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Scope
The Atlas of Genetics and Cytogenetics in Oncology and Haematology is a peer reviewed on-line journal in open
access, devoted to genes, cytogenetics, and clinical entities in cancer, and cancer-prone diseases.
It presents structured review articles (“cards”) on genes, leukaemias, solid tumours, cancer-prone diseases, and also
more traditional review articles (“deep insights”) on the above subjects and on surrounding topics.
It also present case reports in hematology and educational items in the various related topics for students in Medicine
and in Sciences.
Editorial correspondance
Jean-Loup Huret
Genetics, Department of Medical Information,
University Hospital
F-86021 Poitiers, France
tel +33 5 49 44 45 46 or +33 5 49 45 47 67
jlhuret@AtlasGeneticsOncology.org or Editorial@AtlasGeneticsOncology.org
The Atlas of Genetics and Cytogenetics in Oncology and Haematology is published 4 times a year by ARMGHM, a
non profit organisation.
Philippe Dessen is the Database Director, and Alain Bernheim the Chairman of the on-line version (Gustave Roussy
Institute – Villejuif – France).
http://AtlasGeneticsOncology.org
© ATLAS - ISSN 1768-3262
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Scope
The Atlas of Genetics and Cytogenetics in Oncology and Haematology is a peer reviewed on-line journal in open
access, devoted to genes, cytogenetics, 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
jlhuret@AtlasGeneticsOncology.org or Editorial@AtlasGeneticsOncology.org
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 5, Number 1, January - March 2001
Table of contents
Gene Section
GRAF (GTPase activating protein for Rho associated with FAK)
Stig Bojesen, Arndt Borkhardt
1
HMGIY (high mobility group protein (non histone chromosomal) isoform I and Y)
Gilka JF Gattas, Florence Pedeutour
3
PU.1 (hematopoietic transcription factor PU.1)
Françoise Moreau-Gachelin
7
FGFR1 (Fibroblast Growth Factor Receptor 1)
Marie-Josèphe Pébusque
9
MLL (myeloid/lymphoid or mixed lineage leukemia)
Jay L Hess, Jean-Loup Huret
11
PRDX1 (peroxiredoxin 1)
Jean-Loup Huret
14
PTCH1 patched homolog 1 (Drosophila)
Erika Lindström, Rune Toftgård
16
TFF2 (TreFoil Factor 2)
Catherine Tomasetto
19
FGFR1OP (FGFR1 oncogene partner)
Marie-Josèphe Pébusque
21
MST1R (Macrophage stimulating 1 receptor)
Debora Angeloni, Michael I Lerman
23
FIM (fused in myeloproliferative disorders)
Marie-Josèphe Pébusque
27
Leukaemia Section
t(1;3)(p36;q21)
Pascale Cornillet-Lefebvre, Sylvie Daliphard, Stéphanie Struski
29
del(17p) in non-Hodgkin's lymphoma (NHL)
Antonio Cuneo, Gianluigi Castoldi
31
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(1)
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
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del(20q) in myeloid malignancies
Chrystèle Bilhou-Nabera
33
Juvenile Chronic Myelogenous Leukemia (JCML)
Jay L Hess
35
t(6;8)(q27;p12)
Marie-Joséphe Pébusque
37
t(8;13)(p12;q12)
Marie-Josèphe Pébusque, Nicholas CP Cross
39
t(9;12)(q34;p13)
Nyla A Heerema
42
+3 or trisomy 3 in non Hodgkin's lymphoma (NHL)
Antonio Cuneo, Gianluigi Castoldi
44
11q23 rearrangements in leukaemia
Jean-Loup Huret
46
del(11q) in non-Hodgkin's lymphoma (NHL)
Antonio Cuneo, Gianluigi Castoldi
50
del(7q) in non-Hodgkin's lymphoma (NHL)
Antonio Cuneo, Gianluigi Castoldi
52
t(1;14)(p22;q32) in non Hodgkin's lymphoma (NHL)
Antonio Cuneo, Gianluigi Castoldi
54
t(5;10)(q33;q21)
Cristina Mecucci
55
-Y, Y loss in leukemia
Daniel L, Van Dyke
56
Solid Tumour Section
Nervous system: Astrocytic tumors
Anne-Marie Capodano
58
Cancer Prone Disease Section
Beckwith-Wiedemann syndrome
Marcel Mannens
62
Hereditary breast cancer
Kaija Holli
66
Variegated aneuploidy related to premature centromere division (PCD)
Alberto Plaja
69
Hereditary pancreatic cancer
Ralph H Hruban, Scott E Kern
72
Li-Fraumeni syndrome
Jenny M Varley
76
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(1)
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
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Gene Section
Mini Review
GRAF (GTPase activating
associated with FAK)
protein
for
Rho
Stig Bojesen, Arndt Borkhardt
Department of Clinical Biochemistry, Herlev University Hospital, Herlev Ringvej 75, Herlev DK-2730,
Denmark (SEB, AB)
Published in Atlas Database: November 2000
Online updated version: http://AtlasGeneticsOncology.org/Genes/GRAFID291.html
DOI: 10.4267/2042/37688
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2001 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
Protein
Other names: GRAF (GTPase activating protein for
Rho associated with FAK); KIAA0621; OPHN1L
HGNC (Hugo): ARHGAP26
Location: 5q31
Local order: Just centromeric of GRL.
Description
Isoform A: 759 amino acids, 86 kDa; isoform B: 814
amino acids, 92 kDa.
Expression
At least 24 exons.
Highly expressed in epithelial tissues i.e. pancreas islet
beta-cells, testicles, prostate, mammary gland, GI
glands, squamous layer of skin epithelium; highly
expressed in nervous tissues including enteric ganglia;
expressed in cardiomyocytes, erythropoiesis cells and
liver.
Transcription
Localisation
Two isoforms of 2277 bp (leukocytes) and 2442 bp
(brain); transcripts of 4,4 and 9,5 kb.
Mainly cytoplasmatic.
DNA/RNA
Description
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(1)
1
GRAF (GTPase activating protein for Rho associated with FAK)
Bojesen SE, Borkhardt A
Function
Implicated in
Interacts with FAK and RhoA both in vivo and in vitro;
acts as GTPase activating protein (GAP) for the active
GTP-bound RhoA; negative regulator of RhoA.
t(5;11)(q31;q23) / acute non lymphocytic
leukemia --> MLL - GRAF
Homology
Prognosis
Unknown; only a few cases.
Hybrid/Mutated gene
5' MLL 3' GRAF
Abnormal protein
MLL-GRAF
Oligophrenin-1, Beta-chimerin, BCR.
Mutations
Germinal
Not known.
Acute non lymphocytic leukemia and
myelodysplastic syndrome with del(5q)
Somatic
Deletion of four bases (251-254, A in ATG=nt1)
Prognosis
Unknown.
Cytogenetics
del(5q).
Oncogenesis
Basically unknown; a bi-allelic loss of GRAF has been
documented in three cases of ANLL.
Insert 1158.
GRAF-base 1144,
5' 1 TA GAG ACA GGA TTT CAT CAT GTT GGC
CAG GTT GGT TTT GAA
42 TTC CTG ACC TCA AGT GAT CCA CCT GCC
TCG GCC TCC CAA AGT
84 GGT GGG ATT TTG G 3'
......GRAF-base 1145
References
Insert 1299
GRAF-base 1285,
5' 1 TC ATC GTT GTC ATA TAA ATC GGC GAG
GTA ATA TTC CAT CAG
42 GTA GAC ATA CG 3'
...GRAF-base 1286. Predicted STOP codon underlined.
Borkhardt A, Bojesen S, Haas OA, Fuchs U, Bartelheimer D,
Loncarevic IF, Bohle RM, Harbott J, Repp R, Jaeger U,
Viehmann S, Henn T, Korth P, Scharr D, Lampert F. The
human GRAF gene is fused to MLL in a unique
t(5;11)(q31;q23) and both alleles are disrupted in three cases
of myelodysplastic syndrome/acute myeloid leukemia with a
deletion 5q. Proc Natl Acad Sci U S A. 2000 Aug
1;97(16):9168-73
Insert 2002
GRAF-base 1988
5' 1 G GTT CAT GCG AGT TCA GCA AGC AGT
TAC CAT GTC TAC GGC
41 ATG CCA GGA TAC TGT TGG GAA GGT AGT
ATT CCG T 3'
...GRAF-base 1989
This article should be referenced as such:
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(1)
Bojesen SE, Borkhardt A. GRAF (GTPase activating protein for
Rho associated with FAK). Atlas Genet Cytogenet Oncol
Haematol. 2001; 5(1):1-2.
2
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Gene Section
Mini Review
HMGIY (high mobility group protein (non histone
chromosomal) isoform I and Y)
Gilka JF Gattas, Florence Pedeutour
UF Recherche Clinique 952, Laboratoire de Génétique, Université de Nice-Sophia Antipolis, CHU de Nice,
06202 Nice, France (GJFG, FP)
Published in Atlas Database: November 2000
Online updated version: http://AtlasGeneticsOncology.org/Genes/HMGIYID221.html
DOI: 10.4267/2042/37689
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2001 Atlas of Genetics and Cytogenetics in Oncology and Haematology
not transcribed, exons 5-7 encode three
DNA binding domains; exon 5 contains a 33 bp
segment subject to alternative splicing; exon 8 encodes
the acidic carboxy-terminal end; RNA length: 1.85 kb.
Identity
Other names:HMG-I(Y), HMGI/Y
HGNC (Hugo): HMGA1
Location: 6p21.3
Local order: centromeric to HLA-A, telomeric to
D6S19.
Protein
Description
107 amino acids; three DNA binding domains (AT
hooks).
Expression
Expressed in embryonal cells; expressed in a variety of
normal human adult tissues such as heart, brain, lung,
skeletal muscle, kidney, pancreas, spleen, thymus,
testis, ovary, small intestine, submandibular gland and
leukocytes; expressed in transformed cells with a
malignant phenotype and in human malignant tumors
such as prostate, thyroid carcinoma and colorectal
carcinomas and a subset of benign lipomas.
Probe(s) - Courtesy Mariano Rocchi, Resources for Molecular
Cytogenetics.
DNA/RNA
Description
10 144 bp; 8 exons, 7 introns.
Localisation
Transcription
Nuclear.
HMGI and HMGY are encoded by the same gene and
are generated trough alternative splicing; exons 1-4 are
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(1)
3
HMGIY (high mobility group protein (non histone chromosomal) isoform I and Y)
translocations might be more complex than shown by
conventional cytogenetics, with the presence of
additional cryptic rearrangements; translocations
involving
partner
chromosomes
other
than
chromosome 14, such as chromosomes 1, 3, 4, 5, 10,
12, 17 have also been reported; inversions
inv(6)(p21q21) or inv(6)(p21.3q26) have been
described.
Hybrid/Mutated gene
In most cases, the breakpoint was extragenic, located
within a 80 kb region 3' of HMGIY; aberrant
transcripts with truncation of sequences from the 3'
UTR have been described; in only one case with
inversion inv(6)(p21q21), a hybrid intragenic fusion
has been reported: HMGIY was fused to the LAMA4
(laminin a4 chain) gene.
Abnormal protein
The HMGIY-LAMA4 resulted from the fusion of the
three HMGIY DNA-binding domains with the LAMA4
EGF-like domain.
Oncogenesis
The exact role of HMGI(Y)-LAMA4 fusion is not
established yet.
Function
Architectural transcription, non histone, factor that
binds to the minor groove of AT-rich DNA; alters
DNA conformation by introducing bends and
supercoils; HMGIY was shown to be an essential
component
of
enhanceosome
(higher
order
transcription enhancer complex); positive induction of
several genes including IFN-b, E-selectin, interleukin-2
receptor a-chain, the chemokine MGSA/GRO, and the
class II major histocompatibility complex gene HLADRA; negative regulation by binding the promoter
regions of interleukin-4 and GP91-PHOX.
The precise function remains to be elucidated; probable
role in regulation of chromatin structure and gene
expression, and transcriptional regulation; potential
oncogenic role.
Homology
Member of the HMGI protein family, structural (but
not expression pattern) homology with HMGIC.
Lipomas
Disease
Benign adipocyte tumors.
Prognosis
Good.
Cytogenetics
A small subset (5-8%) of ordinary lipomas is
characterized by 6p21 rearrangements, the most
frequent of which being a reciprocal translocation
t(3;6)(q28;p21); in contrast to other benign
mesenchymal tumors with 6p21 rearrangement, there is
no evidence of HMGIY rearrangements in ordinary
lipomas yet; however, to be noticed, the breakpoint on
6p21 was shown to be located whithin a 80 kb region
surrounding HMGIY in one lipoma case and HMGIY
expression was correlated with 6p rearrangements in
two ordinary lipomas and two spindle cell lipomas
Mutations
Somatic
HMGIY is found
rearrangements
in
mesenchymal tumors.
involved in chromosome
benign
tumours,
mainly
Implicated in
Pulmonary chondroid hamartoma
Disease
Benign tumor of the lung.
Prognosis
Good.
Cytogenetics
The most frequent rearrangement is a reciprocal
balanced translocation t(6;14) (p21.3; q24); the
rearrangement between chromosomes 6 and 14 can
sometimes be complex, identifiable by FISH;
molecular results also suggest that the
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(1)
Gattas GJF, Pedeutour F
Uterine leiomyoma
Disease
Benign mesenchymal tumors.
Prognosis
Good.
4
HMGIY (high mobility group protein (non histone chromosomal) isoform I and Y)
Cytogenetics
One case with a t(1;6)(p21;21), involving the HMGIY
gene has been described.
Cytogenetics
Approximately 40% of uterine leiomyomas present
structural chromosomal rearrangements, 5% of which
involve 6p abnormalities; they include t(1;6)(q23;p21),
t(6;14)(p21;q24) and t(6;10)(p21;q22) as well as
inversions and translocations involving other
chromosomal partners; the rearrangements are
sometimes complex, only identifiable by FISH
analysis.
Hybrid/Mutated gene
No hybrid gene has been described yet; as for other
mesenchymal tumors, the breakpoint was extragenic,
located within a 80 kb region 3' of HMGIY; one case of
aberrant transcript with truncation of 1295 bp from the
3' UTR has been described.
Abnormal protein
HMGIY mRNA and protein levels do not always
correlate,
suggesting
that
post-transcriptional
mechanisms are involved in the regulation of HMGIY.
Microfollicular adenoma of the thyroid
Disease
Epithelial tumors.
Prognosis
Favourable.
Cytogenetics
One case with a t(1;6)(p35;21) correlated with an
overexpression of HMGIY has been described.
References
Friedmann M, Holth LT, Zoghbi HY, Reeves R. Organization,
inducible-expression and chromosome localization of the
human HMG-I(Y) nonhistone protein gene. Nucleic Acids Res.
1993 Sep 11;21(18):4259-67
Chiappetta G, Avantaggiato V, Visconti R, Fedele M, Battista
S, Trapasso F, Merciai BM, Fidanza V, Giancotti V, Santoro M,
Simeone A, Fusco A. High level expression of the HMGI (Y)
gene during embryonic development. Oncogene. 1996 Dec
5;13(11):2439-46
Endometrial polyps
Disease
Uterine benign tumors.
Prognosis
Good.
Cytogenetics
Several chromosomal abnormalities involving the
6p21.3 region, including translocations, deletions,
inversions have been described; various chromosomal
partner regions, such as 14q24, 20q13, 2q35, 10q22,
8q12, 1p32, 7p15, 15q21, have been described to be
associated with 6p21.3 in reciprocal translocations.
Hybrid/Mutated gene
No hybrid gene has been described yet; as for other
mesenchymal tumors, the breakpoint is extragenic,
located within a 80 kb region 3' of HMGIY.
Dal Cin P, Wanschura S, Christiaens MR, Van den Berghe I,
Moerman P, Polito P, Kazmierczak B, Bullerdiek J, Van den
Berghe H. Hamartoma of the breast with involvement of 6p21
and rearrangement of HMGIY. Genes Chromosomes Cancer.
1997 Sep;20(1):90-2
Tallini G, Dal Cin P, Rhoden KJ, Chiapetta G, Manfioletti G,
Giancotti V, Fusco A, Van den Berghe H, Sciot R. Expression
of HMGI-C and HMGI(Y) in ordinary lipoma and atypical
lipomatous tumors: immunohistochemical reactivity correlates
with karyotypic alterations. Am J Pathol. 1997 Jul;151(1):37-43
Tkachenko A, Ashar HR, Meloni AM, Sandberg AA, Chada KK.
Misexpression of disrupted HMGI architectural factors
activates alternative pathways of tumorigenesis. Cancer Res.
1997 Jun 1;57(11):2276-80
Williams AJ, Powell WL, Collins T, Morton CC. HMGI(Y)
expression in human uterine leiomyomata. Involvement of
another high-mobility group architectural factor in a benign
neoplasm. Am J Pathol. 1997 Mar;150(3):911-8
Hamartoma of the breast
Disease
Benign tumor-like nodule of the breast, also called
adenolipoma.
Prognosis
Good.
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(1)
Gattas GJF, Pedeutour F
Xiao S, Lux ML, Reeves R, Hudson TJ, Fletcher JA. HMGI(Y)
activation by chromosome 6p21 rearrangements in
multilineage mesenchymal cells from pulmonary hamartoma.
Am J Pathol. 1997 Mar;150(3):901-10
5
HMGIY (high mobility group protein (non histone chromosomal) isoform I and Y)
Bandiera A, Bonifacio D, Manfioletti G, Mantovani F, Rustighi
A, Zanconati F, Fusco A, Di Bonito L, Giancotti V. Expression
of HMGI(Y) proteins in squamous intraepithelial and invasive
lesions of the uterine cervix. Cancer Res. 1998 Feb
1;58(3):426-31
Klotzbücher M, Wasserfall A, Fuhrmann U. Misexpression of
wild-type and truncated isoforms of the high-mobility group I
proteins HMGI-C and HMGI(Y) in uterine leiomyomas. Am J
Pathol. 1999 Nov;155(5):1535-42
Pedeutour F, Ligon AH, Morton CC. [Genetics of uterine
leiomyomata]. Bull Cancer. 1999 Nov;86(11):920-8
Hess JL. Chromosomal translocations in benign tumors: the
HMGI proteins. Am J Clin Pathol. 1998 Mar;109(3):251-61
Sornberger KS, Weremowicz S, Williams AJ, Quade BJ, Ligon
AH, Pedeutour F, Vanni R, Morton CC. Expression of HMGIY
in three uterine leiomyomata with complex rearrangements of
chromosome 6. Cancer Genet Cytogenet. 1999 Oct
1;114(1):9-16
Kazmierczak B, Dal Cin P, Wanschura S, Borrmann L, Fusco
A, Van den Berghe H, Bullerdiek J. HMGIY is the target of
6p21.3 rearrangements in various benign mesenchymal
tumors. Genes Chromosomes Cancer. 1998 Dec;23(4):279-85
Martelli AM, Riccio M, Bareggi R, Manfioletti G, Tabellini G,
Baldini G, Narducci P, Giancotti V. Intranuclear distribution of
HMGI/Y proteins. An immunocytochemical study. J Histochem
Cytochem. 1998 Jul;46(7):863-4
Yie J, Merika M, Munshi N, Chen G, Thanos D. The role of
HMG I(Y) in the assembly and function of the IFN-beta
enhanceosome. EMBO J. 1999 Jun 1;18(11):3074-89
Banks GC, Li Y, Reeves R. Differential in vivo modifications of
the HMGI(Y) nonhistone chromatin proteins modulate
nucleosome and DNA interactions. Biochemistry. 2000 Jul
18;39(28):8333-46
Shannon MF, Himes SR, Attema J. A role for the architectural
transcription factors HMGI(Y) in cytokine gene transcription in
T cells. Immunol Cell Biol. 1998 Oct;76(5):461-6
Dal Cin P, Fusco A, Belge G, Chiappetta G, Fedele M,
Pauwels P, Bullerdiek J, Van den Berghe H. Involvement of the
HMGI(Y) gene in a microfollicular adenoma of the thyroid.
Genes Chromosomes Cancer. 1999 Mar;24(3):286-9
Tallini G, Vanni R, Manfioletti G, Kazmierczak B, Faa G,
Pauwels P, Bullerdiek J, Giancotti V, Van Den Berghe H, Dal
Cin P. HMGI-C and HMGI(Y) immunoreactivity correlates with
cytogenetic abnormalities in lipomas, pulmonary chondroid
hamartomas, endometrial polyps, and uterine leiomyomas and
is compatible with rearrangement of the HMGI-C and HMGI(Y)
genes. Lab Invest. 2000 Mar;80(3):359-69
Kazmierczak B, Meyer-Bolte K, Tran KH, Wöckel W,
Breightman I, Rosigkeit J, Bartnitzke S, Bullerdiek J. A high
frequency of tumors with rearrangements of genes of the
HMGI(Y) family in a series of 191 pulmonary chondroid
hamartomas.
Genes
Chromosomes
Cancer.
1999
Oct;26(2):125-33
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(1)
Gattas GJF, Pedeutour F
This article should be referenced as such:
Gattas GJF, Pedeutour F. HMGIY (high mobility group protein
(non histone chromosomal) isoform I and Y). Atlas Genet
Cytogenet Oncol Haematol. 2001; 5(1):3-6.
6
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Gene Section
Short Communication
PU.1 (hematopoietic transcription factor PU.1)
Françoise Moreau-Gachelin
INSERM U528, Laboratoire de Transduction du Signal et Oncogenèse, Section de Recherche -Institut Curie,
26, rue d'Ulm, 75 248 Paris cedex 05, France (FMG)
Published in Atlas Database: November 2000
Online updated version : http://AtlasGeneticsOncology.org/Genes/SPI1ID269.html
DOI: 10.4267/2042/37690
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2001 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Expression
Identity
Hematopoietic specific; mainly in B lymphocytes and
myeloid lineages; faintly expressed in erythroid
progenitors.
Other names: PU.1; SPI-1
HGNC (Hugo): SPI1
Location: 11p11-22
Localisation
Nuclear.
DNA/RNA
Function
Description
Transcriptional regulator; specific DNA binding sites
with a G/AGAA minimal element in promoter and
enhancers of myeloid and B lymphoid genes; involved
both in transcriptional regulation of genes and in
splicing regulation of pre-mRNAs.
Genomic locus around 50kb; 5 exons.
Transcription
1,4kb. open reading frame (ORF): 991bp.
Protein
Homology
ETS genes family.
Description
264 amino acids. DNA binding protein with a ETS
consensus motif.
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(1)
7
PU.1 (hematopoietic transcription factor PU.1)
Moreau-Gachelin F
Mutations
References
Germinal
Moreau-Gachelin F, Tavitian A, Tambourin P. Spi-1 is a
putative oncogene in virally induced murine erythroleukaemias.
Nature. 1988 Jan 21;331(6153):277-80
Unknown.
Somatic
Klemsz MJ, McKercher SR, Celada A, Van Beveren C, Maki
RA. The macrophage and B cell-specific transcription factor
PU.1 is related to the ets oncogene. Cell. 1990 Apr
6;61(1):113-24
Unknown in human pathologies and cancers;
insertional mutagenesis in murine erythroleukemia.
Implicated in
McKercher SR, Torbett BE, Anderson KL, Henkel GW, Vestal
DJ, Baribault H, Klemsz M, Feeney AJ, Wu GE, Paige CJ,
Maki RA. Targeted disruption of the PU.1 gene results in
multiple hematopoietic abnormalities. EMBO J. 1996 Oct
15;15(20):5647-58
Oncogenesis in mouse; mouse gene
name: Spi-1 (SFFV Proviral Integration
1)
Moreau-Gachelin F, Wendling F, Molina T, Denis N, Titeux M,
Grimber G, Briand P, Vainchenker W, Tavitian A. Spi-1/PU.1
transgenic mice develop multistep erythroleukemias. Mol Cell
Biol. 1996 May;16(5):2453-63
Disease
Murine acute erythroleukemia induced by the Friend
retrovirus SFFV (Spleen Focus Forming Virus).
Prognosis
100%.
Hybrid/Mutated gene
No.
Abnormal protein
No; overexpression of the normal protein in the
proerythroblast.
Scott EW, Fisher RC, Olson MC, Kehrli EW, Simon MC, Singh
H. PU.1 functions in a cell-autonomous manner to control the
differentiation of multipotential lymphoid-myeloid progenitors.
Immunity. 1997 Apr;6(4):437-47
Hallier M, Lerga A, Barnache S, Tavitian A, Moreau-Gachelin
F. The transcription factor Spi-1/PU.1 interacts with the
potential splicing factor TLS. J Biol Chem. 1998 Feb
27;273(9):4838-42
This article should be referenced as such:
Moreau-Gachelin F. PU.1 (hematopoietic transcription factor
PU.1). Atlas Genet Cytogenet Oncol Haematol. 2001; 5(1):7-8.
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(1)
8
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Gene Section
Mini Review
FGFR1 (Fibroblast Growth Factor Receptor 1)
Marie-Josèphe Pébusque
INSERM U119, IFR 57, 27 Blvd Lei Roure, 13009 Marseille, France (MJP)
Published in Atlas Database: December 2000
Online updated version: http://AtlasGeneticsOncology.org/Genes/FGFR1113.html
DOI: 10.4267/2042/37691
This article is an update of: Huret JL. FGFR1 (fibroblast growth factor receptor 1). Atlas Genet Cytogenet Oncol Haematol.1998;2(2):35.
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2001 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
Other names: BFGFR (basic fibroblast growth factor
receptor); FLT2 (FMS-like tyrosine kinase 2); FLG
(FMS-like gene); CEK; FGFBR; N-SAM
Location: 8p11
DNA/RNA
FGFR1 (8p12) - Courtesy Mariano Rocchi, Resources for
Molecular Cytogenetics.
Transcription
2.7 mRNA.
Protein
Description
822 amino acids; 100-135 kDa glycoprotein from a 90-115 kDa
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(1)
9
FGFR1 (Fibroblast Growth Factor Receptor 1)
Pébusque MJ
CEP110-FGFR1, and FIM-FGFR1; they encode large
proteins containing the N-term of either FOP or
CEP110, or FIM, and the catalytic domain of FGFR1 at
their C-term:
-N-term leucine-rich region from FOP fused to the
catalytic domain of FGFR1;
-N-term leucine zipper motifs from CEP110 fused to
the catalytic domain of FGFR1;
-N-term zinc fingers from FIM fused to the Tyrosine
kinase domain of FGFR1in C-term.
Oncogenesis
Constitutive activation of FGFR1.
protein core; tyrosine kinase receptor; contains four
major domains: an extracellular domain with 2 or 3 Iglike loops, a transmembrane domain and an
intracellular domain, a juxtamembrane domain, and an
intracellular domain composed of the tyrosine kinase
domain (two kinase domains interrupted by a short
kinase insert), and a C-terminal tail.
