeks of gestation.
The excess oestrogen produced by some stromal
tumours, such as adult granulosa cell tumours and
thecomas, causes isosexual precocious puberty,
postmenopausal
bleeding,
menorrhagia,
menometrorrhagia,
amenorrhea,
endometrial
hyperplasia or cancer or fibrocystic breast disease
(http://chorus.rad.mcw.edu/doc/00506).
Thecomas
usually develop in postmenopausal women, on average
grow to 7-8 cm, and >97% of cases are unilateral. Most
thecomas are hormone producing and cause
postmenopausal bleeding in two-thirds of patients.
Luteinized thecomas are usually androgenic, and these
tend to present in younger women. Approximately 40%
of patients with Sertoli-Leydig cell tumours and most
patients with Leydig cell tumours show virilization.
This is attributable to the Leydig cells which produce
androgens. Lipid cell tumours usually cause
virilization. A subset of patients with Sertoli-Leydig
cell tumours secrete excess oestrogen.
Pathology
All ovarian sex cord-stromal tumours are derived from
the stroma of the developing ovary. The gonadal stoma
is primitive, and consequently can develop in a
testicular or ovarian differentiation pathway.
Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1)
49
Ovary: Sex cord-stromal tumors
Lee-Jones L
Combination chemotherapies have yielded some
responses in each subtype of sex cord-stromal tumour.
Pelvic radiation has also been used for localised
tumours.
No effective treatment is available for metastatic lipid
cell tumours.
per field. Microscopic analysis reveals round or ovoid
cells with pale nuclei and a lipid-rich cytoplasm.
Hyaline
bands
frequently
intersperse
cells
(http://www.emedicine.com/med/topic928.htm#target5
). Luteinized thecomas contain lipid rich cytoplasmic
cells
and
a
more
fibromatous
stroma
(http://www.emedicine.com/med/topic928.htm#target6
). Less than 5% of thecomas are malignant.
http://pathy.med.nagoyau.ac.jp/atlas/misc/thecoma.html
Sertoli cell tumours
Sertoli cell tumours contain Sertoli cells in a tubular
arrangement.
Sertoli-Leydig cell tumours
As the name suggests, Sertoli-Leydig cells contain both
Sertoli and Leydig cells. They are subclassified in
accordance with the WHO as follows:
1. well-differentiation (predominant tubular pattern)
2. intermediate differentiation (sheets of immature
Sertoli cells with some stroma)
3. poor differentiation (immature Sertoli cells with little
or no stroma)
4. containing heterologous elements with retiform
pattern.
Less than 5% of Sertoli-Leydig tumours are malignant.
Leydig cell tumours
Leydig cell tumours contain Leydig cells, and are
usually benign. When located in the hilus they are
described as hilus cell tumours. Leydig cell tumours
contain Reinke crystals.
Lipid cell tumours
Lipid cell tumours are characterised by round Leydiglike cells, luteinized stroma, adrenocortical cells and
the absence of Reinke crystals. 30% of lipid cell
tumours are malignant.
Gynandroblastoma
These are rare ovarian tumours which contain
granulosa stromal cells and Sertoli stromal cells. 100%
of gynandroblastomas are malignant.
Sex cord tumour with annular tubules (SCTAT)
Histologically SCTAT is intermediate between
granulosa cell tumour and the Sertoli cell tumour. It is
characterised by sex cord cells in the form of a ring
with nuclei orientated around a central hyalonized
body.
Evolution
20% of lipid cell tumours metastasise. In the low
percentage of granulosa cell tumours showing
aggressive behaviour, any organ can be affected by
metastatic disease, although it is usually confined to the
pelvis and abdomen.
Prognosis
The prognosis of sex-cord-stromal tumours is good, as
these tumours usually present when confined to a single
ovary, and are responsive to chemotherapy.
Patients with juvenile granulosa cell tumours have a
good prognosis-mortality is only 1.5% for patients with
stage IA. For individuals with granulosa cell
tumours, diffuse growth pattern, increased mitotic
figures and cellular atypia correlate with poor
prognosis. >90% of adult and juvenile granulosa cell
tumours are diagnosed at stage I. 5-year survival rates
are 90-95 % for stage I tumours, but only 25-50% for
those presenting with advanced disease. Adult
granulosa cell tumours usually develop in
postmenopausal women, recur after longer time
intervals, (average of 5-years), and the average survival
following recurrence is 5-years. Meanwhile, most
juvenile granulosa tumours develop in individuals
under 30-years of age, recur within 3-years and then are
rapidly fatal. Individuals with completely resected
granulosa cell tumours with normal DNA diploid
content, have a much better prognosis than when
residual tumour remains after laparotomy, and the
DNA content is aneuploid.
