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Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Scope
The Atlas of Genetics and Cytogenetics in Oncology and Haematology is a peer reviewed on-line journal in
open access, devoted to genes, cytogenetics, and clinical entities in cancer, and cancer-prone diseases.
It presents structured review articles (“cards”) on genes, leukaemias, solid tumours, cancer-prone diseases, and
also more traditional review articles (“deep insights”) on the above subjects and on surrounding topics.
It also present case reports in hematology and educational items in the various related topics for students in
Medicine and in Sciences.
Editorial correspondance
Jean-Loup Huret
Genetics, Department of Medical Information,
University Hospital
F-86021 Poitiers, France
tel +33 5 49 44 45 46 or +33 5 49 45 47 67
[email protected] or [email protected]
The Atlas of Genetics and Cytogenetics in Oncology and Haematology is published 4 times a year by
ARMGHM, a non profit organisation.
Philippe Dessen is the Database Director, and Alain Bernheim the Chairman of the on-line version (Gustave
Roussy Institute – Villejuif – France).
http://AtlasGeneticsOncology.org
© ATLAS - ISSN 1768-3262
The PDF version of the Atlas of Genetics and Cytogenetics in Oncology and Haematology is a reissue of the original articles published in collaboration with
the Institute for Scientific and Technical Information (INstitut de l’Information Scientifique et Technique - INIST) of the French National Center for Scientific
Research (CNRS) on its electronic publishing platform I-Revues.
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Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Editor
Jean-Loup Huret
(Poitiers, France)
Volume 3, Number 1, January - March 1999
Table of contents
Gene Section
KIT (v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog)
Lidia Larizza, Alessandro Beghini
1
LAZ3 (Lymphoma Associated Zinc finger on chromosome 3)
Jean-Pierre Kerckaert
4
KITLG (KIT ligand)
Lidia Larizza
6
P53 (Protein 53 kDa)
Richard Hamelin, Jean-Loup Huret
8
ABCC1 (ATP-binding cassette, sub-family C (CFTR/MRP), member 1)
Franck Viguié
11
NBS1 (Nijmegen breakage syndrome 1)
Jean-Loup Huret
13
NUP98 (nucleoporin 98 kDa)
Jean-Loup Huret
15
Leukaemia Section
del(6q) in Multiple Myeloma
Christophe Brigaudeau
17
Systemic mast cell disease (SMCD)
Lidia Larizza, Alessandro Beghini
19
t(1;5)(p32;q31)
Jean-Loup Huret
21
t(11;14)(p13;q11), t(7;11)(q35;p13)
Chrystèle Bilhou-Nabera
22
B-cell prolymphocytic leukemia (B-PLL)
Lucienne Michaux
24
Splenic lymphoma with villous lymphocytes
Jean-Loup Huret, Hossain Mossafa
26
+8 or trisomy 8
Jean-Loup Huret
28
Atlas Genet Cytogenet Oncol Haematol. 1999; 3(1)
t(11;14)(q13;q32)
in multiple myeloma
Atlas
of Genetics
and Cytogenetics
in Oncology and Haematology
Huret JL, Laï JL
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t(1;7)(q10;p10)
Jean-Loup Huret
31
del(6q) abnormalities in lymphoid malignancies
Christophe Brigaudeau, Chrystele Bilhou-Nabera
33
t(8;16)(p11;p13)
Christine Pérot, Jean-Loup Huret
36
Solid Tumour Section
Bone: Chordoma
Monica Miozzo
39
Kidney: Nephroblastoma (Wilms tumor)
Monica Miozzo
41
Cancer Prone Disease Section
Familial gastrointestinal stromal tumors (GISTs)
Lidia Larizza, Alessandro Beghini
43
Piebaldism
Lidia Larizza, Alessandro Beghini
44
Nijmegen breakage syndrome
Jérôme Couturier
46
Retinoblastoma
Dietmar R Lohmann
48
Rothmund-Thomson syndrome (RTS)
Lidia Larizza
50
Bannayan-Riley-Ruvalcaba syndrome
Jean-Loup Huret
52
Atlas Genet Cytogenet Oncol Haematol. 1999; 3(1)
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
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Gene Section
Mini Review
KIT (v-kit Hardy-Zuckerman 4 feline sarcoma
viral oncogene homolog)
Lidia Larizza, Alessandro Beghini
Department of Biology and Genetics for Medical Sciences, Medical Faculty, University of Milan, Via
Viotti 3/5, 20133 Milan, Italy (LL, AB)
Published in Atlas Database: September 1998
Online updated version : http://AtlasGeneticsOncology.org/Genes/KITID127.html
DOI: 10.4267/2042/37473
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 1999 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Transcription
Identity
5,23 kb mRNA; alternative splicing of exon 9 gives
rise to two isoforms, KITA and KIT, that differ by
the presence or absence of four amino acids.