Localisation
Plasma membrane.
Function
FGF receptor with tyrosine kinase activity; binding of
ligand (FGF) in association with heparan sulfate
proteoglycans
induces
receptor
dimerization,
autophosphorylation and signal transduction.
Pfeiffer syndrome (inborn disease)
Disease
One form of Pfeiffer syndrome, an autosomal dominant
craniosynostosis syndrome with broad thumbs and
usually no mental deficiency, is due to a mutation in
amino acid 252 (Pro252Arg substitution) of FGFR1.
Homology
With other FGFR (FGFR2, FGFR3, and FGFR4).
Implicated in
Breast cancer
Stem-cell myeloproliferative disorder associated
with chromosomal translocations involving
8p12; to date, seven FGFR1 partners have been
described (see below)
Disease
Stem-cell myeloproliferative disorder characterized by
T- or B-cell lymphoblastic leukemia/lymphoma,
myeloid hyperplasia, and peripheral blood eosinophilia,
and it generally progresses to acute myeloid leukemia;
specific to the 8p12 chromosomal region.
Prognosis
Very poor (median survival: 12 months).
Cytogenetics
The 7 translocations are:
-t(6;8)(q27; p12) involving FOP (FGFR1 Oncogene
Partner);
-t(8;9)(p12;q33) involving CEP110 (Centrosome
protein 110);
-t(8;11)(p12;p15);
-t(8;12)(p12;q15);
-t(8;13)(p12;q12)
involving
FIM
(Fused
In
Myeloproliferative disorder also called ZNF198 or
RAMP);
-t(8;17)(p12;q25);
-t(8;19)(p12;q13.3);
additional anomalies: in the t(8;9)(p12;q33): +der(9),
+21; in the t(8;13)(p12;q12): +8, +der(13), +21.
Hybrid/Mutated gene
-5' FOP - 3' FGFR1 in the t(6;8),
-5' CEP110 - FGFR1 in the t(8;9),
-5' FIM/ZNF198 - 3' FGFR1 in the t(8;13).
Abnormal protein
Three fusion transcripts are identified: FOP-FGFR1,
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(1)
Disease
Gene amplification and overexpression in sporadic
breast tumors.
References
Lee PL, Johnson DE, Cousens LS, Fried VA, Williams LT.
Purification and complementary DNA cloning of a receptor for
basic fibroblast growth factor. Science. 1989 Jul
7;245(4913):57-60
Itoh N, Terachi T, Ohta M, Seo MK. The complete amino acid
sequence of the shorter form of human basic fibroblast growth
factor receptor deduced from its cDNA. Biochem Biophys Res
Commun. 1990 Jun 15;169(2):680-5
Johnson DE, Lu J, Chen H, Werner S, Williams LT. The human
fibroblast growth factor receptor genes: a common structural
arrangement underlies the mechanisms for generating receptor
forms that differ in their third immunoglobulin domain. Mol Cell
Biol. 1991 Sep;11(9):4627-34
Wennström S, Sandström C, Claesson-Welsh L. cDNA cloning
and expression of a human FGF receptor which binds acidic
and basic FGF. Growth Factors. 1991;4(3):197-208
Johnson DE, Williams LT. Structural and functional diversity in
the FGF receptor multigene family. Adv Cancer Res.
1993;60:1-41
Webster MK, Donoghue DJ. FGFR activation in skeletal
disorders: too much of a good thing. Trends Genet. 1997
May;13(5):178-82
Ugolini F, Adélaïde J, Charafe-Jauffret E, Nguyen C,
Jacquemier J, Jordan B, Birnbaum D, Pébusque MJ.
Differential expression assay of chromosome arm 8p genes
identifies Frizzled-related (FRP1/FRZB) and Fibroblast Growth
Factor Receptor 1 (FGFR1) as candidate breast cancer genes.
Oncogene. 1999 Mar 11;18(10):1903-10
This article should be referenced as such:
Pébusque MJ. FGFR1 (Fibroblast Growth Factor Receptor 1).
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(1):9-10.
10
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Gene Section
Mini Review
MLL (myeloid/lymphoid
leukemia)
or
mixed
lineage
Jay L Hess, Jean-Loup Huret
Department of Pathology, The University of Michigan, M5240 Medical Science I, 1301 Catherine Avenue,
Ann Arbor, MI 48109-0602, USA (JLH), Genetics, Dept Medical Information, University of Poitiers, CHU
Poitiers Hospital, F-86021 Poitiers, France (J-LH)
Published in Atlas Database: December 2000
Online updated version: http://AtlasGeneticsOncology.org/Genes/MLL.html
DOI: 10.4267/2042/37692
This article is an update of: Huret JL. MLL (myeloid/lymphoid or mixed lineage leukemia). Atlas Genet Cytogenet Oncol
Haematol.1997;1(2):68-69.
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2001 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Expression
Identity
Wide; especially in: brain, kidney, thyroid; expressed
in Taned B lymphocytes and myeloid cells.
Other names: ALL1; HRX; Htrx (human trithorax);
TRX1
HGNC (Hugo): MLL
Location: 11q23
Local order: Telomeric to PLZF, centromeric from
RCK.
Localisation
Nuclear, in punctate spots.
Function
Transcriptional regulatory factor,
maintenance of Hox gene expression.
DNA/RNA
involved
in
Homology
Description
Trithorax (Drosophila), ALR (human), MLL2 (human).
37 exons, spanning over 100 kb.
Mutations
Transcription
Note
MLL is implicated in at least 10 % of acute leukemias
(AL) of various types: acute lymphoblastic leukemias
(ALL), acute non lymphocytic leukemias (ANLL),
biphenotypic ALs, treatment related leukemias, infant
leukemias; the prognosis is poor.
In a centromeric to telomeric direction; 13 and 15 kb;
coding sequence: 11.9 kb.
Protein
Description
3969 amino acids; 431 kDa; contains two DNA binding
motifs: a AT hook homologous to high mobility group
proteins HMGI-(Y) and HMGI(C) that binds to the
minor groove of DNA, and zinc fingers, a DNA methyl
transferase motif, a bromodomain, and segments of
homology with trithorax, in particular in the C-terminal
SET domain.
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(1)
Implicated in
t(4;11)(q21;q23)/acute leukaemias -->
MLL/AF4
Disease
Typically
CD19+
CD10-precursor
B-ALL,
biphenotypic AL, at times ANLL (M4/M5); common in
11
MLL (myeloid/lymphoid or mixed lineage leukemia)
Hess JL, Huret JL
infants may be congenital; treatment related leukaemia
(secondary to epipodophyllotoxins).
Prognosis
Median survival < 1 year.
Cytogenetics
Additional chromosome anomalies are found in 1/4 of
cases, one of which is the i(7q).
Hybrid/Mutated gene
5' MLL - 3' AF4; 12 kb.
Abnormal protein
240 kDa protein with about 1400 amino acids from
NH2 MLL and 850 from COOH AF4 (variable
breakpoints); the reciprocal may or may not be
expressed.
Abnormal protein
AT hook and DNA methyltransferase from MLL fused
to most of ELL.
Oncogenesis
Potential transcription factor.
t(11;19)(q23;p13.3)/acute leukaemias -->
MLL/ENL
Disease
ALL (CD19+), biphenotypic AL, ANLL (M4/M5);
mainly congenital; treatment-related leukaemia.
Prognosis
Very poor, except in rare T-cell cases.
Cytogenetics
Detected with G banding.
Hybrid/Mutated gene
5' MLL - 3' ENL
Abnormal protein
AT hook and DNA methyltransferase from MLL fused
to, most often, the nearly entire ENL.
t(6;11)(q27;q23)/ANLL --> MLL/AF6
Disease
M5/M4 de novo and therapy related ANLL, T-cell
ALL.
Prognosis
Poor.
trisomy 11/ANLL --> MLL tandem
duplication
t(X;11)(q13;q23)/ANLL, T-ALL --> MLL/AFX1
t(X;11)(q22;q23)/ANLL --> MLL/Septin2
t(1;11)(p32;q23)/ALL --> MLL/AF1p
t(1;11)(q21;q23)/ANLL --> MLL/AF1q
t(2;11)(q11;q23)/MDS --> MLL/LAF4
t(3;11)(p21;q23)/t-ANLL --> MLL/AF3p21
t(3;11)(q25;q23)/t-ANLL --> MLL/GMPS
ins(5;11)(q31;q13q23)/ALL --> MLL/AF5q31
t(5;11)(q31;q23)/ANLL --> MLL/GRAF
t(6;11)(q21;q23)/ANLL --> MLL/AF6q21
t(9;11)(q34;q23)/ALL --> MLL/AF9q34
t(11;14)(q23;q24)/ANLL --> MLL/h-gephyrin
t(11;15)(q23;q14)/ANLL --> MLL/AF15q14
t(11;16)(q23;p13)/t-ANLL --> MLL/CBP
t(11;17)(q23;p13)/t-ANLL --> MLL/GAS7
t(11;17)(q23;q12)/ANLL --> MLL/RARa
t(11;17)(q23;q21)/ANLL --> MLL/AF17
t(11;17)(q23;q25)/ANLL -->
MLL/MSF/AF17q25
t(11;19)(q23;p13)/ANLL --> MLL/EEN
t(9;11)(p22;q23)/ANLL --> MLL/AF9
Disease
M5/M4 de novo and therapy related ANLL.
Prognosis
The prognosis may not be as poor as in other 11q23
leukaemias in de novo cases; very poor prognosis in
secondary ANLL cases.
Cytogenetics
May be overlooked; often as a sole anomaly.
Hybrid/Mutated gene
Variable breakpoints on both genes.
Abnormal protein
N-term -- AT hook and DNA methyltransferase from
MLL fused to the 192 C-term amino acids from AF9
(as breakpoints are variable, this is only an example).
t(10;11)(p12;q23)/ANLL --> MLL/AF10
Disease
M4 or M5 ANLL; ALL at times; therapy related
ANLL.
Prognosis
Poor.
t(11;19)(q23;p13.1)/ANLL --> MLL/ELL
Disease
Mainly M4/M5; treatment related leukemia; all ages.
Prognosis
Very poor.
Cytogenetics
Detected with R banding.
Hybrid/Mutated gene
5' MLL - 3' ELL
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(1)
t(11;22)(q23;q11.2)/ANLL --> MLL/hCDCRel
t(11;22)(q23;q13)/ANLL --> MLL/P300
12
MLL (myeloid/lymphoid or mixed lineage leukemia)
Hess JL, Huret JL
Breakpoints
Note
Spanning a 8 kb genomic region; between exons 5 to 11; highly variable on the partner, ranging from close to the NH2term in ENL, to near the COOH-term in AF9.
References
Bernard OA, Berger R. Molecular basis of 11q23
rearrangements in hematopoietic malignant proliferations.
Genes Chromosomes Cancer. 1995 Jun;13(2):75-85
Waring PM, Cleary ML. Disruption of a homolog of trithorax by
11q23 translocations: leukemogenic and transcriptional
implications. Curr Top Microbiol Immunol. 1997;220:1-23
Schichman SA, Canaani E, Croce CM. Self-fusion of the ALL1
gene. A new genetic mechanism for acute leukemia. JAMA.
1995 Feb 15;273(7):571-6
Dimartino JF, Cleary ML. Mll rearrangements in
haematological malignancies: lessons from clinical and
biological studies. Br J Haematol. 1999 Sep;106(3):614-26
Rubnitz JE, Behm FG, Downing JR. 11q23 rearrangements in
acute leukemia. Leukemia. 1996 Jan;10(1):74-82
Huntsman DG, Chin SF, Muleris M, Batley SJ, Collins VP,
Wiedemann LM, Aparicio S, Caldas C. MLL2, the second
human homolog of the Drosophila trithorax gene, maps to
19q13.1 and is amplified in solid tumor cell lines. Oncogene.
1999 Dec 23;18(56):7975-84
Young BD, Saha V. Chromosome abnormalities in leukaemia:
the 11q23 paradigm. Cancer Surv. 1996;28:225-45
Prasad R, Zhadanov AB, Sedkov Y, Bullrich F, Druck T,
Rallapalli R, Yano T, Alder H, Croce CM, Huebner K, Mazo A,
Canaani E. Structure and expression pattern of human ALR, a
novel gene with strong homology to ALL-1 involved in acute
leukemia and to Drosophila trithorax. Oncogene. 1997 Jul
31;15(5):549-60
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(1)
This article should be referenced as such:
Hess JL, Huret JL. MLL (myeloid/lymphoid or mixed lineage
leukemia). Atlas Genet Cytogenet Oncol Haematol. 2001;
5(1):11-13.
13
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Gene Section
Mini Review
PRDX1 (peroxiredoxin 1)
Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France
(JLH)
Published in Atlas Database: December 2000
Online updated version: http://AtlasGeneticsOncology.org/Genes/PAGID266.html
DOI: 10.4267/2042/37693
This article is an update of: Prosperi MP, Ferbus D, Goubin G. PAG (Proliferation Associated Gene). Atlas Genet Cytogenet Oncol
Haematol 2000;4(4):192
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2001 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Expression
Identity
Widely expressed, in particular in the various cell types
of the central nervous system and in red blood cells;
overexpressed following induction of proliferation and
oxidative stress.
Other names: PAGA (Proliferation Associated Gene
A); PAG; PRX1; Hs.1163; NKEFA (natural killerenhancing factor A); Prx-1 (peroxiredoxin 1); HBP23
(Heme-binding protein 23 kDa); MSP23 (macrophage
23-kD stress protein)
HGNC (Hugo): PRDX1
Location: 1p34.1
Note: PAGA/NKEFA/PRDX1/peroxiredoxin 1, located
in 1p34, is often confused in databases and elsewhere
with PAGB/TDPX2, a pseudogene located in 9p22;
PAGB is not either NKEFB/PRDX2/peroxiredoxin 2,
located in 13q12; the other peroxiredoxins, PRDX3 and
PRDX5, are located in 10q25-26 and in 11q13
respectively.
Localisation
Cytosolic.
Function
Antioxidant, against oxidative stress; Abl SH3-binding
protein; inhibitor of c-Abl tyrosine kinase activity; also
binds to heme.
Homology
Thioperoxiredoxines.
Implicated in
DNA/RNA
Disease
Correlations between the expression level and the stage
of tumor progrssion in squamous cell carcinoma of the
oral cavity; high expression in follicular thyroid
tumors, but not in papillary carcinoma of the thyroid.
Description
6 exons, 13 kb.
Transcription
937 bp mRNA; 599 bp coding sequence.
References
Pseudogene
Prospéri MT, Ferbus D, Karczinski I, Goubin G. A human
cDNA corresponding to a gene overexpressed during cell
proliferation encodes a product sharing homology with
amoebic and bacterial proteins. J Biol Chem. 1993 May
25;268(15):11050-6
Pseudogene in 9p22.
Protein
Description
Prospéri MT, Apiou F, Dutrillaux B, Goubin G. Organization
and chromosomal assignment of two human PAG gene loci:
PAGA encoding a functional gene and PAGB a processed
pseudogene. Genomics. 1994 Jan 15;19(2):236-41
199 amino acids; 22 kDa; form dimers through a
disulfide bridge.
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(1)
14
PRDX1 (peroxiredoxin 1)
Huret JL
Shau H, Butterfield LH, Chiu R, Kim A. Cloning and sequence
analysis of candidate human natural killer-enhancing factor
genes. Immunogenetics. 1994;40(2):129-34
Hirotsu S, Abe Y, Okada K, Nagahara N, Hori H, Nishino T,
Hakoshima T. Crystal structure of a multifunctional 2-Cys
peroxiredoxin heme-binding protein 23 kDa/proliferationassociated gene product. Proc Natl Acad Sci U S A. 1999 Oct
26;96(22):12333-8
Shau H, Kim A. Identification of natural killer enhancing factor
as a major antioxidant in human red blood cells. Biochem
Biophys Res Commun. 1994 Feb 28;199(1):83-8
Sarafian TA, Verity MA, Vinters HV, Shih CC, Shi L, Ji XD,
Dong L, Shau H. Differential expression of peroxiredoxin
subtypes in human brain cell types. J Neurosci Res. 1999 Apr
15;56(2):206-12
Sauri H, Butterfield L, Kim A, Shau H. Antioxidant function of
recombinant human natural killer enhancing factor. Biochem
Biophys Res Commun. 1995 Mar 28;208(3):964-9
Sauri H, Ashjian PH, Kim AT, Shau H. Recombinant natural
killer enhancing factor augments natural killer cytotoxicity. J
Leukoc Biol. 1996 Jun;59(6):925-31
Yanagawa T, Ishikawa T, Ishii T, Tabuchi K, Iwasa S, Bannai
S, Omura K, Suzuki H, Yoshida H. Peroxiredoxin I expression
in human thyroid tumors. Cancer Lett. 1999 Oct 18;145(12):127-32
Wen ST, Van Etten RA. The PAG gene product, a stressinduced protein with antioxidant properties, is an Abl SH3binding protein and a physiological inhibitor of c-Abl tyrosine
kinase activity. Genes Dev. 1997 Oct 1;11(19):2456-67
Mizusawa H, Ishii T, Bannai S. Peroxiredoxin I (macrophage
23 kDa stress protein) is highly and widely expressed in the rat
nervous system. Neurosci Lett. 2000 Mar 31;283(1):57-60
Kang SW, Baines IC, Rhee SG. Characterization of a
mammalian peroxiredoxin that contains one conserved
cysteine. J Biol Chem. 1998 Mar 13;273(11):6303-11
Yanagawa T, Iwasa S, Ishii T, Tabuchi K, Yusa H, Onizawa K,
Omura K, Harada H, Suzuki H, Yoshida H. Peroxiredoxin I
expression in oral cancer: a potential new tumor marker.
Cancer Lett. 2000 Aug 1;156(1):27-35
Prospéri MT, Ferbus D, Rouillard D, Goubin G. The pag gene
product, a physiological inhibitor of c-abl tyrosine kinase, is
overexpressed in cells entering S phase and by contact with
agents inducing oxidative stress. FEBS Lett. 1998 Feb
13;423(1):39-44
This article should be referenced as such:
Huret JL. PRDX1 (peroxiredoxin 1). Atlas Genet Cytogenet
Oncol Haematol. 2001; 5(1):14-15.
Sarafian TA, Huang C, Kim A, de Vellis J, Shau H. Expression
of the antioxidant gene NKEF in the central nervous system.
Mol Chem Neuropathol. 1998 May;34(1):39-51
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(1)
15
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Gene Section
Mini Review
PTCH1 patched homolog 1 (Drosophila)
Erika Lindström, Rune Toftgård
Karolinska Institute, Department of Biosciences, NOVUM, Huddinge, Sweden (EL, RT)
Published in Atlas Database: December 2000
Online updated version: http://AtlasGeneticsOncology.org/Genes/PTCH100.html
DOI: 10.4267/2042/37694
This article is an update of:
Huret JL. PTCH (patched homolog). Atlas Genet Cytogenet Oncol Haematol.1999;3(2):57-58.
Huret JL. PTCH (patched homolog). Atlas Genet Cytogenet Oncol Haematol.1997;1(1):1-2.
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2001 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Function
Identity
Part of a signalling pathway; opposed by the gene
products of hedgehog genes; transmembrane protein; is
thought to have a repressive activity on cell
proliferation; the recent demonstration of NBCCS
syndrome (see below) as a chromosome instability
syndrome suggests that this protein has a role in DNA
maintenance, repair and/or replication.
Other names: PTC, but this term was confusing with
PTC/PKA; PTCH; patched
HGNC (Hugo): PTCH1
Location: 9q22.3
Local order: (between FACC and XPAC PTCH1 is
flanked by the microsatellite markers D9S196 and
D9S287; a microsatellite marker, 1AJL, is located
inside the gene.
Homology
Patched (drosophila segment polarity gene), PTCH2
(human gene with unknown function).
DNA/RNA
Mutations
Description
24 exons, exon 24 is non-coding; 34 kb.
Germinal
Transcription
Germ-line mutations lead to protein truncation in
naevoid basal cell carcinoma syndrome (NBCCS)
patients (see below); mutations types are variable:
nucleotide substitutions (missense/nonsense), small
deletions, or small insertions mainly, leading to protein
truncation; these mutations have been observed in most
exons; there is, so far, no hot-spot.
Alternate splicing: 3 different 5' termini; 6.5 kb mRNA;
coding sequence: CDS 1... 4344.
Protein
Description
Somatic
Glycoprotein; 12 transmembrane domains, 2 extra
cellular loops, intracellular N-term and C-term and
sterol-sensing domain (SSD).
Mutation and allele loss events in basal cell carcinoma,
in NBCCS and in sporadic basal cell carcinoma are, so
far, in accordance with the two-hit model for neoplasia,
as is found in retinoblastoma; mutation and allele loss
have also been found in sporadic primitive
neuroectodermal
tumours
(PNETs),
sporadic
medulloblastomas and in a few cases of esophageal
squamous cell carcinoma and invasive transitional cell
carcinoma of the bladder; mutations have also been
reported in a low frequency of sporadic
Expression
Widely expressed at low levels; increased levels in
cells receiving a hedgehog signal.
Localisation
Transmembrane
protein,
intracellular vesicles.
cellular
membrane,
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(1)
16
PTCH1 patched homolog 1 (Drosophila)
trichoepitheliomas
keratocysts.
and
in
sporadic
Lindström E, Toftgård R
Drosophila patched in sporadic basal cell carcinomas. Nat
Genet. 1996 Sep;14(1):78-81
odontogenic
Hahn H, Christiansen J, Wicking C, Zaphiropoulos PG,
Chidambaram A, Gerrard B, Vorechovsky I, Bale AE, Toftgard
R, Dean M, Wainwright B. A mammalian patched homolog is
expressed in target tissues of sonic hedgehog and maps to a
region associated with developmental abnormalities. J Biol
Chem. 1996 May 24;271(21):12125-8
Implicated in
Naevoid basal cell carcinoma syndrome
(NBCCS) or Gorlin syndrome
Disease
Autosomal dominant condition; cancer prone disease
(multiple basal cell carcinomas, medulloblastomas);
malformations; it is also a chromosome instability
syndrome.
Cytogenetics
Spontaneous and induced chromosome instability.
Hahn H, Wicking C, Zaphiropoulous PG, Gailani MR, Shanley
S, Chidambaram A, Vorechovsky I, Holmberg E, Unden AB,
Gillies S, Negus K, Smyth I, Pressman C, Leffell DJ, Gerrard
B, Goldstein AM, Dean M, Toftgard R, Chenevix-Trench G,
Wainwright B, Bale AE. Mutations of the human homolog of
Drosophila patched in the nevoid basal cell carcinoma
syndrome. Cell. 1996 Jun 14;85(6):841-51
Johnson RL, Rothman AL, Xie J, Goodrich LV, Bare JW,
Bonifas JM, Quinn AG, Myers RM, Cox DR, Epstein EH Jr,
Scott MP. Human homolog of patched, a candidate gene for
the basal cell nevus syndrome. Science. 1996 Jun
14;272(5268):1668-71
Skin cancers
Disease
Sporadic basal cell carcinoma, but also in the benign
trichoepithelioma, a tumor often associated with basal
cell carcinomas.
Sporadic basal cell carcinoma from xeroderma
pigmentosum patients have a high frequency of typical
UV-induced mutations in PTCH1.
Lench NJ, Telford EA, High AS, Markham AF, Wicking C,
Wainwright BJ. Characterisation of human patched germ line
mutations in naevoid basal cell carcinoma syndrome. Hum
Genet. 1997 Oct;100(5-6):497-502
Raffel C, Jenkins RB, Frederick L, Hebrink D, Alderete B, Fults
DW, James CD. Sporadic medulloblastomas contain PTCH
mutations. Cancer Res. 1997 Mar 1;57(5):842-5
Brain diseases
Vorechovský I, Undén AB, Sandstedt B, Toftgård R, StåhleBäckdahl M. Trichoepitheliomas contain somatic mutations in
the overexpressed PTCH gene: support for a gatekeeper
mechanism in skin tumorigenesis. Cancer Res. 1997 Nov
1;57(21):4677-81
Disease
In a subset of sporadic primitive neuroectodermal
tumours (PNETs)of the central nervous system
(cerebral PNETs, medulloblastomas, and desmoplastic
medulloblastomas); note: NBCCS patients have a
predisposition for the development of PNETs, while,
herein mentioned are sporadic PNETs.
PTCH1 have also been found mutated in both familiar
and sporadic cases of Holoprosencephaly (HPE).
Wicking C, Shanley S, Smyth I, Gillies S, Negus K, Graham S,
Suthers G, Haites N, Edwards M, Wainwright B, ChenevixTrench G. Most germ-line mutations in the nevoid basal cell
carcinoma syndrome lead to a premature termination of the
PATCHED protein, and no genotype-phenotype correlations
are evident. Am J Hum Genet. 1997 Jan;60(1):21-6
Wolter M, Reifenberger J, Sommer C, Ruzicka T, Reifenberger
G. Mutations in the human homologue of the Drosophila
segment polarity gene patched (PTCH) in sporadic basal cell
carcinomas of the skin and primitive neuroectodermal tumors
of the central nervous system. Cancer Res. 1997 Jul
1;57(13):2581-5
Various cancers and benign tumors
Disease
Invasive transitional cell carcinoma of the bladder:
PTCH1 has been found mutated in rare cases.
Sporadic esophageal squamous cell carcinoma
Jaws: in sporadic odontogenic keratocysts and in
odontogenic keratocysts from NBCCS patients.
Xie J, Johnson RL, Zhang X, Bare JW, Waldman FM, Cogen
PH, Menon AG, Warren RS, Chen LC, Scott MP, Epstein EH
Jr. Mutations of the PATCHED gene in several types of
sporadic extracutaneous tumors. Cancer Res. 1997 Jun
15;57(12):2369-72
References
Tabata T, Eaton S, Kornberg TB. The Drosophila hedgehog
gene is expressed specifically in posterior compartment cells
and is a target of engrailed regulation. Genes Dev. 1992
Dec;6(12B):2635-45
Aszterbaum M, Rothman A, Johnson RL, Fisher M, Xie J,
Bonifas JM, Zhang X, Scott MP, Epstein EH Jr. Identification of
mutations in the human PATCHED gene in sporadic basal cell
carcinomas and in patients with the basal cell nevus syndrome.
J Invest Dermatol. 1998 Jun;110(6):885-8
Basler K, Struhl G. Compartment boundaries and the control of
Drosophila limb pattern by hedgehog protein. Nature. 1994
Mar 17;368(6468):208-14
Bale SJ, Falk RT, Rogers GR. Patching together the genetics
of Gorlin syndrome. J Cutan Med Surg. 1998 Jul;3(1):31-4
Louhelainen J, Lindström E, Hemminki K, Toftgård R.
