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Atlas of Genetics and Cytogenetics
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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]
The Atlas of Genetics and Cytogenetics in Oncology and Haematology is published 4 times a year by ARMGHM, a
non profit organisation.
Philippe Dessen is the Database Director, and Alain Bernheim the Chairman of the on-line version (Gustave Roussy
Institute – Villejuif – France).
http://AtlasGeneticsOncology.org
© ATLAS - ISSN 1768-3262
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1)
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]
The Atlas of Genetics and Cytogenetics in Oncology and Haematology is published 4 times a year by ARMGHM, a
non profit organisation.
Philippe Dessen is the Database Director, and Alain Bernheim the Chairman of the on-line version (Gustave Roussy
Institute – Villejuif – France).
http://AtlasGeneticsOncology.org
© ATLAS - ISSN 1768-3262
The PDF version of the Atlas of Genetics and Cytogenetics in Oncology and Haematology is a reissue of the original articles published in collaboration with the
Institute for Scientific and Technical Information (INstitut de l’Information Scientifique et Technique - INIST) of the French National Center for Scientific Research
(CNRS) on its electronic publishing platform I-Revues.
Online and PDF versions of the Atlas of Genetics and Cytogenetics in Oncology and Haematology are hosted by INIST-CNRS.
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Editor
Jean-Loup Huret
(Poitiers, France)
Volume 4, Number 1, January - March 2000
Table of contents
Gene Section
EP300 (E1A binding protein p300)
Jean-Loup Huret
1
EXT1 (exostoses (multiple) 1)
Judith VMG Bovée
3
EXT2 (exostoses (multiple) 2)
Judith VMG Bovée
5
NUMA1 (nuclear mitotic apparatus protein 1)
Jean-Loup Huret
7
ABL2 (Abelson homolog 2)
Jean-Loup Huret
9
AMP-19 (AML1 partner from chromosome 19)
Jean-Loup Huret
10
GMPS (guanine monphosphate synthetase)
Jean-Loup Huret
11
AF3p21 (ALL1 fused gene from chromosome 3p21)
Jean-Loup Huret
13
NUP98 (nucleoporin 98 kDa)
Jean-Loup Huret
14
Leukaemia Section
t(11;22)(q23;q13)
Jean-Loup Huret
16
t(2;11)(p21;q23)
Elena W Fleischman
17
+22 or trisomy 22 (solely?)
Jean-Loup Huret
19
12p rearrangements in ALL
Nyla A Heerema
20
Classification of B-cell chronic lymphoproliferative disorders (CLD)
Antonio Cuneo
22
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1)
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
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Classification of B-cell non-Hodgkin lymphomas (NHL)
Antonio Cuneo
24
i(17q) in myeloid malignancies
Chrystèle Bilhou-Nabera
27
t(1;12)(q25;p13)
Jean-Loup Huret
29
t(1;16)(q12;q24)
Jean-Loup Huret
30
t(1;2)(q12;q37)
Jean-Loup Huret
31
t(1;21)(p36;q22)
Jean-Loup Huret
32
t(11;12)(p15;q13)
Jean-Loup Huret
33
t(11;22)(q23;q11.2)
Jean-Loup Huret
35
t(17;21)(q11.2;q22)
Jean-Loup Huret
37
t(18;21)(q21;q22)
Jean-Loup Huret
38
t(19;21)(q13.4;q22)
Jean-Loup Huret
39
t(3;11)(p21;q23)
Jean-Loup Huret
40
t(3;11)(q25;q23)
Jean-Loup Huret
41
Solid Tumour Section
Bone: Chondrosarcoma
Judith VMG Bovée
42
Cancer Prone Disease Section
Hereditary multiple exostoses (HME)
Judith VMG Bovée
46
Rhabdoid predisposition syndrome
Jean-Loup Huret
49
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1)
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Gene Section
Mini Review
EP300 (E1A binding protein p300)
Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France
(JLH)
Published in Atlas Database: January 2000
Online updated version : http://AtlasGeneticsOncology.org/Genes/P300ID97.html
DOI: 10.4267/2042/37578
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2000 Atlas of Genetics and Cytogenetics in Oncology and Haematology
functions during differentiation; there is embryonic
lethality of mice nullizygous for p300 (with defects in
neurulation and heart development), and as well of
mice double heterozygous for p300 and CBP,
underlining their essential and associated role.
Identity
Other names: P300; E1A binding protein p300
HGNC (Hugo): EP300
Location: 22q13.2
Homology
DNA/RNA
CBP
Transcription
Implicated in
9046 bp mRNA; coding sequence: 7244 bp.
t(11;22)(q23;q13)
Protein
Note
Very rare.
Disease
Therapy related acute non lymphocytic leukemia.
Hybrid/Mutated gene
5 MLL-3 P300.
Abnormal protein
N-term MLL fused to C-term P300.
Oncogenesis
Likely to be driven by the MLL part.
Description
2414 amino acids; 264 kDa.
Expression
Widely expressed ; also expressed in the whole
embryo; possesses from N term to C term: a nuclear
localization signal, a poly-serine, a bromodomain, a
poly-glu, a binding region for E1A adenovirus, and a
poly-gln.
Localisation
Gastric and colorectal carcinomas
Nucleus.
Oncogenesis
Mutations in both alleles.
Function
p300 and CBP are highly related proteins implicated in
transcriptional responses to various extracellular and
intracellular signals with chromatin remodeling; they
are non-DNA-binding transcriptional coactivators; they
interact with transcriptional activators as well as
repressors; p300 and CBP are involved in most cellular
programs, including growth, terminal differentiation,
and P53-mediated apoptosis (with MDM2 interaction)
processes; p300 and CBP appear to have distinct
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1)
References
Eckner R, Ewen ME, Newsome D, Gerdes M, DeCaprio JA,
Lawrence JB, Livingston DM.. Molecular cloning and functional
analysis of the adenovirus E1A-associated 300-kD protein
(p300) reveals a protein with properties of a transcriptional
adaptor. Genes Dev. 1994 Apr 15;8(8):869-84.
Eckner R. p300 and CBP as transcriptional regulators and
targets
of
oncogenic
events.
Biol
Chem.
1996
Nov;377(11):685-8
1
EP300 (E1A binding protein p300)
Huret JL
Ida K, Kitabayashi I, Taki T, Taniwaki M, Noro K, Yamamoto
M, Ohki M, Hayashi Y. Adenoviral E1A-associated protein
p300 is involved in acute myeloid leukemia with
t(11;22)(q23;q13). Blood. 1997 Dec 15;90(12):4699-704
Yao TP, Oh SP, Fuchs M, Zhou ND, Ch'ng LE, Newsome D,
Bronson RT, Li E, Livingston DM, Eckner R. Gene dosagedependent embryonic development and proliferation defects in
mice lacking the transcriptional integrator p300. Cell. 1998 May
1;93(3):361-72
Giles RH, Peters DJ, Breuning MH. Conjunction dysfunction:
CBP/p300 in human disease. Trends Genet. 1998
May;14(5):178-83
Giordano A, Avantaggiati ML. p300 and CBP: partners for life
and death. J Cell Physiol. 1999 Nov;181(2):218-30
Grossman SR, Perez M, Kung AL, Joseph M, Mansur C, Xiao
ZX, Kumar S, Howley PM, Livingston DM. p300/MDM2
complexes participate in MDM2-mediated p53 degradation.
Mol Cell. 1998 Oct;2(4):405-15
Ugai H, Uchida K, Kawasaki H, Yokoyama KK. The
coactivators p300 and CBP have different functions during the
differentiation of F9 cells. J Mol Med. 1999 Jun;77(6):481-94
This article should be referenced as such:
Snowden AW, Perkins ND. Cell cycle regulation of the
transcriptional coactivators p300 and CREB binding protein.
Biochem Pharmacol. 1998 Jun 15;55(12):1947-54
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1)
Huret JL. EP300 (E1A binding protein p300). Atlas Genet
Cytogenet Oncol Haematol. 2000; 4(1):1-2.
2
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Gene Section
Mini Review
EXT1 (exostoses (multiple) 1)
Judith VMG Bovée
Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands (JVMGB)
Published in Atlas Database: January 2000
Online updated version : http://AtlasGeneticsOncology.org/Genes/EXT1ID212.html
DOI: 10.4267/2042/37575
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2000 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
Homology
Location : 8q24.11
Human EXT2, EXTL1, EXTL2 and EXTL3, mouse
Ext1, Drosophila tout velu.
DNA/RNA
Mutations
Description
Germinal
11 exons, spans approximately 350 kb of genomic
DNA.
Germline mutations in EXT1 are causative for
hereditary
multiple
exostoses,
a
genetically
heterogeneous autosomal dominant disorder; mutations
include nucleotide substitutions (54%), small deletions
(27%) and small insertions (16%), of which the
majority is predicted to result in a truncated or nonfunctional protein.
Transcription
3.4 kb.
Protein
Description
Somatic
746 amino acids, 86.304 kDa.
No somatic mutations were found in 34 sporadic and
hereditary osteochondromas and secondary peripheral
chondrosarcomas tested.
Expression
mRNA is ubiquitously expressed (also
chondrocytes), highest level of expression in liver.
in
Implicated in
Localisation
Hereditary multiple exostoses
Endoplasmic reticulum.
Prognosis
The main complication in hereditary multiple exostoses
is malignant transformation of an osteochondroma
(exostosis) into chondrosarcoma, which is estimated to
occur in 1-5% of the HME cases.
Cytogenetics
Clonal aberrations were found at band 8q24.1 in
sporadic and hereditary osteochondromas using
cytogenetic analysis; loss of heterozygosity was almost
exclusively found at the EXT1 locus in 5 out of 14
osteochondromas.
Function
A tumour suppressor function is suggested; EXT1 is an
endoplasmic reticulum (ER) resident type II
transmembrane glycoprotein whose expression in cells
alters the synthesis and display of cell surface heparan
sulfate, and EXT1 was suggested to be involved in
chain polymerization of heparan sulphate; an EXT1
homologue in Drosophila melanogaster (tout-velu, Ttv)
was demonstrated to be involved in heparan sulphate
proteoglycan biosynthesis controlling diffusion of an
important segment polarity protein called Hedgehog
(Hh).
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1)
3
EXT1 (exostoses (multiple) 1)
Bovée JVMG
Bridge JA, Nelson M, Orndal C, Bhatia P, Neff JR. Clonal
karyotypic abnormalities of the hereditary multiple exostoses
chromosomal loci 8q24.1 (EXT1) and 11p11-12 (EXT2) in
patients with sporadic and hereditary osteochondromas.
Cancer. 1998 May 1;82(9):1657-63
Oncogenesis
Two patients with multiple osteochondromas
demonstrated a germline mutation combined with loss
of the remaining wild type allele in three
osteochondromas, supporting the Knudson's two hit
model for tumour suppressor genes in osteochondroma
development; these results indicate that in cartilaginous
cells of the growth plate inactivation of both copies of
the EXT1-gene is required for osteochondroma
formation in hereditary cases.
Lin X, Gan L, Klein WH, Wells D. Expression and functional
analysis of mouse EXT1, a homolog of the human multiple
exostoses type 1 gene. Biochem Biophys Res Commun. 1998
Jul 30;248(3):738-43
Lind T, Tufaro F, McCormick C, Lindahl U, Lidholt K. The
putative tumor suppressors EXT1 and EXT2 are
glycosyltransferases required for the biosynthesis of heparan
sulfate. J Biol Chem. 1998 Oct 9;273(41):26265-8
References
McCormick C, Leduc Y, Martindale D, Mattison K, Esford LE,
Dyer AP, Tufaro F. The putative tumour suppressor EXT1
alters the expression of cell-surface heparan sulfate. Nat
Genet. 1998 Jun;19(2):158-61
Cook A, Raskind W, Blanton SH, Pauli RM, Gregg RG,
Francomano CA, Puffenberger E, Conrad EU, Schmale G,
Schellenberg G. Genetic heterogeneity in families with
hereditary multiple exostoses. Am J Hum Genet. 1993
Jul;53(1):71-9
Bovée JV, Cleton-Jansen AM, Kuipers-Dijkshoorn NJ, van den
Broek LJ, Taminiau AH, Cornelisse CJ, Hogendoorn PC. Loss
of heterozygosity and DNA ploidy point to a diverging genetic
mechanism in the origin of peripheral and central
chondrosarcoma. Genes Chromosomes Cancer. 1999
Nov;26(3):237-46
Mertens F, Rydholm A, Kreicbergs A, Willén H, Jonsson K,
Heim S, Mitelman F, Mandahl N. Loss of chromosome band
8q24 in sporadic osteocartilaginous exostoses. Genes
Chromosomes Cancer. 1994 Jan;9(1):8-12
Ahn J, Lüdecke HJ, Lindow S, Horton WA, Lee B, Wagner MJ,
Horsthemke B, Wells DE. Cloning of the putative tumour
suppressor gene for hereditary multiple exostoses (EXT1). Nat
Genet. 1995 Oct;11(2):137-43
Bovée JV, Cleton-Jansen AM, Wuyts W, Caethoven G,
Taminiau AH, Bakker E, Van Hul W, Cornelisse CJ,
Hogendoorn PC. EXT-mutation analysis and loss of
heterozygosity in sporadic and hereditary osteochondromas
and secondary chondrosarcomas. Am J Hum Genet. 1999
Sep;65(3):689-98
Hecht JT, Hogue D, Strong LC, Hansen MF, Blanton SH,
Wagner M. Hereditary multiple exostosis and chondrosarcoma:
linkage to chromosome II and loss of heterozygosity for EXTlinked markers on chromosomes II and 8. Am J Hum Genet.
1995 May;56(5):1125-31
Kitagawa H, Shimakawa H, Sugahara K. The tumor
suppressor EXT-like gene EXTL2 encodes an alpha1, 4-Nacetylhexosaminyltransferase
that
transfers
Nacetylgalactosamine and N-acetylglucosamine to the common
glycosaminoglycan-protein linkage region. The key enzyme for
the chain initiation of heparan sulfate. J Biol Chem. 1999 May
14;274(20):13933-7
Raskind WH, Conrad EU, Chansky H, Matsushita M. Loss of
heterozygosity in chondrosarcomas for markers linked to
hereditary multiple exostoses loci on chromosomes 8 and 11.
Am J Hum Genet. 1995 May;56(5):1132-9
McCormick C, Duncan G, Tufaro F. New perspectives on the
molecular basis of hereditary bone tumours. Mol Med Today.
1999 Nov;5(11):481-6
Lin X, Wells D. Isolation of the mouse cDNA homologous to
the human EXT1 gene responsible for Hereditary Multiple
Exostoses. DNA Seq. 1997;7(3-4):199-202
Simmons AD, Musy MM, Lopes CS, Hwang LY, Yang YP,
Lovett M. A direct interaction between EXT proteins and
glycosyltransferases is defective in hereditary multiple
exostoses. Hum Mol Genet. 1999 Nov;8(12):2155-64
Lohmann DR, Buiting K, Lüdecke HJ, Horsthemke B. The
murine Ext1 gene shows a high level of sequence similarity
with its human homologue and is part of a conserved linkage
group on chromosome 15. Cytogenet Cell Genet. 1997;76(34):164-6
The I, Bellaiche Y, Perrimon N. Hedgehog movement is
regulated through tout velu-dependent synthesis of a heparan
sulfate proteoglycan. Mol Cell. 1999 Oct;4(4):633-9
Lüdecke HJ, Ahn J, Lin X, Hill A, Wagner MJ, Schomburg L,
Horsthemke B, Wells DE. Genomic organization and promoter
structure of the human EXT1 gene. Genomics. 1997 Mar
1;40(2):351-4
This article should be referenced as such:
Bovée JVMG. EXT1 (exostoses (multiple) 1). Atlas Genet
Cytogenet Oncol Haematol. 2000; 4(1):3-4.