Other names: SCFR (Stem cell factor receptor);
CD117
Location: 4q12
Local order: Centromere-PDGFRA-KIT-KDRtelomere.
Protein
Description
976 aa; 145 kDa; type III receptor tyrosine kinase;
contains an extracellular domains with 5 Ig-like
loops, a highly hydrophobic transmembrane domain
(23 aa), and an intracellular domain with tyrosine
kinase activity split in an ATP-binding region and
in the phosphotransferase domain by a kinase insert
(KI).
Expression
Hematopoietic stem cells, mast cells, melanocytes,
germ-cell lineages and ICCs (interstitial cells of
Cajal).
Localisation
Plasma membrane.
Function
DNA/RNA
SCF/MGF receptor with tyrosine kinase activity;
binding of ligand (SCF) induces receptor
dimerization, autophosphorylation and signal
transduction via molecules containing SH2domains.
Description
Homology
Spans over 70 kb; 21 exons; size of intron 1: >30
kb.
With CSF-1R, PDGFRb, PDGFRa, and FLT3.
KIT (4q12) - Courtesy Mariano Rocchi.
Atlas Genet Cytogenet Oncol Haematol. 1999; 3(1)
1
KIT (v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog)
Systemic mast cell disease (SMCD)
Mutations
Disease
Mast cell hyperplasia in the bone marrow, liver,
spleen, lymph nodes, gastrointestinal tract and skin;
gain of function mutations have been detected in a
few patients.
Prognosis
Depending on the four clinical entities recognized:
indolent form, form associated with hematologic
disorder, aggressive SMCD and mast cell leukemia;
leukemic
transformation
with
mast
cell
involvement is characterized by rapid progression
of disease with a survival time less than 1 year.
Oncogenesis
Clinical features of malignant hematopoietic cell
growth are influenced by the time, the location of cKIT mutative events, and the number of associated
lesions.
Germinal
In piebaldism, and in familial gastrointestinal
stromal tumours (see below).
Somatic
In aggressive mastocytosis, mast cell leukemia,
AML
with
mast
cell
involvement,
myeloproliferative disorders, colon carcinoma and
gastrointestinal stromal tumours.
Implicated in
Piebaldism
Disease
Autosomal dominant disorder of pigmentation; loss
of function abnormalities of the c-KIT gene have
been demonstrated in 59% of the typical patients.
Familial gastrointestinal stromal
tumours and sporadic
gastrointestinal stromal tumours
(GISTs)
To be noted
Note
Loss of expression of c-KIT appears to be
associated with progression of some tumors
(melanoma) and autocrine/paracrine stimulation of
the c-KIT/SCF system may participate in human
solid tumors such as lung, breast, testicular and
gynecological malignancies.
Disease
GISTs are the most common mesenchymal tumors
in the human digestive tract; they originate from
KIT-expressing cells (ICCs), and were found to
have activating c-KIT mutations in the
juxtamembrane domain.
Atlas Genet Cytogenet Oncol Haematol. 1999; 3(1)
Larizza L, Beghini A
2
KIT (v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog)
Larizza L, Beghini A
References
mastocytosis: establishment of clonality in a human mast
cell neoplasm. Nat Genet. 1996 Mar;12(3):312-4
Vandenbark GR, deCastro CM, Taylor H, Dew-Knight S,
Kaufman RE. Cloning and structural analysis of the human
c-kit gene. Oncogene. 1992 Jul;7(7):1259-66
Hirota S, Isozaki K, Moriyama Y, Hashimoto K, Nishida T,
Ishiguro S, Kawano K, Hanada M, Kurata A, Takeda M,
Muhammad Tunio G, Matsuzawa Y, Kanakura Y,
Shinomura Y, Kitamura Y. Gain-of-function mutations of ckit in human gastrointestinal stromal tumors. Science.