Dinucleotide repeat polymorphism within the tumor suppressor
gene PTCH at 9q22. Clin Genet. 1998 Sep;54(3):239-41
Capdevila J, Estrada MP, Sánchez-Herrero E, Guerrero I. The
Drosophila segment polarity gene patched interacts with
decapentaplegic in wing development. EMBO J. 1994 Jan
1;13(1):71-82
Maesawa C, Tamura G, Iwaya T, Ogasawara S, Ishida K, Sato
N, Nishizuka S, Suzuki Y, Ikeda K, Aoki K, Saito K, Satodate
R. Mutations in the human homologue of the Drosophila
patched gene in esophageal squamous cell carcinoma. Genes
Chromosomes Cancer. 1998 Mar;21(3):276-9
Gailani MR, Ståhle-Bäckdahl M, Leffell DJ, Glynn M,
Zaphiropoulos PG, Pressman C, Undén AB, Dean M, Brash
DE, Bale AE, Toftgård R. The role of the human homologue of
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(1)
17
PTCH1 patched homolog 1 (Drosophila)
Lindström E, Toftgård R
McGarvey TW, Maruta Y, Tomaszewski JE, Linnenbach AJ,
Malkowicz SB. PTCH gene mutations in invasive transitional
cell carcinoma of the bladder. Oncogene. 1998 Sep
3;17(9):1167-72
Daya-Grosjean L, Sarasin A. UV-specific mutations of the
human patched gene in basal cell carcinomas from normal
individuals and xeroderma pigmentosum patients. Mutat Res.
2000 May 30;450(1-2):193-9
Shafei-Benaissa E, Savage JR, Babin P, Larrègue M,
Papworth D, Tanzer J, Bonnetblanc JM, Huret JL. The naevoid
basal-cell carcinoma syndrome (Gorlin syndrome) is a
chromosomal instability syndrome. Mutat Res. 1998 Feb
2;397(2):287-92
D'Errico M, Calcagnile A, Canzona F, Didona B, Posteraro P,
Cavalieri R, Corona R, Vorechovsky I, Nardo T, Stefanini M,
Dogliotti E. UV mutation signature in tumor suppressor genes
involved in skin carcinogenesis in xeroderma pigmentosum
patients. Oncogene. 2000 Jan 20;19(3):463-7
Bodak N, Queille S, Avril MF, Bouadjar B, Drougard C, Sarasin
A, Daya-Grosjean L. High levels of patched gene mutations in
basal-cell carcinomas from patients with xeroderma
pigmentosum. Proc Natl Acad Sci U S A. 1999 Apr
27;96(9):5117-22
Dong J, Gailani MR, Pomeroy SL, Reardon D, Bale AE.
Identification of PATCHED mutations in medulloblastomas by
direct sequencing. Hum Mutat. 2000 Jul;16(1):89-90
Toftgård R. Hedgehog signalling in cancer. Cell Mol Life Sci.
2000 Nov;57(12):1720-31
Booth DR. The hedgehog signalling pathway and its role in
basal cell carcinoma. Cancer Metastasis Rev. 1999;18(2):26184
This article should be referenced as such:
Lindström E, Toftgård R. PTCH1 patched homolog 1
(Drosophila). Atlas Genet Cytogenet Oncol Haematol.
2001; 5(1):16-18.
Bailey EC, Scott MP, Johnson RL. Hedgehog signaling in
animal development and human disease. Ernst Schering Res
Found Workshop. 2000;(29):211-35
Barreto DC, Gomez RS, Bale AE, Boson WL, De Marco L.
PTCH gene mutations in odontogenic keratocysts. J Dent Res.
2000 Jun;79(6):1418-22
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(1)
18
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Gene Section
Mini Review
TFF2 (TreFoil Factor 2)
Catherine Tomasetto
I.G.B.M.C., BP 163, 1 rue Laurent Fries, 67404 Illkirch, France (CT)
Published in Atlas Database: December 2000
Online updated version: http://AtlasGeneticsOncology.org/Genes/TFF2ID264.html
DOI: 10.4267/2042/37695
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2001 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
Homology
Other names: SP (Spasmolytic Polypeptide)
HGNC (Hugo): TFF2
Location: 21q22.3
Local order: Belongs to the TFF cluster
TFF2 belongs to the Trefoil peptide Family (TFF) and
possesses two tandemly duplicated TFF motifs each
being homologous to the TFF motif of TFF1 and TFF3.
The TFF motif spans about 40 amino acids and is
formed by 6 conserved residues involved in specific
disulfides bridges.
DNA/RNA
Implicated in
Description
600 bp.
TFF2 was found implicated in inflamatory bowel
diseases, cancers of gastrointestinal organs
such as stomach and pancreas; in constrast to
TFF1 and TFF3, TFF2 expression was not found
in breast carcinomas
Protein
References
5.1 kb gene, 4 exons.
Transcription
Description
Thim L, Thomsen J, Christensen M, Jørgensen KH. The amino
acid sequence of pancreatic spasmolytic polypeptide. Biochim
Biophys Acta. 1985 Mar 1;827(3):410-8
Precursor: 129 amino acids; mature peptide: 106 amino
acids; 3-dimentional structure was solved; the129
amino acids TFF2 protein contains a signal peptide; the
mature secreted peptide of 106 amino acids contains
two TFF (TreFoil Factor) domains and one acidic Cterminal domain.
Rio MC, Bellocq JP, Daniel JY, Tomasetto C, Lathe R,
Chenard MP, Batzenschlager A, Chambon P. Breast cancerassociated pS2 protein: synthesis and secretion by normal
stomach mucosa. Science. 1988 Aug 5;241(4866):705-8
Thim L. A new family of growth factor-like peptides. 'Trefoil'
disulphide loop structures as a common feature in breast
cancer associated peptide (pS2), pancreatic spasmolytic
polypeptide (PSP), and frog skin peptides (spasmolysins).
FEBS Lett. 1989 Jun 19;250(1):85-90
Expression
Under normal condition, TFF2 is expressed in mucus
neck cells of the fundus, basal cells of the antral and
pyloric glands and by the Brunner's glands of the
duodenum.
Tomasetto C, Rio MC, Gautier C, Wolf C, Hareuveni M,
Chambon P, Lathe R. hSP, the domain-duplicated homolog of
pS2 protein, is co-expressed with pS2 in stomach but not in
breast carcinoma. EMBO J. 1990 Feb;9(2):407-14
Localisation
Secreted in gastric fluid.
Rio MC, Chenard MP, Wolf C, Marcellin L, Tomasetto C, Lathe
R, Bellocq JP, Chambon P. Induction of pS2 and hSP genes
as markers of mucosal ulceration of the digestive tract.
Gastroenterology. 1991 Feb;100(2):375-9
Function
In repair and epithelial restitution of the gastrointestinal mucosa.
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(1)
19
TFF2 (TreFoil Factor 2)
Tomasetto C
Theisinger B, Welter C, Seitz G, Rio MC, Lathe R, Chambon P,
Blin N. Expression of the breast cancer associated gene pS2
and the pancreatic spasmolytic polypeptide gene (hSP) in
diffuse type of stomach carcinoma. Eur J Cancer.
1991;27(6):770-3
inflammatory bowel
Jan;104(1):12-20
Gastroenterology.
1993
Playford RJ, Marchbank T, Chinery R, Evison R, Pignatelli M,
Boulton RA, Thim L, Hanby AM. Human spasmolytic
polypeptide is a cytoprotective agent that stimulates cell
migration. Gastroenterology. 1995 Jan;108(1):108-16
Welter C, Theisinger B, Seitz G, Tomasetto C, Rio MC,
Chambon P, Blin N. Association of the human spasmolytic
polypeptide and an estrogen-induced breast cancer protein
(pS2) with human pancreatic carcinoma. Lab Invest. 1992
Feb;66(2):187-92
Babyatsky MW, deBeaumont M, Thim L, Podolsky DK. Oral
trefoil peptides protect against ethanol- and indomethacininduced gastric injury in rats. Gastroenterology. 1996
Feb;110(2):489-97
Gajhede M, Petersen TN, Henriksen A, Petersen JF, Dauter Z,
Wilson KS, Thim L. Pancreatic spasmolytic polypeptide: first
three-dimensional structure of a member of the mammalian
trefoil family of peptides. Structure. 1993 Dec 15;1(4):253-62
Seib T, Blin N, Hilgert K, Seifert M, Theisinger B, Engel M,
Dooley S, Zang KD, Welter C. The three human trefoil genes
TFF1, TFF2, and TFF3 are located within a region of 55 kb on
chromosome 21q22.3. Genomics. 1997 Feb 15;40(1):200-2
Lefebvre O, Wolf C, Kédinger M, Chenard MP, Tomasetto C,
Chambon P, Rio MC. The mouse one P-domain (pS2) and two
P-domain (mSP) genes exhibit distinct patterns of expression.
J Cell Biol. 1993 Jul;122(1):191-8
This article should be referenced as such:
Tomasetto C. TFF2 (TreFoil Factor 2). Atlas Genet Cytogenet
Oncol Haematol. 2001; 5(1):19-20.
Wright NA, Poulsom R, Stamp G, Van Noorden S, Sarraf C,
Elia G, Ahnen D, Jeffery R, Longcroft J, Pike C. Trefoil peptide
gene expression in gastrointestinal epithelial cells in
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(1)
disease.
20
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Gene Section
Short Communication
FGFR1OP (FGFR1 oncogene partner)
Marie-Josèphe Pébusque
INSERM U119, IFR 57, 27 Blvd Lei Roure, 13009 Marseille, France (MJP)
Published in Atlas Database: January 2001
Online updated version: http://AtlasGeneticsOncology.org/Genes/FOPID140.html
DOI: 10.4267/2042/37696
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2001 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Transcription
Identity
A single open reading frame of 1 197 bp mRNA;
putative ATG: bp 85; stop codon at bp 1 282;
alternative splicing: multiple FOP transcript variants
resulting from exon 7 or exon 11 splices.
Other names: FOP (Fibroblast Growth Factor
Receptor 1 Oncogene Partner)
HGNC (Hugo): FGFR1OP
Location: 6q27
Protein
Description
399 amino acids; predicted molecular mass: 44.3 kDa;
Hydrophobic protein containing in its N- and C-termini
several regions folding in a-helices with leucine-rich
repeats with the consensus sequence L-X2-L-X3-5-LX3-5-L, in one-third of which the leucine is substituted
by either a valine or an isoleucine.
Expression
Ubiquitous expression.
Localisation
Cell cytoplasm.
FOP (6q27) - Courtesy Mariano Rocchi, Resources for
Molecular Cytogenetics.
Function
DNA/RNA
Unknown.
Description
Full length cDNA: 1 627 bp.
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(1)
21
FGFR1OP (FGFR1 oncogene partner)
Pébusque MJ
Implicated in
Abnormal protein
N-term leucine-rich region from FOP fused to the
catalytic domain of FGFR1 (FGFR1 intracellular
region minus the major part of the juxtamembrane
domain).
Oncogenesis
Constitutive kinase activity of FGFR1 through
constitutive activation of FGFR1 signal transduction
pathways via putative constitutive dimerization
capability mediated by the FOP N-term LRR sequences
t(6;8)(q27; p12) myeloproliferative
disorder --> FOP - FGFR1; stem-cell
myeloproliferative disorder associated with the
8p12 chromosomal translocations with fusions
to the catalytic domain of FGFR1.
Disease
Stem-cell myeloproliferative disorder characterized by
myeloid
hyperplasia,
T
-cell
lymphoblastic
leukemia/lymphoma and peripheral blood eosinophilia,
and it generally progresses to acute myeloid leukemia;
specific to the 8p12 chromosomal region.
Prognosis
Very poor (median survival: 12 mths).
Cytogenetics
Additional abnormalities: 2q+ and +21.
Hybrid/Mutated gene
5' FOP - 3' FGFR1; localisation: der(6).
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(1)
References
Popovici C, Zhang B, Grégoire MJ, Jonveaux P, LafagePochitaloff M, Birnbaum D, Pébusque MJ. The t(6;8)(q27;p11)
translocation in a stem cell myeloproliferative disorder fuses a
novel gene, FOP, to fibroblast growth factor receptor 1. Blood.
1999 Feb 15;93(4):1381-9
This article should be referenced as such:
Pébusque MJ. FGFR1OP (FGFR1 oncogene partner). Atlas
Genet Cytogenet Oncol Haematol. 2001; 5(1):21-22.
22
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Gene Section
Review
MST1R (Macrophage stimulating 1 receptor)
Debora Angeloni, Michael I Lerman
Laboratory of Immunobiology, National Cancer Institute, Frederick Cancer Research Facility Bldg. 560 Rm.
12 26 Frederick, MD 21702, USA (DA, MIL)
Published in Atlas Database: January 2001
Online updated version: http://AtlasGeneticsOncology.org/Genes/RONID287.html
DOI: 10.4267/2042/37697
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2001 Atlas of Genetics and Cytogenetics in Oncology and Haematology
in intracellular transcription factors where they are
involved in DNA binding. Part of exon 12 codes for the
transmembrane domain, (pink). Exons 14 to 20 codes
for the kinase domain (blue).Four-digit numbers refer
to splice sites location, based on RON cDNA sequence.
Identity
Other names: C-MET-related tyrosine kinase (RON);
RON protein tyrosine kinase (RON);; Macrophage
stimulating protein receptor (MSP-receptor)
HGNC (Hugo): MST1R
Location: 3p21.31
Local order: Between LIMD1 and CCXCR1; between
D3S1568 and D3S3822
Transcription
Two major transcripts are detected, respectively 4.5 kb
and 2 kb. ORF: 4204 bp.
Protein
DNA/RNA
Description
Description
The RON protein is a glycosilated heterodimeric
protein composed of one a- (35 kD) and one b-chain
(150 kD) linked by an unknown number of disulfide
bonds. The two chains derive from a single-chain
precursor of about 185 kD that undergoes proteolytic
cleavage at the basic amino acid site KRRRR. The achain is extracellular. The b-chain has an extracellular
part, a one-pass transmembrane helix and an
intracellular part containing the tyrosine kinase domain.
The first 24 amino acids made the putative signal
peptide (green).
Twenty coding exons. All exons are small in size,
ranging from 93 bp to 253 bp, with the exception of
exon 1 (>1 kb). Exon 1, 2 and 3 code for the SEMA
domain of the RON protein (red). Exons 4 codes for a
PSI domain (orange), a modular structure about 50
amino acid long containing eight conserved Cys
residues, putatively involved in protein-protein
interactions. The sequence between exon 4 and 12
codes for four repeated modular structures called IPT
(yellow); these domains are found in cell surface
receptors such as MET and RON as well as
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(1)
23
MST1R (Macrophage stimulating 1 receptor)
Angeloni D, Lerman MI
proposed that plexins, MET RTK family and VESPR
(virus-encoded semaphorin receptor) are classified as
semaphorins. RON orthologs have been identified in
mouse (STK), chicken (c-sea) and Xenopus.
The SEMA domain (consisting of most of a- and part
of b- chain) contains the ligand (MSP) binding pocket
(unpublished data). Tyrosine residues 1238 and 1239
(upward arrowheads in the figure) are essential for upregulation of RON catalytic activity. Tyrosine
residues1353 and 1360 (downward arrowheads, in the
figure) make a docking site that mediates high affinity
interactions with multiple SH2-containing signal
transducers.
Mutations
Germinal
Several Single Nucleotide Polymorphisms (SNPs) were
found in healthy CEPH individuals: A993G:Gln322Arg
(index of heterozygosity: 0.28); C4024T (same-sense
variant, index of heterozygosity: 0.03); A4031G:
Arg1344Gly (index of heterozygosity: 0.46).
Expression
RON is expressed in human keratinocytes (it was
initially cloned from a keratinocytes cDNA library). By
Northern blot was found expressed in the following
normal human tissues: skin, lung, bone marrow, small
intestin, heart, pancreas, thyroid, prostate, testis
(unpublished data), colonic mucosa and in a variety of
cell types: granulocytes and monocytes, hematopoietic
cells such as erythroid and myeloid progenitor cells,
macrophages,
osteoclasts,
bone
marrow
megakaryocytes, epithelial and neuroendocrine cells.
Somatic
T915C: Leu296Pro was found in the tumor DNA of
one single patient affected with adenocarcinoma of the
lung. The mutated protein is not constitutively
activated. The mutation has no causative role in the
disease. Experimental introduction in the RON kinase
domain of amino acid substitutions D1232V and
M1254T - initially found in the oncogenes KIT, RET
and MET, involved respectively in mastocytosis,
Multiple Endocrine Neoplasia type 2B and renal
papillary carcinoma - results in activation of oncogenic
capacity and triggers a strong metastatic activity of
RON. Expression of these RON mutants causes cellular
accumulation of b-catenin via inhibition of its
association with the axin/GSK complex and subsequent
protection
from
proteasomal
degradation
(Danilkovitch-Miagkova, personal communication).
Localisation
Transmembrane protein.
Function
The ligand for RON is MSP. Originally, MSP was
described as a serum factor enhancing the chemotactic
response of murine peritoneal macrophage to the C5a
fraction of complement, but RON/MSP complex has a
much broader spectrum of activity. Ligand-stimulated
RON activates the pathways regulating cell adhesion
and motility, growth and survival. STK (the mouse
ortholog) is essential for peri-implantation development
during gestation, as STK-deficient mice (STK-/-) are
viable only through the blastocyst stage. Hemizygous
mice (STK+/-) grow to adulthood; however, they are
highly susceptible to endotoxic shock and appear to be
compromised in their ability to down-regulate nitric
oxide production. These results suggest STK has a
limiting role not only in the inflammatory response but
also in early mouse development.
Implicated in
RON was found over-expressed in infiltrating breast
carcinomas. A constitutively activated splicing variant of
RON (lacking exon 11) was found in the gastric
carcinoma cell line KATO-III. This variant induces
activation of cell dissociation, motility and invasion of
extracellular matrices. The same variant was found in
malignant colonic mucosa. Another splicing variant,
lacking exons 5 and 6, was found in the human colon
carcinoma cell line HT-29.Truncated STK - the mouse
RON ortholog - confers susceptibility to Friend virusinduced erythroleukemia in mice, and c-sea, the avian
ortholog, causes erythroblastosis in chickens.
Homology
RON belongs to the MET receptor tyrosine kinase
(RTK) family. On the basis of the presence of multiple
PSI domains and a SEMA domain, it has been
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(1)
24
MST1R (Macrophage stimulating 1 receptor)
Angeloni D, Lerman MI
References
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variant of the RON transcript induces constitutive tyrosine
kinase activity and an invasive phenotype. Mol Cell Biol. 1996
Oct;16(10):5518-26
Muraoka RS, Sun WY, Colbert MC, Waltz SE, Witte DP,
Degen JL, Friezner Degen SJ. The Ron/STK receptor tyrosine
kinase is essential for peri-implantation development in the
mouse. J Clin Invest. 1999 May;103(9):1277-85
Kurihara N, Iwama A, Tatsumi J, Ikeda K, Suda T.
Macrophage-stimulating protein activates STK receptor
tyrosine kinase on osteoclasts and facilitates bone resorption
by osteoclast-like cells. Blood. 1996 May 1;87(9):3704-10
Okino T, Egami H, Ohmachi H, Takai E, Tamori Y, Nakagawa
K, Nakano S, Akagi J, Sakamoto O, Suda T, Ogawa M.
Presence of RON receptor tyrosine kinase and its splicing
variant in malignant and non-malignant human colonic
mucosa. Int J Oncol. 1999 Oct;15(4):709-14
Medico E, Mongiovi AM, Huff J, Jelinek MA, Follenzi A,
Gaudino G, Parsons JT, Comoglio PM. The tyrosine kinase
receptors Ron and Sea control "scattering" and morphogenesis
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(1)
25
MST1R (Macrophage stimulating 1 receptor)
Angeloni D, Lerman MI
Persons DA, Paulson RF, Loyd MR, Herley MT, Bodner SM,
Bernstein A, Correll PH, Ney PA. Fv2 encodes a truncated
form of the Stk receptor tyrosine kinase. Nat Genet. 1999
Oct;23(2):159-65
Chen YQ, Zhou YQ, Angeloni D, Kurtz AL, Qiang XZ, Wang
MH. Overexpression and activation of the RON receptor
tyrosine kinase in a panel of human colorectal carcinoma cell
lines. Exp Cell Res. 2000 Nov 25;261(1):229-38
Wahl RC, Hsu RY, Huff JL, Jelinek
P, Patterson SD, Parsons JT,
macrophage stimulating protein is
protein-tyrosine kinase Sea. J
10;274(37):26361-8
Danilkovitch A, Donley S, Skeel A, Leonard EJ. Two
independent signaling pathways mediate the antiapoptotic
action of macrophage-stimulating protein on epithelial cells.
Mol Cell Biol. 2000 Mar;20(6):2218-27
MA, Chen K, Courchesne
Welcher AA. Chicken
a ligand of the receptor
Biol Chem. 1999 Sep
This article should be referenced as such:
Angeloni D, Danilkovitch-Miagkova A, Ivanov SV, Breathnach
R, Johnson BE, Leonard EJ, Lerman MI. Gene structure of the
human receptor tyrosine kinase RON and mutation analysis in
lung cancer samples. Genes Chromosomes Cancer. 2000
Oct;29(2):147-56
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(1)
Angeloni D, Lerman MI. MST1R (Macrophage stimulating 1
receptor). Atlas Genet Cytogenet Oncol Haematol. 2001;
5(1):23-26.
26
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Gene Section
Mini Review
FIM (fused in myeloproliferative disorders)
Marie-Josèphe Pébusque
INSERM U119, IFR 57, 27 Blvd Lei Roure, 13009 Marseille, France (MJP)
Published in Atlas Database: January 2001
Online updated version : http://AtlasGeneticsOncology.org/Genes/ZNF198ID114.html
DOI: 10.4267/2042/37698
This article is an update of :
Huret JL, Leroux D. ZNF198 (zinc finger protein 198). Atlas Genet Cytogenet Oncol Haematol 1998;2(2):52-53
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2001 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
DNA/RNA
Other names: FIM (fused in myeloproliferative
disorders).; ZNF198 (zinc finger protein 198).; RAMP
HGNC (Hugo): ZMYM2
Location: 13q12
Local order: Proximal from FLT1 and FLT3.
Description
Full length cDNA: 5,016 bp; a single open reading
frame of 4,137 bp; alternative spliced cDNA variant.
Transcription
Main transcripts: 5.0 and 7.5 kb.
Protein
Description
1 379 amino acids; hydrophobic protein containing
several motifs: a N-terminal cystein-rich region
containing ten repeats with the consensus sequence CX2-C-X18-24-F/Y-C-X3-C, which correspond to a
novel zinc finger motifs, a highly hydrophobic prolinerich stretch, and a bipartite nuclear localization signal.
Expression
Wide.
FIM (13q12) - Courtesy Mariano Rocchi, Resources for
Molecular Cytogenetics.
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(1)
27
FIM (fused in myeloproliferative disorders)
Pébusque MJ
DNA Diagram.
Localisation
Abnormal protein
Aberrant tyrosine kinase composed of the N-term twothirds of FIM (retaining the 10 putative zinc finger
motifs), and the FGFR1 intracellular region minus the
major part of the juxtamembrane domain.
Oncogenesis
Constitutive kinase activity of FGFR1 through
constitutive activation of FGFR1 signal transduction
pathways via constitutive dimerization capability
mediated by the FIM N-term zinc finger sequences.
Cell nucleus and nucleolus; within the nucleolus,
colocalizes with UBF (Upstream Binding Factor).
Function
May be involved in the regulation of rRNA
transcription.
Homology
FIM is related to DXS6673E, a gene which may be
related with mental retardation.
References
Implicated in
Popovici C, Adélaïde J, Ollendorff V, Chaffanet M, Guasch G,
Jacrot M, Leroux D, Birnbaum D, Pébusque MJ. Fibroblast
growth factor receptor 1 is fused to FIM in stem-cell
myeloproliferative disorder with t(8;13). Proc Natl Acad Sci U S
A. 1998 May 12;95(10):5712-7
t(8;13)(p12;q12)/ANLL-NHL --> 5' FIM - 3'
FGFR1; stem-cell myeloproliferative disorder associated
with the 8p12 chromosomal translocations; fused to the
catalytic domain of FGFR1
Disease
stem-cell myeloproliferative disorder characterized by
myeloid
hyperplasia,
T
-cell
lymphoblastic
leukemia/lymphoma and peripheral blood eosinophilia,
and it generally progresses to acute myeloid leukemia;
specific to the 8p12 chromosomal region.
Prognosis
Very poor (median survival: 12 mths).
Cytogenetics
Usually, t(8;13)(p12;q12) occurs as a single anomaly;
duplication of the der(13) was found during disease
progression, suggesting that the crucial event might lie
on
this
derivative
chromosome;
additional
abnormalities:+8, +21.
Hybrid/Mutated gene
5' FIM - 3' FGFR1; localisation: der(13)
Smedley D, Hamoudi R, Clark J, Warren W, Abdul-Rauf M,
Somers G, Venter D, Fagan K, Cooper C, Shipley J. The
t(8;13)(p11;q11-12) rearrangement associated with an atypical
myeloproliferative disorder fuses the fibroblast growth factor
receptor 1 gene to a novel gene RAMP. Hum Mol Genet. 1998
Apr;7(4):637-42
Xiao S, Nalabolu SR, Aster JC, Ma J, Abruzzo L, Jaffe ES,
Stone R, Weissman SM, Hudson TJ, Fletcher JA. FGFR1 is
fused with a novel zinc-finger gene, ZNF198, in the t(8;13)
leukaemia/lymphoma
syndrome.
Nat
Genet.
1998
Jan;18(1):84-7
Ollendorff V, Guasch G, Isnardon D, Galindo R, Birnbaum D,
Pébusque MJ. Characterization of FIM-FGFR1, the fusion
product of the myeloproliferative disorder-associated t(8;13)
translocation. J Biol Chem. 1999 Sep 17;274(38):26922-30
Xiao S, McCarthy JG, Aster JC, Fletcher JA. ZNF198-FGFR1
transforming activity depends on a novel proline-rich ZNF198
oligomerization domain. Blood. 2000 Jul 15;96(2):699-704
This article should be referenced as such:
Pébusque MJ. FIM (fused in myeloproliferative disorders).
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(1):27-28.
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(1)
28
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Leukaemia Section
Short Communication
t(1;3)(p36;q21)
Pascale Cornillet-Lefebvre, Sylvie Daliphard, Stéphanie Struski
Laboratory of Hematology, Robert Debré(PCL), Hospital and Medical Faculty (UPRES EA 20-70-IFR 53
Biomolecules), 51092, Reims Cedex, France (SD, SS)
Published in Atlas Database: November 2000
Online updated version: http://AtlasGeneticsOncology.org/Anomalies/t0103.html
DOI: 10.4267/2042/37699
This article is an update of: Huret JL. t(1;3)(p36;q21). Atlas Genet Cytogenet Oncol Haematol.1997;1(1):16.