Theca cell tumours have an excellent prognosis, with
5-year survival rates of nearly 100%, as they are
usually benign.
The prognosis of Sertoli-Leydig cell tumours is
governed by the stage and differentiation of the tumour.
97.5% of such tumour entities are stage 1, the
remainder being advanced-stage.
Cytogenetics
Treatment
Cytogenetics Morphological
Surgery may be the only treatment necessary. Surgical
intervention of patients with sex cord-stromal tumours
is age dependent. Trans abdominal hysterectomy or
bilateral salpingo-oophorectomy is appropriate for
women beyond childbearing age, whereas unilateral
oophorectomy is appropriate for younger women.
There is a paucity of data on treatment of advanced or
recurrent stromal tumours due to their rarity, varied
histology and indolence.
Trisomy 12 is a recurrent finding, often as the sole
anomaly in benign sex cord-stromal tumours including
fibromas, fibrothecomas, thecomas, granulosa cell
tumours. The consistent occurrence of trisomy 12 in
different subtypes of sex cord-stromal tumours suggests
a common mechanism of oncogenesis within this
diverse group of neoplasms. Numerical abnormalities
of chromosome 12 can readily be demonstrated by
interphase cytogenetics.
Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1)
50
Ovary: Sex cord-stromal tumors
Lee-Jones L
studies have excluded any major involvement of this
gene in the genesis of ovarian granulosa cell tumours.
As discussed earlier, sex cord tumours with annular
tubules are present at increased frequency in
individuals with PJS, which is caused by germline
inactivating mutations of the STK11 gene at 19p13.3.
A study investigated whether LOH was present in 2
cases of PJS associated sex cord-stromal tumours, and
in 5 sex cord-stromal tumours in individuals without
PJS. LOH was identified in both tumours associated
with PJS. Neither LOH nor somatic mutations of
STK11 were present in the sporadic tumours.
Immunohistochemistry has demonstrated that 32/33
granulosa cell tumours, and 10/11 Sertoli-Leydig cell
tumours show inhibin alpha (INHA) immunopositivity,
and 18/33 granulosa cell tumours and 6/11 SertoliLeydig cell tumours MIC2 (CD99 antigen)
immunopositivity. Knockout mouse models null for the
INHA gene develop granulosa cell tumours suggesting
that this gene may act as a tumour suppressor gene. To
find supporting evidence that this was the case in
human granulosa cell tumours, it has been investigated
whether LOH of the INHA locus at 2q33-qter was
evident in a series of 17 granulosa cell tumours.
However LOH was found in only one case, suggesting
that this gene does not function as a tumour suppressor
gene in granulosa cell tumours in human, contrary to
the findings in the mouse model. However this supports
the observation of elevated expression of inhibin which
has been reported previously in these tumours. Thus
there appears to be an apparent dichotomy between the
human granulosa cell tumour and the mouse models.
A study to address whether trisomy 12 was associated
with amplification of the KRAS2 oncogene (12p12.1)
demonstrated no relationship in 2 fibromas and 1
granulosa cell tumour with trisomy 12 (taking the
ploidy level into account). Cyclin D2 (CCND2) has
been suggested as the candidate gene on 12p, and has
been reported to demonstrate increased expression.
Granulosa cell tumours demonstrated increased
expression of FSHR, CCND2, RII-beta and COX-2
(PTGS2), whereas they showed decreased expression
of
SGK
and
LHCGR
(luteinizing
hormone/choriogonadotropin receptor) compared to
normal ovarian tissue by RT-PCR. Altered expression
levels of the following genes have also been found in
granulosa cell tumours: Mullerian inhibiting substance;
inhibin; p53; ERBB2; and MYC. A role for the INK4
family of cyclin-dependent kinase inhibitors has also
been suggested in granulosa cell tumours.
The role of mutations of WT1 in sex cord-stromal
tumours was investigated. Of 11 granulosa cell
tumours, 3 Leydig cell tumours and 1 Sertoli-Leydig
cell tumour, none harboured a mutation in the zinc
finger domain where >90% of WT1 mutations are
found in sporadic Wilms' tumours, despite most of the
Trisomy 12 and 14, and monosomy 22 are the
characteristic recurrent cytogenetic aberrations in
granulosa cell tumours. There has been a single case of
a Sertoli cell tumour in which cytogenetics was
performed. Supernumerary i(1q) was present as the sole
abnormality. Monosomy 22 was identified as the sole
anomaly in a mixed germ cell-sex cord-stromal tumour
in the ovary, by both karyotyping and CGH, which may
suggest a common pathogenetic mechanism for both
tumour types. Monosomy 22 was also identified as the
sole abnormality in a fibrothecoma. Monosomy 22 and
trisomy 14 may be early events in the pathogenesis of
adult granulosa cell tumour, and particularly adult
granulosa-thecoma cell tumours.