Bellaiche Y, The I, Perrimon N. Tout-velu is a Drosophila
homologue of the putative tumour suppressor EXT-1 and is
needed for Hh diffusion. Nature. 1998 Jul 2;394(6688):85-8
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1)
4
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Gene Section
Mini Review
EXT2 (exostoses (multiple) 2)
Judith VMG Bovée
Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands (JVMGB)
Published in Atlas Database: January 2000
Online updated version : http://AtlasGeneticsOncology.org/Genes/EXT2ID213.html
DOI: 10.4267/2042/37576
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2000 Atlas of Genetics and Cytogenetics in Oncology and Haematology
nucleotide substitutions (57%), small deletions (19%)
and small insertions (24%), of which the majority is
predicted to result in a truncated or non-functional
protein.
Identity
Location: 11p11-p12
DNA/RNA
Somatic
No somatic mutations were found in 34 sporadic and
hereditary osteochondromas and secondary peripheral
chondrosarcomas tested.
Description
Sixteen exons across the EXT2 locus were identified,
two of which (1a and 1b) are alternatively spliced;
spans approximately 108 kb of genomic DNA.
Implicated in
Transcription
Hereditary multiple exostoses
3.5 and 3.7 kb.
Endoplasmic reticulum.
Prognosis
The main complication in hereditary multiple exostoses
is malignant transformation of an osteochondroma
(exostosis) into chondrosarcoma, which is estimated to
occur in 1-5% of the HME cases.
Cytogenetics
11p rearrangement was found in 1 sporadic
osteochondroma (exostosis) using cytogenetic analysis;
loss of heterozygosity at the EXT2 locus was absent in
14 osteochondromas.
Function
References
Protein
Description
718 amino acids; 82.2 kDa.
Expression
mRNA is ubiquitously expressed.
Localisation
A tumour suppressor function is suggested; EXT2 is a
glycosyltransferase, suggested to be involved in chain
polymerization of heparan sulphate.
Cook A, Raskind W, Blanton SH, Pauli RM, Gregg RG,
Francomano CA, Puffenberger E, Conrad EU, Schmale G,
Schellenberg G. Genetic heterogeneity in families with
hereditary multiple exostoses. Am J Hum Genet. 1993
Jul;53(1):71-9
Homology
Human EXT1, EXTL1, EXTL2 and EXTL3, mouse
Ext2.
Wu YQ, Heutink P, de Vries BB, Sandkuijl LA, van den
Ouweland AM, Niermeijer MF, Galjaard H, Reyniers E, Willems
PJ, Halley DJ. Assignment of a second locus for multiple
exostoses to the pericentromeric region of chromosome 11.
Hum Mol Genet. 1994 Jan;3(1):167-71
Mutations
Germinal
Hecht JT, Hogue D, Strong LC, Hansen MF, Blanton SH,
Wagner M. Hereditary multiple exostosis and chondrosarcoma:
linkage to chromosome II and loss of heterozygosity for EXTlinked markers on chromosomes II and 8. Am J Hum Genet.
1995 May;56(5):1125-31
Germline mutations in EXT2 are causative for
hereditary multiple exostoses, a heterogeneous
autosomal dominant disorder; mutations include
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1)
5
EXT2 (exostoses (multiple) 2)
Bovée JVMG
Raskind WH, Conrad EU, Chansky H, Matsushita M. Loss of
heterozygosity in chondrosarcomas for markers linked to
hereditary multiple exostoses loci on chromosomes 8 and 11.
Am J Hum Genet. 1995 May;56(5):1132-9
Bovée JV, Cleton-Jansen AM, Kuipers-Dijkshoorn NJ, van den
Broek LJ, Taminiau AH, Cornelisse CJ, Hogendoorn PC. Loss
of heterozygosity and DNA ploidy point to a diverging genetic
mechanism in the origin of peripheral and central
chondrosarcoma. Genes Chromosomes Cancer. 1999
Nov;26(3):237-46
Wuyts W, Ramlakhan S, Van Hul W, Hecht JT, van den
Ouweland AM, Raskind WH, Hofstede FC, Reyniers E, Wells
DE, de Vries B. Refinement of the multiple exostoses locus
(EXT2) to a 3-cM interval on chromosome 11. Am J Hum
Genet. 1995 Aug;57(2):382-7
Bovée JV, Cleton-Jansen AM, Wuyts W, Caethoven G,
Taminiau AH, Bakker E, Van Hul W, Cornelisse CJ,
Hogendoorn PC. EXT-mutation analysis and loss of
heterozygosity in sporadic and hereditary osteochondromas
and secondary chondrosarcomas. Am J Hum Genet. 1999
Sep;65(3):689-98
Stickens D, Clines G, Burbee D, Ramos P, Thomas S, Hogue
D, Hecht JT, Lovett M, Evans GA. The EXT2 multiple
exostoses gene defines a family of putative tumour suppressor
genes. Nat Genet. 1996 Sep;14(1):25-32
Kitagawa H, Shimakawa H, Sugahara K. The tumor
suppressor EXT-like gene EXTL2 encodes an alpha1, 4-Nacetylhexosaminyltransferase
that
transfers
Nacetylgalactosamine and N-acetylglucosamine to the common
glycosaminoglycan-protein linkage region. The key enzyme for
the chain initiation of heparan sulfate. J Biol Chem. 1999 May
14;274(20):13933-7
Wuyts W, Van Hul W, Wauters J, Nemtsova M, Reyniers E,
Van Hul EV, De Boulle K, de Vries BB, Hendrickx J, Herrygers
I, Bossuyt P, Balemans W, Fransen E, Vits L, Coucke P,
Nowak NJ, Shows TB, Mallet L, van den Ouweland AM,
McGaughran J, Halley DJ, Willems PJ. Positional cloning of a
gene involved in hereditary multiple exostoses. Hum Mol
Genet. 1996 Oct;5(10):1547-57
McCormick C, Duncan G, Tufaro F. New perspectives on the
molecular basis of hereditary bone tumours. Mol Med Today.
1999 Nov;5(11):481-6
Clines GA, Ashley JA, Shah S, Lovett M. The structure of the
human multiple exostoses 2 gene and characterization of
homologs in mouse and Caenorhabditis elegans. Genome
Res. 1997 Apr;7(4):359-67
Simmons AD, Musy MM, Lopes CS, Hwang LY, Yang YP,
Lovett M. A direct interaction between EXT proteins and
glycosyltransferases is defective in hereditary multiple
exostoses. Hum Mol Genet. 1999 Nov;8(12):2155-64
Stickens D, Evans GA. Isolation and characterization of the
murine homolog of the human EXT2 multiple exostoses gene.
Biochem Mol Med. 1997 Jun;61(1):16-21
Stickens D, Brown D, Evans GA. EXT genes are differentially
expressed in bone and cartilage during mouse embryogenesis.
Dev Dyn. 2000 Jul;218(3):452-64
Bridge JA, Nelson M, Orndal C, Bhatia P, Neff JR. Clonal
karyotypic abnormalities of the hereditary multiple exostoses
chromosomal loci 8q24.1 (EXT1) and 11p11-12 (EXT2) in
patients with sporadic and hereditary osteochondromas.
Cancer. 1998 May 1;82(9):1657-63
Wuyts W, Van Hul W. Molecular basis of multiple exostoses:
mutations in the EXT1 and EXT2 genes. Hum Mutat.
2000;15(3):220-7
Lind T, Tufaro F, McCormick C, Lindahl U, Lidholt K. The
putative tumor suppressors EXT1 and EXT2 are
glycosyltransferases required for the biosynthesis of heparan
sulfate. J Biol Chem. 1998 Oct 9;273(41):26265-8
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1)
This article should be referenced as such:
Bovée JVMG. EXT2 (exostoses (multiple) 2) (. Atlas Genet
Cytogenet Oncol Haematol. 2000; 4(1):5-6.
6
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Gene Section
Mini Review
NUMA1 (nuclear mitotic apparatus protein 1)
Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France
(JLH)
Published in Atlas Database: January 2000
Online updated version : http://AtlasGeneticsOncology.org/Genes/NUMAID119.html
DOI: 10.4267/2042/37577
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2000 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Note
Must not be confused with the t(11;17)(q23;q21),
implicating PLZF and RARA, also in M3-ANLL (see
below).
Disease
Atypical M3 acute non lyphoblastic leukemia (ANLL);
only 1 case fully described.
Hybrid/Mutated gene
5' exons of NuMA, fused to the exons encoding the
retinoic acid and DNA-binding domains of RARA.
Abnormal protein
The NuMA-RARA fusion protein forms aggregates in
the nucleus where the normal NuMA partly colocalizes.
Identity
HGNC (Hugo): NUMA1
Location: 11q13
DNA/RNA
Transcription
7217 bp mRNA; coding sequence: 6305 bp.
Protein
Description
2101 amino acids; 239 kDa; the globular COOH tail
domain contains a nuclear targeting sequence, a site for
binding to the mitotic spindle and a site responsible for
nuclear reformation; can build multiarm oligomers.
References
Price CM, Pettijohn DE. Redistribution of the nuclear mitotic
apparatus protein (NuMA) during mitosis and nuclear
assembly. Properties of purified NuMA protein. Exp Cell Res.
1986 Oct;166(2):295-311
Expression
Widely expressed ; also expressed in the whole
embryo.
Compton DA, Szilak I, Cleveland DW. Primary structure of
NuMA, an intranuclear protein that defines a novel pathway for
segregation of proteins at mitosis. J Cell Biol. 1992
Mar;116(6):1395-408
Localisation
Internal nuclear matrix protein in interphase which
relocates to the spindle poles in mitotis.
Yang CH, Lambie EJ, Snyder M. NuMA: an unusually long
coiled-coil related protein in the mammalian nucleus. J Cell
Biol. 1992 Mar;116(6):1303-17
Function
Component of the mitotic spindle matrix: associates
with microtubule motors during mitosis; essential role
in organizing microtubule minus ends at spindle poles
(anchors the microtubule ends); on the other hand, may
not be essential in the nucleoskeleton structural
architecture during interphase.
Compton DA, Cleveland DW. NuMA is required for the proper
completion of mitosis. J Cell Biol. 1993 Feb;120(4):947-57
Kempf T, Bischoff FR, Kalies I, Ponstingl H. Isolation of human
NuMA protein. FEBS Lett. 1994 Nov 14;354(3):307-10
Gueth-Hallonet C, Weber K, Osborn M. NuMA: a bipartite
nuclear location signal and other functional properties of the
tail domain. Exp Cell Res. 1996 May 25;225(1):207-18
Implicated in
Merdes A, Ramyar K, Vechio JD, Cleveland DW. A complex of
NuMA and cytoplasmic dynein is essential for mitotic spindle
assembly. Cell. 1996 Nov 1;87(3):447-58
t(11;17)(q13;q21)
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1)
7
NUMA1 (nuclear mitotic apparatus protein 1)
Huret JL
Wells RA, Catzavelos C, Kamel-Reid S. Fusion of retinoic acid
receptor alpha to NuMA, the nuclear mitotic apparatus protein,
by a variant translocation in acute promyelocytic leukaemia.
Nat Genet. 1997 Sep;17(1):109-13
Harborth J, Wang J, Gueth-Hallonet C, Weber K, Osborn M.
Self assembly of NuMA: multiarm oligomers as structural units
of a nuclear lattice. EMBO J. 1999 Mar 15;18(6):1689-700
This article should be referenced as such:
Merdes A, Cleveland DW. The role of NuMA in the interphase
nucleus. J Cell Sci. 1998 Jan;111 ( Pt 1):71-9
Huret JL. NUMA1 (nuclear mitotic apparatus protein 1). Atlas
Genet Cytogenet Oncol Haematol. 2000; 4(1):7-8.
Dionne MA, Howard L, Compton DA. NuMA is a component of
an insoluble matrix at mitotic spindle poles. Cell Motil
Cytoskeleton. 1999;42(3):189-203
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1)
8
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Gene Section
Short Communication
ABL2 (Abelson homolog 2)
Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France
(JLH)
Published in Atlas Database: February 2000
Online updated version : http://AtlasGeneticsOncology.org/Genes/ABL2ID226.html
DOI: 10.4267/2042/37579
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2000 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Homology
Identity
SRC homology; closely related to ABL1.
Other names: ARG (Abelson related gene); ABLL
HGNC (Hugo): ABL2
Location: 1q25
Implicated in
t(1;12)(q25;p13) --> ABL2-ETV6
Disease
Acute non lymphocytic leukemia.
Abnormal protein
The fusion protein is composed of the HLH
oligomerization domain of ETV6 and the SH2, SH3,
and protein tyrosine kinase domains of ABL2.
References
Kruh GD, King CR, Kraus MH, Popescu NC, Amsbaugh SC,
McBride WO, Aaronson SA. A novel human gene closely
related to the abl proto-oncogene. Science. 1986 Dec
19;234(4783):1545-8
ABL2 (1q25) - Courtesy Mariano Rocchi, Resources for
Molecular Cytogenetics.
Seldin MF, Kruh GD. Mapping of Abll within a conserved
linkage group on distal mouse chromosome 1 syntenic with
human chromosome 1 using an interspecific cross. Genomics.
1989 Feb;4(2):221-3
DNA/RNA
Transcription
Kruh GD, Perego R, Miki T, Aaronson SA. The complete
coding sequence of arg defines the Abelson subfamily of
cytoplasmic tyrosine kinases. Proc Natl Acad Sci U S A. 1990
Aug;87(15):5802-6
Alternate splicing in 5 prime; 3.8 kb mRNA; ORF:
3548 bp.
Protein
Cazzaniga G, Tosi S, Aloisi A, Giudici G, Daniotti M, Pioltelli P,
Kearney L, Biondi A. The tyrosine kinase abl-related gene
ARG is fused to ETV6 in an AML-M4Eo patient with a
t(1;12)(q25;p13): molecular cloning of both reciprocal
transcripts. Blood. 1999 Dec 15;94(12):4370-3
Description
1182 amino acids; 128 kDa; comprises SH3 and SH2
domains, a protein tyrosine kinase domain, a nuclear
localization domain.
This article should be referenced as such:
Huret JL. ABL2 (Abelson homolog 2). Atlas Genet
Cytogenet Oncol Haematol. 2000; 4(1):9.
Function
Cytoplasmic tyrosine kinase.
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1)
9
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Gene Section
Short Communication
AMP-19 (AML1 partner from chromosome 19)
Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France
(JLH)
Published in Atlas Database: February 2000
Online updated version : http://AtlasGeneticsOncology.org/Genes/AMP19ID235.html
DOI: 10.4267/2042/37581
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2000 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
Implicated in
Location : 19q13.4
t(19;21)(q13.4;q22) with AML1
involvement
DNA/RNA
5.5 kB mRNA.
Disease
Acute non lymphocytic leukemia (ANLL) secondary to
toxic exposure.
Protein
References
Transcription
Hromas R, Busse T, Carroll A, Mack D, Shopnick R, Zhang
DE, Nakshatri H, Richkind K. Fusion AML1 transcript in a
radiation-associated leukemia results in a truncated inhibitory
AML1 protein. Blood. 2001 Apr 1;97(7):2168-70
Expression
Wide; highest expression in heart.
Homology
This article should be referenced as such:
None.
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1)
Huret JL. AMP-19 (AML1 partner from chromosome 19). Atlas
Genet Cytogenet Oncol Haematol. 2000; 4(1):10.
10
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Gene Section
Mini Review
GMPS (guanine monphosphate synthetase)
Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France
(JLH)
Published in Atlas Database: February 2000
Online updated version : http://AtlasGeneticsOncology.org/Genes/GMPSID229.html
DOI: 10.4267/2042/37582
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2000 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
Expression
Other names: GMPS-PEN
HGNC (Hugo): GMPS
Location: 3q24
Higher in proliferating, transformed cells than in
nontransformed cells; in normal cells, higher
expression in fibroblasts, followed by bone marrow,
leukocytes, erythrocytes, placenta, and liver.
Localisation
Cytoplasmic.
Function
Enzyme of the de novo synthesis of guanine
nucleotides: amidotransferase that catalyzes the
amination of xanthosine 5 prime monophosphate to
form GMP in the presence of ATP and glutamine; GTP
is also involved in many enzymatic reactions important
for cell division.