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2001 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
t(1;3)(p36;q21) G-banding (left) - Courtesy Diane H. Norback, Eric B. Johnson, and Sara Morrison-Delap, Cytogenetics at the Waisman
Center; R-banding (right) -Courtesy Pascale Cornillet-Lefebvre and Stéphanie Struski.
Clinics and pathology
chronic myelogenous leukemia (CML), 1 multiple
myeloma, 1 waldenstrom's macroglobulinemia.
Disease
Epidemiology
Myeloid lineage (MDS, ANLL, therapy related ANLL,
CML, MPD); very rarely in lymphoid lineage.
Patients are aged: 30-80 years.
Clinics
Phenotype/cell stem origin
Blood data: frequent thrombocytosis or normal platelet
count.
Of 39 available cases, there were: 22 myelodysplastic
syndromes (MDS) (17/22 transformed into refractory
acute non lymphoblastic leukemia (ANLL) of -M1 or M4 type), 8 de novo ANLL, 3 therapy-related MDS, 2
polycythemia vera, 1 essential thrombocythemia, 1
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(1)
Cytology
Frequently characterized by dysmegakaryocytopoiesis.
29
t(1;3)(p36;q21)
Cornillet-Lefebvre P et al.
molecular mechanism may explain the clinical and
morphologic similarities seen in these malignancies.
Pathology
Trilineage dysplasia.
References
Prognosis
Very poor so far: from 16 cases, median survival was 6
months in ANLL, 20 months in MDS.
Welborn JL, Lewis JP, Jenks H, Walling P. Diagnostic and
prognostic significance of t(1;3)(p36;q21) in the disorders of
hematopoiesis. Cancer Genet Cytogenet. 1987 Oct;28(2):27785
Cytogenetics
Grigg AP, Gascoyne RD, Phillips GL, Horsman DE. Clinical,
haematological and cytogenetic features in 24 patients with
structural rearrangements of the Q arm of chromosome 3. Br J
Haematol. 1993 Jan;83(1):158-65
Cytogenetics morphological
del(5q) in 5 of 20 cases (1/4).
Genes involved and proteins
Secker-Walker LM, Mehta A, Bain B. Abnormalities of 3q21
and 3q26 in myeloid malignancy: a United Kingdom Cancer
Cytogenetic Group study. Br J Haematol. 1995 Oct;91(2):490501
Note
Genes involved are yet unknown.
Shimizu S, Suzukawa K, Kodera T, Nagasawa T, Abe T,
Taniwaki M, Yagasaki F, Tanaka H, Fujisawa S, Johansson B,
Ahlgren T, Yokota J, Morishita K. Identification of breakpoint
cluster regions at 1p36.3 and 3q21 in hematologic
malignancies with t(1;3)(p36;q21). Genes Chromosomes
Cancer. 2000 Mar;27(3):229-38
To be noted
Note
It has been hypothesized that the chromosomal
breakpoints at the 3q21 in ANLL/MDS with t(1;3)
overlap with the breakpoints of the 3q21q26
syndrome(inv(3)(q21q26), t(3;3)(q21;q26)); common
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(1)
This article should be referenced as such:
Cornillet-Lefebvre P, Daliphard S, Struski S. t(1;3)(p36;q21).
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(1):29-30.
30
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Leukaemia Section
Short Communication
del(17p) in non-Hodgkin's lymphoma (NHL)
Antonio Cuneo, Gianluigi Castoldi
Hematology Section, Department of Biomedical Sciences, University of Ferrara, Corso Giovecca 203,
Ferrara, Italy (AC, GLC)
Published in Atlas Database: December 2000
Online updated version: http://AtlasGeneticsOncology.org/Anomalies/del17pNHLID2083.html
DOI: 10.4267/2042/37700
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2001 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
Prognosis
Note
the 17p- chromosome is a secondary change in most
cases of NHL
The 17p- chromosome was reported to predict for a
poor prognosis in low grade lymphomas; any
abnormality of chromosome 17 was also reported to
negatively affect survival in lymphomas of all
histologic grades
Cytogenetics
Cytogenetics morphological
The deleted segment may vary in size and many cases
with sub-microscopic deletions involving the 17p13
band were reported by FISH; cases with unbalanced
17p translocations leading to 17p loss were also
described; these cases may be associated with dicentric
rearrangements.
The 17p- is usually associated with transformation of a
low-grade FCCL with t(14;18) into a high grade
lymphoma; likewise, there is a higher incidence of 17pin the blastoid variant of MCL with t(11,14) than in the
typical form.
del(17p) in non-Hodgkin's lymphoma (NHL) G- banding Courtesy Melanie Zenger and Claudia Haferlach.
Clinics and pathology
Cytogenetics molecular
Disease
The deletion may be detected by G or R-banding; FISH
using a 17p13/p53 probe is recommended, this
technique being more sensitive than conventional
cytogenetics.
Virtually all histologic subsets of NHL may harbour a
17p- chromosome; there is variation in the reported
incidence due to heterogeneity of histologic
classification and to the different sensitivity of the
detection methods.
10 to 15% of follicle centre cell lymphoma (FCCL) and
mantle cell lymphomas (MCL) may carry a 17pchromosome; minority of marginal zone B-cell
lymphomas may be associated with 17p deletion.
This anomaly is rarely found in T-cell NHL.
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(1)
Genes involved and proteins
Note
The majority of cases with 17p- carry a p53 gene
deletion, associated with mutation of the remaining
allele; there may be a small fraction of cases with a
more distal deletion involving an as yet unidentified
locus.
31
del(17p) in non-Hodgkin's lymphoma (NHL)
Cuneo A, Castoldi GL
Guillermo A, Piris MA, Cardesa A, Montserrat E, Miró R,
Campo E. Increased number of chromosomal imbalances and
high-level DNA amplifications in mantle cell lymphoma are
associated with blastoid variants. Blood. 1999 Jun
15;93(12):4365-74
References
Cabanillas F, Pathak S, Grant G, Hagemeister FB, McLaughlin
P, Swan F, Rodriguez MA, Trujillo J, Cork A, Butler JJ.
Refractoriness to chemotherapy and poor survival related to
abnormalities of chromosomes 17 and 7 in lymphoma. Am J
Med. 1989 Aug;87(2):167-72
Callet-Bauchu E, Salles G, Gazzo S, Poncet C, Morel D,
Pagès J, Coiffier B, Coeur P, Felman P. Translocations
involving the short arm of chromosome 17 in chronic Blymphoid disorders: frequent occurrence of dicentric
rearrangements and possible association with adverse
outcome. Leukemia. 1999 Mar;13(3):460-8
Schlegelberger B, Himmler A, Gödde E, Grote W, Feller AC,
Lennert K. Cytogenetic findings in peripheral T-cell lymphomas
as a basis for distinguishing low-grade and high-grade
lymphomas. Blood. 1994 Jan 15;83(2):505-11
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
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
Clodi K, Younes A, Goodacre A, Roberts M, Palmer J, Younes
M, Cabanillas F, Andreeff M. Analysis of p53 gene deletions in
patients with non-Hodgkin's lymphoma by dual-colour
fluorescence in-situ hybridization. Br J Haematol. 1997
Sep;98(4):913-21
Cuneo A, Bigoni R, Roberti MG, Milani R, Agostini P,
Cavazzini F, Minotto C, De Angeli C, Bardi A, Tammiso E,
Negrini M, Cavazzini P, Castoldi G. Molecular cytogenetic
characterization of marginal zone B-cell lymphoma: correlation
with clinicopathologic findings in 14 cases. Haematologica.
2001 Jan;86(1):64-70
Sankar M, Tanaka K, Kumaravel TS, Arif M, Shintani T, Yagi
S, Kyo T, Dohy H, Kamada N. Identification of a commonly
deleted region at 17p13.3 in leukemia and lymphoma
associated with 17p abnormality. Leukemia. 1998
Apr;12(4):510-6
This article should be referenced as such:
Cuneo A, Castoldi GL. del(17p) in non-Hodgkin's lymphoma
(NHL). Atlas Genet Cytogenet Oncol Haematol. 2001; 5(1):3132.
Beà S, Ribas M, Hernández JM, Bosch F, Pinyol M,
Hernández L, García JL, Flores T, González M, López-
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(1)
32
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Leukaemia Section
Short Communication
del(20q) 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: December 2000
Online updated version: http://AtlasGeneticsOncology.org/Anomalies/del20qID1040.html
DOI: 10.4267/2042/37701
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2001 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Epidemiology
Identity
An interstitial or terminal deletion of the long arm of
chromosome 20 (20q-) has been described as the
second most frequent sole clonal structural abnormality
(5 %) behind t(9.22).
Prognosis
In MDS, 20q- alone is associated with a good prognosis
regarding survival and potential for AML evolution, as
defined by the International Prognostic Scoring System
(IPSS) for MDS prognosis.
In de novo acute leukemia, a poor response to treatment
and a reduced survival is observed.
In myeloproliferative disorders, the presence of 20q
does not appear to adversely affect survival.
Cytogenetics
del(20q) G- banding (left) - Courtesy Diane H. Norback, Eric B.
Johnson, Sara Morrison-Delap Cytogenetics at theWaisman
Center; R-banding (right) - top: Courtesy Jean-Luc Lai; bottom:
Editor
Cytogenetics morphological
The breakpoint on chromosome 20 is not constant; 20qis frequently associated with other cytogenetic
abnormalities as del(5q), trisomy 8, trisomy 21,
deletions or translocations involving the long arm of
chromosome 13; a newly described translocation
t(11;20)(p15;q11) resulting in a NUP98- TOP1 fusion
gene was described in therapy-related myelodysplastic
syndrome (RAEB); t(11;20)(p15;q11) is a rare
recurrent translocation reported in patients with MDS,
ANLL and polycythemia vera.
Clinics and pathology
Disease
A very large spectrum of hematological malignancies
as myelodysplastic syndromes (MDS), acute non
lymphocytic leukemias (ANLL), polycythemia vera,
chronic neutrophilic leukemia.
Phenotype/cell stem origin
As described in various types of hematological
disorders, 20q- appears as a primary karyotypic
abnormality occurring in a pluripotential hematopoietic
stem cell; the pathogenic mechanism by which 20qalters the hematopoietic stem cells in hematological
disorders remains unknown; 20q- may confer a
proliferative advantage to myeloid cells through
deletion of a tumor suppressor gene.
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(1)
Cytogenetics molecular
A small fragment (around 8 Mb), proximally flanked
by D20S206 and distally by D20S119 and UT 654 was
identified using FISH.
Additional anomalies
del(5q), trisomy 8, deletions or translocations involving
13q and trisomy 21.
33
del(20q) in myeloid malignancies
Bilhou-Nabera C
Greenberg P, Cox C, LeBeau MM, Fenaux P, Morel P, Sanz
G, Sanz M, Vallespi T, Hamblin T, Oscier D, Ohyashiki K,
Toyama K, Aul C, Mufti G, Bennett J. International scoring
system for evaluating prognosis in myelodysplastic syndromes.
Blood. 1997 Mar 15;89(6):2079-88
Genes involved and proteins
Note
Genes remaining within this deleted region are
topoisomerase 1 (TPO1-OMIN 126420), phospholipase
C (PLC1), hepatocyte factor nuclear 4 (HNF4) and
adenosine desaminase (ADA); recently, a new gene
KRML transcriptional regulator was mapped in the
smallest commonly deleted region in malignant
myeloid leukemias.
Wang PW, Iannantuoni K, Davis EM, Espinosa R 3rd, Stoffel
M, Le Beau MM. Refinement of the commonly deleted
segment in myeloid leukemias with a del(20q). Genes
Chromosomes Cancer. 1998 Feb;21(2):75-81
Ahuja HG, Felix CA, Aplan PD. The t(11;20)(p15;q11)
chromosomal translocation associated with therapy-related
myelodysplastic syndrome results in an NUP98-TOP1 fusion.
Blood. 1999 Nov 1;94(9):3258-61
References
Wang PW, Eisenbart JD, Cordes SP, Barsh GS, Stoffel M, Le
Beau MM. Human KRML (MAFB): cDNA cloning, genomic
structure, and evaluation as a candidate tumor suppressor
gene in myeloid leukemias. Genomics. 1999 Aug 1;59(3):27581
Mitelman F, Kaneko Y, Trent J. Report of the committee on
chromosome changes in neoplasia. Cytogenetic Cell Genet
1990; 55(1-4):358-86.
Campbell LJ, Garson OM. The prognostic significance of
deletion of the long arm of chromosome 20 in myeloid
disorders. Leukemia. 1994 Jan;8(1):67-71
This article should be referenced as such:
Bilhou-Nabera C. del(20q) in myeloid malignancies. Atlas
Genet Cytogenet Oncol Haematol. 2001; 5(1):33-34.
Kurtin PJ, Dewald GW, Shields DJ, Hanson CA. Hematologic
disorders associated with deletions of chromosome 20q: a
clinicopathologic study of 107 patients. Am J Clin Pathol. 1996
Nov;106(5):680-8
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(1)
34
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Leukaemia Section
Mini Review
Juvenile Chronic Myelogenous Leukemia (JCML)
Jay L Hess
Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, 413b
Stellar Chance Laboratories, Philadelphia, PA 19104, USA (JLH)
Published in Atlas Database: December 2000
Online updated version: http://AtlasGeneticsOncology.org/Anomalies/JCMLID1099.html
DOI: 10.4267/2042/37702
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2001 Atlas of Genetics and Cytogenetics in Oncology and Haematology
of left shift; myeloblasts average about 5% of total
nucleated cells; elevation of fetal hemoglobin (hbF)
very common; absence of the Philadelphia
chromosome in all cases.
Proposed clinical criteria from the International
Juvenile Myelomonocytic Leukemia Working Group
includes:
1. White blood cell count > 13 x 109/L (corrected for
nucleated red blood cells).
2. Absolute monocyte count >1 x 109/L (corrected).
3. Presence of immature myeloid precursors
(myelocytes, promyelocytes, and myeloblasts) in the
peripheral blood.
4. Bone marrow aspirate revealing < 30% blasts
5. No Ph chromosome on cytogenetic assessment.
About 15% of cases are associated with
neurofibromatosis type 1 (NF-1 mutation).
Identity
Alias
Juvenile myelomonocytic leukemia (JMML)
Juvenile myelomonocytic leukemia syndrome (JMML
syndrome)
Note
The proper terminology of this disorder is
controversial; many authors, including the European
Working Group on MDS in Childhood favor the term
JMML; another working group suggests using the term
JMML syndrome with a qualifier with or without
monosomy 7 or 7q-.
Clinics and pathology
Disease
Pathology
JCML is a chronic myeloproliferative disorder that
typically affects young children: more than 95% of
cases are diagnosed before age 4.
Blood: leukocytosis, monocytosis, left shift in myeloid
maturation, circulating mucleated red blood cells.
Bone marrow: hypercellular marrow with mildly
increased M:E ratio (typically 5:1), dispersed erythroid
elements, and decreased numbers of megakaryocytes;
dyplasia is usually not prominent.
Phenotype/cell stem origin
Evidence exists for leukemic involvement of CD34positive stem cells and monocyte-macrophage,
erythroid, and B-lymphoid lineages in cases with
cytogenetic abnormalities.
Treatment
Annual incidence is estimated to be roughly 4/million;
median age 1-4 yrs; sex ratio: 1.4M/1F.
Intensive chemotherapy and all trans retinoic have not
been shown to induce durable remissions; complete
remissions have been achieved with stem cell
transplantation.
Clinics
Prognosis
Splenomegaly, lymphadenopathy, and skin rash are
common; typical peripheral blood findings include
leukocytosis (usually less than 100 x 109/L),
monocytosis, and thrombocytosis with variable degree
The disease is uniformly fatal when treated with
conventional chemotherapy; among those who undergo
bone marrow transplantations, the majority ultimately
relapse, with an overall survival rate of 25%.
Epidemiology
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(1)
35
Juvenile Chronic Myelogenous Leukemia (JCML)
Hess JL
Lutz P, Zix-Kieffer I, Souillet G, Bertrand Y, Dhooge C, Rubie
C, Mazingue F, Marguerite F, Machinaud-Lacroix F, Rialland
X, Plouvier E, Behar C, Vilmer E, Philippe N, Otten J. Juvenile
myelomonocytic leukemia: analyses of treatment results in the
EORTC Children's Leukemia Cooperative Group (CLCG).
Bone Marrow Transplant. 1996 Dec;18(6):1111-6
Cytogenetics
Cytogenetics morphological
Other than the frequent association with monosomy 7,
no consistent cytogenetic abnormalities have been
identified; whether the infantile monosomy 7 syndrome
is distinct from JCML is controversial.
Kai S, Sumita H, Fujioka K, Takahashi H, Hanzawa N,
Funabiki T, Ikuta K, Sasaki H. Loss of heterozygosity of NF1
gene in juvenile chronic myelogenous leukemia with
neurofibromatosis type 1. Int J Hematol. 1998 Jul;68(1):53-60
Genes involved and proteins
Zhang YY, Vik TA, Ryder JW, Srour EF, Jacks T, Shannon K,
Clapp DW. Nf1 regulates hematopoietic progenitor cell growth
and ras signaling in response to multiple cytokines. J Exp Med.
1998 Jun 1;187(11):1893-902
Note
Mechanisms of Oncogenesis:
JCML patients show spontaneous growth of
granulocyte-macrophage colony forming units (CFUGM) from peripheral blood, which appears to be the
result of hypersensitivity to GM-CSF, IL-3, or SCF;
cases associated with NF-1 are likely to be the result of
constitutive activation of the Ras pathway as a result of
decreased GT Pase activity although there is also
evidence of a GAP independent function; up to 30% of
cases show mutations in K-ras and N-ras; the
importance of the RAS pathway has been confirmed in
mouse models with targeted disrupted of Nf-1; recently
data suggest that TNFa produced by neoplastic cells
may prevent expansion of hematopoietic progenitors.
Hasle H, Aricò M, Basso G, Biondi A, Cantù Rajnoldi A,
Creutzig U, Fenu S, Fonatsch C, Haas OA, Harbott J, Kardos
G, Kerndrup G, Mann G, Niemeyer CM, Ptoszkova H, Ritter J,
Slater R, Starý J, Stollmann-Gibbels B, Testi AM, van Wering
ER, Zimmermann M. Myelodysplastic syndrome, juvenile
myelomonocytic leukemia, and acute myeloid leukemia
associated with complete or partial monosomy 7. European
Working Group on MDS in Childhood (EWOG-MDS).
Leukemia. 1999 Mar;13(3):376-85
Smith FO, Sanders JE. Juvenile myelomonocytic leukemia:
what we don't know. J Pediatr Hematol Oncol. 1999 NovDec;21(6):461-3
Birnbaum RA, O'Marcaigh A, Wardak Z, Zhang YY, Dranoff G,
Jacks T, Clapp DW, Shannon KM. Nf1 and Gmcsf interact in
myeloid leukemogenesis. Mol Cell. 2000 Jan;5(1):189-95
References
Cooper LJ, Shannon KM, Loken MR, Weaver M, Stephens K,
Sievers EL. Evidence that juvenile myelomonocytic leukemia
can arise from a pluripotential stem cell. Blood. 2000 Sep
15;96(6):2310-3
Bollag G, Clapp DW, Shih S, Adler F, Zhang YY, Thompson P,
Lange BJ, Freedman MH, McCormick F, Jacks T, Shannon K.
Loss of NF1 results in activation of the Ras signaling pathway
and leads to aberrant growth in haematopoietic cells. Nat
Genet. 1996 Feb;12(2):144-8
Novitzky N. Myelodysplastic syndromes in children. A critical
review of the clinical manifestations and management. Am J
Hematol. 2000 Apr;63(4):212-22
Hess JL, Zutter MM, Castleberry RP, Emanuel PD. Juvenile
chronic myelogenous leukemia. Am J Clin Pathol. 1996
Feb;105(2):238-48
This article should be referenced as such:
Hess JL. Juvenile Chronic Myelogenous Leukemia (JCML).
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(1):35-36.
Largaespada DA, Brannan CI, Jenkins NA, Copeland NG. Nf1
deficiency causes Ras-mediated granulocyte/macrophage
colony stimulating factor hypersensitivity and chronic myeloid
leukaemia. Nat Genet. 1996 Feb;12(2):137-43
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(1)
36
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Leukaemia Section
Short Communication
t(6;8)(q27;p12)
Marie-Josèphe Pébusque
INSERM U119, IFR 57, 27 Blvd Lei Roure, 13009 Marseille, France (MJP)
Published in Atlas Database: December 2000
Online updated version: http://AtlasGeneticsOncology.org/Anomalies/t68ID1090.html
DOI: 10.4267/2042/37703
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2001 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Clinics and pathology
Genes involved and proteins
Disease
FGFR1
Multilineage disorder with combined occurrence of
myeloid malignancy and T- cell NHL, or myeloid
metaplasia.
Location: 8p12
Protein
FGF receptor with tyrosine kinase activity.
Phenotype/cell stem origin
FOP (FGFR1 Oncogene Partner)
The same t(6;8)(q27;p12) is found both in the bone
marrow and in the lymph node: the multilineage
involvement suggests the malignant transformation of a
primitive hematopoietic stem cell.
Location: 6q27
Protein
Hydrophobic protein containing alpha-helices in the Nand C-termini with leucine-rich repeats.
Epidemiology
Result of the chromosomal
anomaly
4 cases are described; median age 29 years (range 2348); sex ratio: 2M/2F.
Clinics
Aggressive disease; complex picture of myeloid
hyperplasia progressing to myelodysplasia and Tlymphoma, and acute non lymphocytic leukemia;
enlarged lymph node infiltrated by myeloid blast cells;
blood data: high WBC (median 40 X 109/l); myelemia;
monocytosis and eosinophilia.
Hybrid gene
Evolution
Description
Aberrant tyrosine kinase composed of the putative
leucine-rich N-terminal region of FOP, and the FGFR1
intracellular region minus the major part of the
juxtamembrane domain.
Oncogenesis
Through constitutive activation of FGFR1 signal
transduction pathways, via putative dimerization of the
fusion protein via the FOP leucine-rich repeats.
Description
Breakpoint in FGFR1 intron 8 which encodes the
juxtamembrane domain, breakpoint in FOP intron 6.
Fusion protein
CR is obtained, but is promptly followed by relapse
progressing rapidly to acute non lymphocytic leukemia.
Prognosis
Median survival: 6 months.
Cytogenetics
Cytogenetics morphological
References
Occurs as a single anomaly.
Cytogenetics molecular
Vannier JP, Bizet M, Bastard C, Bernard A, Ducastelle T, Tron
P. Simultaneous occurrence of a T-cell lymphoma and a
chronic myelogenous leukemia with an unusual karyotype.
Leuk Res. 1984;8(4):647-57
Mega YAC 959-A -4 (1260 kb) from CEPH; FGFR1specific cosmid 134.8.
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(1)
37
t(6;8)(q27;p12)
Pébusque MJ
Elsner S, Martin H, Rode C, Wassman B, Ganser A, Hoelzer
D. An uncommon chromosomal translocation t(6;8) associated
with atypical myelogenous leukemia/myeloproliferative disease
detected by fluorescence in situ hybridisation. Br J Haematol,
1994;87:124
disorders have close or identical breakpoints in chromosome
region 8p11-12. Oncogene. 1998 Feb 19;16(7):945-9
Popovici C, Zhang B, Grégoire MJ, Jonveaux P, LafagePochitaloff M, Birnbaum D, Pébusque MJ. The t(6;8)(q27;p11)
translocation in a stem cell myeloproliferative disorder fuses a
novel gene, FOP, to fibroblast growth factor receptor 1. Blood.
1999 Feb 15;93(4):1381-9
Macdonald D, Aguiar RC, Mason PJ, Goldman JM, Cross NC.
A new myeloproliferative disorder associated with
chromosomal translocations involving 8p11: a review.
Leukemia. 1995 Oct;9(10):1628-30
This article should be referenced as such:
Chaffanet M, Popovici C, Leroux D, Jacrot M, Adélaïde J,
Dastugue N, Grégoire MJ, Hagemeijer A, Lafage-Pochitaloff M,
Birnbaum D, Pébusque MJ. t(6;8), t(8;9) and t(8;13)
translocations associated with stem cell myeloproliferative
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(1)
Pébusque MJ. t(6;8)(q27;p12). Atlas Genet Cytogenet
Oncol Haematol. 2001; 5(1):37-38.
38
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Leukaemia Section
Short Communication
t(8;13)(p12;q12)
Marie-Josèphe Pébusque, Nicholas CP Cross
INSERM U119, IFR 57, 27 Blvd Leï Roure, 13009 Marseille, France (MJP); Wessex Regional Genetics
Laboratory, Salisbury District Hospital, Salisbury, SP2 8BJ, UK (NCPC)
Published in Atlas Database: December 2000
Online updated version: http://AtlasGeneticsOncology.org/Anomalies/t813ID1094.html
DOI: 10.4267/2042/37704
This article is an update of: Huret JL, Leroux D, Bernheim A. t(8;13)(p12;q12). Atlas Genet Cytogenet Oncol Haematol.1998;2(3):95-96.
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2001 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
t(8;13)(p12;q12) G- banding - Top: Courtesy Melanie Zenger and Claudia Haferlach; Middle and bottom: Courtesy Charles Bangs and
Patty Jones.
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(1)
39
t(8;13)(p12;q12)
Pébusque MJ, Cross NCP
der(13) was found during disease progression,
suggesting that the crucial event might lie on this
derivative chromosome; +8, +21 are also recurrently
found.
Clinics and pathology
Disease
A myeloproliferative disorder that is frequently
associated with T cell, or less commonly, B-cell non
Hodgkin lymphoma.
Genes involved and proteins
Phenotype/cell stem origin
FGFR1
May involve a stem cell involving both myeloid, T
lineage, and B-cell lineage.
Location: 8p12
Epidemiology
Location: 13q12
Protein
zinc finger protein (ten repeats in the N-terminal region
with the consensus sequence C-X2-C-X18-24-(F/Y)-CX3-C that corresponds to a novel type of zing finger
motifs), a hydrophobic repeat (proline-rich), and
potentially two putative nuclear localisation signals.
ZNF198 (also called FIM or ID_P)
14 cases are described; median age 43 yrs (range 1868); sex ratio: 6M/8F.
Clinics
Aggressive disease; complex picture of myeloid
hyperplasia progressing to myelodysplasia and Tor -Bcell lymphoma; enlarged lymph node; blood data: high
WBC (median 40 X 109/l); myelemia; monocytosis and
eosinophilia.
Result of the chromosomal
anomaly
Evolution
Hybrid gene
The disease transforms to ANLL, or occasionally ALL,
in a median of 6 months.