Other abnormalities found include:
44,XX,dup(p13p31),del(3)(p14),add(10p),-16,-22
in
one case of fibrothecoma,
57,XX,+4,+5,+6,+10,+12,+12,+14,+17,+18,+19,+20 in
another fibrothecoma case,
+4,+9,+12 in fibrothecoma,
trisomy 12 and 4 as only cytogenetic aberrations in a
thecoma.
Cytogenetics Molecular
CGH and FISH analysis of an ovarian metastasising
Sertoli-Leydig cell tumour demonstrated trisomy 8 as
the sole anomaly, suggesting that the molecular
pathogenesis of Sertoli-Leydig cell tumours differs
from the other subtypes of sex cord-stromal tumours.
In a study, FISH using DNA-specific probes for
chromosome 12, 17, 22 and X on granulosa cell
tumours revealed monosomy 22 in 6/20; trisomy 12 in
5/20; monosomy X in 2/20 and monosomy 17 in 1/20.
They also analysed this series of tumours by CGH and
identified gains of chromosome 12 (6/20) and 14 (6/20)
and losses of chromosome 22 (7/20) and X (1/20) as
the predominant findings. These findings corroborate
previous reports of the prevalence of trisomy 12 and 14
and monosomy 22 in granulosa cell tumours.
Genes involved and proteins
Note
Involvement of the follicle stimulating hormone
receptor, FSHR, gene in granulosa cell tumours has
now been excluded. An initial study found mutations in
9 out of 13 sex cord tumours, which were later shown
to arise from contamination in the tissue processing
procedures. Other studies have confirmed the absence
of somatic mutations in the FSHR in sex cord-stromal
tumours, and in particular granulosa cell tumours.
Activating mutations of the G-protein subunit, G-alpha
I-2, have been found in 30% of ovarian sex cord
tumours, however none were found in a series of 13
granulosa cell tumours. Data for involvement of the
mutations in G-alpha I-2 (Gia2) gene, in ovarian
granulosa cell tumours is contradictory. However, 2
Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1)
51
Ovary: Sex cord-stromal tumors
Lee-Jones L
Pejovic T, Heim S, Alm P, Iosif S, Himmelmann A, Skjaerris J,
Mitelman F. Isochromosome 1q as the sole karyotypic
abnormality in a Sertoli cell tumor of the ovary. Cancer Genet
Cytogenet. 1993 Jan;65(1):79-80
tumours expressing WT1 mRNA. However loss of the
normal wild type allele of WT1 was observed in a
granulosa cell tumour present in a patient with DenysDrash attributable to a germline mutation of WT1.
Studies on the role of TP53 mutations in granulosa cell
tumours have been contradictory. It was found that
over-expression of TP53 was not characteristic of 19
ovarian granulosa cell tumours; whereas other workers
found a correlation between expression of mutated
TP53 with poor prognosis, which was supported by
other findings. Neither point mutations (exons 5-8
analysed only), nor LOH of TP53 were evident in a
series of 17 granulosa cell tumours, suggesting that
they have a distinct molecular pathogenesis to that of
epithelial ovarian tumours. Mutations outside the
hotspot exon 5-8 were not excluded by their study, but
are unlikely to be significant since an association
between TP53 and granulosa cell tumour by
immunohistochemistry was not demonstrated in the
first study.
Taruscio D, Carcangiu ML, Ward DC. Detection of trisomy 12
on ovarian sex cord stromal tumors by fluorescence in situ
hybridization. Diagn Mol Pathol. 1993 Jun;2(2):94-8
Ferry JA, Young RH, Engel G, Scully RE. Oxyphilic Sertoli cell
tumor of the ovary: a report of three cases, two in patients with
the Peutz-Jeghers syndrome. Int J Gynecol Pathol. 1994
Jul;13(3):259-66
Hales SA, Cree IA, Pinion S. A poorly differentiated SertoliLeydig cell tumour associated with an ovarian sex cord tumour
with annular tubules in a woman with Peutz-Jeghers
syndrome. Histopathology. 1994 Oct;25(4):391-3
Shashi V, Golden WL, von Kap-Herr C, Andersen WA, Gaffey
MJ. Interphase fluorescence in situ hybridization for trisomy 12
on archival ovarian sex cord-stromal tumors. Gynecol Oncol.