1998 Jan 23;279(5350):577-80
Ezoe K, Holmes SA, Ho L, Bennett CP, Bolognia JL,
Brueton L, Burn J, Falabella R, Gatto EM, Ishii N. Novel
mutations and deletions of the KIT (steel factor receptor)
gene in human piebaldism. Am J Hum Genet. 1995
Jan;56(1):58-66
This article should be referenced as such:
Larizza L, Beghini A. KIT (v-kit Hardy-Zuckerman 4 feline
sarcoma viral oncogene homolog). Atlas Genet Cytogenet
Oncol Haematol. 1999; 3(1):1-3.
Longley BJ, Tyrrell L, Lu SZ, Ma YS, Langley K, Ding TG,
Duffy T, Jacobs P, Tang LH, Modlin I. Somatic c-KIT
activating mutation in urticaria pigmentosa and aggressive
Atlas Genet Cytogenet Oncol Haematol. 1999; 3(1)
3
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
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Gene Section
Mini Review
LAZ3 (Lymphoma Associated Zinc finger on
chromosome 3)
Jean-Pierre Kerckaert
Unite 124 INSERM, Institut de Recherche sur le Cancer, Place de Verdun, 59045 Lille cedex, France
(JPK)
Published in Atlas Database: September 1998
Online updated version : http://AtlasGeneticsOncology.org/Genes/BCL6ID20.html
DOI: 10.4267/2042/37472
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 1999 Atlas of Genetics and Cytogenetics in Oncology and Haematology
protein interaction motif and repressing domain)
and C-term with 6 Krüppel-like zinc fingers
(sequence specific DNA binding domain).
Identity
Other names: BCL6 (B-Cell Lymphoma 6)
Location: 3q27
Local order: Gene orientation: telomere - 5' LAZ3
3' - centromere.
Expression
Normally expressed in germinal center B and T
cells, in skeletal muscle cells and in keratinocytes.
Localisation
Nuclear dots.
Function
Sequence-specific DNA binding transcriptional
repressor;
consensus
DNA-binding
site:
TTC(C/T)T(A/C)GAA; the LAZ3/BCL6 protein
mediates transcriptional repression by recruiting
(through the BTB/POZ domain) a nuclear hormone
receptor co-repressor (SMRT) and histone
deacetylation; it is required for the formation of
germinal centers and the Th2 mediated response.
BCL6 (3q27) - Courtesy Mariano Rocchi.
Homology
DNA/RNA
BTB/POZ - Zinc Finger proteins (PLZF, HIC1,
KUP, BAZF, ttk (drosophila); BrC (drosophila)...).
Description
Spans on a 25 kb genomic fragment. 11 exons; the
two first exons 1A and 1B are alternative;
translational ATG in exon 3.
Implicated in
3q27 rearrangements / NHL (non
Hodgkin lymphomas)
Transcription
3.8 kb mRNA.
Disease
NHL: in 30-40% of diffuse large cell lymphoma, 514% of follicular lymphoma.
Prognosis
Still controversial (favourable in BCL6- vs BCL2rearranged non Hodgkin lymphomas according to
some studies or not significative in other reports).
Protein
Description
706 amino acids; 79 kDa; BTB/POZ Zinc finger
protein: N-term BTB/POZ domain (130-aa protein-
Atlas Genet Cytogenet Oncol Haematol. 1999; 3(1)
4
LAZ3 (Lymphoma Associated Zinc finger on chromosome 3)
Kerckaert JP
transcripts driven by the 5' regulatory region of
LAZ3 fused to the partner gene coding region, have
been characterised.
Abnormal protein
No fusion protein.
Cytogenetics
3q27 rearrangements are diverse : translocations,
micro-deletions,
point
mutations
and
hypermutation); about half of 3q27 translocations
Ig genes at 14q32 (IgH), 2p12 (IgK) and 22q12
(IgL) (e.g. t(3;14)(q27;q32)); the other half includes
a variety of other chromosomal regions (1q21,
2q21, 4p11, 5q31, 6p21, 7p12, 8q24, 9p13, 11q13,
11q23, 12q11, 13q14-21, 14q11, 15q21, 16p11...);
frequent bi-allelic alterations (translocation and
deletion or mutation on the non-translocated allele).