Prognosis
Description
Breakpoint in FGFR1 intron 8.
Median survival: 12 months.
Fusion protein
Cytogenetics
Description
Aberrant tyrosine kinase composed of the N-term twothirds of FIM (retaining the 10 putative zinc finger
motifs), and the FGFR1 intracellular region minus the
major part of the juxtamembrane domain (and deleting
the N-term immunoglobulin-like and central
transmembrane domains of FGFR1).
Expression / Localisation
Cytoplasmic.
Oncogenesis
Through constitutive activation of FGFR1 signal
transduction pathways, possibly via dimerization
capability mediated by the FIM N-term sequences of
the fusion protein.
Cytogenetics morphological
The same t(8;13) is found both in the bone marrow and
in the lymph node, ruling out the hypothesis of a
leukemoid reaction caused by a lymphoma; the
multilineage involvement suggests the malignant
transformation of a primitive hematopoietic stem cell.
Probes
Megac Yacs 770-c-2 (1390 kb) and 959-a-4 (1260kb),
856-b-6, 967; 899e2 - (CEPH); BAC 7M15; PAC RPCI
20-G12; FGFR1-specific cosmid 134.8;
Additional anomalies
Usually occurs as a single anomaly; duplication of the
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(1)
40
t(8;13)(p12;q12)
Pébusque MJ, Cross NCP
To be noted
receptor 1 gene to a novel gene RAMP. Hum Mol Genet. 1998
Apr;7(4):637-42
Case Report
t(8;13)(p12;q12) in an atypical chronic myeloid
leukaemia case.
Xiao S, Nalabolu SR, Aster JC, Ma J, Abruzzo L, Jaffe ES,
Stone R, Weissman SM, Hudson TJ, Fletcher JA. FGFR1 is
fused with a novel zinc-finger gene, ZNF198, in the t(8;13)
leukaemia/lymphoma
syndrome.
Nat
Genet.
1998
Jan;18(1):84-7
References
Kulkarni S, Reiter A, Smedley D, Goldman JM, Cross NC. The
genomic structure of ZNF198 and location of breakpoints in the
t(8;13) myeloproliferative syndrome. Genomics. 1999 Jan
1;55(1):118-21
Aguiar RC, Chase A, Coulthard S, Macdonald DH, Carapeti M,
Reiter A, Sohal J, Lennard A, Goldman JM, Cross NC.
Abnormalities of chromosome band 8p11 in leukemia: two
clinical syndromes can be distinguished on the basis of MOZ
involvement. Blood. 1997 Oct 15;90(8):3130-5
Ollendorff V, Guasch G, Isnardon D, Galindo R, Birnbaum D,
Pébusque MJ. Characterization of FIM-FGFR1, the fusion
product of the myeloproliferative disorder-associated t(8;13)
translocation. J Biol Chem. 1999 Sep 17;274(38):26922-30
Popovici C, Adélaïde J, Ollendorff V, Chaffanet M, Guasch G,
Jacrot M, Leroux D, Birnbaum D, Pébusque MJ. Fibroblast
growth factor receptor 1 is fused to FIM in stem-cell
myeloproliferative disorder with t(8;13). Proc Natl Acad Sci U S
A. 1998 May 12;95(10):5712-7
Smedley D, Demiroglu A, Abdul-Rauf M, Heath C, Cooper C,
Shipley J, Cross NC. ZNF198-FGFR1 transforms Ba/F3 cells
to growth factor independence and results in high level tyrosine
phosphorylation of STATS 1 and 5. Neoplasia. 1999
Oct;1(4):349-55
Reiter A, Sohal J, Kulkarni S, Chase A, Macdonald DH, Aguiar
RC, Gonçalves C, Hernandez JM, Jennings BA, Goldman JM,
Cross NC. Consistent fusion of ZNF198 to the fibroblast growth
factor receptor-1 in the t(8;13)(p11;q12) myeloproliferative
syndrome. Blood. 1998 Sep 1;92(5):1735-42
Xiao S, McCarthy JG, Aster JC, Fletcher JA. ZNF198-FGFR1
transforming activity depends on a novel proline-rich ZNF198
oligomerization domain. Blood. 2000 Jul 15;96(2):699-704
Smedley D, Hamoudi R, Clark J, Warren W, Abdul-Rauf M,
Somers G, Venter D, Fagan K, Cooper C, Shipley J. The
t(8;13)(p11;q11-12) rearrangement associated with an atypical
myeloproliferative disorder fuses the fibroblast growth factor
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(1)
This article should be referenced as such:
Pébusque MJ, Cross NCP. t(8;13)(p12;q12). Atlas Genet
Cytogenet Oncol Haematol. 2001; 5(1):39-41.
41
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Leukaemia Section
Short Communication
t(9;12)(q34;p13)
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: December 2000
Online updated version: http://AtlasGeneticsOncology.org/Anomalies/t912ID1080.html
DOI: 10.4267/2042/37705
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2001 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Protein
Contains Helix-Loop-Helix (HLH) at N-terminal end
and ETS DNA binding domain at C-terminal end; wide
expression; nuclear localization; ETS- related
transcription factor.
Clinics and pathology
Disease
Described in only 6 cases; acute lymphoblastic
leukemia (ALL), acute non lymphocytic leukemia
(ANLL) and chronic myeloid leukemia (CML).
Result of the chromosomal
anomaly
Prognosis
Numbers small, but one CML case had allogeneic
BMT and is in complete remission, the remaining cases
had rapid disease progression and died of shortly after
diagnosis.
Hybrid gene
Description
5’ ETV6–3’ ABL; two different fusion breakpoints
have been described; ETV6 exon 4 fused in frame to
ABL exon 2 (Type A) and ETV6 exon 5 fused in frame
to ABL exon 2 (Type B); ETV6 maintains the HLH
domain and ABL the tyrosine kinase domain.
Cytogenetics
Cytogenetics morphological
t(9;12)(q34;p13), cryptic at the cytogenetic level.
Fusion protein
Variants
Description
a 155 kDa protein in Type A, 180 kDa protein in Type
B; has elevated tyrosine kinase activity, localized in the
cytoplasm and co-localizes with the actin filaments of
the cells.
Oncogenesis
The HLH domain of ETV6 induces oligomerization,
which results in the constitutive activation of the kinase
domain of ABL; this is thought to result in
phosphorylation of JAK2 and activation of the STAT
pathway.
Biological activity very similar to BCR-ABL.
t(9;12;14)(q34;p13;q22) and complex insertions of
ETV6 into ABL.
Genes involved and proteins
ABL
Location: 9q34
DNA/RNA
ETV6 is fused to exon 2 of ABL in the three cases
described.
Protein
Tyrosine kinase, localized primarily to the nucleus.
References
ETV6
Papadopoulos P, Ridge SA, Boucher CA, Stocking C,
Wiedemann LM. The novel activation of ABL by fusion to an
ets-related gene, TEL. Cancer Res. 1995 Jan 1;55(1):34-8
Location: 12p13
DNA/RNA
9 exons; alternate splicing.
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(1)
42
t(9;12)(q34;p13)
Heerema NA
Golub TR, Goga A, Barker GF, Afar DE, McLaughlin J,
Bohlander SK, Rowley JD, Witte ON, Gilliland DG.
Oligomerization of the ABL tyrosine kinase by the Ets protein
TEL in human leukemia. Mol Cell Biol. 1996 Aug;16(8):410716
Lacronique V, Boureux A, Monni R, Dumon S, Mauchauffé M,
Mayeux P, Gouilleux F, Berger R, Gisselbrecht S, Ghysdael J,
Bernard OA. Transforming properties of chimeric TEL-JAK
proteins in Ba/F3 cells. Blood. 2000 Mar 15;95(6):2076-83
Van Limbergen H, Beverloo HB, van Drunen E, Janssens A,
Hählen K, Poppe B, Van Roy N, Marynen P, De Paepe A,
Slater R, Speleman F. Molecular cytogenetic and clinical
findings
in
ETV6/ABL1-positive
leukemia.
Genes
Chromosomes Cancer. 2001 Mar;30(3):274-82
Andreasson P, Johansson B, Carlsson M, Jarlsfelt I, Fioretos
T, Mitelman F, Höglund M. BCR/ABL-negative chronic myeloid
leukemia with ETV6/ABL fusion. Genes Chromosomes
Cancer. 1997 Nov;20(3):299-304
Hannemann JR, McManus DM, Kabarowski JH, Wiedemann
LM. Haemopoietic transformation by the TEL/ABL oncogene.
Br J Haematol. 1998 Jul;102(2):475-85
This article should be referenced as such:
Heerema NA. t(9;12)(q34;p13). Atlas Genet Cytogenet Oncol
Haematol. 2001; 5(1):42-43.
Gesbert F, Griffin JD. Bcr/Abl activates transcription of the BclX gene through STAT5. Blood. 2000 Sep 15;96(6):2269-76
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(1)
43
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Leukaemia Section
Short Communication
+3 or trisomy 3 in non Hodgkin's lymphoma (NHL)
Antonio Cuneo, Gianluigi Castoldi
Hematology Section, Department of Biomedical Sciences, University of Ferrara, Corso Giovecca 203,
Ferrara, Italy (AC)
Published in Atlas Database: January 2001
Online updated version: http://AtlasGeneticsOncology.org/Anomalies/tri3NHLID2008.html
DOI: 10.4267/2042/37711
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2001 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
+3 (right) and partial trisomy 3 due to i(3)(q10) (left) FISH - Courtesy Hossein Mossafa.
exception of marginal zone lymphomas (MZL) and
mantle cell lymphoma (MCL); in MZL, total or partial
trisomy 3 may occur in 50-70% of cytogenetically
abnormal cases, with a reported incidence by interphase
FISH in the 50-85% range; the incidence does not
appear to vary according to the clinicopathologic
features, with similar frequency in the extra-nodal
MALT lymphoma, in the nodal and the splenic form of
MZL; trisomy 3/3q was reported in 10-15% of MCL
with an higher incidence (up to 40%) by molecular
cytogenetic techniques; sporadically, other low-grade
and high grade B-lymphoid tumors may carry trisomy
3/3q.
Clinics and pathology
Disease
Trisomy 3 occurs more frequently in T-cell lymphomas
than in B-cell lymphomas.
Globally, 20-30% of T-NHL may carry trisomy 3, the
highest
incidence
having
been
noted
in
lymphoepithelioid lymphoma, in low-grade peripheral
T-cell
lymphoma,
in
angioimmonoblastic
lymphadenopathy and in adult T-cell leukemialymphoma.
Trisomy 3 is relatively rare in B-NHL, with the
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(1)
44
+3 or trisomy 3 in non Hodgkin's lymphoma (NHL)
Cuneo A, Castoldi GL
on Chromosomes in Leukemia-Lymphoma. Blood. 1987
Nov;70(5):1554-64
Prognosis
The prognostic significance of trisomy 3 in T-cell and
B-cell lymphomas is unknown; there does not appear to
be a role for trisomy 3 in tumor progression from lowgrade MALT lymphoma to the high grade form,
whereas gains of 3q may be associated with the
aggressive blastoid variant of MCL.
Schlegelberger B, Himmler A, Gödde E, Grote W, Feller AC,
Lennert K. Cytogenetic findings in peripheral T-cell lymphomas
as a basis for distinguishing low-grade and high-grade
lymphomas. Blood. 1994 Jan 15;83(2):505-11
Dierlamm J, Pittaluga S, Wlodarska I, Stul M, Thomas J,
Boogaerts M, Michaux L, Driessen A, Mecucci C, Cassiman
JJ, De Wolf-Peeters C, Van den Berghe H. Marginal zone Bcell lymphomas of different sites share similar cytogenetic and
morphologic features. Blood. 1996 Jan 1;87(1):299-307
Cytogenetics
Cytogenetics morphological
Michaux L, Dierlamm J, Wlodarska L, Criel A, Louwagie A,
Ferrant A, Hagemeijer A, Van den Berghe H. Trisomy 3q11q29 is recurrently observed in B-cell non-Hodgkin's lymphomas
associated with cold agglutinin syndrome. Ann Hematol. 1998
May;76(5):201-4
Trisomy 3 may be total or partial; commonly
overrepresented segments in partial trisomy 3 include
the q21-23 region and the q25-29 region; total/partial
trisomy 3 may occur as an isolated anomaly in a
minority of cases.
Beà S, Ribas M, Hernández JM, Bosch F, Pinyol M,
Hernández L, García JL, Flores T, González M, LópezGuillermo A, Piris MA, Cardesa A, Montserrat E, Miró R,
Campo E. Increased number of chromosomal imbalances and
high-level DNA amplifications in mantle cell lymphoma are
associated with blastoid variants. Blood. 1999 Jun
15;93(12):4365-74
Cytogenetics molecular
The anomaly is readily detectable by G- and R-banding
in most cases; however, FISH using a centromeric
probe is more sensitive than conventional cytogenetics,
allowing for the study of non-dividing cells and for the
detection of partial trisomy in complex karyotypes with
marker chromosomes.
Hoeve MA, Gisbertz IA, Schouten HC, Schuuring E, Bot FJ,
Hermans J, Hopman A, Kluin PM, Arends JW, van Krieken JH.
Gastric low-grade MALT lymphoma, high-grade MALT
lymphoma and diffuse large B cell lymphoma show different
frequencies of trisomy. Leukemia. 1999 May;13(5):799-807
Genes involved and proteins
Bigoni R, Cuneo A, Milani R, Roberti MG, Bardi A, Rigolin GM,
Cavazzini F, Agostini P, Castoldi G. Secondary chromosome
changes in mantle cell lymphoma: cytogenetic and
fluorescence in situ hybridization studies. Leuk Lymphoma.
2001 Feb;40(5-6):581-90
Note
The gene(s) involved in the transformation process by
gene dosage effect or by other mechanisms are not
known.
This article should be referenced as such:
Cuneo A, Castoldi GL. +3 or trisomy 3 in non Hodgkin's
lymphoma (NHL). Atlas Genet Cytogenet Oncol Haematol.
2001; 5(1):44-45.
References
. Correlation of chromosome abnormalities with histologic and
immunologic characteristics in non-Hodgkin's lymphoma and
adult T cell leukemia-lymphoma. Fifth International Workshop
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(1)
45
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Leukaemia Section
Mini Review
11q23 rearrangements in leukaemia
Jean-Loup Huret
Genetics, Dept Medical Information, UMR 8125 CNRS, University of Poitiers, CHU Poitiers Hospital, F86021 Poitiers, France (JLH)
Published in Atlas Database: January 2001
Online updated version: http://AtlasGeneticsOncology.org/Anomalies/11q23ID1030.html
DOI: 10.4267/2042/37706
This article is an update of: Huret JL. 11q23 rearrangements in leukaemia. Atlas Genet Cytogenet Oncol Haematol.1998;2(4):137-139.
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2001 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Clinics and pathology
Cytogenetics
Disease
Cytogenetics morphological
De novo and therapy related leukaemias; acute non
lymphocytic leukaemia (ANLL) and acute lymphocytic
leukaemia (ALL) grossly represent half cases each;
myelodysplasia (MDS) in the remaining 5%;
biphenotypic leukaemia at times (likely to be more
frequent
with
more
investigations);
11q23
rearrangements in treatment related leukaemias (5-10%
of 11q23 cases) are found mainly following a treatment
with anti-topoisomerase II, or an intercalating
topoisomerase II inhibitor, but also after alkylating
agents treatment and/or radiotherapy; the prior cancer
is variable.
I-The most frequent are:
-Normal karyotype: a partial tandem duplication (in
situ) of MLL is present in a percentage of ANLL with a
normal karyotype; LARG, in 11q23, has been found
fused to MLL;
-+11: 1% of ANLL and MDS as well; M1, M2, and M4
ANLL; therapy related ANLL; MDS evolving towards
ANLL; partial tandem duplication (in situ) of MLL;
visible dup(11q) also occur;
-t(4;11)(q21;q23): represent 1/3 of cases; found mainly
(95%) in B-ALL (CD19+ in 75%, CD10+ in 15%);
treatment related ALL in 5%; unbalanced sex ratio t(6;11)(q27;q23): 5% of cases; mostly; children and
young adults; male predominance; the gene involved in
6q27 is AF6; role in signal transduction;
-t(9;11)(p23;q23): represent 1/4 of cases; found in
ANLL mainly in M5a (70%), or M4 (10%); in ALL in
10%; de novo and therapy related AL; children
represent half cases (infants (- t(10;11)(p12;q23): 5%
of cases; M4 or M5 ANLL; ALL at times; from infants
and children to (rare) adult cases; the gene involved in
10p12 is AF10, a transcription activator;
-t(11;19)(q23;p13.1): 5% of cases; M4 or M5 ANLL
most often; de novo and therapy related AL; adults
mainly; the gene involved in 19p13.1 is ELL, a
transcription activator;
-t(11;19)(q23;p13.3): 5% of cases; ALL, biphenotypic
AL and ANLL (M4/M5 mainly); therapy related AL;
T-cell ALL at times, these T-cell cases are the only
cases of t(11;19) with an excellent prognosis, a rather
Phenotype/cell stem origin
ANLL: M5a in half cases, M4 (20%), M1 or M5b (10%
each), M2 (5%); ALL: B-cell mostly, L1 or L2, CD19+
in 60% of B-ALL cases, CD10+ 35%; T-ALL in rare
cases (<1%); MDS: most often RA or RAEB1T.
Epidemiology
25% are infant (<1 yr) cases; children and adults each
represent 50% of cases; M/F=0.9 (NS).
Clinics
Organomegaly; frequent CNS involvement (5%); high
WBC (>50 X 109/l in 40%).
Prognosis
Very poor in general; variable according to the
translocation, the phenotype, the age, and whether the
leukaemia is de novo or treatment related.
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(1)
46
11q23 rearrangements in leukaemia
Huret JL
-t(11;19)(q23;p13): ANLL; the gene in 19p13 is EEN;
-t(11;21)(q23;q11);
-t(11;22)(q23;q13): ANLL; the gene in 22q13 is P300;
-t(11;22)(q23;q11.2): ANLL; the gene in 22q11.2 is
hCDCRel.
III-Finally, various other breakpoints with 11q23 have
been described, but without gene ascertainment: Xq24,
1q32, 2q37, 7q22, 7q32, 8q11, 9p11, 9q33, 12p13,
12q24, 14q11, 14q32, 17q11, 18q12, 20q13...
rare feature in this page!!; mostly found in infants (half
cases), and other children (altogether: 70%), or young
adults (cases> 40 yrs are 4%; 23 unpublished cases and
a review of 90 cases); the gene involved in 19p13.3 is
ENL, a transcription activator.
II-Various other 11q23 rearrangements have be
described; these are rare, some are even poorly known,
but the ones listed below are recurrent and/or with
ascertainement of a partner gene to MLL:
-inv(11)(p15q23): ANLL and MDS;
-del(11q): one case (t-ANLL) showed involvement of
GAS7, a gene sitting in 17p13; del(11q) with MLL
rearrangement is likely to be heterogeneous, as MLL
shows multiple possible partners, and, not rarely,
complex translocations;
-t(X;11)(q13;q23): ANLL; the gene involved in Xq13
is AFX1, a transcription regulator;
-t(X;11)(q22;q23): the gene in Xq22 is Septin2;
-t(1;11)(p32;q23): ALL and ANLL; the gene involved
in 1p32 is AF1P;
-t(1;11)(q21;q23): mostly M4 ANLL; the gene
involved in 1q21 is AF1q;
-t(2;11)(p21;q23): ANLL and MDS; may be found
associated with del(5q);
-t(2;11)(q11;q23): the gene in 2q11 is LAF4;
-t(3;11)(p21;q23): the gene involved in 3p21 is
AF3p21;
-t(3;11)(q25;q23): the gene in 3q25 is GMPS;
-t(5;11)(q31;q23) and ins(5;11)(q31;q13q23): the latter
involve AF5q31 in 5q31; very rare;
-t(5;11)(q31;q23): the gene in 5q31 is GRAF;
-t(6;11)(q21;q23): ANLL; the gene in 6q21 is AF6q21,
a transcription regulator;
-t(9;11)(q34;q23): the gene in 9q34 is AF9q34;
-t(10;11)(p11.2;q23): the gene in 10p11.2 is ABI1;
-t(10;11)(q22;q23);
-t(11;11)(q13;q23);
-t(11;12)(q23;q13);
-t(11;14)(q23;q24): the gene in 14q24 is h-gephyrin;
-t(11;15)(q23;q14): the gene in 15q14 is AF15q14;
-t(11;15)(q23;q15);
-t(11;16)(q23;p13): treatment related ANLL/MDS;
most cases are children cases; the gene involved in
16p13 is CBP, a transcriptional adaptor/coactivator;
- t(11;17)(q23;p13): the gene in 17p13 is GAS7;
- t(11;17)(q23;q12): the gene in 17q12 is RARa;
- t(11;17)(q23;q21): ANLL; the gene involved in 17q21
is AF17; not to be confused with the in M3 ANLL
variant, with involvement of PLZF in 11q23 and
RARA in 17q21;
-t(11;17)(q23;q25): ANLL and MDS; the gene in
17q25 is MSF/AF17q25;
-t(11;18)(q23;q23);
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(1)
Additional anomalies
+X and i(7q) in the t(4;11); +8, +19, +21 in the t(6;11);
+8 and +19 in the t(9;11); inv(11) in the t(10;11); +X,
+6 and +8 in the 19p13.3; +8 in the 19p13.1.
Genes involved and proteins
MLL
Location: 11q23
DNA/RNA
21 exons, spanning over 100 kb; 13-15 kb mRNA;
coding sequence: 11.9 kb.
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; wide expression; homology
with trithorax (drosophila).
Variable gene, from a variable chromosome
partner (see below)
DNA/RNA
These genes appear to have, in most cases, no apparent
homology to each other; for DNA and protein
description of each, refer to their gene entry.
Result of the chromosomal
anomaly
Hybrid gene
Description
5' MLL-3' partner; highly variable breakpoints on the
partner.
Fusion protein
Description
N-term AT hook and DNA methyltransferase from
MLL fused to (little or most of) the partner C-term part;
the reciprocal (partner-MLL) may or may not be
expressed.
47
11q23 rearrangements in leukaemia
Huret JL
Huret JL, Brizard A, Slater R, Charrin C, Bertheas MF, Guilhot
F, Hählen K, Kroes W, van Leeuwen E, Schoot EV.
Cytogenetic heterogeneity in t(11;19) acute leukemia: clinical,
hematological and cytogenetic analyses of 48 patients-updated published cases and 16 new observations. Leukemia.
1993 Feb;7(2):152-60
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Harrison CJ, Cuneo A, Clark R, Johansson B, LafagePochitaloff M, Mugneret F, Moorman AV, Secker-Walker LM.
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This article should be referenced as such:
Huret JL. 11q23 rearrangements in leukaemia. Atlas Genet
Cytogenet Oncol Haematol. 2001; 5(1):46-49.
49
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Leukaemia Section
Short Communication
del(11q) in non-Hodgkin's lymphoma (NHL)
Antonio Cuneo, Gianluigi Castoldi
Hematology Section, Department of Biomedical Sciences, University of Ferrara, Corso Giovecca 203,
Ferrara, Italy (AC, GLC)
Published in Atlas Database: January 2001
Online updated version : http://AtlasGeneticsOncology.org/Anomalies/del11qNHLID2020.html
DOI: 10.4267/2042/37707
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2001 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
del(11q) G- banding (the 3 left partial karyotypes) - Courtesy Diane H. Norback, Eric B. Johnson, Sara Morrison-Delap UW Cytogenetic
Services; R-banding (right) - Editor
Clinics and pathology
Cytogenetics
Disease
Cytogenetics morphological
The overall incidence in NHL is 4-5%, the highest
incidence having been reported in mantle cell
lymphoma, where up to 70% of the cases studied by
FISH may harbour a cryptic deletion in association
with the classical t(11;14) translocation; FISH detects
an approximate 10% incidence of 11q deletion among
other histologic subsets of B-NHL; among diffuse large
B-cell lymphoma the 11q- chromosome shows a
preferential association with the immunoblastic variant;
sensitive molecular cytogenetic methods may show 5070% of T-cell prolymphocytic leukemia to carry an 11q
deletion involving the ATM gene.
The chromosome 11q deletion occurring in NHL most
frequently affects the q22-23 bands; the 11q- anomaly
occurs as a secondary change in the majority of cases.
Prognosis
Note
The region of minimal deletion was narrowed down to
a 2-3 Mb pair segment where the ataxia teleangiectasia
(ATM) gene is located; sequencing studies showed
mutation in the remaining ATM allele in a significant
fraction of cases.
Cytogenetics molecular
Because the size of the deleted segment may be beyond
the resolution power of conventional banding analysis,
many cases can only be detected by interphase FISH or
other genetic methods using probes targeting the
11q22.3-q23.1 region.
Genes involved and proteins
A possible association between 11q-/ATM- and poor
prognosis in B-cell NHL was reported.
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(1)
50
del(11q) in non-Hodgkin's lymphoma (NHL)
Cuneo A, Castoldi GL
Stoppa-Lyonnet D, Soulier J, Laugé A, Dastot H, Garand R,
Sigaux F, Stern MH. Inactivation of the ATM gene in T-cell
prolymphocytic leukemias. Blood. 1998 May 15;91(10):3920-6
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significance of chromosomal abnormalities in patients with
blastic peripheral B-cell lymphoma. Kiel-Wien-Lymphoma
Study Group. Blood. 1999 Nov 1;94(9):3114-20
Vandenberghe E, De Wolf Peeters C, Wlodarska I, Stul M,
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Molecular cytogenetic delineation of a novel critical genomic
region
in
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bands
11q22.3-923.1
in
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Cuneo A, Bigoni R, Rigolin GM, Roberti MG, Milani R, Bardi A,
Minotto C, Agostini P, De Angeli C, Narducci MG, Sabbioni S,
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deletion involving the ataxia teleangiectasia locus in B-cell nonHodgkin's lymphoma: correlation with clinicobiologic features. J
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carrying BCL1 translocation. Cancer Res. 1997 Mar
15;57(6):1144-50
This article should be referenced as such:
Cuneo A, Castoldi GL. del(11q) in non-Hodgkin's lymphoma
(NHL). Atlas Genet Cytogenet Oncol Haematol. 2001; 5(1):5051.