1994 Dec;55(3 Pt 1):349-54
Srivatsa PJ, Keeney GL, Podratz KC. Disseminated cervical
adenoma malignum and bilateral ovarian sex cord tumors with
annular tubules associated with Peutz-Jeghers syndrome.
Gynecol Oncol. 1994 May;53(2):256-64
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This article should be referenced as such:
Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1)
Lee-Jones L. Ovary: Sex cord-stromal tumors. Atlas Genet
Cytogenet Oncol Haematol. 2004; 8(1):48-53.
53
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Solid Tumour Section
Mini Review
Soft tissue tumors: Elastofibroma
Roberta Vanni
Dip Scienze e Tecnologie Biomediche, Sezione di Biologia e Genetica, Universita di Cagliari, Cittadella
Universitaria, 09142 Monserrato (CA), Italy (RV)
Published in Atlas Database: November 2003
Online updated version : http://AtlasGeneticsOncology.org/Tumors/ElastofibromaID5173.html
DOI: 10.4267/2042/38057
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2004 Atlas of Genetics and Cytogenetics in Oncology and Haematology
degeneration of preformed fibers. It has been suggested
that repeated trauma by mechanical friction of the
scapula against the ribs may induce the tumorlike
process, since there is an increased prevalence in
persons having a history of hard manual labor. A
family history of the lesion is reported in up to onethird of cases, suggesting that its origin may be
influenced genetically.
Identity
Alias: Elastofibroma dorsi
Note: Elastofibroma is a rare, slow-growing benign
lesion of unknown origin, typically arising from the
connective tissue between the subscapular area and the
chest wall in elderly persons. It was first reported by
Jarvi and Saxen in 1959 and published in 1961.
Epidemiology
Clinics and pathology
Elastofibroma is a rare condition whose exact incidence
is unknown. Using computerized tomography, an
incidence of 2% has been reported in the elderly, but it
is found in autopsies, with lesions 3 cm in diameter or
smaller, in 11.2% of men and 24.4% of women.
Etiology
The etiology of this lesion remains unclear. It seems
likely that the pseudotumor mass is the product of
abnormal elastogenesis rather than of
CT of the lower thorax: a semilunar-shaped mass (M) of soft tissue density with foci of fatty attenuations abutting two left-side ribs. A
smaller heterogeneous mass is seen at the same location on the right. From Rivka Zissin MD and Myra Shapiro-Feinberg MD. IMAJ
2001; 3: 780. Courtesy of the Editor.
Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1)
54
Soft tissue tumors: Elastofibroma
Vanni R
A. H & E stain: paucicellular, hyalinized stroma containing large, coarse, pale eosinophilic collagen and elastic fibers.
B. Vehoeff's elastic stain showing numerous globular and fiber-like elastic materials. Courtesy of Dr. Margaret Grimes,
http://www.pathology.vcu.edu/residentcases.
fragmented into small petaloid or serrated globules
arranged in a linear pattern.
On ultrastructural examination, the elastic fibers appear
as granular or fibrillary aggregations of electron-dense
material surrounded by an amorphous matrix with
scattered microfibrils.
It is more common in women (93%, usually older than
55 years) than men, whereas cases in young adults,
teenagers and children have not been reported.
Clinics
In 99% of reported cases, elastofibroma appears in the
periscapsular area as a well-circumscribed large mass,
most often not adhering to overlying skin. It is usually
located in the lower subscapular area, deep in the
rhomboid and latissimus dorsi muscles, firmly attached
to the chest wall. Other, but very uncommon, locations
include the deltoid muscle, ischial tuberosity, greater
trochanter, olecranon, thoracic wall, foot, stomach,
mediastinum, orbita and cornea. It is slow-growing.
10% of cases show bilateral lesions. Most patients are
asymptomatic; hence the lesion can be overlooked.
Elastofibroma has a distinctive appearance in
ultrasonography, computed tomography and magnetic
resonance imaging. Its MR and CT features are
different from those of most other soft-tissue tumors,
reflecting entrapped fat within a predominantly-fibrous
mass. Although not pathognomonic, the presence of
these features in a subscapular lesion in an older patient
suggests a diagnosis of elastofibroma. Nonetheless, a
biopsy is mandatory to confirm clinical diagnosis, since
the subscapular site may be the location of neoplasms
such as lipomas and sarcoma, as well as of metastases,
extra-abdominal fibromatosis and hemangioma.
Treatment
Complete surgical excision is the treatment of choice in
symptomatic patients. Recurrence after surgery is very
rare. Spontaneous regression without treatment has
been observed in exceptional cases.
Evolution
Elastofibroma is a benign condition, and malignant
transformation has not been described.
Cytogenetics
Note
Very few lesions have been studied using chromosome
banding.