Hybrid/Mutated gene
Hybrid gene and transcripts are formed following
promoter substitution between LAZ3 and its
different partner: Ig-LAZ3 in t(3;14)(q27;q32);
RHOH-LAZ3 in t(3;4)(q27;p13); Histone H4LAZ3 in t(3;6)(q27;p21); OBF1-LAZ3 in
t(3;11)(q27;q23),
L-Plastin-LAZ3
in
t(3;13)(q27;q14-21); chimeric transcripts are
generally detected containing the 5' part of the gene
partner fused to the normal LAZ3 exon 2 splice
acceptor site; in some cases reciprocal chimeric
Atlas Genet Cytogenet Oncol Haematol. 1999; 3(1)
Breakpoints
Note
Clustered in a 3,3 kb EcoRI fragment (MTC)
includind exon 1A and intron 1.
References
Kerckaert JP, Deweindt C, Tilly H, Quief S, Lecocq G,
Bastard C. LAZ3, a novel zinc-finger encoding gene, is
disrupted by recurring chromosome 3q27 translocations in
human lymphomas. Nat Genet. 1993 Sep;5(1):66-70
This article should be referenced as such:
Kerckaert JP. LAZ3 (Lymphoma Associated Zinc finger on
chromosome 3). Atlas Genet Cytogenet Oncol Haematol.
1999; 3(1):4-5.
5
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
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Gene Section
Mini Review
KITLG (KIT ligand)
Lidia Larizza
Department of Biology and Genetics for Medical Sciences, Medical Faculty, University of Milan, Via
Viotti 3/5, 20133 Milan, Italy (LL)
Published in Atlas Database: October 1998
Online updated version : http://AtlasGeneticsOncology.org/Genes/MGFID142.html
DOI: 10.4267/2042/37474
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 1999 Atlas of Genetics and Cytogenetics in Oncology and Haematology
involves the region corresponding to exon 6 of the
SCF cDNA, which contains the proteolytic
cleavage site, encodes for a surface molecule.
Identity
Other names: SCF (Stem cell factor)
Location: 12q22
Expression
SCF transcripts have been found in the cells
surrounding kit-positive cells, such as granulosa
and Sertoli cells, bone marrow stromal cells and in
fibroblasts, keratinocytes and mature granulocytes;
SCF expression of peripheral lymphocytes and
monocytes is still controversial.
DNA/RNA
Localisation
Plasma membrane or interstitial space.
Function
SCF/MGF binding of receptor KIT, with tyrosine
kinase activity, induces receptor dimerization,
autophosphorylation and signal transduction via
molecules containing SH2-domains; the soluble and
the transmembrane protein have a different
biological activity; the soluble form mainly
stimulates cellular proliferation.
Description
Genomic sequence not known; 9 exons.
Transcription
1,4 kb mRNA; alternative splicing gives rise to
different transcripts, mainly represented by those
for a membrane and a soluble form.
Homology
With PDGFRb, PDGFRa, and CSF-1.
Protein
Mutations
Description
Germinal
The membrane bound form is a surface molecule of
248 aa, that includes 23 aa of the highly
hydrophobic transmembrane domain; the second
form corresponds to a soluble protein constituted by
the first 165 aa of the extracellular domain released
by a posttranslational processing, consisting in a
proteolytic cleavage of the mature SCF in the
extracellular juxtamembrane region; the full length
transcripts encode for a transmembrane precursor of
the soluble protein; an alternative splicing that
Human mutations are yet unknown in human
MGF/SCF gene; mouse mutations at the murine
steel (Sl) locus that encodes MGF are known and
give rise to deficiencies in pigment cells, germ
cells, and blood cells; in particular the steel-Dickie
(Sld) mouse has a 4.0-kb intragenic deletion that
truncates the Sl coding sequence; Sld mice are only
capable of encoding a soluble truncated growth
factor that lacks both transmembrane and
cytoplasmic domains.
Atlas Genet Cytogenet Oncol Haematol. 1999; 3(1)
6
KITLG (KIT ligand)
Larizza L
Implicated in
References
Mastocytosis
Martin FH, Suggs SV, Langley KE, Lu HS, Ting J, Okino
KH, Morris CF, McNiece IK, Jacobsen FW, Mendiaz EA.
Primary structure and functional expression of rat and
human stem cell factor DNAs. Cell. 1990 Oct 5;63(1):20311
Disease
In skin from patients with mastocytosis, MGF was
found prevalently free in the dermis and in
extracellular
spaces
between
keratinocytes
suggesting the presence of a soluble form of the
protein; altered distribution of mast cell growth
factor in the skin of patients with cutaneous
mastocytosis is consistent with abnormal
production of the soluble form of the factor,
resulting by an increased cleavage of SCF with
excessive release of a soluble form from the
normally membrane bound form; no sequence
abnormalities were detected in MGF mRNA.