Stilgenbauer S, Schaffner C, Litterst A, Liebisch P, Gilad S,
Bar-Shira A, James MR, Lichter P, Döhner H. Biallelic
mutations in the ATM gene in T-prolymphocytic leukemia. Nat
Med. 1997 Oct;3(10):1155-9
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(1)
51
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Leukaemia Section
Short Communication
del(7q) in non-Hodgkin's lymphoma (NHL)
Antonio Cuneo, Gianluigi Castoldi
Hematology Section, Department of Biomedical Sciences, University of Ferrara, Corso Giovecca 203,
Ferrara, Italy (AC, GLC)
Published in Atlas Database: January 2001
Online updated version : http://AtlasGeneticsOncology.org/Anomalies/del7qNHLID2082.html
DOI: 10.4267/2042/37708
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2001 Atlas of Genetics and Cytogenetics in Oncology and Haematology
usually involve a relatively large segment, usually
centered around the 7q22-q32 region
Identity
Cytogenetics molecular
conventional G- or R-banded preparations detect the
majority of cases; however some patients with
submicroscopic deletion were detected by FISH or
loss-of-heterozigosity studies
Genes involved and proteins
Note
the involved gene(s) are unknown; the minimal region
of deletion in MZBCL carrying a 7q- chromosome was
narrowed down to a 5cM segment defined by the
D7S685 and D7S514 markers; homozygous deletion of
the D7S685 was reported, suggesting that a tumor
suppressor gene relevant to lymphomagenesis may be
located in this region; a recurrent 7q21 translocation
involving a small 3.6 Kb segment upstream of the
cyclin-dependent kinase 6 gene (CDK6), with resultant
CDK6 overexpression, was described
del(7q) in non-Hodgkin's lymphoma (NHL) G- banding Courtesy Melanie Zenger and Claudia Haferlach.
Clinics and pathology
Disease
The frequency of 7q deletions in unseletced NHL is
less than 5%; an association with splenic marginal zone
B-cell lymphomas (MZBCL) was established, with a
20-30% incidence; sensitive molecular genetic studies
found a 40% incidence in splenic MZBCL, as against a
7% incidence in other forms of NHL
References
Oscier DG, Matutes E, Gardiner A, Glide S, Mould S, BritoBabapulle V, Ellis J, Catovsky D. Cytogenetic studies in splenic
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Nov;85(3):487-91
Prognosis
There may be an association of 7q- with tumor
progression or transformation into a high-grade
MZBCL
Corcoran MM, Mould SJ, Orchard JA, Ibbotson RE, Chapman
RM, Boright AP, Platt C, Tsui LC, Scherer SW, Oscier DG.
Dysregulation of cyclin dependent kinase 6 expression in
splenic marginal zone lymphoma through chromosome 7q
translocations. Oncogene. 1999 Nov 4;18(46):6271-7
Cytogenetics
Cytogenetics morphological
Mateo M, Mollejo M, Villuendas R, Algara P, Sanchez-Beato
M, Martínez P, Piris MA. 7q31-32 allelic loss is a frequent
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7q deletions or unbalanced 7q translocations in NHL
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(1)
52
del(7q) in non-Hodgkin's lymphoma (NHL)
Cuneo A, Castoldi GL
Cuneo A, Bigoni R, Roberti MG, Milani R, Agostini P,
Cavazzini F, Minotto C, De Angeli C, Bardi A, Tammiso E,
Negrini M, Cavazzini P, Castoldi G. Molecular cytogenetic
characterization of marginal zone B-cell lymphoma: correlation
with clinicopathologic findings in 14 cases. Haematologica.
2001 Jan;86(1):64-70
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(1)
This article should be referenced as such:
Cuneo A, Castoldi GL. del(7q) in non-Hodgkin's lymphoma
(NHL). Atlas Genet Cytogenet Oncol Haematol. 2001; 5(1):5253.
53
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Leukaemia Section
Short Communication
t(1;14)(p22;q32) in non Hodgkin's lymphoma (NHL)
Antonio Cuneo, Gianluigi Castoldi
Hematology Section, Department of Biomedical Sciences, University of Ferrara, Corso Giovecca 203,
Ferrara, Italy (AC)
Published in Atlas Database: January 2001
Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t114ID2044.html
DOI: 10.4267/2042/37709
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2001 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Protein
322 amino acids; contains a caspase recruitment
domain; role in the apoptosis.
Clinics and pathology
Disease
IgH
The translocation is cytogenetically detectable in a
minority of extranodal MALT lymphomas; irrespective
of the presence of the 1;14 translocation, mutation or
deletion of the BCL10 gene located at 1p22 can be
detected by molecular genetic methods in 5-10% of
extra-nodal MALT lymphomas, follicle centre cell
lymphoma and diffuse large B-cell lymphoma; among
MALT lymphoma a preferential association was noted
with high-grade histology.
Location: 14q32
References
Wotherspoon AC, Pan LX, Diss TC, Isaacson PG. Cytogenetic
study of B-cell lymphoma of mucosa-associated lymphoid
tissue. Cancer Genet Cytogenet. 1992 Jan;58(1):35-8
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
Prognosis
In MALT lymphoma there may be an association with
aggressive histology and antibiotic-unresponsive forms.
Zhang Q, Siebert R, Yan M, Hinzmann B, Cui X, Xue L,
Rakestraw KM, Naeve CW, Beckmann G, Weisenburger DD,
Sanger WG, Nowotny H, Vesely M, Callet-Bauchu E, Salles G,
Dixit VM, Rosenthal A, Schlegelberger B, Morris SW.
Inactivating mutations and overexpression of BCL10, a
caspase recruitment domain-containing gene, in MALT
lymphoma with t(1;14)(p22;q32). Nat Genet. 1999
May;22(1):63-8
Cytogenetics
Cytogenetics morphological
The translocation is readily detectable by conventional
karyotyping.
Du MQ, Peng H, Liu H, Hamoudi RA, Diss TC, Willis TG, Ye H,
Dogan A, Wotherspoon AC, Dyer MJ, Isaacson PG. BCL10
gene mutation in lymphoma. Blood. 2000 Jun 15;95(12):388590
Genes involved and proteins
Note
The breakpoints on chromosome 1p22 are located
upstream of the promoter of the BCL10 gene, which
shows inactivating mutations or deletions.
This article should be referenced as such:
Cuneo A, Castoldi GL. t(1;14)(p22;q32) in non Hodgkin's
lymphoma (NHL). Atlas Genet Cytogenet Oncol Haematol.
2001; 5(1):54.
BCL10
Location: 1p22
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(1)
54
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Leukaemia Section
Short Communication
t(5;10)(q33;q21)
Cristina Mecucci
Hematology, Policlinico Monteluce, Via Brunamonti, 06123 Perugia, Italy (CM)
Published in Atlas Database: January 2001
Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t510ID1166.html
DOI: 10.4267/2042/37710
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2001 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Clinics and pathology
Genes involved and proteins
Disease
PDGFRB (Platelet Derived Growth Factor
Myeloid lineage.
Receptor Beta)
Location: 5q33
Protein
Transmembrane and tyrosine kinase domains.
Phenotype/cell stem origin
Atypical chronic
myeloid
leukemia (CML),
Philadelphia negative, bcr-abl negative with
eosinophilia.
H4(D10S170)
Epidemiology
Location: 10q21
Protein
Carboxyterminal putative
cytoskeletal protein?
Only two cases available.
Clinics
Massive splenomegaly in one case; some clinical
features of accelerated CML.
SH3
binding
site;
Result of the chromosomal
anomaly
Cytology
Peripheral blood leukoerythroblastosis; bone marrow
granulocytic hyperplasia, bone marrow fibrosis (grade
III-IV reticulin), dry tap
Hybrid gene
Transcript
H4-PDGFBR chimeric RNA constantly present.
Pathology
Extramedullary hemopoiesis in the spleen.
References
Treatment
Siena S, Sammarelli G, Grimoldi MG, Schiavo R, Nozza A,
Roncalli M, Mecucci C, Santoro A, Carlo-Stella C. New
reciprocal translocation t(5;10)(q33;q22) associated with
atypical chronic myeloid leukemia. Haematologica. 1999
Apr;84(4):369-72
Control of disease by hydroxyurea in both cases.
Cytogenetics
Cytogenetics morphological
Kulkarni S, Heath C, Parker S, Chase A, Iqbal S, Pocock CF,
Kaeda J, Cwynarski K, Goldman JM, Cross NC. Fusion of
H4/D10S170 to the platelet-derived growth factor receptor beta
in BCR-ABL-negative myeloproliferative disorders with a
t(5;10)(q33;q21). Cancer Res. 2000 Jul 1;60(13):3592-8
Cytogenetic result: add(5q), del(10q).
Probes
cosB for PDGFBR (5q33); PAC29F6 for H4/D10S170
(10q21)
This article should be referenced as such:
Mecucci C. t(5;10)(q33;q21). Atlas Genet Cytogenet Oncol
Haematol. 2001; 5(1):55.
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(1)
55
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Leukaemia Section
Mini Review
-Y, Y loss in leukemia
Daniel L Van Dyke
Department of Medical Genetics, Henry Ford Health System, 2799 West Grand Boulevard, Clara Ford
Pavillion, Detroit, MI 48202, USA (DLV)
Published in Atlas Database: January 2001
Online updated version : http://AtlasGeneticsOncology.org/Anomalies/YlossID1089.html
DOI: 10.4267/2042/37712
This article is an update of: Desangles F. Y loss in leukemia. Atlas Genet Cytogenet Oncol Haematol.1999;3(2):80-81.
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2001 Atlas of Genetics and Cytogenetics in Oncology and Haematology
In MDS, the proportion of -Y cells has been observed
to increase, decrease, remain stable, or fluctuate up and
down on follow-up studies.
In four cases of Hodgkin disease, simultaneous
fluorescence immunophenotyping and FISH showed
that the -Y cell population was probably independent of
the Hodgkin disease in at least two of the patients. It is
notable that the -Y cells represented fewer than 10-15%
of the metaphase cells in all four cases.
Identity
Note
Loss of the Y chromosome from individual metaphases
is common in metaphase cells from both PHAstimulated lymphocytes and spontaneously dividing
bone marrow cells. The frequency of Y loss is greater
in older men, and the size of the 45,X,-Y cell
population probably increases gradually with
advancing age. (In females, a corollary loss of one X
chromosome also occurs with advancing age.) This
natural phenomenon challenges our ability to
distinguish between a normal and a disease-associated
45,X,-Y clone.
Cytology
No known association.
Prognosis
In ANLL, a 45,X,-Y karyotype is believed to have an
intermediate prognosis. In MDS, the prognosis appears
to be neutral or favorable. There are insufficient data
for MPD or lymphoproliferative disease.
Clinics and pathology
Disease
Cytogenetics
-Y is frenquently observed in myeloproliferative
diseases (MPD), myelodysplasic syndromes (MDS),
acute non lymphocytic leukemias (ANLL), and can
also be seen in lymphoproliferations.
Cytogenetics morphological
In PHA-stimulated lymphocyte karyotype studies of
males, about 2% have one or more cells with loss of the
Y chromosome. Cells with -Y are observed more often
in males over age 55 than in younger males. In all age
groups, the proportion of -Y cells is usually under 10%.
The pattern of Y loss is more striking in bone marrow
aspirate karyotype studies. Here, clonal Y chromosome
loss as a sole abnormality in the karyotype is a common
finding. A 45,X,-Y karyotype is observed in about 6%
of bone marrow karyotype studies from males, and it
represents 15-20% of abnormal karyotypes.
The frequency of -Y cells increases with advancing age
and is significantly greater in cases with MDS, MPD,
ANLL, or lymphoproliferative disease than in subjects
Epidemiology
In CML with t(9;22) and in ANLL with a t(8;21), loss
of the Y chromosome tends to occurs at a younger age
than in the general population.
Clinics
Partial or complete reappearance of the Y chromosome
has been described in several cases of ANLL in
remission. In most or all of these ANLL cases, the
45,X,-Y cell population represented 80-100% of preremission metaphases. These observations support the
interpretation that the leukemia cell karyotype is 45,X,Y.
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(1)
56
-Y, Y loss in leukemia
Van Dyke DL
XXXV. The missing Y in acute non-lymphocytic leukemia
(ANLL). Cancer. 1980 Jan 1;45(1):84-90
who have no evidence of disease. Subjects with no
evidence of disease rarely exhibit more than 75% of
cells with 45,X,-Y. Thus, if fewer than 75% of
metaphase cells are -Y, the disease association is
uncertain. However, if 75-100% of metaphase cells are
-Y, the karyotype probably is disease-associated, even
in older men.
Chromosome rearrangements involving the Y
chromosome are rare in cancer and leukemia. Loss of
the Y chromosome, in contrast, is a common secondary
change in cancer cells and in a few leukemias (see
below).
Holmes RI, Keating MJ, Cork A, Trujillo JM, McCredie KB,
Freireich EJ. Loss of the Y chromosome in acute myelogenous
leukemia: a report of 13 patients. Cancer Genet Cytogenet.
1985 Jul;17(3):269-78
. Acute myelogenous leukemia with an 8;21 translocation. A
report on 148 cases from the Groupe Français de
Cytogénétique Hématologique. Cancer Genet Cytogenet. 1990
Feb;44(2):169-79
Nowinski GP, Van Dyke DL, Tilley BC, Jacobsen G, Babu VR,
Worsham MJ, Wilson GN, Weiss L. The frequency of
aneuploidy in cultured lymphocytes is correlated with age and
gender but not with reproductive history. Am J Hum Genet.
1990 Jun;46(6):1101-11
Probes
All available probe for the Y chromosome.
Additional anomalies
. Loss of the Y chromosome from normal and neoplastic bone
marrows. United Kingdom Cancer Cytogenetics Group
(UKCCG) Genes Chromosomes Cancer. 1992 Jul;5(1):83-8
In association with t(9;22) in CML and with t(8;21) in
FAB-M2 ANLL, loss of the Y chromosome is
generally considered a secondary event of no added
clinical significance.
Abeliovich D, Yehuda O, Ben-Neriah S, Or R. Loss of Y
chromosome. An age-related event or a cytogenetic marker of
a malignant clone? Cancer Genet Cytogenet. 1994
Aug;76(1):70-1
Kirk JA, VanDevanter DR, Biberman J, Bryant EM. Y
chromosome loss in chronic myeloid leukemia detected in both
normal and malignant cells by interphase fluorescence in situ
hybridization.
Genes
Chromosomes
Cancer.
1994
Nov;11(3):141-5
Genes involved and proteins
Note
Genes involved, if any, are unknown.
Riske CB, Morgan R, Ondreyco S, Sandberg AA. X and Y
chromosome loss as sole abnormality in acute nonlymphocytic leukemia (ANLL) Cancer Genet Cytogenet. 1994
Jan;72(1):44-7
To be noted
Note
It is not known whether the Y chromosome loss is the
critical mutational event. Likewise, it is not known
whether the Y chromosome loss is a secondary genetic
change, or if the critical (submicroscopic) genetic
change simply occurs by chance in a -Y cell.
Speculatively, loss of the Y could provide a
proliferative advantage simply because it tends to
replicate late in S-phase. Its loss might therefore
shorten the cell cycle slightly.
Weber-Matthiesen K, Deerberg J, Poetsch M, Grote W,
Schlegelberger B. Clarification of dubious karyotypes in
Hodgkin's
disease
by
simultaneous
fluorescence
immunophenotyping and interphase cytogenetics (FICTION).
Cytogenet Cell Genet. 1995;70(3-4):243-5
Slovak ML, Kopecky KJ, Cassileth PA, Harrington DH, Theil
KS, Mohamed A, Paietta E, Willman CL, Head DR, Rowe JM,
Forman SJ, Appelbaum FR. Karyotypic analysis predicts
outcome of preremission and postremission therapy in adult
acute myeloid leukemia: a Southwest Oncology Group/Eastern
Cooperative Oncology Group Study. Blood. 2000 Dec
15;96(13):4075-83
References
Wiktor A, Rybicki BA, Piao ZS, Shurafa M, Barthel B, Maeda K,
Van Dyke DL. Clinical significance of Y chromosome loss in
hematologic disease. Genes Chromosomes Cancer. 2000
Jan;27(1):11-6
Pierre RV, Hoagland HC. Age-associated aneuploidy: loss of Y
chromosome from human bone marrow cells with aging.
Cancer. 1972 Oct;30(4):889-94
Berger R, Bernheim A. Y chromosome loss in leukemias.
Cancer Genet Cytogenet. 1979;1:1-8.
This article should be referenced as such:
Van Dyke DL. -Y, Y loss in leukemia. Atlas Genet Cytogenet
Oncol Haematol. 2001; 5(1):56-57.
Abe S, Golomb HM, Rowley JD, Mitelman F, Sandberg AA.
Chromosomes and causation of human cancer and leukemia.
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(1)
57
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Solid Tumour Section
Mini Review
Nervous system: Astrocytic tumors
Anne-Marie Capodano
Laboratoire de Cytogénétique Oncologique, Hôpital de la Timone, 264 rue Saint Pierre, 13005 Marseille,
France (AMC)
Published in Atlas Database: November 2000
Online updated version : http://AtlasGeneticsOncology.org/Tumors/AstrocytID5007.html
DOI: 10.4267/2042/37713
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2001 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Clinics
Classification
1- Pilocytic Astrocytomas/Grade I: pilocytic
astrocytomas arise throughout the neuraxis and are
common in children and in young adults; pilocytic
tumors of the optic nerve cause loss of vision; pilocytic
astrocytoma of the hypothalamus and third ventricular
region primarily affect children; but tumors of the
cerebral hemispheres generally occur in patients older
than those with visual system or hypothalamic
involvement.
2- Fibrillary Astrocytomas/Grade II: fibrillary
astrocytomas arise in the cerebral hemisphere of young
to middle-aged adults and the brain stem of children;
occasional examples occur in the cerebellum or spinal
cord; at any site these astrocytomas must be
distinguished from pilocytic astrocytomas; all such
tumors are pilocytic astrocytomas in the optic nerve
whereas most are of the fibrillary type in the brain
stem.
3- Anaplastic Astrocytomas / Grade III: anaplastic
astrocytomas occur in the same locations as
astrocytomas (I-II) and glioblastoma, but the majority
affect
the
cerebral
hemispheres;
anaplastic
astrocytomas generally occur in patients a decade older
than those with better differenciated astrocytomas and a
decade younger than those with glioblastomas.
4- Glioblastoma Multiforme / Grade IV: glioblastoma
is by far the most common glioma; it affects principally
the cerebral hemispheries in adults and the brain stem
in children; but they are most frequent after the fifth
decade; most glioblastomas are solitary but occasional
examples are geographically separate in the same
patient and warrant the designation " multicentric ";
usually, it appears as a central area of hypodensity
surrounded by a ring of contrast enhanced and
penumbra of cerebral oedema.
Note
Astrocytic tumors comprise a wide range of neoplasms
that differ in their location within the central nervous
system (CNS), age and gender distribution, growth
potential, extent of invasiveness, morphological
features, tendency for progression and clinical course;
there is increasing evidence that these differences
reflect the type and sequence of genetic alterations
acquired during the process of transformation.
Classification
The following clinicopathological entities can be
distinguished:
Pilocytic Astrocytomas (Grade I).
Fibrillary Astrocytomas (Grade II).
Anaplastic Astrocytomas (Grade III).
Glioblastoma Multiforme (Grade IV).
Clinics and pathology
Etiology
Gliomas have been observed following therapeutic
irradiation.
Familial clustering of gliomas is not uncommon: the
association with defined inherited tumor syndrome
incuding the Li-Fraumeni syndrome, Turcot syndrome,
and the NF1 syndrome.
Epidemiology
Diffuse astrocytomas are the most frequent intracranial
neoplasm and account for more than 60% of all
primary brain tumors; the incidence differs between
regions, but there are 5 to 7 new cases per 100.000
population per year.
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(1)
58
Nervous system: Astrocytic tumors
Capodano AM
Glioblastoma multiforme may develop de novo
(primary glioblastoma) or though progression from
low-grade or anaplastic astrocytoma (secondary
glioblastoma); patients with a primary glioblastoma are
usually older, present a rapid tumor progression and a
poor prognosis; patient with secondary glioblastomas
are younger and tumor progress more slowly, with a
better prognosis; these two groups are histologically
indistinguishable.
time after surgery is 6-8 years in low-grade
astrocytomas; after surgery, the prognosis depends on
whether the neoplasm undergoes progression to a more
malignant phenotype; in pilocytic astrocytomas, total
cure is possible after total resection; in fibrillary
astrocytomas reccurrence is frequent.
In anaplastic astrocytomas and in glioblastomas,
evaluation of the extent of resection can be a prognostic
factor; prognosis is generally poor (about one year);
patients below 45 yrs have a considerably better
prognosis than elderly patients; primary glioblastomas
have a short clinical history with a poor prognosis;
survival is better in secondary glioblastomas.
Pathology
1- Pilocytic Astrocytomas / Grade I: this predominantly
peadiatric brain tumor is a circumscribed astrocytoma
composed in varying proportions of compacted and
loose textured astrocytes associated with rosenthal
fibers, eosinophilic granular bodies, or both; the lesion
described is sometimes referred to as the " juvenile
pilocytic astrocytoma ".
2- Fibrillary Astrocytomas / Grade II: this tumor is a
well differanciated diffusely infiltrating neoplasm of
fibrillary astrocytes.
3- Anaplastic Astrocytomas / Grade III: this tumor is an
astrocytic tumor of fibrillary type which is intermediate
in differenciation between the better differenciated
astrocytoma and glioblastoma; it is an astrocytic
neoplasm that typically exceeds well differenciated
astrocytoma in terms of cellularity, nuclear
pleomorphism and hyperchromasia necrosis of
glioblastoma.
4- Glioblastoma Multiforme / Grade IV: this tumor is a
highly malignant glioma most closely related to
fibrillary or diffuse astrocytic neoplasms; glioblastomas
are cellular masses with varied tissue patterns; it
appears either infiltrating or discrete, with typical or
atypical mitoses, endothelial vascular proliferation and
necrosis another subgroup of glioblastoma can be
distinguished:
the
giant
cell
glioblastomas;
histologically it is a glioblastoma with giant cells (500
mm in diameter): it develops clinically "de novo"; it is
associated with a favorable prognosis
Cytogenetics
Cytogenetics Morphological
In astrocytomas grade I, normal karyotype is observed
most frequently; among the cases with abnormal
karyotypes, the most frequent chromosomal
abnormalityis loss of the X and Y sex- chromosomes;
loss of 22q is found in 20-30% of astrocytomas; other
abnormalities observed in low grade tumors include
gains on chromosome 8q, 10p, and 12p, and losses on
chromosomes 1p, 4q, 9p, 11p 16p, 18 and 19.
In anaplastic astrocytomas, chromosome gains or losses
are frequent: trisomy 7 (the most frequent), loss of
chromosome 10, loss of chromosome 22, loss of 9p,
13q; other abnormalities, less frequently described are:
gains of chromosomes 1q, 11q, 19, 20, and Xq.
Glioblastomas show several chromosomal changes: by
frequency order, gain of chromosome 7 (50-80% of
glioblastomas), double minute chromosomes, total or
partial monosomy for chromosome 10 (70% of tumors)
associated with the later step in the progression of
glioblastomas partial deletion of 9p is frequent (64% of
tumors): 9pter-23; partial loss of 22q in 22q13 is
frequently reported. Loss or deletion of chromosome
13, 13q14-q31 is found in some glioblastomas.
Trisomy 19 was reported in glioblastomas by
cytogenetic and comparative genomic hybridization
(CGH) analysis; the loss of 19q in 19q13.2-qter was
detected by loss of heterozigocity (LOH) studies in
glioblastomas.
Deletion of chromosome 4q, complete or partial gains
of chromosome 20 has been described; gain or
amplification of 12q14-q21 has been reported.
The loss of chromosome Y might be considered, when
it occurs in addition to other clonal abnormalities.
Treatment
Treatment differs according to grade and location of
tumor.
Pilocytic astrocytomas can be cured by complete
resection of tumor; if exeresis is not possible due to the
location of the tumor, chemotherapy is indicated in
young children and radiotherapy in adults in fibrillary
astrocytomas, the treatment consists of total and extent
resection of tumor in anaplastic tumors and
glioblastoma multiforme, the treatment consists of total
resection and radiotherapy and chemotherapy after
surgery.
Genes involved and proteins
Note
Alteration of genes involved in cell-cycle control: it is
known that the progression of the-cell cycle is
controled by positive and negative regulators; some
autors report alteration in cell-cycle gene expression in
human brain tumors. The p16 gene and the p15 gene
Prognosis
In low grade astrocytomas, a correlation of
proliferation was reported (Ki67 index) with clinical
outcome; the proliferative potential correlates inversely
with survival and time to recurrence; the mean survival
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(1)
59
Nervous system: Astrocytic tumors
Capodano AM
The LG11 novel gene located in 10p24 region is a
suppressor gene rearranged in several glioblastomas
tumors.
Allelic loss of chromosome 22q wich contains the
neurofibromatosis type 2, tumor suppressor gene NF2
is observed in 20-30% of astrocytomas. But another
possibility is the involvement of another gene located
on chromosome 22 in the tumorogenesis of
astrocytomas.
Most of these genes participate in the progression of
astrocytomas (fig 1).
Expression of growth factors and growth factor
receptors:
The epidermal growth factor receptor (EGFR) coded by
the EGFR cellular oncogene is located on human
chromosome 7 at locus 7p12-p14; EGRF is amplified
in 40-60% of glioblastomas; it constitues a hallmark:
primary glioblastomas rarely contain EGFR
overexpression; patients with anaplastic astrocytomas
or glioblastomas have a poorer prognosis when EGFR
gene amplification is present; amplification could be a
significant prognostic factor in these tumors
Over expression of PDGFR-a (platelet derived growth
factor) is asociated with loss of heterozygosity of
chromosome 17p and p53 mutations in secondary
glioblastomas
Others growth factors expressed in gliomas include
fibroblast growth factors (FGFs), insulin-like growth
factors (IGFs), and vascular endothelial growth factor
(VEGF).
are located in 9p21, a chromosome region commonly
deleted in astrocytomas; expression of p16 gene is
frequently altered in these tumors: in 33-68% of
primary glioblastomas and 25% of anaplastic
astrocytomas. The Rb gene located on13q chromosome
plays an important role in the malignant progression of
gliomas.
The p53 gene is a tumor suppressor gene located on
chromosome 17p13.1; loss or mutation of p53 gene has
been detected in many types of gliomas and represents
an early genetic event in these tumors. Overexpression
of MDM2 is also seen in primary glioblastomas. Others
oncogenes have been found to be amplified in a few
cases of astrocytomas: oncogenes Gli, MYC, MYCN,
MET and N-Ras.
Loss or inactivation of tumor suppressor genes:
In addition to p53 gene, others tumor suppression genes
play a role in astrocytomas
Loss of chromosome 10 is the most frequent
abnormality associated with the progression of
malignant astrocytic tumors; more than 70% of
glioblastomas show LOH on chromosome 10;
amplification of EGFR is always associated with loss
of chromosome 10
The PTEN gene located at the 10q23 locus is
implicated more frequently in glioblastomas than in
anaplastic astrocytomas.