Cytogenetics Morphological
The prominent cytogenetic feature of elastofibroma is
remarkably high karyotypic instability, responsible for
structural changes involving virtually all chromosomes.
Changes are usually random, and when clonal they
have always been observed in no more than two cells.
The most frequently nonrandomly affected breakpoint
is at the 1p32 band, but breakpoints at 1p36 and 3q21
have been recorded.
Pathology
Macroscopically the lesion appears as a grey-white
spherical mass 5-10 cm in diameter. On microscopic
examination, it appears as a dermal unencapsulated
tumorlike mass composed of eosinophilic collagen and
elastic fibers, with scattered aggregates of fat cells. The
elastic fibers have a degenerated, beaded appearance or
are
Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1)
Cytogenetics Molecular
One study performed using comparative genomic
hybridization showed the presence of DNA imbalances
in 33% of the examined cases, with DNA gains at
Xq12-q22 being the most common.
55
Soft tissue tumors: Elastofibroma
Vanni R
Batstone P, Forsyth L, Goodlad J. Clonal chromosome
aberrations secondary to chromosome instability in an
elastofibroma. Cancer Genet Cytogenet. 2001 Jul 1;128(1):467
References
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Microbiol Scand Suppl. 1961;51(Suppl 144):83-4
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Vaissalo VT. Elastofibroma--a degenerative pseudotumor.
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McComb EN, Feely MG, Neff JR, Johansson SL, Nelson M,
Bridge JA. Cytogenetic instability, predominantly involving
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Genet Cytogenet. 2001 Apr 1;126(1):68-72
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cytologic features and review of its pathogenesis. Diagn
Cytopathol. 2000 Dec;23(6):393-6
Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1)
Vanni R. Soft tissue tumors: Elastofibroma. Atlas Genet
Cytogenet Oncol Haematol. 2004; 8(1):54-56.
56
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Solid Tumour Section
Mini Review
Testis: Spermatocytic seminoma
Ewa Rajpert-De Meyts
Dept. of Growth & Reproduction, Copenhagen University Hospital, Rigshospitalet, Section GR-5064, 9
Blegdamsvej, DK-2100 Copenhagen, Denmark (ERDM)
Published in Atlas Database: November 2003
Online updated version : http://AtlasGeneticsOncology.org/Tumors/SpermatSeminID5119.html
DOI: 10.4267/2042/38059
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2004 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
Clinics and pathology
Alias: Spermatocytoma
Note: Spermatocytic seminoma is a rare testicular
neoplasm derived from germ cells. It was first
described by Masson in 1946. This tumour occurs
exclusively in the testes, in relatively older men. There
is no female (ovarian) equivalent.
Disease
Spermatocytic seminoma has a relatively mild clinical
course. Most patients present with a painless swelling
of one testis, but in some cases tenderness was
reported. Metastases are very rare and have been
basically reported only in cases with sarcomatous
transformation.
Classification
Phenotype / cell stem origin
Note
Classification of germ cell tumours has not been
adapted uniformly in the world. Two classifications
most commonly used are the modified WHO
classification and the British Testicular Panel (BTTP)
classification. In addition Grigor proposed in 1993 a
new classification based on biological features, and it
was suggested in the AFIP Atlas of Tumor Pathology a
modified classification of testicular and paratesticular
tumours and tumour-like lesions. Spermatocytic
seminoma is classified in these four systems as follows:
Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1)
The origin of spermatocytic seminoma from the germ
cell lineage has been clearly demonstrated by a number
of studies, however the cell of origin have been a
matter of debate. The initial hypothesis suggested that
the spermatocyte was the progenitor cell and the
tumour might contain post-meiotic haploid cells.
Subsequent studies failed to find haploid DNA values,
thus arguing against a true meiotic-phase tumour.
57
Testis: Spermatocytic seminoma
Rajpert-De Meyts E
En example of spermatocytic seminoma, HE-stained.
A high power image showing characteristic polymorphism of the cell nucleus size of spermatocytic seminoma.
Other hypotheses stipulated that spermatocytic
seminoma might be a better differentiated variant of
classical seminoma (composed of cells differentiating
in the direction of spermatocytes but which have not
yet reached this stage) or may originate from type B
(dark) spermatogonia, which are committed to enter
meiosis.
Finally, some researchers suggested that spermatocytic
seminoma might be derived from primordial germ cells
or gonocytes. The current consensus, based on
comparative studies of the phenotypes of spermatocytic
seminoma, normal germ cells and other germ cell
derived tumours, is that spermatocytic seminoma is
derived from spermatogonia that are committed to enter
meiosis but have not yet done so.