Implicated in
Probe(s) - Courtesy Mariano Rocchi, Resources for Molecular
Cytogenetics.
t(3;11)(q25;q23)
DNA/RNA
Protein
Disease
Treatment related acute non lymphoblastic leukemia
(M4 ANLL).
Hybrid/Mutated gene
Fusion of MLL to GMPS.
Description
References
693 amino acids; 76 kDa; there are two variant forms
of human GMP synthetase; homodimerization; GMP
synthetase contains two functional domains: a
glutamine amidotransferase (glutaminase domain, with
a conserved Cys-His-Glu triad), responsible for
glutamine hydrolysis, and a synthetase domain;
responsible for ATP hydrolysis and GMP formation.
Page T, Bakay B, Nyhan WL. Human GMP synthetase. Int J
Biochem. 1984;16(1):117-20
Transcription
2212 bp mRNA; ORF: 2081 bp.
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1)
Hirst M, Haliday E, Nakamura J, Lou L. Human GMP
synthetase. Protein purification, cloning, and functional
expression of cDNA. J Biol Chem. 1994 Sep
23;269(38):23830-7
11
GMPS (guanine monphosphate synthetase)
Huret JL
Lou L, Nakamura J, Tsing S, Nguyen B, Chow J, Straub K,
Chan H, Barnett J. High-level production from a baculovirus
expression system and biochemical characterization of human
GMP synthetase. Protein Expr Purif. 1995 Aug;6(4):487-95
Fedorova L, Kost-Alimova M, Gizatullin RZ, Alimov A,
Zabarovska VI, Szeles A, Protopopov AI, Vorobieva NV,
Kashuba VI, Klein G, Zelenin AV, Sheer D, Zabarovsky ER.
Assignment and ordering of twenty-three unique NotI-linking
clones containing expressed genes including the guanosine 5'monophosphate synthetase gene to human chromosome 3.
Eur J Hum Genet. 1997 Mar-Apr;5(2):110-6
Nakamura J, Lou L. Biochemical characterization of human
GMP synthetase. J Biol Chem. 1995 Mar 31;270(13):7347-53
Nakamura J, Straub K, Wu J, Lou L. The glutamine hydrolysis
function of human GMP synthetase. Identification of an
essential active site cysteine. J Biol Chem. 1995 Oct
6;270(40):23450-5
Pegram LD, Megonigal MD, Lange BJ, Nowell PC, Rappaport
EF, Felix CA. t(3;11)(q25;q23) fuses MLL with the GMPS
(guanosine 5'-monophosphate synthetase) gene in treatmentrelated acute myeloid leukemia (AML). Blood 1999; 94 Suppl
1: Abst 2227
Tesmer JJ, Klem TJ, Deras ML, Davisson VJ, Smith JL. The
crystal structure of GMP synthetase reveals a novel catalytic
triad and is a structural paradigm for two enzyme families. Nat
Struct Biol. 1996 Jan;3(1):74-86
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1)
This article should be referenced as such:
Huret JL. GMPS (guanine monphosphate synthetase). Atlas
Genet Cytogenet Oncol Haematol. 2000; 4(1):11-12.
12
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Gene Section
Short Communication
AF3p21 (ALL1 fused gene from chromosome
3p21)
Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France
(JLH)
Published in Atlas Database: February 2000
Online updated version : http://AtlasGeneticsOncology.org/Genes/AF3p21ID228.html
DOI: 10.4267/2042/37580
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2000 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
Implicated in
HGNC (Hugo): NCKIPSD
Location: 3p21
t(3;11)(p21;q23) --> AF3p21-MLL
Disease
Treatment related acute non lymphoblastic leukemia (tANLL).
Hybrid/Mutated gene
5 prime MLL - 3 prime AF3q21.
Abnormal protein
AT hooks and methyltransferase domains of MLL in
the N-term fused to the proline-rich domain and nuclear
localization signal of AF3p21.
Probe(s) - Courtesy Mariano Rocchi, Resources for Molecular
Cytogenetics.
DNA/RNA
References
Description
Sano K, Hayakawa A, Jin-Hua P. A novel sh3 protein encoded
by the AF3p21 gene is fused to MLL in a therapy-related
leukemia with t(3; 11)(p21;q23). Blood 1999;94 Suppl 1:Abst
221
2990 bp cDNA.
Protein
Description
This article should be referenced as such:
722 amino acids; N-term SH3 domain, proline-rich
domain, and a nuclear localization signal in C-term.
Huret JL. AF3p21 (ALL1 fused gene from chromosome 3p21).
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1):13.
Expression
Wide.
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1)
13
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Gene Section
Mini Review
NUP98 (nucleoporin 98 kDa)
Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France
(JLH)
Published in Atlas Database: February 2000
Online updated version : http://AtlasGeneticsOncology.org/Genes/NUP98.html
DOI: 10.4267/2042/37583
This article is an update of:
Huret JL. NUP98 (nucleoporin 98 kDa). Atlas Genet Cytogenet Oncol Haematol.1999;3(1):15-16.
Huret JL. NUP98 (nucleoporin 98 kDa). Atlas Genet Cytogenet Oncol Haematol.1998;2(1):7.
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2000 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Disease
M2-M4 ANLL mostly; occasionally: CML-like cases.
Prognosis
Mean survival: 15 months.
Cytogenetics
Sole anomaly most often.
Hybrid/Mutated gene
5' NUP98 - 3' HOXA9.
Abnormal protein
Fuses the GLFG repeat domains of NUP98 to the
HOXA9 homeobox.
Identity
HGNC (Hugo): NUP98
Location: 11p15
DNA/RNA
Transcription
3.6, 6.5, 7.0 kb mRNA.
Protein
Description
inv (11)(p15q22)/MDS or ANLL -->
NUP98/DDX10
920 amino acids; 97 kDa; contains repeated motifs
(GLFG and FG) in N-term and a RNA binding motif in
C-term.
Disease
Therapy related MDS and ANLL; de novo ANLL.
Hybrid/Mutated gene
5' NUP98 - 3' DDX10.
Abnormal protein
Fuses the GLFG repeat domains of NUP98 to the
acidic domain of DDX11.
Expression
Wide.
Localisation
Nuclear membrane localisation.
Function
t(1;11)(q23;p15) --> NUP98/PMX1
t(2;11)(q31;p15)/treatment related
leukaemia --> NUP98/HOXD13
Nucleoporin: associated with the nuclear pore complex;
role in nucleocytoplasmic transport processes.
Homology
Member of the GLFG nucleoporins.
Disease
So far, only 1 case of treatment related myelodysplasia
evolving towards M6 acute non lymphocytic
leukaemia.
Implicated in
t(7;11)(p15;p15)/ANLL --> NUP98/HOXA9
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1)
14
NUP98 (nucleoporin 98 kDa)
Huret JL
Arai Y, Hosoda F, Kobayashi H, Arai K, Hayashi Y, Kamada N,
Kaneko Y, Ohki M. The inv(11)(p15q22) chromosome
translocation of de novo and therapy-related myeloid
malignancies results in fusion of the nucleoporin gene, NUP98,
with the putative RNA helicase gene, DDX10. Blood. 1997 Jun
1;89(11):3936-44
Hybrid/Mutated gene
5' NUP98 - 3' HOXD13.
Abnormal protein
Fuses the GLFG repeat domains of NUP98 to the
HOXD13 homeodomain.
Powers MA, Forbes DJ, Dahlberg JE, Lund E. The vertebrate
GLFG nucleoporin, Nup98, is an essential component of
multiple RNA export pathways. J Cell Biol. 1997 Jan
27;136(2):241-50
t(11;12)(p15;q13)/treatment related
leukemia
Hybrid/Mutated gene
5' NUP98 - 3' unknown.
Raza-Egilmez SZ, Jani-Sait SN, Grossi M, Higgins MJ, Shows
TB, Aplan PD. NUP98-HOXD13 gene fusion in therapy-related
acute myelogenous leukemia. Cancer Res. 1998 Oct
1;58(19):4269-73
References
Kobzev YN, Rowley JD.. NUP98 gene rearrangements in
leukemia detected by fluorescence in situ hybridization (FISH).
Blood 1999; 94 Suppl 1: Abst 2221.
Nakamura T, Largaespada DA, Lee MP, Johnson LA,
Ohyashiki K, Toyama K, Chen SJ, Willman CL, Chen IM,
Feinberg AP, Jenkins NA, Copeland NG, Shaughnessy JD Jr.
Fusion of the nucleoporin gene NUP98 to HOXA9 by the
chromosome translocation t(7;11)(p15;p15) in human myeloid
leukaemia. Nat Genet. 1996 Feb;12(2):154-8
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1)
This article should be referenced as such:
Huret JL. NUP98 (nucleoporin 98 kDa). Atlas Genet Cytogenet
Oncol Haematol. 2000; 4(1):14-15.
15
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Leukaemia Section
Short Communication
t(11;22)(q23;q13)
Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France
(JLH)
Published in Atlas Database: January 2000
Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t1122P300ID1121.html
DOI: 10.4267/2042/37585
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2000 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Protein
264 kDa; widely expressed; possesses a nuclear
localization signal, a poly-serine, a bromodomain, a
poly-glu, a binding region for E1A adenovirus, and a
poly-gln;. interact with transcriptional activators as
well as repressors; involved (with CBP) in growth,
differentiation, and apoptosis.
Identity
Note: Not to be confused with the t(11;22)(q23;q11),
involving MLL and hCDCrel.
Clinics and pathology
Disease
Result of the chromosomal
anomaly
A case of therapy related leukemia, 2.5 years after the
treatment of a non Hodgkin lymphoma.
Phenotype/cell stem origin
Hybrid gene
Acute non lymphocytic leukemia.
Transcript
Chimeric mRNAs from both derivative chromosomes
are found.
Prognosis
Unknown (relapse at 20 months) but likely to be
similar to the prognosis associated with other 11q23
therapy related leukemia.
Fusion protein
Description
The MLL/p300 fusion transcript encodes a protein of
about 3000 amino acids, the N-term half comprising
the AT hook and DNA methyltransferase (exons 1 to 9)
from MLL and the C-term half comprising the
acetyltransferase domain and the TFIIB-binding
domain of p300, excluding the nuclear localisation
signal and the bromodomain.
Genes involved and proteins
MLL
Location : In 11q23.
DNA/RNA
13-15 kb mRNA.
Protein
431 kDa; contains two DNA binding motifs (a AT
hook, and Zinc fingers), a DNA methyl transferase
motif, a bromodomain; transcriptional regulatory
factor; nuclear localisation.
References
Ida K, Kitabayashi I, Taki T, Taniwaki M, Noro K, Yamamoto
M, Ohki M, Hayashi Y. Adenoviral E1A-associated protein
p300 is involved in acute myeloid leukemia with
t(11;22)(q23;q13). Blood. 1997 Dec 15;90(12):4699-704
P300
Location : 22q13
DNA/RNA
9 kb mRNA.
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1)
This article should be referenced as such:
Huret JL. t(11;22)(q23;q13). Atlas Genet Cytogenet Oncol
Haematol. 2000; 4(1):16.
16
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Leukaemia Section
Short Communication
t(2;11)(p21;q23)
Elena W Fleischman
Cancer Research Center, Moscow, Russia (EWF)
Published in Atlas Database: January 2000
Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t0211ID1109.html
DOI: 10.4267/2042/37584
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2000 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
t(2;11)(p21;q23) G- banding (left) - Courtesy Eric Crawford, and R- banding (Editor).
Clinics and pathology
diagnosed: 4 ANLL, 2 ALL; ANLL FAB-types were:
M0 evolving into M4, M1, M2 and atypical M3.
Disease
Epidemiology
Myelodysplastic syndromes (MDS), acute non
lymphocytic
leukemia
(ANLL)
and
acute
lymphoblastic leukemia (ALL).
Male predominance: 13 M:7 F; the majority of patients
(16 out of 20) were over 50 years of age and 8 of them
were over 60 years of age.
Phenotype/cell stem origin
Clinics
20 cases were documented, 14 of them were MDS; in
three cases, type of MDS was not described; the
remaining cases were: 2 AISA, 5 RA and 4 RAEB; in 6
patients, MDS has transformed into ANLL (M1, M5a,
M6 and unidentified); in 6 cases acute leukemia was
Variable.
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1)
Prognosis
Due to heterogeneity of cases and lack of molecular
data, the prognostic importance of t(2;11)(p21;q23)
17
t(2;11)(p21;q23)
Fleischman EW
hook and zinc fingers), a DNA methyl transferase
motif.
cannot be assessed; in 6 cases of MDS transformation
into ANLL, MDS phase varied from 18 months to 5
years; in 4 out of 5 ANLL cases treated in 1986-1993,
remission duration varied from 6 to 13 months.
Cytogenetics
Result of the chromosomal
anomaly
Cytogenetics morphological
Hybrid gene
A high variability of breakpoints on both chromosome
2 (2p16-2p21) and chromosome 11 (11q13-11q25)
were found by conventional cytogenetics.
Description
Unknown.
Cytogenetics molecular
Description
Unknown.
Fusion protein
MLL gene involvement was observed in 2 out of 3
cases studied.
References
Additional anomalies
Feder M, Finan J, Besa E, Nowell P. A 2p;11q chromosome
translocation in dysmyelopoietic preleukemia. Cancer Genet
Cytogenet. 1985 Feb 1;15(1-2):143-50
Additional abnormalities were observed in 10 out of 20
cases; in 8 cases, del(5)(q13q33) is found; it is of note,
that deletions of 5q usually are not seen in cases with
MLL-associated translocations.
de la Chapelle A, Knuutila S, Elonen E. Translocation (2;11)
(p21;q23) in acute non-lymphocytic leukaemia: a non-random
association. Scand J Haematol Suppl. 1986;45:91-7
Genes involved and proteins
Thirman MJ, Gill HJ, Burnett RC, Mbangkollo D, McCabe NR,
Kobayashi H, Ziemin-van der Poel S, Kaneko Y, Morgan R,
Sandberg AA. Rearrangement of the MLL gene in acute
lymphoblastic and acute myeloid leukemias with 11q23
chromosomal translocations. N Engl J Med. 1993 Sep
23;329(13):909-14
Note
The gene involved in 2p is unknown.
MLL
Location
11q23
DNA/RNA
37 exons, spanning about 120 kb; 13-15 mRNA.
Protein
431 kD; transcriptional regulatory factor, nuclear
localization; Contains two DNA binding motifs (a AT
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1)
Fleischman EW, Reshmi S, Frenkel MA, Konovalova WI,
Guleva GP, Kulagina OE, Konstantinova LN, Tupitsyn NN,
Rowley JD. MLL is involved in a t(2;11)(p21;q23) in a patient
with acute myeloblastic leukemia. Genes Chromosomes
Cancer. 1999 Feb;24(2):151-5
This article should be referenced as such:
Fleischman EW. t(2;11)(p21;q23). Atlas Genet Cytogenet
Oncol Haematol. 2000; 4(1):17-18.
18
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in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Leukaemia Section
Short Communication
+22 or trisomy 22 (solely?)
Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France
(JLH)
Published in Atlas Database: February 2000
Online updated version : http://AtlasGeneticsOncology.org/Anomalies/tri22ID1042.html
DOI: 10.4267/2042/37601
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2000 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Cytogenetics molecular
Identity
Is appropriate to exclude or discover the presence of a
hidden inv(16), inasmuch as inv(16) is associated with
a relatively good prognosis.
Note: +22 is often associated with inv(16)(p13q22) or
its equivalents; the existence of trisomy 22 solely is
debated.
Additional anomalies
Clinics and pathology
Anomalies associated with +22 are del(7q) and/or +8,
found in 15% of cases each; this percentage is similar
in cases with or without inv(16).
Disease
Acute non lymphocytic leukemia (ANLL).
Phenotype/cell stem origin
References
M4eo ANLL most often in cases associated with
inv(16); M4 also, but only in 2/3 of cases, when +22 is
apparently without inv(16); and eosinophilia may be
missing in the latter case.