Zsebo KM, Williams DA, Geissler EN, Broudy VC, Martin
FH, Atkins HL, Hsu RY, Birkett NC, Okino KH, Murdock
DC. Stem cell factor is encoded at the Sl locus of the
mouse and is the ligand for the c-kit tyrosine kinase
receptor. Cell. 1990 Oct 5;63(1):213-24
Hibi K, Takahashi T, Sekido Y, Ueda R, Hida T, Ariyoshi Y,
Takagi H, Takahashi T. Coexpression of the stem cell
factor and the c-kit genes in small-cell lung cancer.
Oncogene. 1991 Dec;6(12):2291-6
Ferrari S, Grande A, Manfredini R, Tagliafico E, Zucchini
P, Torelli G, Torelli U. Expression of interleukins 1, 3, 6,
stem cell factor and their receptors in acute leukemia blast
cells and in normal peripheral lymphocytes and
monocytes. Eur J Haematol. 1993 Mar;50(3):141-8
Gynecological tumors
Disease
Findings obtained on three cervical carcinomas
(ovarian serous adenocarcinoma, small cell
carcinoma and ovarian immature teratoma) and two
gynecological cancer cell lines (ME180 and
HGCM) demonstrate coexpression of c-Kit receptor
and SCF; these observations are consistent with the
possibility that an autocrine activation of SCF/KIT
system might be involved in gynecological
malignancies.
Longley BJ Jr, Morganroth GS, Tyrrell L, Ding TG,
Anderson DM, Williams DE, Halaban R. Altered
metabolism of mast-cell growth factor (c-kit ligand) in
cutaneous mastocytosis. N Engl J Med. 1993 May
6;328(18):1302-7
Inoue M, Kyo S, Fujita M, Enomoto T, Kondoh G.
Coexpression of the c-kit receptor and the stem cell factor
in gynecological tumors. Cancer Res. 1994 Jun
1;54(11):3049-53
Ramenghi U, Ruggieri L, Dianzani I, Rosso C, Brizzi MF,
Camaschella C, Pietsch T, Saglio G. Human peripheral
blood granulocytes and myeloid leukemic cell lines
express both transcripts encoding for stem cell factor.
Stem Cells. 1994 Sep;12(5):521-6
Small-cell lung cancer
Disease
SCF is expressed in small-cell lung cancer (SCLC);
abundant expression of SCF and c-Kit mRNA was
seen in 32% of SCLC cell lines and 66% of SCLC
tumors; an autocrine mechanism in the
pathogenesis of SCLC is strongly suggested.
Atlas Genet Cytogenet Oncol Haematol. 1999; 3(1)
This article should be referenced as such:
Larizza L. KITLG (KIT ligand). Atlas Genet Cytogenet
Oncol Haematol. 1999; 3(1):6-7.
7
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Gene Section
Mini Review
P53 (Protein 53 kDa)
Richard Hamelin, Jean-Loup Huret
INSERM U434, Laboratoire de Genetique des Tumeurs, CEPH, Paris, France (RH), Genetics, Dept
Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France (JLH)
Published in Atlas Database: October 1998
Online updated version : http://AtlasGeneticsOncology.org/Genes/P53ID88.html
DOI: 10.4267/2042/37475
This article is an update of: Hamelin R, Huret JL. P53 (protein 53 kDa). Atlas Genet Cytogenet Oncol Haematol.1998;2(4):119.
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 1999 Atlas of Genetics and Cytogenetics in Oncology and Haematology
eliminated. In both cases, the consequence is to
prevent propogation of cells containing genetic
alterations.
Identity
Other names: TP53 (Tumour Protein 53)
Location: 17p13
Homology
DNA/RNA
The five domains are highly-conserved regions
between species.
Description
Mutations
The gene encompasses 20 kb of DNA; 11 exons
(the first is non-coding).
Germinal
Transcription
In Li-Fraumeni syndrome, a dominantly inherited
disease in which affected individuals are
predisposed to develop sarcomas, osteosarcomas,
leukemias and breast cancers at unusually early
ages.
3.0 kb mRNA; 1179 bp open reading frame.