Importantly, spermatocytic seminoma is not derived
from carcinoma in situ (CIS), the gonocytes-like
Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1)
intratubular precursor lesion for germ cell tumours of
adolescents and young adults (classical seminoma and
non-seminoma).
Etiology
Aetiology of spermatocytic seminoma is unknown.
Epidemiology
Spermatocytic seminoma is rare and represents around
2-5% of seminomas. It occurs in patients at 45-80 years
of age, and is extremely rare in young men under than
35. This is in contrast to the classical seminoma, which
demonstrates the peak of age-specific incidence around
35 years of age.
Cytology
A characteristic feature of spermatocytic seminoma is
the presence of three types of cells with different
58
Testis: Spermatocytic seminoma
Rajpert-De Meyts E
nuclear size: large, small and intermediate. Some nuclei
may exhibit a presence of nuclear thread-like
chromatin.
Evolution
Some cases of spermatocytic seminoma may
undergo sarcomatous transformation and spread outside
the testis. An anaplastic variant was also described.
Pathology
There is no specific marker for spermatocytic
seminoma. Proteins/antigens that are highly expressed
in spermatogonia (most of them also present in
gonocytes and primary spermatocytes), such as SSX
(synovial sarcoma on X chromosome), NSE (neuronspecific enolase), CHK2, MAGE-A4, NY-ESO-1,
VASA are present in spermatocytic seminoma.
Antigens expressed in embryonic germ cells but not in
the normal adult testis, e.g. PLAP (placental-like
alkaline phosphatase), TRA-1-60, or KIT are usually
undetectable in spermatocytic seminoma. High
expression of p53 protein in a subset of cells was
demonstrated in approximately 80% of cases. Proteins
highly abundant in post-meiotic spermatids, e.g.
p19INK4d, are usually not present in spermatocytic
seminoma. The expression of telomerase (the RNA
component) in spermatocytic seminoma was found to
be moderate: lower than in classical seminomas but
higher than in mature teratomas.
Genetics
Note
No specific germ-line chromosomal aberration or gene
mutations were reported in patients with spermatocytic
seminoma.
Cytogenetics
Note
Cytogenetic studies demonstrated variable ploidy of the
different cell populations in spermatocytic seminoma,
with prevalence of diploid and polyploid cells. No
haploid values were found.
Cytogenetics Molecular
Only one molecular study of 4 spermatocytic
seminomas was performed to date. A uniform gain of
chromosome 9, and less consistent gains of
chromosomes 1 and 20, and loss of chromosome 22
material were found by comparative genomic
hybridisation.
Treatment
Spermatocytic seminoma
(orchiectomy).
is
treated
by
surgery
MAGE-A4 antigen is abundant is spermatocytic seminoma (visible in a lower part of the picture). Note that MAGE-A4 is also present in
spermatogonia (visible in the upper part) (from Rajpert-De Meyts et al. Histopathology 2003).
Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1)
59
Testis: Spermatocytic seminoma
Rajpert-De Meyts E
Delgado R, Rathi A, Albores-Saavedra J, Gazdar AF.
Expression of the RNA component of human telomerase in
adult testicular germ cell neoplasia. Cancer. 1999 Nov
1;86(9):1802-11
References
Rosai J, Silber I, Khodadoust K. Spermatocytic seminoma. I.
Clinicopathologic study of six cases and review of the
literature. Cancer. 1969 Jul;24(1):92-102
Kraggerud SM, Berner A, Bryne M, Pettersen EO, Fossa SD.
Spermatocytic seminoma as compared to classical seminoma:
an immunohistochemical and DNA flow cytometric study.
APMIS. 1999 Mar;107(3):297-302
Pugh RC. Testicular tumours - Introduction. In: Pugh RC (ed.)
Pathology of the testis. Blackwell Scientific, Oxford 1976, 139159
Ulbright TM, Amin MB, Young RH. Tumors of the testis,
adnexa, spermatic cord, and scrotum. In: Atlas of Tumor
Pathology. Third Series, Fascicle 25. Armed Forces Institute of
Pathology, Washington DC, 1999, 1-375
Mostofi FK. Comparison of various clinical and pathological
classifications of tumors of testes. Semin Oncol. 1979
Mar;6(1):26-30
Romanenko AM, Persidskiĭ IuV. [Ultrastructure and
histogenesis of spermatocytic seminoma]. Vopr Onkol.