Larson RA, Williams SF, Le Beau MM, Bitter MA, Vardiman
JW, Rowley JD. Acute myelomonocytic leukemia with
abnormal eosinophils and inv(16) or t(16;16) has a favorable
prognosis. Blood. 1986 Dec;68(6):1242-9
Epidemiology
Ohyashiki K, Ohyashiki JH, Iwabuchi A, Ito H, Toyama K.
Central nervous system involvement in acute nonlymphocytic
leukemia with inv(16)(p13q22). Leukemia. 1988 Jun;2(6):398-9
Young age, both in cases with or without inv(16).
Clinics
Grois N, Nowotny H, Tyl E, Krieger O, Kier P, Haas OA. Is
trisomy 22 in acute myeloid leukemia a primary abnormality or
only a secondary change associated with inversion 16? Cancer
Genet Cytogenet. 1989 Nov;43(1):119-29
inv(16) may be at increased CNS relapse when +22 is
also present.
Prognosis
Johansson B, Mertens F, Mitelman F. Secondary chromosomal
abnormalities in acute leukemias. Leukemia. 1994
Jun;8(6):953-62
A fair prognosis is associated with +22 accompanying
inv(16), and with +22 solely, comparable to the
prognosis associated with inv(16).
Langabeer SE, Grimwade D, Walker H, Rogers JR, Burnett
AK, Goldstone AH, Linch DC. A study to determine whether
trisomy 8, deleted 9q and trisomy 22 are markers of cryptic
rearrangements
of
PML/RARalpha,
AML1/ETO
and
CBFB/MYH11 respectively in acute myeloid leukaemia. MRC
Adult Leukaemia Working Party. Medical Research Council. Br
J Haematol. 1998 May;101(2):338-40
Cytogenetics
Cytogenetics morphological
+22 is a frequent anomaly additional to inv(16), but
was not found associated with other anomalies
recurrently found in de novo ANLL; +22 may also
occur apparently in the absence of inv(16), but cryptic
rearrangements of MYH11 (16p13) and CBFB (16q22)
have been found in a number of cases; for some
authors, +22 indicates the obligate existence of an
inv(16); for others +22 solely is a true entity.
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1)
Wong KF, Kwong YL. Trisomy 22 in acute myeloid leukemia: a
marker for myeloid leukemia with monocytic features and
cytogenetically cryptic inversion 16. Cancer Genet Cytogenet.
1999 Mar;109(2):131-3
This article should be referenced as such:
Huret JL. +22 or trisomy 22 (solely?). Atlas Genet Cytogenet
Oncol Haematol. 2000; 4(1):19.
19
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Leukaemia Section
Short Communication
12p rearrangements in ALL
Nyla A Heerema
The Ohio State University, Division of Clinical Pathology, Department of Pathology, 167 Hamilton Hall,
1645 Neil Ave, Columbus, OH 43210, USA (NAH)
Published in Atlas Database: February 2000
Online updated version : http://AtlasGeneticsOncology.org/Anomalies/12pALLID1074.html
DOI: 10.4267/2042/37586
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2000 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
del(12)(p12) G-banding - Courtesy Diane H. Norback, Eric B. Johnson, and Sara Morrison-Delap, UW Cytogenetic Services.
Clinics and pathology
Cytogenetics
Disease
Cytogenetics morphological
Various aberrations result in an abnormal 12p; these
include morphological balanced translocations with
12p breakpoints, del(12p), add(12p), monosomy 12,
der(12)t(V;12)(V;p), and dic(V;12)(V;p); an abnormal
12p usually occurs as part of a more complex
karyotype, and occurs as the sole aberration in less than
20% of cases with an abnormal 12p; in greater than
10% of cases both 12p homologues are abnormal; few
cases with an abnormal 12p have more than 50
chromosomes.
Additional anomalies
del(6q), del(13q) or monosomy 13, acquired +21; few
recurring anomalies.
Acute lyphocytic leukemia (ALL).
Phenotype/cell stem origin
Lack of specificity for particular immunophenotype,
although more stem origin frequent in B-lineage cases.
Epidemiology
Approximately 10-15% of pediatric ALL cases, and 5%
of adult ALL.
Prognosis
Recent data indicate no difference in overall outcome
between childhood ALL cases with versus without 12p
abnormalities, although there was an improved
outcome for pseudodiploid patients with versus without
a cytogenetic 12p abnormality; although a dic(9;12) has
been reported to be associated with an excellent
outcome, in a recent study, there was no difference in
outcome between those patients with a dic(9;12) versus
patients lacking an abnormal 12p.
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1)
Genes involved and proteins
Note
Approximately half of patients with an abnormal 12p
have a rearranged TEL gene.
20
12p rearrangements in ALL
Heerema NA
Cytogenetic abnormalities in adult acute lymphoblastic
leukemia: correlations with hematologic findings outcome. A
Collaborative Study of the Group Français de Cytogénétique
Hématologique. Blood. 1996 Apr 15;87(8):3135-42
TEL (or ETV6)
Location
12p13
Protein
TEL proteins belong to the ETS family transcription
factors; important in the vitelline angiogenesis and in
the bone marrow hematopoiesis.
Chessels JM, Swansbury GJ, Reeves B, Bailey CC, Richards
SM. Cytogenetics and prognosis in childhood lymphoblastic
leukaemia: results of MRC UKALL X. Medical Research
Council Working Party in Childhood Leukaemia. Br J
Haematol. 1997 Oct;99(1):93-100
Raimondi SC, Shurtleff SA, Downing JR, Rubnitz J, Mathew S,
Hancock M, Pui CH, Rivera GK, Grosveld GC, Behm FG. 12p
abnormalities and the TEL gene (ETV6) in childhood acute
lymphoblastic leukemia. Blood. 1997 Dec 1;90(11):4559-66
References
Behrendt H, Charrin C, Gibbons B, Harrison CJ, Hawkins JM,
Heerema NA, Horschler-Bötel B, Huret JL, Laï JL, Lampert F.
Dicentric (9;12) in acute lymphocytic leukemia and other
hematological malignancies: report from a dic(9;12) study
group. Leukemia. 1995 Jan;9(1):102-6
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1)
This article should be referenced as such:
Heerema NA. 12p rearrangements in ALL. Atlas Genet
Cytogenet Oncol Haematol. 2000; 4(1):20-21.
21
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Leukaemia Section
Mini Review
Classification of B-cell chronic
lymphoproliferative disorders (CLD)
Antonio Cuneo
Hematology Section, Department of Biomedical Sciences, University of Ferrara, Corso Giovecca 203,
Ferrara, Italy (AC)
Published in Atlas Database: February 2000
Online updated version : http://AtlasGeneticsOncology.org/Anomalies/BCLDClassifID2072.html
DOI: 10.4267/2042/37587
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2000 Atlas of Genetics and Cytogenetics in Oncology and Haematology
immunoglobulins; cyIg: cytoplasmic Ig; IgV genes:
genes encoding for the variable portion of the Ig. MTC
and mTC1: major translocation cluster and minor
translocation cluster 1 of BCL1 region, respectively.
Identity
Note: A classification of chronic (mature) B-cell
lymphoproliferative disorders based on reproducible
morphologic and immunologic criteria was proposed
by the FAB group in 1989. Ever since a number of
cytogenetic studies disclosed a remarkable degree of
heterogeneity within each disease category. Herein, the
main cytogenetic entities of chronic lymphocytic
leukemia and related disorders, B-cell prolymphocytic
leukemia, splenic lymphoma with villous lymphocytes
are presented.
Other disease subsets of B-cell CLD include the
leukemic phase of follicle centre cell lymphoma,
mantle cell lymphoma and lymphoplasmacytic
lymphoma. The cytogenetic features of these forms of
leukemic lymphoma are the described in the B-NHL
classification.
Comment: The incidence for each of these
chromosome lesions (below) is higher when
investigated by the more sensitive fluorescence in situ
hybridization (FISH) technique: FISH detected 13q14
deletions in 40-50% of the cases, +12 in 15-20% of the
cases; 11q22-23 deletions in 7-10% of the cases; 17p13
deletions in 15-20% of the cases. The prognostic
significance for each of these anomalies, 11qexcluded, mainly derives from studies that used
conventional cytogenetics and needs to be reassessed in
the light of the more recent data provided by FISH
analysis.
Legend for immunophenotypes (below): +: positive in
>90% of the cases; +/-: positive in more than 50% of
the cases; -/+: positive in less than 50% of cases; -:
positive in <10% of the cases; pan-B markers include
CD19; CD20; CD79a R = rearranged; sIg: surface
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1)
Clinics and pathology
Disease
Chronic lymphocytic leukemia CD5+ B cell that has
encountered the antigen and harbours hypermutated
IgV genes.
Phenotype/cell stem origin
CD5+; CD23+; CD38+/-; CD22 weak+; FMC7-; sIg+
weak.
Cytogenetics
del(13q) (10-15% of the cases): Typical morphology;
indolent disease; favourable prognosis if present as the
sole change (Note: typical morphology (FAB criteria):
more than 90% of neoplastic cells are represented by
small lymphocytes (diameter less than 14 m, i.e. < two
red blood cells); atypical morphology: 10-55% of the
lymphocytes are larger than 14 m with few
prolymphocytes (CLL mixed-cell type); the cases are
usually referred to as CLL/PL if prolymphocytes
predominate among large lymphoid cells; PLL: more
than 55%, and usually >70% of the cells are
prolymphocytes.).
Disease
Chronic lymphocytic leukemia CD5+ virgin
recirculating B-cell with germline IgV genes.
Phenotype/cell stem origin
CD5+; CD23+; CD38-/+; CD22 weak+; FMC7-; sIg+
weak.
22
Classification of B-cell chronic lymphoproliferative disorders (CLD)
Cuneo A
Cytogenetics
+12 (10-15% of the cases): Frequent atypical
morphology; relatively indolent disease; unfavourable
prognosis as compared with other single chromosome
aberrations, but not against complex karyotypes, 11qor 17p-.
Cases with t(11;14) showed frequent CD5-positivity
and featured an indolent course.
Cytogenetics
(20% of the cases) (breaks outside the MTC and mTC1
of BCL1).
(20-40% of cases) with or without +3.
Disease
References
Chronic lymphocytic leukemia CD5+ recirculating Bcell.
Phenotype/cell stem origin
CD5+; CD23+; CD22 weak+; FMC7-; sIg+ weak.
Cytogenetics
11q22-23 deletion (ATM gene involved) (5-6% of the
cases): Usually typical morphology with karyotype
instability; Relatively aggressive disease, with
development of multiple adenopathies; Unfavourable
prognosis.
del(17p) (p53 gene involved) (<5% of the cases):
Morphology consistent with CLL/PL Advanced
disease;
Refractoriness
to
purine
analougs;
Unfavourable prognosis.
t(11;14)(q13;q32) (BCL1 involved, mainly in the MTC
and mTC1)(<5% of the cases): Rare cases of CLL/PL,
transforming into prolymphocytic leukemia; Primary
blood and marrow involvement, usually with
splenomegaly, without adenopathy.
Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA,
Gralnick HR, Sultan C. Proposals for the classification of
chronic (mature) B and T lymphoid leukaemias. FrenchAmerican-British (FAB) Cooperative Group. J Clin Pathol. 1989
Jun;42(6):567-84
Juliusson G, Oscier DG, Fitchett M, Ross FM, Stockdill G,
Mackie MJ, Parker AC, Castoldi GL, Guneo A, Knuutila S.
Prognostic subgroups in B-cell chronic lymphocytic leukemia
defined by specific chromosomal abnormalities. N Engl J Med.
1990 Sep 13;323(11):720-4
Döhner H, Fischer K, Bentz M, Hansen K, Benner A, Cabot G,
Diehl D, Schlenk R, Coy J, Stilgenbauer S. p53 gene deletion
predicts for poor survival and non-response to therapy with
purine analogs in chronic B-cell leukemias. Blood. 1995 Mar
15;85(6):1580-9
Hernandez JM, Mecucci C, Criel A, Meeus P, Michaux I, Van
Hoof A, Verhoef G, Louwagie A, Scheiff JM, Michaux JL.
Cytogenetic analysis of B cell chronic lymphoid leukemias
classified according to morphologic and immunophenotypic
(FAB) criteria. Leukemia. 1995 Dec;9(12):2140-6
Bigoni R, Cuneo A, Roberti MG, Bardi A, Rigolin GM, Piva N,
Scapoli G, Spanedda R, Negrini M, Bullrich F, Veronese ML,
Croce CM, Castoldi G. Chromosome aberrations in atypical
chronic lymphocytic leukemia: a cytogenetic and interphase
cytogenetic study. Leukemia. 1997 Nov;11(11):1933-40
Disease
Prolymphocytic leukemia (PLL).
Phenotype/cell stem origin
Peripheral B-lymphocyte that has encountered the
antigen and harbours hypermutated IgV genes.
Clinics
Rare and aggressive disease with a majority of
relatively large lymphocytes with round nucleus and a
prominent central nucleolus.
Cytogenetics
t(11;14)(q13;q32) (BCL1 involved in the MTC and
mTC1).
Cuneo A, Bigoni R, Negrini M, Bullrich F, Veronese ML,
Roberti MG, Bardi A, Rigolin GM, Cavazzini P, Croce CM,
Castoldi G. Cytogenetic and interphase cytogenetic
characterization of atypical chronic lymphocytic leukemia
carrying BCL1 translocation. Cancer Res. 1997 Mar
15;57(6):1144-50
Döhner H, Stilgenbauer S, James MR, Benner A, Weilguni T,
Bentz M, Fischer K, Hunstein W, Lichter P. 11q deletions
identify a new subset of B-cell chronic lymphocytic leukemia
characterized by extensive nodal involvement and inferior
prognosis. Blood. 1997 Apr 1;89(7):2516-22
Naylor M, Capra JD. Mutational status of Ig V(H) genes
provides clinically valuable information in B-cell chronic
lymphocytic leukemia. Blood. 1999 Sep 15;94(6):1837-9
Disease
Splenic lymphoma with villous lymphocytes.
Phenotype/cell stem origin
Marginal zone lymphocytes harbouring hypermutated
IgV genes.
Pan-B+; CD5-/+; CD23-/+; CD11c+/-; CD25-/+;
FMC7+/-; sIg+ bright.
Clinics
Indolent disease; There are not established correlations
between chromosome lesions and hematologic features;
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1)
Stankovic T, Weber P, Stewart G, Bedenham T, Murray J,
Byrd PJ, Moss PA, Taylor AM. Inactivation of ataxia
telangiectasia mutated gene in B-cell chronic lymphocytic
leukaemia. Lancet. 1999 Jan 2;353(9146):26-9
This article should be referenced as such:
Cuneo A. Classification of B-cell chronic lymphoproliferative
disorders (CLD). Atlas Genet Cytogenet Oncol Haematol.
2000; 4(1):22-23.
23
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Leukaemia Section
Mini Review
Classification of B-cell non-Hodgkin lymphomas
(NHL)
Antonio Cuneo
Hematology Section, Department of Biomedical Sciences, University of Ferrara, Corso Giovecca 203,
Ferrara, Italy (AC)
Published in Atlas Database: February 2000
Online updated version : http://AtlasGeneticsOncology.org/Anomalies/BNHLClassifID2067.html
DOI: 10.4267/2042/37588
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2000 Atlas of Genetics and Cytogenetics in Oncology and Haematology
cases may derive from post-germinal centre quiescent
B-cells that harbour hypermutated IgV genes).
Clinics
Indolent disease;
Leukemic involvement by lymphoid cells, including
prolymphocytes
and/or
paraimmunoblasts
Splenomegaly.
Cytogenetics
del(6)(q21-23) (20-30% of the cases).
Identity
Note: B-cell NHL include a number of
clinicopathologic subsets of lymphoid neoplasms
having heterogeneous features. This situation is
reflected by variations in the classification systems that
were proposed over the last decade. Cytogenetic
findings were recognized to help defining a rationale
biologic ground for the nosologic classification of
lymphomas.
An outlook of the salient cytogenetic entities in this
spectrum of disorders is presented herein; a complete
illustration of the cytogenetic profile of each disease is
provided in specific cards. Unless otherwise specified
the WHO classification system will be used.