Protein
Description
Somatic
393 amino acids; 53 kDa phosphoprotein; contains,
from N-term to C-term, a transactivation domain, a
DNA-binding domain, nuclear localization signals
and a tetramerization domain.
P53 is mutated in about 50% of human cancers, and
the non-mutated allele is generally lost; the
frequency and the type of mutation may vary from
one tumor type to another; in general, mutations are
found in the central part (exons 4-8) of the p53
gene; these mutations are missense, non-sense,
deletions, insertions or splicing mutations; there are
some hot-spots for mutations at CpG dinucleotides
at positions 175, 24 H8, 273 and 282; P53 mutation
is an adverse prognostic feature in a number of
cancer types, but not in all.
Expression
Widely expressed.
Localisation
Nucleus.
Function
Tumour suppressor gene; P53 is a transcriptional
regulator acting as a guardian of the genome; in
response to DNA damage, p53 is overexpressed and
activates the transcription of genes such as p21
(implicated in cell-cycle arrest) and BAX
(implicated in apoptosis); these activations allow
either the cells to repair DNA damage before
entering further in the cell cycle, or to be
Atlas Genet Cytogenet Oncol Haematol. 1999; 3(1)
Implicated in
Li-Fraumeni syndrome
Disease
Autosomal dominant condition; cancer prone
disease; Li-Fraumeni syndrome is defined by the
8
P53 (Protein 53 kDa)
Hamelin R, Huret JL
lung
tumours
(squamous
carcinomas,
adenocarcinomas, large cell carcinomas).
Oncogenesis
Is multistep, through C-MYC or N-MYC
activation, H-RAS1 or K-RAS2 mutation, P53,
RB1, and P16 inactivation, loss of heterozygosity
(LOH) at 3p, 13q, 17p; P53 mutations, in this
particular case, does not seem to have prognostic
implication; P53 is mutated in 30% of lung
adenocarcinomas to 80% of small cell lung
carcinomas; hotspots at codons 157, 179, 245, 248,
and 273.
existence of both a proband with a sarcoma and two
other first-degree relatives with a cancer by age 45
years; a mutation of P53 is found in at least 50% of
cases; a percentage of mutations may be uncovered;
a gene, upstream P53, could also be implicated in
other cases with germline P53; therefore,
heterogeneity is likely.
Prognosis
Most common cancer in Li-Fraumeni children are:
soft tissues sarcoma before the age of 5 years and
osteosarcoma afterwards, and breast cancer in
young adults; other frequent cancers: brain
tumours, leukaemias, adrenocortical carcinoma; 1/3
of patients have developped more than one primary
cancer, which is quite characteristic of Li-Fraumeni
syndrome but may also be representative of Blooms
syndrome; cancers in this disease, as in other
cancer-prone diseases, often occur early in life:
50% of patients aged 30 years have had a cancer
(i.e. penetrance is 50%, according to this disease
definition); and penetrance is 90% at age 60 years.
Oncogenesis
(Known) germinal mutation are variable, but are
mostly missense mutations located in exons 5 to 8
(DNA binding domain); in tumours occurring in
these patients, the other (wildtype) allele is lost, in
accordance with the two-hit model for neoplasia, as
is found in retinoblastoma.
Colorectal cancers
Disease
There are two types of colorectal cancers, according
to the ploidy:
- the diploid form, RER+ (Replication Error+),
sporadic, without loss of heterozygosity (LOH),
with few mutations of p53 and APC, and rightsided;
- the polyploid form, RER-, with LOH (5q, 17p,
18q), mutations in p53, and more often left-sided,
they have a worse prognosis.
Prognosis
Survival, although improving, is not much more
than 50% after 5 years.
Cytogenetics
Diploid tumours without frequent allelic losses;
aneuploid tumours with numerous allelic losses;
LOH on chromosomes 17 and 18 in more than 75%
of cases; other chromosome arms losses in about
50% of cases.
Oncogenesis
A number of genes are known to be implicated in
tumour progression in colorectal cancers: APC,
P53, KRAS2, mismatch repair genes (MMR genes);
P53 is mutated in 60-65% of colorectal cancer
cases; mutations of P53 are mostly located in exons
4 to 8 with hotspots at codons 175, 245, 248, 273
and 282.