Another suppressor gene the MXII gene has also been
located on the distal portion of chromosome 10 at the
10q24 at the 10q24-p25 locus.
Homozygous deletion in the DMTB gene located on
the region 10q25.3-26.1 have been reported in
glioblastomas.
Molecular pathways in the progression of astrocytomas (from Ho-Keung and Paula Y.P. Lam).
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(1)
60
Nervous system: Astrocytic tumors
Capodano AM
genomic alterations associated with glioma progression by
comparative genomic hybridization. Oncogene. 1996 Sep
5;13(5):983-94
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Bello MJ, de Campos JM, Kusak ME, Vaquero J, Sarasa JL,
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Wechsler DS, Shelly CA, Petroff CA, Dang CV. MXI1, a
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Rasheed BK, McLendon RE, Herndon JE, Friedman HS,
Friedman AH, Bigner DD, Bigner SH. Alterations of the TP53
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N, Kiessling M. Amplification of the epidermal-growth-factorreceptor gene correlates with different growth behaviour in
human glioblastoma. Int J Cancer. 1994 Jan 2;56(1):72-7
Ng HK, Lam PY. The molecular genetics of central nervous
system tumors. Pathology. 1998 May;30(2):196-202
Collins VP. Gene amplification in human gliomas. Glia. 1995
Nov;15(3):289-96
Nishizaki T, Ozaki S, Harada K, Ito H, Arai H, Beppu T, Sasaki
K. Investigation of genetic alterations associated with the grade
of astrocytic tumor by comparative genomic hybridization.
Genes Chromosomes Cancer. 1998 Apr;21(4):340-6
Moulton T, Samara G, Chung WY, Yuan L, Desai R, Sisti M,
Bruce J, Tycko B. MTS1/p16/CDKN2 lesions in primary
glioblastoma multiforme. Am J Pathol. 1995 Mar;146(3):613-9
Sehgal A. Molecular changes during the genesis of human
gliomas. Semin Surg Oncol. 1998 Jan-Feb;14(1):3-12
Schwechheimer K, Huang S, Cavenee WK. EGFR gene
amplification--rearrangement in human glioblastomas. Int J
Cancer. 1995 Jul 17;62(2):145-8
Burger PC, Scheithauer BW, Paulus W, Giannini C, Kleihues
P. Pilocytc astrocytoma.In Pathology and Genetics of Tumors
of the Nervous System-Kleihues P, Cavenee WK (eds) 2000;
IARC Press, pp 29-33.
Rosenberg JE, Lisle DK, Burwick JA, Ueki K, von Deimling A,
Mohrenweiser HW, Louis DN. Refined deletion mapping of the
chromosome 19q glioma tumor suppressor gene to the
D19S412-STD interval. Oncogene. 1996 Dec 5;13(11):2483-5
Goussia AC, Agnantis NJ, Rao JS, Kyritsis AP. Cytogenetic
and molecular abnormalities in astrocytic gliomas (Review).
Oncol Rep. 2000 Mar-Apr;7(2):401-12
Schlegel J, Scherthan H, Arens N, Stumm G, Kiessling M.
Detection of complex genetic alterations in human
glioblastoma
multiforme
using
comparative
genomic
hybridization. J Neuropathol Exp Neurol. 1996 Jan;55(1):81-7
This article should be referenced as such:
Capodano AM. Nervous system: Astrocytic tumors. Atlas
Genet Cytogenet Oncol Haematol. 2001; 5(1):58-61.
Weber RG, Sabel M, Reifenberger J, Sommer C, Oberstrass J,
Reifenberger G, Kiessling M, Cremer T. Characterization of
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(1)
61
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Cancer Prone Disease Section
Mini Review
Beckwith-Wiedemann syndrome
Marcel Mannens
DNA-diagnostics laboratory, University of Amsterdam, Academic Medical Center Department of Clinical
Genetics PO Box 22700 1100 DE Amsterdam, the Netherlands (MM)
Published in Atlas Database: November 2000
Online updated version : http://AtlasGeneticsOncology.org/Kprones/BeckwithWiedemannID10037.html
DOI: 10.4267/2042/37714
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2001 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
Clinics
Alias
Exomphalos-macroglossia-gigantism triad
Inheritance
Incidence of 7/105; given the variable expression of the
symptoms, the actual frequency is likely to be higher;
generally there is sporadic occurrence of the syndrome
(85%); inheritance is mostly maternal (imprinting) with
a more severe phenotype after maternal transmission.
Note
Clinically and genetically heterogeneous; three distinct
regions on 11p15 have been associated with BWS
(BWSCR1/2/3); BWSCR2 seems to be particularly
associated with hemihypertrophy.
Phenotype and clinics
Multiple features that occur variably; most prominent is
the EMG triad (exomphalos-macroglossia-gigantism):
apart from the abdominal wall defects and pre- and
postnatal growth abnormalities, earlobe pits or creases,
facial nevus flammeus, hypoglycemia, renal
abnormalities
and
hemihypertrophy
(unilateral
overgrowth) are frequently seen.
Patient with Beckwith-Wiedemann syndrome. The face shows the enlarged tongue (macroglossia), the ear the typical earlobe creases Marcel Mannens.
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(1)
62
Beckwith-Wiedemann syndrome
Mannens M
Neoplastic risk
Protein
Description: Untranslated.
Expression: Highly expressed in endodermal and
mesodermal embryonic tissues; in adult brain, only in
the pons and globus pallidus; in adult tissues,
expression is primarily confined to skeletal and cardiac
muscle; other tissues are down-regulated postnatal but
re-expressed in tumours that express the gene during
embryogenesis.
Function: Putative tumour suppressor; proposed
regulatory function for IGF2 expression (under debate).
Mutations
Germinal: Hypermethylated in 10-20% of sporadic
BWS cases; familial transmission unclear yet; loss of
imprinting (LOI) can be induced in deletion mouse
models.
Somatic: Hypermethylated in 10-20% of sporadic BWS
cases mostly somatic events due to UPD in mosaic
form; LOI in tumours.
The increased risk for childhood solid tumours is 7.5%
(thousand fold increase); tumours most frequently seen
are nephroblastoma (Wilms tumour), adrenocortical
carcinoma, rhabdomyosarcoma and hepatoblastoma;
clinical risk factors are hemihypertrophy and
nephromegaly; genetic risk factors are uniparental
disomy (UPD) and H19/IGF2 imprinting defects.
Treatment
In general surgical correction of the abdominal wall
defects and macroglossia; monitoring the glycemia
during the first 3 days and early treatment of
hypoglycemia (deleterious for central nervous system)
is of importance to avoid further complications;
frequent screening for tumour development.
Prognosis
Clinical features tend to become less with ageing;
tumour risk decreases strongly after the 4-7th year of
birth.
IGF2 (insulin-like growth factor 2
(somatomedin A))
Cytogenetics
Alias: IGF-II, somatomedin A, Hs.75963
Location: 11p15.5
DNA/RNA
Transcription: 1356 bp mRNA, paternally expressed,
maternal imprint.
Protein
Description: 180 amino acids, 20,14 kDa
(unprocessed).
Expression: IGF2 has the highest levels of expression
in tissues that are affected by prenatal overgrowth in
BWS; the main source of expression is liver;
expression depends on promoter usage; P1 is
exclusively active in adult liver, whereas P3 and P4
exert their action in liver prenatal; P2 is only active in
certain tumour cell lines.
Localisation: Secreted.
Function: Embryonal growth factor, mitogen.
Homology: Belongs to the insulin/IGF/relaxin family.
Mutations
Germinal: Hypomethylated; LOI in sporadic BWS
cases; familial transmission unclear yet; BWS
phenotype can be induced in igf2 overexpressing
mouse models.
Somatic: Hypomethylated, LOI in sporadic BWS cases;
mostly somatic events due to UPD in mosaic form; LOI
in tumours.
Inborn conditions
Paternal duplications of chromosome region 11p15,
maternal translocations involving chromosome region
11p15.3-p15.5.
Cytogenetics of cancer
Apart from chromosome 11 aberrations, multiple
chromosomes are involved in tumour development;
promising prognostic indicators in Wilms tumour might
be chromosome 1p and 16q aberrations; tther molecular
abnormalities associated with an adverse outcome in
Wilms tumour are 22q allele loss or P53 aberrations.
Other findings
Note
In 10-20% of BWS cases, uniparental disomy of
chromosome region 11p15 is seen, mostly in a mosaic
form.
Genes involved and proteins
H19
Alias: D11S813E, D11S878E, ASM, ASM1
Location: 11p15.5
Note
Imprinted, maternally expressed, untranslated mRNA.
DNA/RNA
Description: The human H19 gene is 2.7 kb long and
includes 4 small introns; maternally expressed, paternal
imprint.
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(1)
CDKN1C (cyclin-dependent kinase
inhibitor 1C)
Alias: KIP2, P57KIP2, P57, CDKN5
Location: 11p15.5
63
Beckwith-Wiedemann syndrome
Mannens M
ZNF215
DNA/RNA
Description: 1511 bp messenger, preferentially
maternally expressed (paternal imprint).
Protein
Description: 316 amino acids; 32,177 kDa, CDK
inhibitory domain, PAPA repeat, conserved C-terminal
domain.
Expression: It is expressed in the heart, brain, lung,
skeletal muscle, kidney, pancreas and testis; high levels
are seen in the placenta, low levels in liver.
Localisation: Nuclear.
Function
Summary: Cyclin-dependent kinase inhibitor 1C is a
tight-binding inhibitor of several G1 cyclin/Cdk
complexes and a negative regulator of cell
proliferation; mutations of CDKN1C are implicated in
sporadic cancers and Beckwith-Wiedemann syndrome
suggesting that it is a tumour suppressor candidate; in
BWS however, no evidence for tumour association was
found.
Homology: p21CIP1 CdK inhibitor gene family.
Mutations
Germinal: Mostly maternal, nucleotide substitutions,
small deletions.
Somatic: CDKN1C mutations are described in tumour
formation; mouse mutation-models reveal part of the
BWS phenotype in particular the abdominal-wall
defects.
Alias: zinc finger protein 215, BAZ2
Location: 11p15.4
DNA/RNA
Description: mRNA of 3480 bp, 9 exons, at least 5
splice variants; exon 9 runs antisense of a second gene:
ZNF214.
Transcription: Imprinted in a tissue specific manner,
the maternal allele being preferentially expressed.
Protein
Description: 517 amino acids, 60,048 kDa; KRABA
domain; similarities to a KRABB domain; SCAN box;
nuclear localisation signal KKKR; 2 x 2 zinc-fingers.
Expression: Widely expressed at low levels; expression
is highest in testis; splice variants of ZNF215 show
tissue specific expression.
Localisation: Nuclear.
Function: Putative transcription factor; ZNF215 was
cloned from a region associated with hemihypertrophy,
cardiac abnormalities, Wilms tumour and minor BWS
features; as such the gene might be responsible for a
distinct phenotype in BWS.
Homology: Belongs to the Krueppel family of C2H2type zinc finger proteins.
Mutations
Germinal: Various amino acids substitutions found in
BWS / hemihypertrophy patients; causal relationship
with phenotype unclear.
Somatic: In tumours no mutations found so far.
KCNQ1OT1 (KCNQ1 overlapping
transcript)
References
Alias: KCNQ1 overlapping transcript 1, LIT1,
KvDMR1, KvLQT1-AS, Long QT intronic transcript 1
Location: 11p15.5
DNA/RNA
Description: Maternally imprinted gene, > 80 kb RNA.
Transcription: Intronic transcript 1, embedded in intron
9 (and 10) of KCNQ1, in opposite orientation;
expressed in most human tissues and from the paternal
allele, the maternal allele being imprinted through a
specific methylation of a CpG island; abnormally
expressed in patients with Beckwith-Wiedemann
syndrome, independently of IGF2 imprinting; no
abnormal imprinting in Wilms tumour.
Protein
Expression: Untranslated.
Function: Unknown; it is postulated that KCNQ1OT1
might influence the expression of nearby imprinted
genes such as CDKN1C or IGF2/H19.
Mutations
Germinal: Aberrant methylation in 50-80% of BWS
patients not always 100% (might be due to UPD in
some cases); inheritance unclear.
Somatic: Unclear; there is no association between
aberrant methylation and tumour development.
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(1)
Beckwith J. Extreme cytomegaly of the adrenal fetal cortex,
omphalocele, hyperplasia of kidneys and pancreas, and
Leydig-cell hyperplasia: Another syndrome? Western Society
for Pediatric Research (abst) Los Angeles 1963 (Nov 11).
WIEDEMANN HR. [FAMILIAL MALFORMATION COMPLEX
WITH UMBILICAL HERNIA AND MACROGLOSSIA--A "NEW
SYNDROME"?]. J Genet Hum. 1964 Sep;13:223-32
Beckwith J. Macroglossia, omphalocele, adrenal cytomegaly,
gigantism, and hyperplastic visceromegaly. Birth Defects
1969;5:188-96.
Elliott M, Bayly R, Cole T, Temple IK, Maher ER. Clinical
features and natural history of Beckwith-Wiedemann
syndrome: presentation of 74 new cases. Clin Genet. 1994
Aug;46(2):168-74
Hoovers JM, Kalikin LM, Johnson LA, Alders M, Redeker B,
Law DJ, Bliek J, Steenman M, Benedict M, Wiegant J,
Lengauer C, Taillon-Miller P, Schlessinger D, Edwards MC,
Elledge SJ, Ivens A, Westerveld A, Little P, Mannens M,
Feinberg AP. Multiple genetic loci within 11p15 defined by
Beckwith-Wiedemann syndrome rearrangement breakpoints
and subchromosomal transferable fragments. Proc Natl Acad
Sci U S A. 1995 Dec 19;92(26):12456-60
Schneid H, Vazquez MP, Vacher C, Gourmelen M, Cabrol S,
Le Bouc Y. The Beckwith-Wiedemann syndrome phenotype
and the risk of cancer. Med Pediatr Oncol. 1997 Jun;28(6):4115
64
Beckwith-Wiedemann syndrome
Mannens M
DeBaun MR, Tucker MA. Risk of cancer during the first four
years of life in children from The Beckwith-Wiedemann
Syndrome Registry. J Pediatr. 1998 Mar;132(3 Pt 1):398-400
Alders M, Ryan A, Hodges M, Bliek J, Feinberg AP, Privitera
O, Westerveld A, Little PF, Mannens M. Disruption of a novel
imprinted zinc-finger gene, ZNF215, in Beckwith-Wiedemann
syndrome. Am J Hum Genet. 2000 May;66(5):1473-84
Li M, Squire JA, Weksberg R. Molecular genetics of
Wiedemann-Beckwith syndrome. Am J Med Genet. 1998 Oct
2;79(4):253-9
Steenman M, Westerveld A, Mannens M. Genetics of
Beckwith-Wiedemann syndrome-associated tumors: common
genetic pathways. Genes Chromosomes Cancer. 2000
May;28(1):1-13
Lee MP, DeBaun MR, Mitsuya K, Galonek HL, Brandenburg S,
Oshimura M, Feinberg AP. Loss of imprinting of a paternally
expressed transcript, with antisense orientation to KVLQT1,
occurs frequently in Beckwith-Wiedemann syndrome and is
independent of insulin-like growth factor II imprinting. Proc Natl
Acad Sci U S A. 1999 Apr 27;96(9):5203-8
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(1)
This article should be referenced as such:
Mannens M. Beckwith-Wiedemann syndrome. Atlas Genet
Cytogenet Oncol Haematol. 2001; 5(1):62-65.
65
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Cancer Prone Disease Section
Mini Review
Hereditary breast cancer
Kaija Holli
Department of Palliative Medicine, Department of Oncology, Tampere University Hospital, Tampere,
Finland (KH)
Published in Atlas Database: November 2000
Online updated version : http://AtlasGeneticsOncology.org/Kprones/HeredBreastCanID10062.html
DOI: 10.4267/2042/37715
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2001 Atlas of Genetics and Cytogenetics in Oncology and Haematology
male breast cancer (6 %) and ovarian breast cancer
(10% -20%); increased risk of prostate, laryngeal
cancer and pancreatic cancer.
Other genetic conditions associated with increased
breast cancer risk are:
Li-Fraumeni syndroma (p53 mutation on chromosome
17p13) is characterized by very early onset of
neoplasms,
including
soft
tissue
sarcoma,
osteosarcoma, brain tumours, leukemia, lung cancer,
laryngeal cancer and adrenocorteal cancer.; lifetime
risk for cancer: about 90 % for women and 70 % for
men.
Cowden syndroma (PTEN, 10q23) is a rare type of
autosomal dominant inherited condition of multiple
hamartomas with increased risk of bilateral breast
cancers and thyroid tumours.
Muir-Torre Syndroma (MSH2, MLH1), with also
cancers of the gastro intestinal (GI)-tract, skin, genito
urinary (Gu)-system.
Peutz-Jeghers Syndroma, with also abnormal melarin
deposits, GI-polyposis, cancers of the GI-tract, uterus,
ovary and testis.
Ataxia-teleangiectasia (linked to chromosome 11q21)
autosomal recessive disorder with many clinical signs
including increased risk for breast cancer; homozygous
AT carriers have around 100-fold risk of cancer.
One third of familiar breast cancers with hereditary
background is still unknown; recent findings indicated
that genotyping "BRCA3" locus at 13q and "BRCA2"
locus at 2q may lead identifing the next mutations.
Breast cancers of BRCA1 and, to lesser extent BRCA2
carriers differ from those of sporadic breast cancers:
more high-grade tumours, pleomorphism, a higher
mitotic count, less tubule formation, more often steroid
receptor negative, DNA-aneuploid and more often
higher s-phase fractions.
Identity
Alias: Site-specific breast cancer; Familiar breastovarian cancer
Note: Hereditary or familiar form of breast cancerwith
a familiar background.
Inheritance
Follows an autosomal dominant pattern.
5-10 % of all breast cancers have hereditary
background.
Hereditary susceptibility for breast cancer has been
counted to be 30-40 % of BRCA1 (see below, gene
section), 10-30 % of BRCA2, less than 1 % of Tp 53,
less than 1 % of PTEN and one third of unknown
mutations; frequency of BRCA1 mutation is around 0.2
% in general population, 200 carriers among 100 000
individuals.
Clinics
Note
Hereditary breast cancer is a heterogenous entity
including several clinical variants.
Phenotype and clinics
"Site specific breast cancer" is characterized by the
predominance of breast cancer, while "hereditary
breast-ovarian cancer" has neoplasms in both organs.
BRCA1 mutation carrier (chromosome 17q12-21) has
early age at onset, and lifetime risk for breast cancer 50
% - 85 % and ovarian cancer 15 %-45 %; about 500
different mutations have been reported; possible
increased risk of prostate cancer and colon cancer.
BRCA2 (chromosome 13q12-13) mutation carrier has
risk for breast cancer 30 %-85 %; about 300 different
mutations have been reported; it is also associated for
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(1)
66
Hereditary breast cancer
Holli K
Treatment
PTEN
Prophylactic bilateral mastectomy (reduces the risk of
about 90 %) and/or ovarian ablation. Chemoprevention
(antiestrogens, aromataze inhibitors, retinoids) mainly
in clinical trials (tamoxifen may reduce the risk about
45 %).
Early detection of cancers by screening mammograms
(ultrasound) yearly, palpation, transvaginal ultrasound.
Location: 10q23
DNA/RNA
Description: 9 exons.
Protein
Description: the PTEN protein (also called MMA1) is
an evolutionary conserved dual-extensive similarity
with the cyto-skeletal protein tensin
Function: tumour suppression since bi allealic
inactivations, inactivating germline mutations are
responsible for a cancer prone síndrome.
Mutations
Germinal: heterozygeous germline mutations are
responsible for the Cowden disease.
Prognosis
Prognosis is more dependent on extent of the disease at
diagnosis than on the hereditary susceptibility.
Genes involved and proteins
NOTE: see also breast cancer.
LKB1
BRCA1
Location: 19p13
DNA/RNA
Description: 10 exons spanning 23 kb.
Protein
Description: 433 amino acids.
Expression: wide.
Function: serine/threonine kinase; tumor suppressor
gene.
Homology: Heterozygous mutations are responsible for
the Peutz-Jeghers síndrome.
Location: 17q21
DNA/RNA
Description: 22 coding exons spanning over 70 kb of
genomic DNA the BRCA1 mRNA has a size of 7.8 kb.
Protein
Description: the corresponding protein has 1863 amino
acids, and 190-220 kDa.
Expression: wide.
Function: involved in DNA replication, repair
transcriptional activation, cell cycle progression.
Mutations
Germinal: more than 500 sequence variations of the
germline level have been reported.
ATM
Location: 11q22-23
DNA/RNA
Description: 66 exons spanning 184 kb.
Protein
Description: 3056 amino acids, 350 kDa.
Function: at the cell cycle checkpoint; induces G1
phase arrest.
BRCA2
Location: 13q12-13
DNA/RNA
Description: gene spanning more than 17 kb of
genomic DNA; the coding sequence comprisons 26
exons (10 254 nucleotides).
Protein
Description: the corresponding protein has 3 418 amino
acid residives (384 kDa).
Mutations
Germinal: more than 300 unique germ-line mutations
have been reported.
References
Eng C, Murday V, Seal S, Mohammed S, Hodgson SV,
Chaudary MA, Fentiman IS, Ponder BA, Eeles RA. Cowden
syndrome and Lhermitte-Duclos disease in a family: a single
genetic syndrome with pleiotropy? J Med Genet. 1994
Jun;31(6):458-61
Easton DF, Ford D, Bishop DT. Breast and ovarian cancer
incidence in BRCA1-mutation carriers. Breast Cancer Linkage
Consortium. Am J Hum Genet. 1995 Jan;56(1):265-71
P53
Location: 17p13
DNA/RNA
Description: 11 exons.
Protein
Function: gene p53 encodes an ubiquitous nuclear
protein involved in the control of genome integrity by
preventing cells dividing before DNA damage is
repaired.
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(1)
Eeles R, Cole T, Taylor R, Lunt P, Baum M. Prophylactic
mastectomy for genetic predisposition to breast cancer: the
proband's story. Clin Oncol (R Coll Radiol). 1996;8(4):222-5
Knudson AG. Hereditary cancer: two hits revisited. J Cancer
Res Clin Oncol. 1996;122(3):135-40
Struewing JP, Hartge P, Wacholder S, Baker SM, Berlin M,
McAdams M, Timmerman MM, Brody LC, Tucker MA. The risk
of cancer associated with specific mutations of BRCA1 and
BRCA2 among Ashkenazi Jews. N Engl J Med. 1997 May
15;336(20):1401-8
67
Hereditary breast cancer
Holli K
Fisher B, Costantino JP, Wickerham DL, Redmond CK,
Kavanah M, Cronin WM, Vogel V, Robidoux A, Dimitrov N,
Atkins J, Daly M, Wieand S, Tan-Chiu E, Ford L, Wolmark N.
Tamoxifen for prevention of breast cancer: report of the
National Surgical Adjuvant Breast and Bowel Project P-1
Study. J Natl Cancer Inst. 1998 Sep 16;90(18):1371-88
BRCA1 and BRCA2 mutations. J Natl Cancer Inst. 1998 Aug
5;90(15):1138-45
Thorlacius S, Struewing JP, Hartge P, Olafsdottir GH,
Sigvaldason H, Tryggvadottir L, Wacholder S, Tulinius H,
Eyfjörd JE. Population-based study of risk of breast cancer in
carriers
of
BRCA2
mutation.
Lancet.
1998
Oct
24;352(9137):1337-9
Fodor FH, Weston A, Bleiweiss IJ, McCurdy LD, Walsh MM,
Tartter PI, Brower ST, Eng CM. Frequency and carrier risk
associated with common BRCA1 and BRCA2 mutations in
Ashkenazi Jewish breast cancer patients. Am J Hum Genet.
1998 Jul;63(1):45-51
Peto J, Collins N, Barfoot R, Seal S, Warren W, Rahman N,
Easton DF, Evans C, Deacon J, Stratton MR. Prevalence of
BRCA1 and BRCA2 gene mutations in patients with earlyonset breast cancer. J Natl Cancer Inst. 1999 Jun
2;91(11):943-9
Ford D, Easton DF, Stratton M, Narod S, Goldgar D, Devilee P,
Bishop DT, Weber B, Lenoir G, Chang-Claude J, Sobol H,
Teare MD, Struewing J, Arason A, Scherneck S, Peto J,
Rebbeck TR, Tonin P, Neuhausen S, Barkardottir R, Eyfjord J,
Lynch H, Ponder BA, Gayther SA, Zelada-Hedman M. Genetic
heterogeneity and penetrance analysis of the BRCA1 and
BRCA2 genes in breast cancer families. The Breast Cancer
Linkage Consortium. Am J Hum Genet. 1998 Mar;62(3):676-89
Kainu T, Juo SH, Desper R, Schaffer AA, Gillanders E,
Rozenblum E, Freas-Lutz D, Weaver D, Stephan D, BaileyWilson J, Kallioniemi OP, Tirkkonen M, Syrjäkoski K,
Kuukasjärvi T, Koivisto P, Karhu R, Holli K, Arason A,
Johannesdottir G, Bergthorsson JT, Johannsdottir H, Egilsson
V, Barkardottir RB, Johannsson O, Haraldsson K, Sandberg T,
Holmberg E, Grönberg H, Olsson H, Borg A, Vehmanen P,
Eerola H, Heikkila P, Pyrhönen S, Nevanlinna H. Somatic
deletions in hereditary breast cancers implicate 13q21 as a
putative novel breast cancer susceptibility locus. Proc Natl
Acad Sci U S A. 2000 Aug 15;97(17):9603-8
Lakhani SR, Jacquemier J, Sloane JP, Gusterson BA,
Anderson TJ, van de Vijver MJ, Farid LM, Venter D, Antoniou
A, Storfer-Isser A, Smyth E, Steel CM, Haites N, Scott RJ,
Goldgar D, Neuhausen S, Daly PA, Ormiston W, McManus R,
Scherneck S, Ponder BA, Ford D, Peto J, Stoppa-Lyonnet D,
Bignon YJ, Struewing JP, Spurr NK, Bishop DT, Klijn JG,
Devilee P, Cornelisse CJ, Lasset C, Lenoir G, Barkardottir RB,
Egilsson V, Hamann U, Chang-Claude J, Sobol H, Weber B,
Stratton MR, Easton DF. Multifactorial analysis of differences
between sporadic breast cancers and cancers involving
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(1)
This article should be referenced as such:
Holli K. Hereditary breast cancer. Atlas Genet Cytogenet Oncol
Haematol. 2001; 5(1):66-68.