Legend for immunophenotypes (below): +: positive in
>90% of the cases; +/-: positive in more than 50% of
the cases; -/+: positive in less than 50% of cases; -:
positive in <10% of the cases; pan-B markers include
CD19; CD20; CD79a; R = rearranged; sIg: surface
immunoglobulins; cyIg: cytoplasmic Ig; IgV genes:
genes encoding for the variable portion of the Ig.
Disease
Lymphoplasmacytic lymphoma
Phenotype/cell stem origin
Histologic subset and Immunophenotype: Pan-B+;
CD5-; CD10-; cyIgM+.
Putative cell of origin: Peripheral B-lymphocyte
transforming into plasma cell with mutated IgV genes
and ongoing mutations.
Clinics
Indolent low-grade disease, with possible clinical
and/or histologic progression.
Cytogenetics
t(9;14)(p13;q32) PAX5/IgH (50% of cases).
Clinics and pathology
Disease
Disease
Small lymphocytic lymphoma (SLL)
Phenotype/cell stem origin
Histologic subset and Immunophenotype: Pan-B+;
CD5+; CD23+; CD10-; sIgM+ faint.
Putative cell of origin: CD5+ virgin B-cell with
germline IgV genes (as was recently demonstrated to
be the case with chronic lymphocytic leukemia, the
leukemic counterpart of SLL, it is likely that part of the
Follicle centre cell lymphoma
Phenotype/cell stem origin
Histologic subset and Immunophenotype: Pan-B+;
CD10+/-; CD5-; sIg+. Putative cell of origin:
Centrocytes / centroblasts of germinal centre origin
with somatic hypermutation of the IgV genes and
ongoing mutations (antigen driven stimulation).
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1)
24
Classification of B-cell non-Hodgkin lymphomas (NHL)
Cuneo A
Clinics
Indolent. Advanced stages predominate.
Conflicting data as to the prognostic significance of the
t(14;18)/BCL2.
Cytogenetics
t(14;18)(q32;q21) / BCL2 Rearr (70-80% of cases).
Cases with dual 8;14 and 14;18 translocations have a
worse outcome (data requiring confirmation -1 study
only).
Cytogenetics
t(8;14) or variants (25% of cases).
t(8;14)+ t(14;18) (30% of cases).
Disease
Disease
Diffuse large cell lymphoma
Phenotype/cell stem origin
Histologic subset and Immunophenotype: CD19+;
CD22+; CD10-/+; SIg+.
Putative cell of origin: Large transformed B-cells
harbouring somatic hypermutation of the Ig genes
(ongoing mutations in some cases).
Clinics
Usually aggressive.
Immunoblastic lymphoma (Kiel classification) do
worse than centroblastic lymphomas.
No convincing demonstration that any "primary"
cytogenetic / molecular defect has prognostic
significance; complex karyotype confers a shorter
survival.
Cytogenetics
t(14;18) and p53 mutations (20% of the cases).
t(3;V)(q27;V)/ BCL6 Rearr (6-30% of cases (%
variations depending on detection methods: molecular
genetics and FISH more sensitive that conventional
cytogenetics)).
Or variants c-MYC Rearr (7-10% of cases).
Mantle cell lymphoma
Phenotype/cell stem origin
Histologic subset and Immunophenotype: Pan-B +;
CD5+; CD23-; CD10-/+; sIgM+ bright.
Putative cell of origin: CD5+ B-cells of the follicle
mantle having germline IgV gene sequences.
Clinics
Advanced stages predominate.
Response to chemotherapy often unsatisfactory.
Short survival.
Complex karyotype carries an unfavourable prognostic
significance.
Cytogenetics
t(11;14)(q13;q32)/BCL1 Rearr (50-90%) (molecular
genetic methods have limited application due to
variability of breakpoints; FISH is the most sensitive
technique).
Disease
Marginal zone B-cell lymphoma (MZBCL)
Phenotype/cell stem origin
Histologic subset and Immunophenotype: pan-B+;
CD5-/+; CD10-; CD23-; CD11c+/-; cyIg + (40% of the
cells), sIgM+ bright; sIgD-).
Putative cell of origin: Marginal zone lymphocytes
harbouring hypermutated IgV genes.
Cytogenetics
t(11;18)(q21;q21) PI2/MLT fusion (30-50% of the lowgrade MALT): Extra-nodal low-grade MALT
lymphoma; indolent disease.
t(1;14)(p21;q32): Extra-nodal MALT lymphoma.
del(7)(q22-31) (40% of the cases): Splenic MZBCL.
+3/+3q (30-70% of the cases): Nodal, extra-nodal and
splenic MZBCL.
Disease
Burkitt's lymphoma
Phenotype/cell stem origin
Histologic subset and Immunophenotype: Pan-B+;
TdT-; CD10+; CD5-; sIgM+.
Putative cell of origin: Peripheral B-cells that have
encountered the antigen and harbours somatic
hypermutation of the Ig genes.
Clinics
Extremely aggressive disease.
Specific treatment mandatory.
Cytogenetics
Or variants / c-MYC R earr (80% of the cases).
References
Offit K, Parsa NZ, Filippa D, Jhanwar SC, Chaganti RS.
t(9;14)(p13;q32) denotes a subset of low-grade non-Hodgkin's
lymphoma with plasmacytoid differentiation. Blood. 1992 Nov
15;80(10):2594-9
Disease
Burkitt-like lymphoma
Phenotype/cell stem origin
Histologic subset and Immunophenotype: Pan-B+;
TdT-; CD10-/+ CD5-; sIg+.
Putative cell of origin: Peripheral B-cells that have
encountered the antigen.
Clinics
Aggressive disease.
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1)
Tilly H, Rossi A, Stamatoullas A, Lenormand B, Bigorgne C,
Kunlin A, Monconduit M, Bastard C. Prognostic value of
chromosomal abnormalities in follicular lymphoma. Blood.
1994 Aug 15;84(4):1043-9
Kramer MH, Hermans J, Wijburg E, Philippo K, Geelen E, van
Krieken JH, de Jong D, Maartense E, Schuuring E, Kluin PM.
Clinical relevance of BCL2, BCL6, and MYC rearrangements in
25
Classification of B-cell non-Hodgkin lymphomas (NHL)
Cuneo A
diffuse large B-cell lymphoma. Blood. 1998 Nov 1;92(9):315262
Macpherson N, Lesack D, Klasa R, Horsman D, Connors JM,
Barnett M, Gascoyne RD. Small noncleaved, non-Burkitt's
(Burkit-Like) lymphoma: cytogenetics predict outcome and
reflect
clinical
presentation.
J
Clin
Oncol.
1999
May;17(5):1558-67
Cuneo A, Bigoni R, Rigolin GM, Roberti MG, Bardi A, Piva N,
Milani R, Bullrich F, Veronese ML, Croce C, Birg F, Döhner H,
Hagemeijer A, Castoldi G. Cytogenetic profile of lymphoma of
follicle mantle lineage: correlation with clinicobiologic features.
Blood. 1999 Feb 15;93(4):1372-80
Panayiotidis P, Kotsi P. Genetics of small lymphocyte
disorders. Semin Hematol. 1999 Apr;36(2):171-7
Dierlamm J, Baens M, Wlodarska I, Stefanova-Ouzounova M,
Hernandez JM, Hossfeld DK, De Wolf-Peeters C, Hagemeijer
A, Van den Berghe H, Marynen P. The apoptosis inhibitor gene
API2 and a novel 18q gene, MLT, are recurrently rearranged in
the t(11;18)(q21;q21) associated with mucosa-associated
lymphoid tissue lymphomas. Blood. 1999 Jun 1;93(11):3601-9
Richardson MA. Research of complementary/alternative
medicine therapies in oncology: promising but challenging. J
Clin Oncol. 1999 Nov;17(11 Suppl):38-43
Willis TG, Jadayel DM, Du MQ, Peng H, Perry AR, Abdul-Rauf
M, Price H, Karran L, Majekodunmi O, Wlodarska I, Pan L,
Crook T, Hamoudi R, Isaacson PG, Dyer MJ. Bcl10 is involved
in t(1;14)(p22;q32) of MALT B cell lymphoma and mutated in
multiple tumor types. Cell. 1999 Jan 8;96(1):35-45
Küppers R, Klein U, Hansmann ML, Rajewsky K. Cellular
origin of human B-cell lymphomas. N Engl J Med. 1999 Nov
11;341(20):1520-9
This article should be referenced as such:
López-Guillermo A, Cabanillas F, McDonnell TI, McLaughlin P,
Smith T, Pugh W, Hagemeister F, Rodríguez MA, Romaguera
JE, Younes A, Sarris AH, Preti HA, Lee MS. Correlation of bcl2 rearrangement with clinical characteristics and outcome in
indolent follicular lymphoma. Blood. 1999 May 1;93(9):3081-7
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1)
Cuneo A. Classification of B-cell non-Hodgkin lymphomas
(NHL). Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1):2426.
26
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Leukaemia Section
Mini Review
i(17q) in myeloid malignancies
Chrystèle Bilhou-Nabera
Laboratoire d'Hématologie, Hôpital du Haut-Lévêque, CHU de Bordeaux, Ave de Magellan, 33 604 Pessac,
France (CBN)
Published in Atlas Database: February 2000
Online updated version : http://AtlasGeneticsOncology.org/Anomalies/i17qID1038.html
DOI: 10.4267/2042/37589
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2000 Atlas of Genetics and Cytogenetics in Oncology and Haematology
lymphoid leukemias, and Hodgkin and non-Hodgkin
lymphomas.
In chronic myeloid leukemia, i(17q) is a frequent and
well known secondary anomaly, either solely in 10% of
cases, or with other additional anomalies, in at least
another 10% of cases, in particular with +8.
Identity
Clinics and pathology
Disease
Myeloproliferative
(MPD/MDS).
/
myelodysplastic
diseases
Phenotype/cell stem origin
Previous studies on isolated i(17q) have suggested this
aberration was associated with chronic myeloid
abnormalities with a high rate of progression to ANLL;
a new clinico-pathological entity in which i(17q) is the
sole abnormality has been reported in a mixed
myeloproliferative
disorder
/
myelodysplastic
syndrome with an aggressive course; if teen patients
were included in this study classified as chronic
myeloid malignancy at initial presentation: these
features were not confirmed after a negative molecular
BCR-ABL analysis in all cases studied (eleven
patients).
i(17q) G- banding (left) - Courtesy Jean-Luc Lai (top) and Diane
H. Norback, Eric B. Johnson, and Sara Morrison-Delap, UW
Cytogenetic Services (middle and bottom); and R- banding
(right) - top: Editor, bottom: Courtesy Jacques Boyer.
Etiology
i(17q) as sole cytogenetic aberration represents only
1% of cases in myeloid malignancies.
Note: An isochromosome 17 results in a loss of the
short arm (17p) and duplication of the long arm (17q)
leading to a single copy of 17p and three copies of 17q.
An i(17q), usually observed in a complex karyotype,
has been reported in solid tumors and in various types
of hematological diseases: acute and chronic myeloid
leukemias, acute lymphoid leukemiasand chronic
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1)
Cytology
A severe hyposegmentation of neutrophil nuclei
(pseudo-Pelger Huet neutrophils (PHH)) and a
prominence of the monocyte/macrophage lineage has
been noted; other studies have identified an association
between hyposegmented neutrophils and loss of 17p
27
i(17q) in myeloid malignancies
Bilhou-Nabera C
(called 17p- syndrome), always included in complex
karyotypes; the i(17q) appeared to be a part of the
malignant clone as demonstrated in cases available for
a FISH analysis: all myeloid cell lines observed
contained the abnormal i(17q), whereas none of the
lymphocytes were affected.
References
Borgström GH, Vuopio P, de la Chapelle A. Abnormalities of
chromosome No. 17 in myeloproliferative disorders. Cancer
Genet Cytogenet. 1982 Feb;5(2):123-35
Testa JR, Cohen BC. Dicentric chromosome 17 in patients with
leukemia. Cancer Genet Cytogenet. 1986 Sep;23(1):47-52
Prognosis
Becher R, Carbonell F, Bartram CR. Isochromosome 17q in
Ph1-negative leukemia: a clinical, cytogenetic, and molecular
study. Blood. 1990 Apr 15;75(8):1679-83
By standard Kaplan-Meier analysis, the median
survival was 2.5 years (range 0.85-5.25 years).
Weh HJ, Fiedler W, Hossfeld DK. Cytogenetics in multiple
myeloma: are we studying the 'right' cells? Eur J Haematol.
1990 Oct;45(4):236-7
Genes involved and proteins
Note
The underlying molecular defect that produces the
isolated i(17q) is unknown: breakage of the proximal p
arm (17p11.2) with rejoining of both centromerecontaining chromatids and subsequent inactivation of
one centromere; breakpoints could involve important
genetic material whose disruption could result in
oncogene or tumor suppression gene deregulation.
In understanding the specific i(17q) phenotype, loss of
genes localized on 17p were suggested as p53
(17p13.1); a direct correlation between p53 loss and
PHH neutrophils was found in a series of MDS and
ANLL with 17p- syndrome.
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
Fugazza G, Bruzzone R, Puppo L, Sessarego M. Granulocytes
with segmented nucleus retain normal chromosomes 17 in
Philadelphia chromosome-positive chronic myeloid leukemia
with i(17q) and pseudo-Pelger anomaly. A case report studied
with fluorescence in situ hybridization. Cancer Genet
Cytogenet. 1996 Sep;90(2):166-70
Jary L, Mossafa H, Fourcade C, Genet P, Pulik M, Flandrin G.
The 17p-syndrome: a distinct myelodysplastic syndrome
entity? Leuk Lymphoma. 1997 Mar;25(1-2):163-8
This article should be referenced as such:
Bilhou-Nabera C. i(17q) in myeloid malignancies. Atlas Genet
Cytogenet Oncol Haematol. 2000; 4(1):27-28.
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1)
28
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Leukaemia Section
Short Communication
t(1;12)(q25;p13)
Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France
(JLH)
Published in Atlas Database: February 2000
Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t0112ID1147.html
DOI: 10.4267/2042/37591
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2000 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Protein
Belong to the ETS transcription factors family
characterized by the ETS domain, domain which is
responsible for the sequence specific DNA-binding
activity.
Clinics and pathology
Disease
Acute non lymphocytic leukemia (ANLL).
Phenotype/cell stem origin
Result of the chromosomal
anomaly
M4Eo ANLL.
Epidemiology
Only one case available.
Hybrid gene
Cytogenetics
Transcript
Both reciprocal transcripts are detected.
Cytogenetics morphological
Fusion protein
A cryptic inv(16) was present, ascertained by a
CBFb/MYH11 rearrangement; there fore, the t(1;12)
may be a secondary anomaly.
Description
The fusion protein is composed of the HLH
oligomerization domain of ETV6 and the SH2, SH3,
and protein tyrosine kinase domains of ABL2.
Genes involved and proteins
ABL2
References
Location
1q25
Protein
Tyrosine kinase; closely related to ABL1.
Cazzaniga G, Tosi S, Aloisi A, Giudici G, Daniotti M, Pioltelli P,
Kearney L, Biondi A. The tyrosine kinase abl-related gene
ARG is fused to ETV6 in an AML-M4Eo patient with a
t(1;12)(q25;p13): molecular cloning of both reciprocal
transcripts. Blood. 1999 Dec 15;94(12):4370-3
ETV6
Cazzaniga G, Tosi S, Aloisi A, Giudici G, Pioltelli P, Kearney L,
Biondi A. The tyrosine kinase ABL-related gene 'ARG' is fused
to ETV6 in an AML-M4Eo patient with a t(1;12)(q25;p13):
molecular cloning of both reciprocal transcripts. Blood 1999;94
Suppl 1:Abst 233
Location
12p13
DNA/RNA
Alternative transcripts.
This article should be referenced as such:
Huret JL. t(1;12)(q25;p13). Atlas Genet Cytogenet Oncol
Haematol. 2000; 4(1):29.