Haematological malignancies
Oncogenesis
P53 gene alterations have been found in:
- 20-30% of blast crisis CML (mostly in the
myeloid type), often associated with i(17q); in
- 5% of MDS cases and 15% of ANLL often with a
visible del(17p); in
- 2% of ALL (but with high variations according to
the ALL type, reaching 50% of L3 ALL (and
Burkitt lymphomas)); in
- 15% of CLL (and 40% in the aggressive CLL
transformation into the Richter's syndrome) and
30% of adult T-cell leukiaemia (only found in the
aggressive form); in
- 5-10% of multiple myelomas; in
- 60-80% of Hodgkin disease; in
- 30% of high grade B-cell NHL (rare in low grade
NHL), and 50% of HIV-related NHL;
- P53 gene alterations in haematological
malignancies are associated with a poor prognosis.
Bladder cancer
Prognosis
Highly variable, according to the stage and the
grade.
Cytogenetics
-9, -11 or del(11p), del(17p) and LOH at 17p,
del(13q), frequent other LOH, aneuploidy,
polyploidy, complex karyotypes.
Oncogenesis
Multi-step and largely unknown process; loss of 9q
and P53 mutations would be early events; RB1, and
P16 inactivation, EGFR overexpression, LOH at
3p, 8p, 11p, 13q, 17p, 18q; P53 is mutated in 40-
Lung cancers
Disease
Lung cancers are neuroendocrine lung tumours
(small cell lung carcinomas, carcinoids, large cell
neuroendocrine carcinomas) or non neuroendocrine
Atlas Genet Cytogenet Oncol Haematol. 1999; 3(1)
9
P53 (Protein 53 kDa)
Hamelin R, Huret JL
Specific mutation at codon 249 related to aflatoxin
B1 dietary exposure; hot spots otherwise at codons
249 and 273.
60% of bladder cancer cases; hotspot at codon 280;
P53 mutations bear a prognostic implication.
Breast cancer
To be noted
Oncogenesis
P53 is mutated in 30% of breast cancers;
preferentially observed in advanced and aggressive
forms; probably a late event; hotspots at codons
175, 248, and 273.
Note
As bove quoted, heterogeneity concerning the
gene(s) mutated in Li-fraumeni is probable; on the
other hand, germinal mutations of P53 have also
been found in families where the criteria for the LiFraumeni syndrome were not reached.
Skin cancers
Disease
Skin cancers include basal cell carcinomas,
squamous cell cercinomas, and melanomas.
Prognosis
Highly different prognosis according to the
pathological group.
Oncogenesis
P53 is mutated in 40-60% of skin cancers; hotspots
at codons 196, 248, 278.
References
P53 mutations in breast cancer: incidence and relations to
tumor aggressiveness and evolution of the disease. Path
Biol 1997 Dec; 45(10):882-892
P53 and lung cancer. Path Biol 1997 Dec; 45(10):852-863.
(Review)
The Li-Fraumeni syndrome: an inherited susceptibility to
cancer. Mol Med Today 1997 Sep;3(9):390-5. (Review).
Oesophagus cancers
TP53 and oesophageal
Dec;45(10):871-875
Disease
Two main forms: squamous cell carcinoma and
adenocarcinoma.
Oncogenesis
P53 is mutated in 50% of oesophagus cancers (80%
in squamous cell carcinoma); probably an early
event; hotspots at codons 175, and 248.
Path
Biol
1997
Cancer. p53, guardian of the genome. Nature 1992 Jul 2;
358(6381):15-16
The role of p53 in normal cells and in cancer development.
Pathol Biol (Paris) 1997 Dec; 45(10):781-784
Alternative genetic pathways in colorectal carcinogenesis.
Proc Natl Acad Sci USA 1997 Oct 28; 94(22):12122-12127
TP53 and hepatocellular carcinoma. Path Biol 1997 Dec;
45(10):864-870. (Review)
Liver cancer
Cytogenetics
Losses of 1p, 4q, 5p, 5q, 8q, 13q, 16p, 16q, and 17p
in 20 to 50% of cases.
Oncogenesis
Atlas Genet Cytogenet Oncol Haematol. 1999; 3(1)
Cancer.
This article should be referenced as such:
Hamelin R, Huret JL. P53 (Protein 53 kDa). Atlas Genet
Cytogenet Oncol Haematol. 1999; 3(1):8-10.