1983;29(7):60-6
Stoop H, van Gurp R, de Krijger R, Geurts van Kessel A,
Köberle B, Oosterhuis W, Looijenga L. Reactivity of germ cell
maturation stage-specific markers in spermatocytic seminoma:
diagnostic and etiological implications. Lab Invest. 2001
Jul;81(7):919-28
Müller J, Skakkebaek NE, Parkinson MC. The spermatocytic
seminoma: views on pathogenesis. Int J Androl. 1987
Feb;10(1):147-56
Satie AP, Rajpert-De Meyts E, Spagnoli GC, Henno S, Olivo L,
Jacobsen GK, Rioux-Leclercq N, Jégou B, Samson M. The
cancer-testis gene, NY-ESO-1, is expressed in normal fetal
and adult testes and in spermatocytic seminomas and
testicular carcinoma in situ. Lab Invest. 2002 Jun;82(6):775-80
Dekker I, Rozeboom T, Delemarre J, Dam A, Oosterhuis JW.
Placental-like alkaline phosphatase and DNA flow cytometry in
spermatocytic seminoma. Cancer. 1992 Feb 15;69(4):993-6
Grigor KM. A new classification of germ cell tumours of the
testis. Eur Urol. 1993;23(1):93-100; discussion 101-3
Rajpert-De Meyts E, Jacobsen GK, Bartkova J, Aubry F,
Samson
M,
Bartek
J,
Skakkebaek
NE.
The
immunohistochemical expression pattern of Chk2, p53,
p19INK4d, MAGE-A4 and other selected antigens provides
new evidence for the premeiotic origin of spermatocytic
seminoma. Histopathology. 2003 Mar;42(3):217-26
Eble JN. Spermatocytic seminoma. Hum Pathol. 1994
Oct;25(10):1035-42
Albores-Saavedra J, Huffman H, Alvarado-Cabrero I, Ayala
AG. Anaplastic variant of spermatocytic seminoma. Hum
Pathol. 1996 Jul;27(7):650-5
This article should be referenced as such:
Rosenberg C, Mostert MC, Schut TB, van de Pol M, van
Echten J, de Jong B, Raap AK, Tanke H, Oosterhuis JW,
Looijenga LH. Chromosomal constitution of human
spermatocytic seminomas: comparative genomic hybridization
supported by conventional and interphase cytogenetics. Genes
Chromosomes Cancer. 1998 Dec;23(4):286-91
Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1)
Rajpert-De Meyts E. Testis: Spermatocytic seminoma. Atlas
Genet Cytogenet Oncol Haematol. 2004; 8(1):57-60.
60
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Cancer Prone Disease Section
Mini Review
Familial clear cell renal cancer
Anita Bonné, Danielle Bodmer, Marc Eleveld, Eric Schoenmakers, Ad Geurts van Kessel
Department of Human Genetics, University Medical Center Nijmegen, Nijmegen, the Netherlands (AB, DB,
ME, ES, AGVK)
Published in Atlas Database: October 2003
Online updated version : http://AtlasGeneticsOncology.org/Kprones/FamClearCellRenalID10081.html
DOI: 10.4267/2042/38060
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2004 Atlas of Genetics and Cytogenetics in Oncology and Haematology
carcinomas, with median age 45 yrs at diagnosis
(range 18-79 yrs, most cases being between 35 and 55
yrs old).
Identity
Note: Renal cell carcinomas (RCC) represent 85% of
all primary renal tumors. In general, RCCs are sporadic
tumors but cases of familial RCC have also been
reported. If detected early and without metastases, the
disease can be cured surgically with conservation of
renal function. Both familial and sporadic cases have in
common the presence of abnormalities involving
chromosome 3, suggesting a primary role for this
chromosome in RCC causation, particularly the clear
cell type. An early gene rearrangement due to
translocation may be a primary event. Loss of 3p and
somatic mutation(s) in a tumor-surpressor-gene(s) on
3p (e.g.VHL) may be recurring events related to tumor
progression.
Inheritance: The inherited form of renal cancer is
characterized by:
- the tumor is found at an early age compared to
sporadic tumors (see below)
- the tumors are found frequently bilateral
- multiple occurrence.
Other (well known) classes of inherited renal cell
carcinomas are:
the Von Hippel-Lindau syndrome, and
the Lynch syndrome II.
Also chromosome abnormalities may be related to
inherited renal cancer.
Treatment
If the tumor is detected at an early stage the tumor can
be surgical removed, without the lost of the renal
function.
Prognosis
Depends on the stage of the tumor at the time of
detection.
Cytogenetics
Clear-cell renal cell carcinomas are associated with
chromosome 3 translocations and deletions of 3p.
Genes involved and proteins
FHIT
Clinics
Location
3p14.2
Note
FHIT is a breakpoint spanning gene on chromosome 3
in a constitutional familial case of a t(3;8)(p14;q24)
translocation.
DNA/RNA
Description: 10 exons.
Protein
Description: 147 amino acids.