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1)
29
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Leukaemia Section
Short Communication
t(1;16)(q12;q24)
Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France
(JLH)
Published in Atlas Database: February 2000
Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t0116q12q24ID1318.html
DOI: 10.4267/2042/37592
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2000 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Clinics and pathology
Cytogenetics
Disease
Cytogenetics morphological
Acute non lymphocytic leukemia (ANLL).
Note
Poorly known: only 2 cases to date.
The t(1;16) presented as a der(16)t(1;16) in the 2 cases,
resulting in trisomy 1q. The t(1;16) was the sole
anomaly in each case.
Phenotype/cell stem origin
References
A case of Fanconi anemia and a case of M1-ANLL.
Busson-Le Coniat M, Salomon-Nguyen F, Dastugue N, Maarek
O, Lafage-Pochitaloff M, Mozziconacci MJ, Baranger L, Brizard
F, Radford I, Jeanpierre M, Bernard OA, Berger R.
Fluorescence in situ hybridization analysis of chromosome 1
abnormalities in hematopoietic disorders: rearrangements of
DNA satellite II and new recurrent translocations. Leukemia.
1999 Dec;13(12):1975-81
Epidemiology
The Fanconi anemia patient was a 9 yr old girl, and the
ANLL case was a 22 yr old male patient.
Prognosis
Unknown.
This article should be referenced as such:
Huret JL. t(1;16)(q12;q24). Atlas Genet Cytogenet Oncol
Haematol. 2000; 4(1):30.
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1)
30
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Leukaemia Section
Short Communication
t(1;2)(q12;q37)
Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France
(JLH)
Published in Atlas Database: February 2000
Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t0102q12q37ID1317.html
DOI: 10.4267/2042/37590
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2000 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Clinics and pathology
Cytogenetics
Disease
Cytogenetics morphological
Acute leukemias.
Note
Poorly known: only 3 cases to date.
The t(1;2) presented as a der(2)t(1;2) in at least 2 of the
3 cases, resulting in trisomy 1q. The t(1;2) was
associated with a t(9;22) in 1 ANLL case and in the
ALL case; +8 was found in 1 ANLL case and del(7q)
in the ALL case. The karyotypes were complex in 2
cases. The t(1;2) is likely to be a secondary anomaly.
Phenotype/cell stem origin
1 case of M0 acute non lymphocytic leukemia (ANLL),
1 case of M4 ANLL, and 1 case of acute lymphoblastic
leukemia (ALL).
References
Epidemiology
Busson-Le Coniat M, Salomon-Nguyen F, Dastugue N, Maarek
O, Lafage-Pochitaloff M, Mozziconacci MJ, Baranger L, Brizard
F, Radford I, Jeanpierre M, Bernard OA, Berger R.
Fluorescence in situ hybridization analysis of chromosome 1
abnormalities in hematopoietic disorders: rearrangements of
DNA satellite II and new recurrent translocations. Leukemia.
1999 Dec;13(12):1975-81
A 76 yr old female patient, a 81 yr old male patient,
and a 69 yr old male patient.
Prognosis
Unknown.
This article should be referenced as such:
Huret JL. t(1;2)(q12;q37). Atlas Genet Cytogenet Oncol
Haematol. 2000; 4(1):31.
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1)
31
Atlas of Genetics and Cytogenetics
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OPEN ACCESS JOURNAL AT INIST-CNRS
Leukaemia Section
Short Communication
t(1;21)(p36;q22)
Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France
(JLH)
Published in Atlas Database: February 2000
Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t0121ID1186.html
DOI: 10.4267/2042/37593
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2000 Atlas of Genetics and Cytogenetics in Oncology and Haematology
The gene involved in 1p36 is unknown.
Identity
AML1
Note: Only two cases, one with features identical to a
case of t(18;21)(q21;q22), and a case of
t(19;21)(q13.4;q22).
Location
21q22
DNA/RNA
Transcription is from telomere to centromere.
Protein
Contains a Runt domain and, in the C-term, a
transactivation domain; forms heterodimers; widely
expressed; nuclear localisation; transcription factor
(activator) for various hematopoietic-specific genes.
Clinics and pathology
Disease
Acute non lymphocytic leukemia (ANLL) secondary to
toxic exposure.
Etiology
ANLL occurred about 50 years after radiation exposure
from nuclear explosion in one case, 5 years after
treatment with antitopoisomerase II for lung cancer in
the other case.
References
Roulston D, Espinosa R 3rd, Nucifora G, Larson RA, Le Beau
MM, Rowley JD. CBFA2(AML1) translocations with novel
partner chromosomes in myeloid leukemias: association with
prior therapy. Blood. 1998 Oct 15;92(8):2879-85
Evolution
Complete remission in the two patients; relapse in the
one documented case.
Prognosis
Hromas RA, Busse TM, Shopnick R, Jumean H, Bowers C,
Richkind K. Cloning of an AML1 translocation in a novel
syndrome of radiation-induced acute myeloid leukemia. Blood
1999; 94 suppl 1: Abst 3056
Unknown.
This article should be referenced as such:
Genes involved and proteins
Huret JL. t(1;21)(p36;q22). Atlas Genet Cytogenet Oncol
Haematol. 2000; 4(1):32.
Note
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1)
32
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Leukaemia Section
Short Communication
t(11;12)(p15;q13)
Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France
(JLH)
Published in Atlas Database: February 2000
Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t1112ID1185.html
DOI: 10.4267/2042/37595
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2000 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
t(11;12)(p15;q13) G- banding - Courtesy Melanie Zenger and Claudia Haferlach.
DNA/RNA
Alternate splicing.
Protein
Contains repeated motifs and a RNA binding motif;
nucleoporin: role in nucleo-cytoplasmic transport.
Clinics and pathology
Disease
Treatment related acute non lymphoblastic leukemia (tANLL) so far.
Epidemiology
Result of the chromosomal
anomaly
Only one case; a female patient aged 39 yrs and treated
with antitopoisomerase II for Hodgkin disease.
Hybrid gene
Cytogenetics
Description
5 prime NUP98 - 3 prime unknown.
Cytogenetics morphological
Showed also
rearrangement.
a
t(17;21)(q11;q22)
with
AML1
Fusion protein
Genes involved and proteins
Description
Fuses the N-term domains
undetermined sequence.
Note
The gene involved in 12q13 is unknown.
References
NUP98
NUP98
to
an
Roulston D, Espinosa R 3rd, Nucifora G, Larson RA, Le Beau
MM, Rowley JD. CBFA2(AML1) translocations with novel
partner chromosomes in myeloid leukemias: association with
prior therapy. Blood. 1998 Oct 15;92(8):2879-85
Location : 11p15
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1)
of
33
t(11;12)(p15;q13)
Huret JL
Kobzev YN, Rowley JD. NUP98 gene rearrangements in
leukemia detected by fluorescence in situ hybridization (FISH).
Blood. 1999 ; 94 (numero Suppl 1).
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1)
This article should be referenced as such:
Huret JL. t(11;12)(p15;q13). Atlas Genet Cytogenet Oncol
Haematol. 2000; 4(1):33-34.
34
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Leukaemia Section
Short Communication
t(11;22)(q23;q11.2)
Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France
(JLH)
Published in Atlas Database: February 2000
Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t1122hCDCrelID1183.html
DOI: 10.4267/2042/37596
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2000 Atlas of Genetics and Cytogenetics in Oncology and Haematology
431 kDa; contains two DNA binding motifs (a AT
hook, and Zinc fingers), a DNA methyl transferase
motif, a bromodomain; transcriptional regulatory
factor; nuclear localisation.
Identity
Note: Not to be confused with the t(11;22)(q23;q13),
involving MLL and P300.
hCDCRel
Clinics and pathology
Location
22q11
DNA/RNA
2 kb mRNA
Protein
hCDCRel (human cell division cycle related) is a septin
(family of filament forming proteins, involved in
cytosqueletal organization).
Disease
De novo acute non lymphocytic leukemia (ANLL), so
far.
Phenotype/cell stem origin
2 cases of M4, one M2, and one M1.
Epidemiology
Yet poorly known; 2 young adults (22 and 34 yrs) and
2 infant twins; 2M/2F.
Result of the chromosomal
anomaly
Prognosis
Documented in only 2 cases (dead at 10 and 21 mths);
likely to be comparable with that of other entities with
11q23/MLL11q23/MLL involvement.
Hybrid gene
Cytogenetics
Description
5 prime MLL - 3 prime hCDCRel, with fusion of MLL
exon 7 to hCDCRel exon 3.
Cytogenetics morphological
References
Sole anomaly in 3 of 3 cases.
Marukawa O, Akao Y, Inazawa J, Ariyama T, Abe T, Naoe T,
Tanimoto M, Saito H, Otsuki Y, Tsujimoto Y. Molecular cloning
of the breakpoint of t(11;22) (q23;q11) chromosome
translocation in an adult acute myelomonocytic leukaemia. Br J
Haematol. 1996 Mar;92(3):687-91
Genes involved and proteins
MLL
Baer MR, Stewart CC, Lawrence D, Arthur DC, Mrózek K,
Strout MP, Davey FR, Schiffer CA, Bloomfield CD. Acute
myeloid leukemia with 11q23 translocations: myelomonocytic
immunophenotype by multiparameter flow cytometry.
Leukemia. 1998 Mar;12(3):317-25
Location
In 11q23.
DNA/RNA
13-15 kb mRNA.
Megonigal MD, Rappaport EF, Jones DH, Williams TM, Lovett
BD, Kelly KM, Lerou PH, Moulton T, Budarf ML, Felix CA.
Protein
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1)
35
t(11;22)(q23;q11.2)
Huret JL
t(11;22)(q23;q11.2) In acute myeloid leukemia of infant twins
fuses MLL with hCDCrel, a cell division cycle gene in the
genomic region of deletion in DiGeorge and velocardiofacial
syndromes. Proc Natl Acad Sci U S A. 1998 May
26;95(11):6413-8
Yagi M, Zieger B, Roth GJ, Ware J. Structure and expression
of the human septin gene HCDCREL-1. Gene. 1998 Jun
8;212(2):229-36
This article should be referenced as such:
Huret JL. t(11;22)(q23;q11.2). Atlas Genet Cytogenet Oncol
Haematol. 2000; 4(1):35-36.
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1)
36
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Leukaemia Section
Short Communication
t(17;21)(q11.2;q22)
Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France
(JLH)
Published in Atlas Database: February 2000
Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t1721ID1181.html
DOI: 10.4267/2042/37597
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2000 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Protein
Contains a Runt domain and, in the C-term, a
transactivation domain; forms heterodimers; widely
expressed; nuclear localisation; transcription factor
(activator) for various hematopoietic-specific genes.
Clinics and pathology
Disease
Acute non lymphoblastic leukemia (ANLL) and
myelodysplastic syndromes (MDS); de novo ANLL
and treatment related leukemias (t-ANLL).
Result of the chromosomal
anomaly
Phenotype/cell stem origin
One M2, one treatment related RAEBt/M4, one tANLL.
Hybrid gene
Etiology
Description
5 prime AML1-3 prime unknown; breakpoint in intron
5 or 6 of AML1.
Two cases are secondary to treatment with
topoisomerase II inhibitors for Hodgkin disease and
neuroblastoma.
Fusion protein
Epidemiology
Description
The N-term is provided by AML1, as in the t(3;21) and
in the t(8;21) associated with ANLLs, whereas, in the
ALL with t(12;21), the fusion protein comprises the Cterm part of AML1.
3 cases to date; 1M/2F, aged 2yrs, 39 yrs and 76 yrs.
Prognosis
Unknown.
Cytogenetics
References
Additional anomalies
Sole anomaly in one case; one case was also -7, +8, one
case showed also a t(11;12)(p15;q13) with NUP98
rearrangement.
Roulston D, Espinosa R 3rd, Nucifora G, Larson RA, Le Beau
MM, Rowley JD. CBFA2(AML1) translocations with novel
partner chromosomes in myeloid leukemias: association with
prior therapy. Blood. 1998 Oct 15;92(8):2879-85
Genes involved and proteins
Kobzev YN, Rowley JD. NUP98 gene rearrangements in
leukemia detected by fluorescence in situ hybridization (FISH).
Blood. 1999 ; 94 (numero Suppl 1).
Note
The gene involved in 17q11 is unknown; the breakpoint
on chromosome 17 is between the loci for NF1 and
RARA.
LySunnaram B, Gandemer V, Le Mee F, Cayuela JM, Edan C,
Le Gall E, Goasguen JE. Secondary raeb-t associated with
t(17;21) in a child treated by VP16 for neuroblastoma. Blood.
1999 ; 94 (numero Suppl 1).
AML1
This article should be referenced as such:
Location
21q22
DNA/RNA
Transcription is from telomere to centromere.
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1)
Huret JL. t(17;21)(q11.2;q22). Atlas Genet Cytogenet Oncol
Haematol. 2000; 4(1):37.
37
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Leukaemia Section
Short Communication
t(18;21)(q21;q22)
Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France
(JLH)
Published in Atlas Database: February 2000
Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t1821ID1187.html
DOI: 10.4267/2042/37598
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2000 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Clinics and pathology
Genes involved and proteins
Disease
Note
The gene involved in 18q21 is unknown.
Acute non lymphocytic leukemia (ANLL) secondary to
toxic exposure.
Note
Only one case, but with features identical to 2 other
cases: one case of t(1;21)(p36;q22), and one case of
t(19;21)(q13.4;q22).
AML1
Location
21q22
DNA/RNA
Transcription is from telomere to centromere.
Protein
Contains a Runt domain and, in the C-term, a
transactivation domain; forms heterodimers; widely
expressed; nuclear localisation; transcription factor
(activator) for various hematopoietic-specific genes.
Phenotype/cell stem origin
M2-ANLL
Etiology
About 50 years after radiation exposure from nuclear
explosion.
Clinics
References
Pancytopenia preceeded leukemia.
Hromas RA, Busse TM, Shopnick R, Jumean H, Bowers C,
Richkind K. Cloning of an AML1 translocation in a novel
syndrome of radiation-induced acute myeloid leukemia. Blood.
1999; 94 (suppl1).
Evolution
Complete remission was obtained and the patient
returned to the previous pancytopenia; subsequent
relapse occurred.
This article should be referenced as such:
Huret JL. t(18;21)(q21;q22). Atlas Genet Cytogenet Oncol
Haematol. 2000; 4(1):38.
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1)
38
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Leukaemia Section
Short Communication
t(19;21)(q13.4;q22)
Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France
(JLH)
Published in Atlas Database: February 2000
Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t1921ID1182.html
DOI: 10.4267/2042/37599
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2000 Atlas of Genetics and Cytogenetics in Oncology and Haematology
DNA/RNA
Transcription is from telomere to centromere.
Protein
Contains a Runt domain and, in the C-term, a
transactivation domain; forms heterodimers; widely
expressed; nuclear localisation; transcription factor
(activator) for various hematopoietic-specific genes.
Clinics and pathology
Disease
Acute non lymphocytic leukemia (ANLL) secondary to
toxic exposure.
Note
Only one case, but with features identical to 2 other
cases: one case of t(1;21)(p36;q22), and one case of
t(18;21)(q21;q22).
Phenotype/cell stem origin
Result of the chromosomal
anomaly
M2-ANLL
Hybrid gene
Etiology
Description
AMP-19 is fused to AML1 out of frame.
About 50 years after radiation exposure from nuclear
explosion.
Fusion protein
Clinics
Description
Truncated AML1 with the DNA binding domain, but
not a transcriptional activation region.
Oncogenesis
Could function as a dominant negative inhibitor of
normal AML1.
Pancytopenia preceeded leukemia.
Evolution
Complete remission was obtained and the patient
returned to the previous pancytopenia; subsequent
relapse occurred.
References
Genes involved and proteins
Hromas RA, Busse TM, Shopnick R, Jumean H, Bowers C,
Richkind K. Cloning of an AML1 translocation in a novel
syndrome of radiation-induced acute myeloid leukemia. Blood.
1999; 94 (suppl1).
AMP19
Location
19q13.4
This article should be referenced as such:
AML1
Huret JL. t(19;21)(q13.4;q22). Atlas Genet Cytogenet Oncol
Haematol. 2000; 4(1):39.