68
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Cancer Prone Disease Section
Mini Review
Variegated aneuploidy related
centromere division (PCD)
to
premature
Alberto Plaja
Unitat de Genètica, Hospital Materno- Infantil Vall d'Hebron Pg. Vall d'Hebron 119- 129, 08035- Barcelona,
Spain (AP)
Published in Atlas Database: November 2000
Online updated version : http://AtlasGeneticsOncology.org/Kprones/VariegAneuplPCDID10069.html
DOI: 10.4267/2042/37716
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2001 Atlas of Genetics and Cytogenetics in Oncology and Haematology
found in other patients with an expected increased
cellular mortality (variegated aneuploidy without PCD
and the "ring syndrome").
Identity
Alias: (Variegated aneuploidy or mosaic aneuploidy)
related to (PCD, C-anaphases,premature anaphase,
premature chromatid separation or asynchrony of
mitotic stages)
Note
The term premature centromere division has also been
utilized to describe an unrelated cytogenetic
phenomenon, the age related loss of centromeric
function in chromosome X.
Variegated aneuploidy has also been described in
patients without PCD and patients with Roberts
syndrome.
Inheritance
Only 11 patients known.
Premature centromere division (PCD) without
variegated aneuploidy has been shown to have an
autosomal dominant inheritance, with an estimated
frequency of 0.1% of the population.
It has been proposed that patients with variegated
aneuploidy related to PCD are homozygotes for this
trait, but in several cases one of the parents do not show
elevated frequency of PCD.
A recessive inheritance with hormonal factors
modifying the expression of PCD in a carrier,
isodisomy of one chromosome or loss of
heterozygosity has been suggested.
Phenotype and clinics
the clinical phenotype of the 11 patients described in
the literature includes microcephaly (11/11), central
nervous system (CNS) anomalies (5/6) with cerebellar
defects and migration defects, mental retardation (8/9),
prenatal (always noted over 23 weeks of gestation) and
postnatal growth retardation (10/10), flat and broad
nasal bridge (4/7), apparently low-set ears (5/8), eye
abnormalities (8/10), skin abnormalities (3/9) and
ambiguous genitalia in male patients (4/6); seizures
have been reported in 5 patients; cancer is a major
concern in the clinical management of these patients
(5/11); birth weight corrected for gestational age ranges
from -1.3 to -4.1 SD, birth length from -0.8 to -5.4 SD
and OFC from -2.6 to -5.8.
Neoplastic risk
The occurrence of Wilms tumor in three patients,
rhabdomyosarcoma in two others and acute leukemia in
a fifth characterizes this condition as a chromosome
instability disorder with a high risk of malignancy;
interestingly enough, preferential loss of maternal
11p15.5 chromosome region has been repeatedly
reported in Wilms tumor as well as in
rhabdomyosarcoma.
Prognosis
Clinics
Although published data is incomplete, at least 4
patients have died before 2 years of age, a fifth
deceased at 42 years and one patient aged 18 month has
an advanced, relapsed rhabdomyosarcoma; patient's
death had been related to pneumonia (one patient),
leukemia (one patient), and Wilms tumor (three cases).
Note
Patients show a remarkably constant clinical phenotype
probably due to high cellular mortality induced by the
aneuploidies; similar clinical findings have also been
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(1)
69
Variegated aneuploidy related to premature centromere division (PCD)
Plaja A
mosaic aneuploidies, microcephaly, mental retardation
and a variety of malformations; in these patients,
trisomy is by far more frequent than monosomy;
trisomies of chromosome 8, 18 and X predominate in
lymphocyte cultures and trisomy 2, 7, 12 and 20
predominate in fibroblasts; usually, at least one of the
parents shows an elevated PCD frequency (range 12.642.5) but not variegated aneuploidy.
High levels of PCD have been reported in skin
fibroblasts (althought in at least one case no
aneupoidies where found), hair-root, bone marrow and
trophoblastic cells of chorionic villi; there is no data of
PCD expression in amniocytes but pseudomosaicism of
chromosome 7 and 21 has been reported in amniocytes;
cord blood chromosome analysis in one case showed
PCD and variegated aneuploidies.
Cytogenetics
Inborn conditions
The terms premature centromere division (PCD), Canaphases, premature anaphase, premature chromatid
separation and asynchrony of mitotic stages describe
cells in division which have overcome a colchicineinduced metaphase block; the resulting mitotic
configuration shows split centromeres and splayed
chromatids in all or most of the chromosomes.
Control individuals generally show low frequencies of
PCD (up to 3% of the mitoses), which seems to have no
pathological relevance, but in 0.1% of the population
an elevated PCD frequency (>5%) is found in
colchicine exposed lymphocyte cultures; this type of
PCD shows autosomal dominant inheritance and has
traditionally considered to be harmless with the
possible exception of some patients with subfertility or
repeated abortion.
In few patients high levels of PCD (25- 87%) are found
in combination with an increased number of cells with
Cytogenetics of cancer
Cytogenetic analysis of one embryonal rhabdosarcoma
showed normal karyotype in cultured cells and
extensive aneuploidy with some estructural aberrations
in the only two cells obtained from direct harvest.
cell showing premature centromere division (PCD) phenomenon, with split centromeres and splayed chromatids in all the chromosomes
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(1)
70
Variegated aneuploidy related to premature centromere division (PCD)
Plaja A
References
premature chromatid separation trait. Am J Med Genet. 1998
Jul 7;78(3):245-9
Gabarrón J, Jimenez A, Glover G. Premature centromere
division dominantly inherited in a subfertile family. Cytogenet
Cell Genet. 1986;43(1-2):69-71
Kawame H, Sugio Y, Fuyama Y, Hayashi Y, Suzuki H,
Kurosawa K, Maekawa K. Syndrome of microcephaly, DandyWalker malformation, and Wilms tumor caused by mosaic
variegated aneuploidy with premature centromere division
(PCD): report of a new case and review of the literature. J Hum
Genet. 1999;44(4):219-24
Scheres JM JC, Hustinx TWJ, Madam K, Beltman J D,
Lindhout D. A mitotic mutant causing non- disjunction in man.
In: 7h International Congress of Human Genetics. Berlin.
1986;Abst p163.
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mosaic
variegated
aneuploidy
and
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case reports on patients with a ring autosome. Hum Genet.
1987 Feb;75(2):174-9
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Mosaic variegated aneuploidies in a newborn with growth
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(PCD): a dominantly inherited cytogenetic anomaly. Hum
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Matsuura S, Ito E, Tauchi H, Komatsu K, Ikeuchi T, Kajii T.
Chromosomal instability syndrome of total premature
chromatid separation with mosaic variegated aneuploidy is
defective in mitotic-spindle checkpoint. Am J Hum Genet. 2000
Aug;67(2):483-6
Chamla Y. C-anaphases in lymphocyte cultures versus
premature centromere division syndromes. Hum Genet. 1988
Feb;78(2):111-4
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Mitotic disturbance associated with mosaic aneuploidies. Hum
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Plaja A, Vendrell T, Smeets D, Sarret E, Gili T, Català V,
Mediano C, Scheres JM. Variegated aneuploidy related to
premature centromere division (PCD) is expressed in vivo and
is a cancer-prone disease. Am J Med Genet. 2001 Jan
22;98(3):216-23
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Mosaic variegated aneuploidy with microcephaly: a new
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This article should be referenced as such:
Plaja A. Variegated aneuploidy related to premature
centromere division (PCD). Atlas Genet Cytogenet Oncol
Haematol. 2001; 5(1):69-71.
Kajii T, Kawai T, Takumi T, Misu H, Mabuchi O, Takahashi Y,
Tachino M, Nihei F, Ikeuchi T. Mosaic variegated aneuploidy
with multiple congenital abnormalities: homozygosity for total
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(1)
71
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Cancer Prone Disease Section
Review
Hereditary pancreatic cancer
Ralph H Hruban, Scott E Kern
The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA (RHH, SEK)
Published in Atlas Database: December 2000
Online updated version : http://AtlasGeneticsOncology.org/Kprones/HeredPancrCanID10068.html
DOI: 10.4267/2042/37717
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2001 Atlas of Genetics and Cytogenetics in Oncology and Haematology
have a 56-fold increased risk of developing pancreatic
cancer.
Each of the five clinically recognized syndromes
associated with the familial aggregation of pancreatic
cancer has its own unique clinical findings.
Second breast cancer syndrome: the BRCA2 tumor
suppressor gene is located on chromosome 13q and
carriers of germline BRCA2 mutations have a
significant lifetime risk of developing breast cancer
(30-85%) at a young age; they are also at risk for
bilateral breast cancer; BRCA2 is also associated with
an increased risk of male breast cancer, ovarian cancer,
prostate cancer and pancreatic cancer; the lifetime risk
of pancreatic cancer in carriers of germline BRCA2
mutations is approximately 10%; germline BRCA2
mutations are particularly common amongst individuals
of Ashkenazi Jewish heritage because of a founder
effect.
Familial atypical multiple mole melanoma (FAMMM)
syndrome has an autosomal dominant mode of
transmission; most cases are caused by germline
mutations in the p16 tumor suppressor gene on
chromosome 9p; individuals affected with FAMMM
develop multiple melanocytic nevi, some of which can
be atypical; they also are at increased risk of
developing melanoma and pancreatic cancer; the
lifetime risk of pancreatic cancer in individuals with
germline p16 mutations is about 20%.
The Peutz-Jeghers Syndrome is inhertied in an
autosomal dominant mode; it has recently been shown
to be caused by germline mutaitons in the
STK11/LKB1 gene on chromosome 19p; individuals
with this syndrome typically develop multiple
mucocutaneus melanin macules, harmartomatous
gastrointestinal polyps and they have an increased risk
of developing cancers of the gastrointestinal tract; it has
been estimated that the lifetime risk of pancreatic
cancer in patient with the Peutz-Jeghers Syndrome is
approximately 30%.
Identity
Alias: Familial pancreatic cancer
Inheritance
It has been estimated that as many as 10% of pancreatic
cancers have a hereditary basis; five genetic syndromes
have been identified that are associated with the
familial aggregation of pancreatic cancer; these
include:
The second breast cancer syndrome (BRCA2), the
familial atypical multiple mole melanoma (FAMMM),
the Peutz-Jeghers Syndrome, the hereditary pancreatitis
and the hereditary non-polyposis colorectal cancer
(HNPCC) syndrome.
Most kindreds with familial pancreatic cancer,
however, do not fall into one of these well-defined
syndromes and these are referred to simply as "family
pancreatic cancer."
Clinics
Note
a generally accepted definition of familial pancreatic
cancer is a kindred in which at least a pair of firstdegree relatives (sibling-sibling or parent-child) have
been diagnosed with pancreatic cancer; several large
registries have been established to define the patterns of
inheritance and genetic basis for the familial
aggregation of pancreatic cancer in these kindreds, the
National Pancreas Tumor Registry (NFPTR) is the
largest such registry; over 260 familial pancreatic
cancer kindreds have enrolled in this registry and
studies of these kindreds has revealed that when
followed prospectively, apparently healthy, first-degree
relatives of patients with familial pancreatic cancer
have an 18-fold increased risk of developing pancreatic
cancer; when there are three or more family members
with pancreatic cancer in a kindred, the first-degree
relatives of the index patient with pancreatic cancer
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(1)
72
Hereditary pancreatic cancer
Hruban RH, Kern SE
Hereditary pancreatitis has an autosomal dominant
mode of transmission; it is caused by germline
mutations in the cationic trypsinogen gene (called
PRSS1) on chromosome 7q35; affected individuals
develop recurrent episodes of pancreatitis at a young
age and they have an elevated lifetime risk of
developing pancreatic cancers that approaches 40%.
The hereditary nonpolyposis colorectal cancer
(HNPCC) syndrome is caused by germiline mutations
in one of the DNA mismatch repair genes (such as
hMLH1 on chromosome 3 p and hMSH2 on
chromosome 2p); in addition to colorectal neoplasia,
affected family members have an increased risk of
developing pancreatic cancer; the pancreatic cancers
that arise in patients with HNPCC often have a distinct
histologic appearance referred to as "medullary"
histology.
The ataxia-telangectasia and familial adenomatous
polyposis syndromes have also been associated with an
increased risk of developing pancreatic cancer,
however, these associations are not well-established.
DNA/RNA
Description: the coding sequence comprises 3 exons:
this locus gives rise to 2 distinct transcripts from
different promoters (p16 and p16(ARF)).
Protein
Description: the corresponding protein, called cyclindependent kinase inhibitor-2A, has 156 amino acid
residues.
Function: cyclin-dependent kinase inhibitor 2A binds to
CDK4 and inhibits the ability of CDK4 to interact with
cyclinA thereby inducing a G1 cell cycle arrest.
Mutations
Germinal: germline mutations are associated with the
FAMMM Syndrome.
Somatic: virtually all invasive pancreatic carcinomas
show inactivation of the p16 gene; forty percent by
homozygous deletion, 40% by an intragenic mutation
coupled with loss of heterozygocity (LOH) and 15% by
hypermethylation of the p16 promoter.
STK11
Treatment
Location: 19p13.3
DNA/RNA
Description: gene Spanning 23kb of genomic DNA, the
coding sequence comprises 9 exons (1446bp).
Protein
Description: the corresponding protein has 433 amino
acid residues.
Function: serine throeonine protein kinase 11.
Mutations
Germinal: almost all germline mutations are predicted
to disrupt the function of the kinase domain.
Somatic: approximately 4% of sporadic pancreatic
cancers have somatic inactivation of STK11.
Currently, there are no effective methods to screen
individuals at-risk for early pancreatic cancer; several
studies are underway to examine the effectiveness of
endoscopic ultrasound (EUS) in the early detection of
pancreatic cancer.
Prognosis
Prognosis will depend on the stage of the disease at
diagnosis more than it does on hereditary sysceptibility.
Genes involved and proteins
BRCA2
Location: 13q12 3
DNA/RNA
Description: gene spanning more than 70kb of genomic
DNA; the coding sequence comprises 27 exons (11 395
nucleotides).
Protein
Description: the corresponding protein has 3 418 amino
acid residues (384 kDa).
Function: the Brca2 protein binds to Rad51 and serves
as an important co-factor in the Rad51 -dependent
DNA repair of double strand breaks; the Brca2 protein
may also have transcription activation potential.
Mutations
Germinal: more than 300 unique germ-line mutations
have been reported; the 6174 delT mutation is
particularly common in Jewish subjects
Somatic: acquired mutations in BRCA2 rare in
pancreatic cancer.
PRSS1
Location: 7q35
DNA/RNA
Description: the coding sequence comprise 5 exons
(800bp).
Protein
Description: trypsin, which is active in the pacreas, in
inactivated by cleavage; mutations which abrogate this
cleavage site can result in autodigestion and
pancreatitis.
Mutations
Germinal: the arg117-to-his mutation (R117H) is the
most common mutation identified to date.
hMLH1
Location: 3p21.3
DNA/RNA
Description: the coding sequence comprises 2484b.
p16
Location: 9p21
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(1)
73
Hereditary pancreatic cancer
Hruban RH, Kern SE
ST, Toskes PP, Liddle R, McGrath K, Uomo G, Post JC,
Ehrlich GD. Hereditary pancreatitis is caused by a mutation in
the cationic trypsinogen gene. Nat Genet. 1996 Oct;14(2):1415
Protein
Description: MLH1 forms a complex with other DNA
mismatch repair gene; functions in DNA mismatch
repairs2.
Mutations
Germinal: one of at least 5 known human mismatch
repair genes associated with the hereditary nonpolyposis colorectal cancer syndrome: the neoplasms
that develop in these patients typically show
microsatellite instability.
Whitcomb DC, Preston RA, Aston CE, Sossenheimer MJ,
Barua PS, Zhang Y, Wong-Chong A, White GJ, Wood PG,
Gates LK Jr, Ulrich C, Martin SP, Post JC, Ehrlich GD. A gene
for hereditary pancreatitis maps to chromosome 7q35.
Gastroenterology. 1996 Jun;110(6):1975-80
Lowenfels AB, Maisonneuve P, DiMagno EP, Elitsur Y, Gates
LK Jr, Perrault J, Whitcomb DC. Hereditary pancreatitis and
the risk of pancreatic cancer. International Hereditary
Pancreatitis Study Group. J Natl Cancer Inst. 1997 Mar
19;89(6):442-6
hMSH2
Location: 2p22-p21
DNA/RNA
Description: the MSH2 locus covers approximately
73kb and contains 16 exons.
Protein
Description: MSH2 functions in DNA mismatch repair.
Mutations
Germinal: one of at least 5 known human mismatch
repair genes associated with the hereditary nonpolyposis colorectal cancer syndrome; the neoplasms
that develop in these patients typically show
microsatellite instability.
Ozçelik H, Schmocker B, Di Nicola N, Shi XH, Langer B,
Moore M, Taylor BR, Narod SA, Darlington G, Andrulis IL,
Gallinger S, Redston M. Germline BRCA2 6174delT mutations
in Ashkenazi Jewish pancreatic cancer patients. Nat Genet.
1997 May;16(1):17-8
Abbott DW, Freeman ML, Holt JT. Double-strand break repair
deficiency and radiation sensitivity in BRCA2 mutant cancer
cells. J Natl Cancer Inst. 1998 Jul 1;90(13):978-85
Goggins M, Offerhaus GJ, Hilgers W, Griffin CA, Shekher M,
Tang D, Sohn TA, Yeo CJ, Kern SE, Hruban RH. Pancreatic
adenocarcinomas with DNA replication errors (RER+) are
associated with
wild-type
K-ras
and characteristic
histopathology. Poor differentiation, a syncytial growth pattern,
and pushing borders suggest RER+. Am J Pathol. 1998
Jun;152(6):1501-7
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Hemminki A, Markie D, Tomlinson I, Avizienyte E, Roth S,
Loukola A, Bignell G, Warren W, Aminoff M, Höglund P,
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T, Bodmer W, Olschwang S, Olsen AS, Stratton MR, de la
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defective in Peutz-Jeghers syndrome. Nature. 1998 Jan
8;391(6663):184-7
JEGHERS H, McKUSICK VA, KATZ KH. Generalized intestinal
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Pancreatic carcinoma and hereditary nonpolyposis colorectal
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Hruban RH, Petersen GM, Ha PK, Kern SE. Genetics of
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Giardiello FM, Welsh SB, Hamilton SR, Offerhaus GJ,
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Engl J Med. 1987 Jun 11;316(24):1511-4
Jenne DE, Reimann H, Nezu J, Friedel W, Loff S, Jeschke R,
Müller O, Back W, Zimmer M. Peutz-Jeghers syndrome is
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Genet. 1998 Jan;18(1):38-43
Caldas C, Hahn SA, da Costa LT, Redston MS, Schutte M,
Seymour AB, Weinstein CL, Hruban RH, Yeo CJ, Kern SE.
Frequent somatic mutations and homozygous deletions of the
p16 (MTS1) gene in pancreatic adenocarcinoma. Nat Genet.
1994 Sep;8(1):27-32
Mattson K. Docetaxel (Taxotere) in the neo-adjuvant setting in
non-small-cell lung cancer. Ann Oncol. 1999;10 Suppl 5:S6972
Su GH, Hruban RH, Bansal RK, Bova GS, Tang DJ, Shekher
MC, Westerman AM, Entius MM, Goggins M, Yeo CJ, Kern
SE. Germline and somatic mutations of the STK11/LKB1
Peutz-Jeghers gene in pancreatic and biliary cancers. Am J
Pathol. 1999 Jun;154(6):1835-40
Goldstein AM, Fraser MC, Struewing JP, Hussussian CJ,
Ranade K, Zametkin DP, Fontaine LS, Organic SM, Dracopoli
NC, Clark WH Jr. Increased risk of pancreatic cancer in
melanoma-prone kindreds with p16INK4 mutations. N Engl J
Med. 1995 Oct 12;333(15):970-4
Tascilar M, Tersmette AC, Offerhaus GJ, Hruban RH.
Pancreatic cancer--more familial than you thought. Anal Cell
Pathol. 1999;19(3-4):105-10
Berman DB, Costalas J, Schultz DC, Grana G, Daly M, Godwin
AK. A common mutation in BRCA2 that predisposes to a
variety of cancers is found in both Jewish Ashkenazi and nonJewish individuals. Cancer Res. 1996 Aug 1;56(15):3409-14
Giardiello FM, Brensinger JD, Tersmette AC, Goodman SN,
Petersen GM, Booker SV, Cruz-Correa M, Offerhaus JA. Very
high risk of cancer in familial Peutz-Jeghers syndrome.
Gastroenterology. 2000 Dec;119(6):1447-53
Goggins M, Schutte M, Lu J, Moskaluk CA, Weinstein CL,
Petersen GM, Yeo CJ, Jackson CE, Lynch HT, Hruban RH,
Kern SE. Germline BRCA2 gene mutations in patients with
apparently sporadic pancreatic carcinomas. Cancer Res. 1996
Dec 1;56(23):5360-4
Lal G, Liu G, Schmocker B, Kaurah P, Ozcelik H, Narod SA,
Redston M, Gallinger S. Inherited predisposition to pancreatic
adenocarcinoma: role of family history and germ-line p16,
BRCA1, and BRCA2 mutations. Cancer Res. 2000 Jan
15;60(2):409-16
Whitcomb DC, Gorry MC, Preston RA, Furey W,
Sossenheimer MJ, Ulrich CD, Martin SP, Gates LK Jr, Amann
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Lynch HT, Brand RE, Lynch JF, Fusaro RM, Smyrk TC,
Goggins M, Kern SE. Genetic counseling and testing for
germline p16 mutations in two pancreatic cancer-prone
families. Gastroenterology. 2000 Dec;119(6):1756-60
Tersmette AC, Petersen GM, Offerhaus GJ, Falatko FC, Brune
KA, Goggins M, Rozenblum E, Wilentz RE, Yeo CJ, Cameron
JL, Kern SE, Hruban RH. Increased risk of incident pancreatic
cancer among first-degree relatives of patients with familial
pancreatic cancer. Clin Cancer Res. 2001 Mar;7(3):738-44
Wilentz RE, Goggins M, Redston M, Marcus VA, Adsay NV,
Sohn TA, Kadkol SS, Yeo CJ, Choti M, Zahurak M, Johnson K,
Tascilar M, Offerhaus GJ, Hruban RH, Kern SE. Genetic,
immunohistochemical, and clinical features of medullary
carcinoma of the pancreas: A newly described and
characterized entity. Am J Pathol. 2000 May;156(5):1641-51
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(1)
This article should be referenced as such:
Hruban RH, Kern SE. Hereditary pancreatic cancer. Atlas
Genet Cytogenet Oncol Haematol. 2001; 5(1):72-75.
75
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Cancer Prone Disease Section
Mini Review
Li-Fraumeni syndrome
Jenny M Varley
Cancer Genetics Group, Paterson Institute for Cancer Research, Wilmslow Road, Manchester M20 9BX, UK
(JMV)
Published in Atlas Database: December 2000
Online updated version : http://AtlasGeneticsOncology.org/Kprones/LiFraumeniID10011.html
DOI: 10.4267/2042/37718
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2001 Atlas of Genetics and Cytogenetics in Oncology and Haematology
DNA/RNA
Description: 11 exons, the first of which is non-coding.
Protein
Description: p53, a 393 amino acid protein.
Function: p53 is the most commonly mutated gene in
human cancers possessing multiple properties; p53 has
two major roles.
Firstly in cell cycle arrest, predominantly in the G1
phase of the cell cycle, but also with a role in G2 and
mitotic checkpoints.
Secondly the induction of apoptosis (programmed cell
death).
Both these are induced upon DNA damage, and the
response depends on many things including the type of
damage and the cell type.
p53 is a transcription factor with a central sequencespecific DNA binding domain and a N-terminal
transactivation domain; upon DNA damage, the level
of p53 increases markedly, and the DNA-binding
properties are activated; the levels of p53 are regulated
primarily
post-transcriptionally
(including
phosphorylation and acetylation).
Mutations
Germinal: there are over 200 published reports of
germline mutations.
Over 75% of families with classic LFS have a germline
TP53 mutation.
Lower proportions of families with some features of
LFS have such mutations.
Children with adrenocortical carcinoma have an
extremely high incidence of germline mutations (over
80%).
The spectrum of mutations in the germline is
superficially the same as somatic mutations, but there
are some significant differences.
Identity
Note
Families with Li-Fraumeni syndrome (LFS) are defined
by: a proband with a sarcoma aged under 45 years, with
a first degree relative with cancer under 45 years and
another first or second degree relative with any cancer
under 45 years or a sarcoma at any age.
Inheritance
Autosomal dominant, high penetrance (100% lifetime
risk in females, 75% in males).
Clinics
Phenotype and clinics
No associated dysmorphologies or abnormalities.
Neoplastic risk
Very high.
The main neoplastic risks are bone, cartilage and soft
tissue sarcomas, early-onset female breast cancer, brain
and spinal cord tumours, childhood adrenocortical
tumours, Wilms' tumour and malignant phyllodes
tumours.
There is no increased incidence of a number of cancers
which occur frequently within the population, such as
colorectal, lung, bladder and gynaecological
malignancies.
Some other tumour types occur rarely, but more
frequently than expected; these include pancreas,
peripheral nervous system, leukaemia and stomach.
Genes involved and proteins
TP53
Location: 17p13
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(1)
76
Li-Fraumeni syndrome
Varley JM
21 Li-Fraumeni families. Cancer Res. 1994 Mar 1;54(5):1298304
hCHK2
Location: 22q12.1
DNA/RNA
Description: 14 exons.
Protein
Description: a 543 amino acid protein with homology.
To
Saccharomyces
cerevisiae
RAD53
andSchizosaccharomyces pombe cds1.
Function: a protein kinase which is required for DNA
damage and replication checkpoints; CHK2 is
phosphorylated by ATM, and in turn can phosphorylate
p53 at serine-20; it appears that germline hCHK2
mutations are uncommon in LFS.
Varley JM, Evans DG, Birch JM. Li-Fraumeni syndrome--a
molecular and clinical review. Br J Cancer. 1997;76(1):1-14
Varley JM, McGown G, Thorncroft M, Santibanez-Koref MF,
Kelsey AM, Tricker KJ, Evans DG, Birch JM. Germ-line
mutations of TP53 in Li-Fraumeni families: an extended study
of 39 families. Cancer Res. 1997 Aug 1;57(15):3245-52
Birch JM, Blair V, Kelsey AM, Evans DG, Harris M, Tricker KJ,
Varley JM. Cancer phenotype correlates with constitutional
TP53 genotype in families with the Li-Fraumeni syndrome.
Oncogene. 1998 Sep 3;17(9):1061-8
Bell DW, Varley JM, Szydlo TE, Kang DH, Wahrer DC,
Shannon KE, Lubratovich M, Verselis SJ, Isselbacher KJ,
Fraumeni JF, Birch JM, Li FP, Garber JE, Haber DA.
Heterozygous germ line hCHK2 mutations in Li-Fraumeni
syndrome. Science. 1999 Dec 24;286(5449):2528-31
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