No phenotypic sign.
TRC8
Neoplastic risk
Location
8q24
Multiple and/or bilateral nonpapillary renal cell
Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1)
61
Familial clear cell renal cancer
Bonné A et al.
Note
TRC8 is a breakpoint spanning gene on chromosome 8
in a constitutional familial case of a t(3;8)(p14;q24)
translocation.
References
Wegner RD. A new inducible fragile site on chromosome
3(p14.2) in human lymphocytes. Hum Genet. 1983;63(3):297-8
Wang N, Perkins KL. Involvement of band 3p14 in t(3;8)
hereditary renal carcinoma. Cancer Genet Cytogenet. 1984
Apr;11(4):479-81
DIRC2
Location
3q21
Note
Dirc2 is a breakpointspanning gene on chromosome 3
in a constitutional familial case of a t(2;3)(q35;q21)
translocation.
DNA/RNA
Description: The gene spans 73 kb, 9 exons.
Protein
Description: 478 amino acids.
Expression: Expression in pancreas, kidney, skeletal
muscle, liver, lung, placenta, brain and heart.
Localisation: Proximal tubular cells of the kidney.
Function: May be a transporter.
Bodmer D, Eleveld MJ, Ligtenberg MJ, Weterman MA,
Janssen BA, Smeets DF, de Wit PE, van den Berg A, van den
Berg E, Koolen MI, Geurts van Kessel A. An alternative route
for multistep tumorigenesis in a novel case of hereditary renal
cell cancer and a t(2;3)(q35;q21) chromosome translocation.
Am J Hum Genet. 1998 Jun;62(6):1475-83
Druck T, Podolski J, Byrski T, Wyrwicz L, Zajaczek S, Kata G,
Borowka A, Lubinski J, Huebner K. The DIRC1 gene at
chromosome 2q33 spans a familial RCC-associated
t(2;3)(q33;q21) chromosome translocation. J Hum Genet.
2001;46(10):583-9
Podolski J, Byrski T, Zajaczek S, Druck T, Zimonjic DB,
Popescu NC, Kata G, Borowka A, Gronwald J, Lubinski J,
Huebner K. Characterization of a familial RCC-associated
t(2;3)(q33;q21) chromosome translocation. J Hum Genet.
2001;46(12):685-93
Bodmer D, Eleveld M, Kater-Baats E, Janssen I, Janssen B,
Weterman M, Schoenmakers E, Nickerson M, Linehan M, Zbar
B, van Kessel AG. Disruption of a novel MFS transporter gene,
DIRC2, by a familial renal cell carcinoma-associated
t(2;3)(q35;q21). Hum Mol Genet. 2002 Mar 15;11(6):641-9
DIRC3
Location
2q35
Note
Dirc3 is a breakpointspanning gene on chromosome 2
in a constitutional familial case of a t(2;3)(q35;q21)
translocation.
DNA/RNA
Description: The gene spans 3071 bp and contains 12
exons.
Gemmill RM, Bemis LT, Lee JP, Sozen MA, Baron A, Zeng C,
Erickson PF, Hooper JE, Drabkin HA. The TRC8 hereditary
kidney cancer gene suppresses growth and functions with VHL
in a common pathway. Oncogene. 2002 May 16;21(22):350716
Bodmer D, Schepens M, Eleveld MJ, Schoenmakers EF,
Geurts van Kessel A. Disruption of a novel gene, DIRC3, and
expression of DIRC3-HSPBAP1 fusion transcripts in a case of
familial renal cell cancer and t(2;3)(q35;q21). Genes
Chromosomes Cancer. 2003 Oct;38(2):107-16
DIRC1
Location
2q33
Note
Dirc1 is a breakpointspanning gene on chromosome 2
in a constitutional familial case of a t(2;3)(q33;q22)
translocation.
DNA/RNA
Description: DIRC1 gene contains 2 exons and spans
approximately 57 kb of genomic DNA.
Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1)
Meléndez B, Rodríguez-Perales S, Martínez-Delgado B, Otero
I, Robledo M, Martínez-Ramírez A, Ruiz-Llorente S, Urioste M,
Cigudosa JC, Benítez J. Molecular study of a new family with
hereditary renal cell carcinoma and a translocation
t(3;8)(p13;q24.1). Hum Genet. 2003 Feb;112(2):178-85
This article should be referenced as such:
Bonné A, Bodmer D, Eleveld M, Schoenmakers EFPMG,
Geurts van Kessel A. Familial clear cell renal cancer. Atlas
Genet Cytogenet Oncol Haematol. 2004; 8(1):61-62.
62
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Familial clear cell renal cancer
Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1)
Bonné A et al.
64