Location
21q22
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1)
39
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Leukaemia Section
Short Communication
t(3;11)(p21;q23)
Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France
(JLH)
Published in Atlas Database: February 2000
Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t0311ID1165.html
DOI: 10.4267/2042/37594
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2000 Atlas of Genetics and Cytogenetics in Oncology and Haematology
hook, and Zinc fingers), a DNA methyl transferase
motif, a bromodomain; transcriptional regulatory
factor; nuclear localisation.
Clinics and pathology
Disease
AF3p21
Treatment related acute non lymphoblastic leukemia (tANLL).
Location
3p21
Phenotype/cell stem origin
M5b ANLL.
Result of the chromosomal
anomaly
Epidemiology
Only one case; a female patient aged 23 yrs and treated
9 years ago for T-ALL.
Hybrid gene
Prognosis
Description
Breakpoints of MLL between exons 9 and 10 and
upstream of exon 1 of the AF3p21 gene.
Unknown; likely to be poor, both as it carries a MLL
rearrangements and as occurs in t-ANLL.
Fusion protein
Cytogenetics
Description
AT hooks and methyltransferase domains of MLL in
the N-term fused to the proline-rich domain and nuclear
localization signal of AF3p21.
Cytogenetics morphological
Sole anormaly.
Genes involved and proteins
References
MLL
Sano K, Hayakawa A, JinHua P. A novel sh3 protein encoded
by the AF3p21 gene is fused to MLL in a therapy-related
leukemia with t(3; 11)(p21;q23). Blood. 1999 ; 94 (numero
Suppl 1).
Location
In 11q23
DNA/RNA
13-15 kb mRNA.
Protein
431 kDa; contains two DNA binding motifs (a AT
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1)
This article should be referenced as such:
Huret JL. t(3;11)(p21;q23). Atlas Genet Cytogenet Oncol
Haematol. 2000; 4(1):40.
40
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Leukaemia Section
Short Communication
t(3;11)(q25;q23)
Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France
(JLH)
Published in Atlas Database: February 2000
Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t311GMPSID1173.html
DOI: 10.4267/2042/37600
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2000 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Protein
431 kDa; contains two DNA binding motifs (a AT
hook, and Zinc fingers), a DNA methyl transferase
motif, a bromodomain; transcriptional regulatory
factor; nuclear localisation.
Clinics and pathology
Disease
Treatment related acute non lymphoblastic leukemia.
Phenotype/cell stem origin
Result of the chromosomal
anomaly
M4 ANLL.
Etiology
One case, a 13 yr old boy; occurred 9 yrs after
treatment for neuroblastoma with antitopoisomerase II.
Hybrid gene
Genes involved and proteins
Description
Fusion of MLL exon 7 to GMPS.
GMPS
References
Location
3q24
DNA/RNA
2.2 kb mRNA.
Protein
76 kDa; enzyme of the de novo synthesis of guanine
nucleotides: amidotransferase that catalyzes the
amination of xanthosine 5 prime monophosphate to
form GMP.
Hirst M, Haliday E, Nakamura J, Lou L. Human GMP
synthetase. Protein purification, cloning, and functional
expression of cDNA. J Biol Chem. 1994 Sep
23;269(38):23830-7
Nakamura J, Straub K, Wu J, Lou L. The glutamine hydrolysis
function of human GMP synthetase. Identification of an
essential active site cysteine. J Biol Chem. 1995 Oct
6;270(40):23450-5
Pegram LD, Megonigal MD, Lange BJ, Nowell PC, Rappaport
EF, Felix CA. t(3;11)(q25;q23) fuses MLL with the GMPS
(guanosine 5'-monophosphate synthetase) gene in treatmentrelated acute myeloid leukemia (AML). Blood. 1999 ; 94
(numero Suppl 1).
MLL
Location
In 11q23.
DNA/RNA
13-15 kb mRNA.
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1)
This article should be referenced as such:
Huret JL. t(3;11)(q25;q23). Atlas Genet Cytogenet Oncol
Haematol. 2000; 4(1):41.
41
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Solid Tumour Section
Mini Review
Bone: Chondrosarcoma
Judith VMG Bovée
Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands (JVMGB)
Published in Atlas Database: January 2000
Online updated version : http://AtlasGeneticsOncology.org/Tumors/chondrosarcID5063.html
DOI: 10.4267/2042/37602
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2000 Atlas of Genetics and Cytogenetics in Oncology and Haematology
chondrosarcoma (2%) and extra-skeletal myxoid
chondrosarcoma (5%). Furthermore, dedifferentiated
chondrosarcoma is a relatively rare high grade sarcoma
next to a low-grade conventional malignant cartilageforming
tumor,
comprising
6-10%
of
all
chondrosarcomas. Conventional chondrosarcoma can
be categorized according to their location in bone.
Identity
Figure 1: En bloc resection specimen of the proximal fibula of a
43 year old female, containing a lobulated bluish white,
translucent tumour (4.5 x 2 x 1.9 cm) located centrally within the
medullary cavity, consistent with central chondrosarcoma.
Classification
Note: Approximately 90% of chondrosarcomas are
histologically of the conventional type; in addition to
conventional chondrosarcoma, some rare variants with
distinctive microscopic and clinical features are
discerned:
clear
cell
chondrosarcoma
(1%),
mesenchymal chondrosarcoma (2%), juxtacortical
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1)
Figure 2: Corresponding macro-slice showing a lobular
architecture, and endosteal cortical thinning. Cytonuclear
appearance can be more readily appreciated in figure 3.
42
Bone: Chondrosarcoma
Bovée JVMG
Figure 3: Micrograph displaying low cellularity with limited cytonuclear atypia, and a high amount of chondroid matrix surrounding tumor
cells consistent with a grade I chondrosarcoma. Note the presence of a binucleated cell.
The majority of chondrosarcomas (75%) are located
centrally within the medullary cavity (central
chondrosarcoma), whereas a minority (15%) develops
from the surface of bone (peripheral chondrosarcoma)
as a result of malignant transformation within the
cartilaginous cap of a solitary or hereditary pre-existent
osteochondroma.
Clinics and pathology
mainly chondroid matrix and the absence of mitoses;
In contrast, grade III chondrosarcomas are highly
cellular, with nuclear polymorphism, mitoses and a
mostly myxoid matrix;
Increasing histological grade is correlated with higher
metastatic potential; it is considered difficult to assess
the histological grade of cartilaginous tumours and to
reliably distinguish between benign tumours and those
of low-grade malignancy.
Epidemiology
Treatment
Primary malignant bone tumours occur 1/100,000, of
which 17-24% consists of chondrosarcoma; the
majority of patients are between 35 and 60 years old
with equal sex distribution.
Because chondrosarcoma is highly resistant to
chemotherapy and radiotherapy, surgical treatment is
the only option for curative treatment.
Clinics
The majority of central chondrosarcomas are
considered to arise de novo and malignant
transformation of solitary enchondroma is extremely
rare (<1%); in patients demonstrating multiple
enchondromas, such as Ollier's disease, the incidence
of secondary central chondrosarcoma is much higher
(30-35%); peripheral chondrosarcomas usually
originate from the cartilaginous cap of an
osteochondroma; malignant transformation is low in
solitary osteochondromas (<1%) but is estimated to
occur in 1-5% of cases of hereditary multiple
exostoses; furthermore, an occasional recurrent
chondrosarcoma may exhibit a higher grade of
Evolution
Compared
to
benign
cartilaginous
tumours,
chondrosarcomas more frequently present with pain
and tenderness; they usually develop in the trunk,
pelvis and long bones.
Pathology
There are no apparent cytonuclear differences between
central and peripheral conventional chondrosarcomas
and both are histologically classified into three grades
using the criteria of Evans et al.
Grade I chondrosarcomas demonstrate low cellularity,
limited cytonuclear atypia, few multinucleated cells, a
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1)
43
Bone: Chondrosarcoma
Bovée JVMG
malignancy than the original neoplasm, suggesting that
tumours may additionally progress from low to high
grade.
chondrosarcoma, an identical somatic 6 bp deletion in
exon 7 of p53 and loss of the same copy of
chromosome 13 provided compelling evidence for a
common origin instead of the 'collision tumor' theory;
in addition, many different genetic alterations were
found, indicating that the separation of the two clones
is a relatively early event in the histogenesis of
dedifferentiated chondrosarcoma.
Unfortunately, most other genetic analyses on
chondrosarcoma were performed on a heterogeneous
group
including
all
different
subtypes
of
chondrosarcoma; ploidy-analysis of chondrosarcomas
has been described and aneuploidy is more frequently
found in high-grade chondrosarcomas; two series of
chondrosarcomas (n=23 and n=50) studied by CGH
revealed extensive genetic aberrations; the majority of
these changes were gains of whole chromosomes or
whole chromosome arms, most frequent at 20q (3238%), 20p (24-31%), and 14q23-qter (24-28%); a
correlation between gain at 8q24.1 and shorter overall
survival was reported; amplification of the c-myc
proto-oncogene, located at 8q24, was found in four of
12 chondrosarcomas, and was not associated with any
clinicopathological features; the only recurrent highlevel amplification, seen in two tumours (7%), affected
the minimal common region 12cen-q15; although both
cytogenetic analysis and CGH point at 12cen-q15,
CDK4, MDM2 and SAS were not frequently amplified
in chondrosarcoma.
Partial allelotypings of a heterogeneous group of
chondrosarcoma revealed that in addition to LOH at the
EXT-loci on chromosomes 8 (4/17) and 11 (7/17),
LOH was found at 10q11 (12/18), the Rb - (9/25) and
p53-locus (7/28). Overexpression of the p53 protein
and TP53 mutations have been observed mainly in
high-grade chondrosarcomas, suggesting that the p53
gene could play a role in the progression of
chondrosarcoma.
Prognosis
Metastasis in chondrosarcoma highly depends on the
histological grade of malignancy; grade I
chondrosarcomas demonstrate local recurrence, but
seldom metastasize; grade II chondrosarcomas
demonstrate metastases in 10-30% of the cases,
whereas grade III chondrosarcomas demonstrate
metasases in the majority of cases; in contrast to
chondrosarcomas located elsewhere in the skeleton,
those located in the phalanx behave as a locally
aggressive lesion with minimal metastatic potential.
Cytogenetics
Cytogenetics Morphological
Extra-skeletal myxoid chondrosarcoma, comprising 5%
of all chondrosarcomas, is characterized by a reciprocal
translocation t(9;22)(q22;q12), fusing the EWS to the
CHN gene.
Cytogenetic analysis on a heterogeneous group of
chondrosarcomas revealed that structural aberrations of
chromosomes 1, 6, 9, 12 and 15 and numerical
aberrations of chromosomes 5, 7, 8 and 18 were most
frequent; abnormalities of chromosome 1 and 7 were
confined to malignant cartilaginous tumours; like in
other mesenchymal neoplasms, band 12q13-15 is
prominently involved in the aberrations; the presence
of chromosome aberrations was found to strongly
correlate with increasing histological grade; complex
aberrations were mainly seen in the high-grade
chondrosarcomas.
Cytogenetics Molecular
In a comparative study of central and peripheral
chondrosarcomas, 19 of 20 peripheral chondrosarcomas
showed LOH at all loci (EXT, EXTL, 13q14, 17p13,
9p21 and chromosome 10) tested while only 3 of 12
central chondrosarcomas exhibited LOH, restricted to
9p21, 10, 13q14 and 17p13. DNA-flow-cytometry
demonstrated a wide variation in the ploidy status in
peripheral chondrosarcomas (DNA-indices 0.56 - 2.01),
whereas central chondrosarcomas were predominantly
peridiploid; these results indicate that peripheral
chondrosarcomas, arising secondarily to an exostosis,
may obtain genetic alterations during malignant
transformation, with subsequent genetic instability as
demonstrated by a high percentage of LOH and a wide
variation in ploidy status; in contrast, peridiploidy and
a low percentage of LOH in central tumors suggest that
a different oncogenic molecular mechanism may be
operative; no mutations in the EXT1 and EXT2 genes
were found in secondary peripheral chondrosarcoma.
Investigating both the cartilaginous as well as the highgrade malignant component of dedifferentiated
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1)
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Cuvelier CA, Roels HJ. Cytophotometric studies of the nuclear
DNA content in cartilaginous tumors. Cancer. 1979
Oct;44(4):1363-74
Kreicbergs A, Boquist L, Borssén B, Larsson SE. Prognostic
factors in chondrosarcoma: a comparative study of cellular
DNA content and clinicopathologic features. Cancer. 1982 Aug
1;50(3):577-83
Kreicbergs A, Silvferswärd C, Tribukait B. Flow DNA analysis
of primary bone tumors. Relationship between cellular DNA
content and histopathologic classification. Cancer. 1984 Jan
1;53(1):129-36
Xiang JH, Spanier SS, Benson NA, Braylan RC. Flow
cytometric analysis of DNA in bone and soft-tissue tumors
using nuclear suspensions. Cancer. 1987 Jun 1;59(11):1951-8
Castresana JS, Barrios C, Gómez L, Kreicbergs A.
Amplification of the c-myc proto-oncogene in human
chondrosarcoma. Diagn Mol Pathol. 1992 Dec;1(4):235-8
44
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Barrios C, Castresana JS, Ruiz J, Kreicbergs A. Amplification
of c-myc oncogene and absence of c-Ha-ras point mutation in
human bone sarcoma. J Orthop Res. 1993 Jul;11(4):556-63
Brody RI, Ueda T, Hamelin A, Jhanwar SC, Bridge JA, Healey
JH, Huvos AG, Gerald WL, Ladanyi M. Molecular analysis of
the fusion of EWS to an orphan nuclear receptor gene in
extraskeletal myxoid chondrosarcoma. Am J Pathol. 1997
Mar;150(3):1049-58
Bridge JA, Bhatia PS, Anderson JR, Neff JR. Biologic and
clinical significance of cytogenetic and molecular cytogenetic
abnormalities in benign and malignant cartilaginous lesions.
Cancer Genet Cytogenet. 1993 Sep;69(2):79-90
Larramendy ML, Tarkkanen M, Valle J, Kivioja AH, Ervasti H,
Karaharju E, Salmivalli T, Elomaa I, Knuutila S. Gains, losses,
and amplifications of DNA sequences evaluated by
comparative genomic hybridization in chondrosarcomas. Am J
Pathol. 1997 Feb;150(2):685-91
Wadayama B, Toguchida J, Yamaguchi T, Sasaki MS,
Yamamuro T. p53 expression and its relationship to DNA
alterations in bone and soft tissue sarcomas. Br J Cancer.
1993 Dec;68(6):1134-9
Oshiro Y, Chaturvedi V, Hayden D, Nazeer T, Johnson M,
Johnston DA, Ordóñez NG, Ayala AG, Czerniak B. Altered p53
is associated with aggressive behavior of chondrosarcoma: a
long term follow-up study. Cancer. 1998 Dec 1;83(11):2324-34
Coughlan B, Feliz A, Ishida T, Czerniak B, Dorfman HD. p53
expression and DNA ploidy of cartilage lesions. Hum Pathol.
1995 Jun;26(6):620-4
Bovée JV, Cleton-Jansen AM, Kuipers-Dijkshoorn NJ, van den
Broek LJ, Taminiau AH, Cornelisse CJ, Hogendoorn PC. Loss
of heterozygosity and DNA ploidy point to a diverging genetic
mechanism in the origin of peripheral and central
chondrosarcoma. Genes Chromosomes Cancer. 1999
Nov;26(3):237-46
Hasegawa T, Seki K, Yang P, Hirose T, Hizawa K, Wada T,
Wakabayashi J. Differentiation and proliferative activity in
benign and malignant cartilage tumors of bone. Hum Pathol.
1995 Aug;26(8):838-45
Hecht JT, Hogue D, Strong LC, Hansen MF, Blanton SH,
Wagner M. Hereditary multiple exostosis and chondrosarcoma:
linkage to chromosome II and loss of heterozygosity for EXTlinked markers on chromosomes II and 8. Am J Hum Genet.
1995 May;56(5):1125-31
Bovée JV, Cleton-Jansen AM, Rosenberg C, Taminiau AH,
Cornelisse CJ, Hogendoorn PC. Molecular genetic
characterization of both components of a dedifferentiated
chondrosarcoma, with implications for its histogenesis. J
Pathol. 1999 Dec;189(4):454-62
Heliö H, Karaharju E, Böhling T, Kivioja A, Nordling S.
Chondrosarcoma of bone. A clinical and DNA flow cytometric
study. Eur J Surg Oncol. 1995 Aug;21(4):408-13
Bovée JV, Cleton-Jansen AM, Wuyts W, Caethoven G,
Taminiau AH, Bakker E, Van Hul W, Cornelisse CJ,
Hogendoorn PC. EXT-mutation analysis and loss of
heterozygosity in sporadic and hereditary osteochondromas
and secondary chondrosarcomas. Am J Hum Genet. 1999
Sep;65(3):689-98
Raskind WH, Conrad EU, Chansky H, Matsushita M. Loss of
heterozygosity in chondrosarcomas for markers linked to
hereditary multiple exostoses loci on chromosomes 8 and 11.
Am J Hum Genet. 1995 May;56(5):1132-9
Bovée JV, van der Heul RO, Taminiau AH, Hogendoorn PC.
Chondrosarcoma of the phalanx: a locally aggressive lesion
with minimal metastatic potential: a report of 35 cases and a
review of the literature. Cancer. 1999 Nov 1;86(9):1724-32
Simms WW, Ordóñez NG, Johnston D, Ayala AG, Czerniak B.
p53 expression in dedifferentiated chondrosarcoma. Cancer.
1995 Jul 15;76(2):223-7
Raskind WH, Conrad EU, Matsushita M. Frequent loss of
heterozygosity for markers on chromosome arm 10q in
chondrosarcomas. Genes Chromosomes Cancer. 1996
Jun;16(2):138-43
Larramendy ML, Mandahl N, Mertens F, Blomqvist C, Kivioja
AH, Karaharju E, Valle J, Böhling T, Tarkkanen M, Rydholm A,
Akerman M, Bauer HC, Anttila JP, Elomaa I, Knuutila S.
Clinical significance of genetic imbalances revealed by
comparative genomic hybridization in chondrosarcomas. Hum
Pathol. 1999 Oct;30(10):1247-53
Yamaguchi T, Toguchida J, Wadayama B, Kanoe H,
Nakayama T, Ishizaki K, Ikenaga M, Kotoura Y, Sasaki MS.
Loss of heterozygosity and tumor suppressor gene mutations
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Anticancer
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Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1)
This article should be referenced as such:
Bovée JVMG. Bone: Chondrosarcoma. Atlas Genet Cytogenet
Oncol Haematol. 2000; 4(1):42-45.
45
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Cancer Prone Disease Section
Mini Review
Hereditary multiple exostoses (HME)
Judith VMG Bovée
Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands (JVMGB)
Published in Atlas Database: January 2000
Online updated version : http://AtlasGeneticsOncology.org/Kprones/HeredMultExostosID10061.html
DOI: 10.4267/2042/37603
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2000 Atlas of Genetics and Cytogenetics in Oncology and Haematology
representing approximately 50% of all primary benign
tumours of bone; they gradually develop and increase
in size in the first decade of life; the stratified zones of
chondrocytes that are normally found in the growth
plate can still be recognised on the interface of cartilage
and bone in osteochondroma; consequently,
osteochondromas cease growing as the growth plates
close during puberty; the majority is asymptomatic and
is located in bones that developed from cartilage,
especially the long bones in the extremities.
Identity
Alias: Diaphyseal aclasis
Inheritance: Autosomal dominant disorder, genetically
heterogeneous; males are more often affected, possibly
partly due to an incomplete penetrance in females;
approximately 62% of the patients have a positive
family history.
Clinics
Neoplastic risk
Phenotype and clinics
Malignant transformation is low in solitary
osteochondromas (<1%) but is estimated to occur in 15% of cases of hereditary multiple exostoses.
Presence
of
multiple
osteochondromas
(osteocartilaginous exostosis), bony protrusions
covered by a cartilaginous cap on the outer surface of
bone, resulting in a variety of orthopaedic deformities
such as disproportionate short stature and bowing of the
forearm; osteochondromas are the most common
benign bone tumours,
Treatment
Osteochondromas can be surgically removed for
cosmetic or functional reasons.
Figure 1: X-ray of the upper arm of a patient coming from a family with hereditary multiple exostoses (HME), demonstrating multiple
osteochondromas (exostoses).
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1)
46
Hereditary multiple exostoses (HME)
Bovée JVMG
Cook A, Raskind W, Blanton SH, Pauli RM, Gregg RG,
Francomano CA, Puffenberger E, Conrad EU, Schmale G,
Schellenberg G. Genetic heterogeneity in families with
hereditary multiple exostoses. Am J Hum Genet. 1993
Jul;53(1):71-9
Cytogenetics
Cytogenetics of cancer
Clonal karyotypic abnormalities in the cartilaginous
cap of osteochondroma involving 8q22-24.1 were
found in ten out of 30 sporadic and in 1 out of 13
hereditary osteochondromas, supporting a neoplastic
origin; this was confirmed since aneuploidy was found
in 4 out of 10 osteochondromas and LOH was almost
exclusively found at the EXT1 locus in 5 out of 14
osteochondromas; no somatic EXT1 cDNA alterations
were found in sporadic osteochondromas.
Le Merrer M, Legeai-Mallet L, Jeannin PM, Horsthemke B,
Schinzel A, Plauchu H, Toutain A, Achard F, Munnich A,
Maroteaux P. A gene for hereditary multiple exostoses maps to
chromosome 19p. Hum Mol Genet. 1994 May;3(5):717-22
Ahn J, Lüdecke HJ, Lindow S, Horton WA, Lee B, Wagner MJ,
Horsthemke B, Wells DE. Cloning of the putative tumour
suppressor gene for hereditary multiple exostoses (EXT1). Nat
Genet. 1995 Oct;11(2):137-43
Wicklund CL, Pauli RM, Johnston D, Hecht JT. Natural history
study of hereditary multiple exostoses. Am J Med Genet. 1995
Jan 2;55(1):43-6
Genes involved and proteins
Stickens D, Clines G, Burbee D, Ramos P, Thomas S, Hogue
D, Hecht JT, Lovett M, Evans GA. The EXT2 multiple
exostoses gene defines a family of putative tumour suppressor
genes. Nat Genet. 1996 Sep;14(1):25-32
EXT1 and EXT2
Location
8q24 and 11p11-p12.
Note
HME is a genetically heterogeneous disorder for which
at present, two genes, EXT1 and EXT2 located
respectively on 8q24 and 11p11-p12, have been
isolated; the EXT1 gene was reported to show linkage
in 44%-66% of the HME families, whereas EXT2
would be involved in 27%; additional linkage to
chromosome 19p has been found, suggesting the
existence of an EXT3 -gene, although loss of
heterozygosity studies could not confirm this; two
patients with multiple osteochondromas demonstrated a
germline mutation in EXT1 combined with loss of the
remaining wild type allele in three osteochondromas,
confirming the tumour suppressor function of the EXT
genes and indicating that in cartilaginous cells of the
growth plate inactivation of both copies of the EXT1gene is required for osteochondroma formation in
hereditary cases.
Protein
Function: A tumour suppressor function is suggested
for the EXT genes, which was confirmed by the
combination of EXT1 germline mutations with loss of
the remaining wildtype allele in osteochondroma; the
EXT gene products were shown to be involved in
heparan sulphate biosynthesis.
Mutations
Germinal: Germline mutations of EXT1 and EXT2 in
HME patients have been studied extensively in
Caucasian as well as Asian populations.
Somatic: No somatic mutations were found in the
EXT1 and EXT2 gene in 34 sporadic and hereditary
osteochondromas and chondrosarcomas tested.
Wuyts W, Van Hul W, Wauters J, Nemtsova M, Reyniers E,
Van Hul EV, De Boulle K, de Vries BB, Hendrickx J, Herrygers
I, Bossuyt P, Balemans W, Fransen E, Vits L, Coucke P,
Nowak NJ, Shows TB, Mallet L, van den Ouweland AM,
McGaughran J, Halley DJ, Willems PJ. Positional cloning of a
gene involved in hereditary multiple exostoses. Hum Mol
Genet. 1996 Oct;5(10):1547-57
Hecht JT, Hogue D, Wang Y, Blanton SH, Wagner M, Strong
LC, Raskind W, Hansen MF, Wells D. Hereditary multiple
exostoses (EXT): mutational studies of familial EXT1 cases
and EXT-associated malignancies. Am J Hum Genet. 1997
Jan;60(1):80-6
Legeai-Mallet L, Margaritte-Jeannin P, Lemdani M, Le Merrer
M, Plauchu H, Maroteaux P, Munnich A, Clerget-Darpoux F.
An extension of the admixture test for the study of genetic
heterogeneity in hereditary multiple exostoses. Hum Genet.
1997 Mar;99(3):298-302
Legeai-Mallet L, Munnich A, Maroteaux P, Le Merrer M.
Incomplete penetrance and expressivity skewing in hereditary
multiple exostoses. Clin Genet. 1997 Jul;52(1):12-6
Philippe C, Porter DE, Emerton ME, Wells DE, Simpson AH,
Monaco AP. Mutation screening of the EXT1 and EXT2 genes
in patients with hereditary multiple exostoses. Am J Hum
Genet. 1997 Sep;61(3):520-8
Raskind WH, Conrad EU 3rd, Matsushita M, Wijsman EM,
Wells DE, Chapman N, Sandell LJ, Wagner M, Houck J.
Evaluation of locus heterogeneity and EXT1 mutations in 34
families with hereditary multiple exostoses. Hum Mutat.
1998;11(3):231-9
Wuyts W, Van Hul W, De Boulle K, Hendrickx J, Bakker E,
Vanhoenacker F, Mollica F, Lüdecke HJ, Sayli BS, Pazzaglia
UE, Mortier G, Hamel B, Conrad EU, Matsushita M, Raskind
WH, Willems PJ. Mutations in the EXT1 and EXT2 genes in
hereditary multiple exostoses. Am J Hum Genet. 1998
Feb;62(2):346-54
Bovée JV, Cleton-Jansen AM, Wuyts W, Caethoven G,
Taminiau AH, Bakker E, Van Hul W, Cornelisse CJ,
Hogendoorn PC. EXT-mutation analysis and loss of
heterozygosity in sporadic and hereditary osteochondromas
and secondary chondrosarcomas. Am J Hum Genet. 1999
Sep;65(3):689-98
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Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1)
47
Hereditary multiple exostoses (HME)
Bovée JVMG
Park KJ, Shin KH, Ku JL, Cho TJ, Lee SH, Choi IH, Phillipe C,
Monaco AP, Porter DE, Park JG. Germline mutations in the
EXT1 and EXT2 genes in Korean patients with hereditary
multiple exostoses. J Hum Genet. 1999;44(4):230-4
Legeai-Mallet L, Rossi A, Benoist-Lasselin C, Piazza R, Mallet
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EXT 1 gene mutation induces chondrocyte cytoskeletal
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Xu L, Xia J, Jiang H, Zhou J, Li H, Wang D, Pan Q, Long Z,
Fan C, Deng HX. Mutation analysis of hereditary multiple
exostoses in the Chinese. Hum Genet. 1999 Jul-Aug;105(12):45-50
Porter DE, Emerton ME, Villanueva-Lopez F, Simpson AH.
Clinical and radiographic analysis of osteochondromas and
growth disturbance in hereditary multiple exostoses. J Pediatr
Orthop. 2000 Mar-Apr;20(2):246-50
Bernard MA, Hogue DA, Cole WG, Sanford T, Snuggs MB,
Montufar-Solis D, Duke PJ, Carson DD, Scott A, Van Winkle
WB, Hecht JT. Cytoskeletal abnormalities in chondrocytes with
EXT1 and EXT2 mutations. J Bone Miner Res. 2000
Mar;15(3):442-50
Bernard MA, Hall CE, Hogue DA, Cole WG, Scott A, Snuggs
MB, Clines GA, Lüdecke HJ, Lovett M, Van Winkle WB, Hecht
JT. Diminished levels of the putative tumor suppressor proteins
EXT1 and EXT2 in exostosis chondrocytes. Cell Motil
Cytoskeleton. 2001 Feb;48(2):149-62
Bovée JV, van den Broek LJ, Cleton-Jansen AM, Hogendoorn
PC. Up-regulation of PTHrP and Bcl-2 expression
characterizes the progression of osteochondroma towards
peripheral chondrosarcoma and is a late event in central
chondrosarcoma. Lab Invest. 2000 Dec;80(12):1925-34
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1)
This article should be referenced as such:
Bovée JVMG. Hereditary multiple exostoses (HME). Atlas
Genet Cytogenet Oncol Haematol. 2000; 4(1):46-48.
48
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Cancer Prone Disease Section
Mini Review
Rhabdoid predisposition syndrome
Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France
(JLH)
Published in Atlas Database: January 2000
Online updated version : http://AtlasGeneticsOncology.org/Kprones/rhabdKpronID10051.html
DOI: 10.4267/2042/37604
This article is an update of: Huret JL. Rhabdoid predisposition syndrome. Atlas Genet Cytogenet Oncol Haematol.1999;3(2).107
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2000 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Clinics
Genes involved and proteins
Note
The following observations have suggested that a new
cancer-prone disease, related to the gene hSNF5/INI,
could be delineated:
- Two siblings with a paravertebral malignant rhabdoid
tumor in the first year of life and a poor outcome; no
family history;
- renal rhabdoid tumors associated with tumors of the
central nervous system in a given patient;
- germ-line mutations of INI1 identified in four
children, three with renal rhabdoid tumors and one with
an atypical teratoid tumor of the brain (out of 18
atypical teratoid and rhabdoid tumors studied);
- and 4 recent pedigrees with - malignant rhabdoid
tumor, choroid plexus carcinoma, atypical teratoid
tumor,
medulloblastoma,
and/or
primitive
neuroectodermal tumor, - either occurring in sibs or in
a given patient, - with a INI1 point mutation in the
tumor DNA and loss of wild type allele and/or
heterozygosity for the mutation in constitutional DNA.
hSNF5/INI1
Location
22q11.2
Mutations
Germinal: Are found in this syndrome.
Somatic: Mutation and allele loss events in sporadic
rhabdoid tumors are in accordance with the two-hit
model for neoplasia, as is found in retinoblastoma.
References
Lynch HT, Shurin SB, Dahms BB, Izant RJ Jr, Lynch J, Danes
BS. Paravertebral malignant rhabdoid tumor in infancy. In vitro
studies of a familial tumor. Cancer. 1983 Jul 15;52(2):290-6
Fort DW, Tonk VS, Tomlinson GE, Timmons CF, Schneider
NR. Rhabdoid tumor of the kidney with primitive
neuroectodermal tumor of the central nervous system:
associated tumors with different histologic, cytogenetic, and
molecular findings. Genes Chromosomes Cancer. 1994
Nov;11(3):146-52
Biegel JA, Zhou JY, Rorke LB, Stenstrom C, Wainwright LM,
Fogelgren B. Germ-line and acquired mutations of INI1 in
atypical teratoid and rhabdoid tumors. Cancer Res. 1999 Jan
1;59(1):74-9
Phenotype and clinics
No apparent stigmata.
Neoplastic risk
Sévenet N, Sheridan E, Amram D, Schneider P, Handgretinger
R, Delattre O. Constitutional mutations of the hSNF5/INI1 gene
predispose to a variety of cancers. Am J Hum Genet. 1999
Nov;65(5):1342-8
Malignant rhabdoid tumors and atypical teratoid
tumors, choroid plexus carcinomas, medulloblastomas,
and primitive neuroectodermal tumors; highly
aggressive tumors; very early onset in children or
infants, and, apparently, high penetrance.
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1)
This article should be referenced as such:
Huret JL. Rhabdoid predisposition syndrome. Atlas Genet
Cytogenet Oncol Haematol. 2000; 4(1):49.
49
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
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Mini Review
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51