10
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Gene Section
Mini Review
ABCC1 (ATP-binding cassette, sub-family C
(CFTR/MRP), member 1)
Franck Viguié
Laboratoire de Cytogénétique - Service d'Hématologie Biologique, Hôpital Hôtel-Dieu, 75181 Paris
Cedex 04, France (FV)
Published in Atlas Database: November 1998
Online updated version : http://AtlasGeneticsOncology.org/Genes/MRPID106.html
DOI: 10.4267/2042/37476
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 1999 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Localisation
Identity
Other names: MRP
associated protein)
HGNC (Hugo): ABCC1
Location: 16p13.1
Note: MRP is a gene
resistance, discovered in
glycoprotein negative,
carcinoma cell line.
(multidrug
In normal cells, predominant localisation in the
cytoplasm; in tumor cells, predominant in plasma
membrane, but also found in endoplasmic
reticulum, indicating a probable different function
as in normal cells.
resistance-
Function
involved in multidrug
a multidrug-resistant, Pnon small cell lung
Plasma membrane drug-efflux pump; MRP induces
a multidrug resistance phenotype (MDR
phenotype); overexpression confers tumor cell
resistance to a wide variety of hydrophobic drugs:
doxorubicin, daunorubicin, vinblastine, vincristine,
colchicine, VP16, Rhodamin 123; glutathione is
required for the effective expulsion of the
chemotherapeutic agents; the mode of action of
MRP is very similar to the one of P-glycoprotein,
the main protein responsible for the MDR
phenotype; however, MRP does not confer
resistance to Taxol or m-AMSA, but it is able to
transport metallic oxyanions, glutathione and other
glutathione conjugates; inhibitors of organic anion
transport, such as probenecid, can block MRP
activity.
DNA/RNA
Description
Spans at least 200 kb and contains 31 exons
Transcription
7 kb mRNA transcript; significant level of variant
transcripts due to alternative splicing.
Protein
Description
1531 amino acids, 190 kDa; contains two ATP
binding domains and three membrane-spanning
helices; member of the ATP-binding cassette
proteins (ABC proteins).
Homology
Structural and/or functional homology with other
ABC transporter proteins (CFTR, Pgp, MOAT).
Expression
Implicated in
Expressed at a basal level in a wide variety of
normal tissues, including epithelial cells and all
hematopoietic cell types, which suggests a function
common to most cell types; increased expression in
various tumor cell type.
Atlas Genet Cytogenet Oncol Haematol. 1999; 3(1)
Induced resistance to
chemotherapeutic agents
11
ABCC1 (ATP-binding cassette, sub-family C (CFTR/MRP), member 1)
multidrug resistance-associated protein (MRP) in acute
and chronic leukemias. Leukemia. 1994 Jun;8(6):990-7
Disease
In a wide variety of solid and hematological
tumors.
Oncogenesis
MRP hyperexpression may confer therapeutic
resistance in leukemia and solid tumor; however its
relative importance, in comparison with other
proteins able to induce the MDR phenotype (P-gp,
LRP), is not yet clear; hyperexpression is probably
linked to transcriptional activation of the gene
and/or increased mRNA stability, and not to gene
amplification; increased expression of MRP mRNA
and protein is a factor of bad prognostic in
neuroblastoma, retinoblastoma, and non small cell
lung carcinoma. In haematological malignancies,
overexpression is frequent in chronic lymphocytic
leukemia and prolymphocytic leukemia, occasional
in acute myeloid leukemia and rare in acute
lymphoid leukemia, lymphoma, multiple myeloma
and myeloproliferative disorders.
Zaman GJ, Flens MJ, van Leusden MR, de Haas M,
Mülder HS, Lankelma J, Pinedo HM, Scheper RJ, Baas F,
Broxterman HJ. The human multidrug resistanceassociated protein MRP is a plasma membrane drug-efflux
pump. Proc Natl Acad Sci U S A. 1994 Sep
13;91(19):8822-6
Barrand MA, Bagrij T, Neo SY. Multidrug resistanceassociated protein: a protein distinct from P-glycoprotein
involved in cytotoxic drug expulsion. Gen Pharmacol. 1997
May;28(5):639-45
Deeley RG, Cole SP. Function, evolution and structure of
multidrug resistance protein (MRP). Semin Cancer Biol.
1997 Jun;8(3):193-204
Kavallaris M. The role of multidrug resistance-associated
protein (MRP) expression in multidrug resistance.
Anticancer Drugs. 1997 Jan;8(1):17-25
Ling V. Multidrug resistance: molecular mechanisms and
clinical relevance. Cancer Chemother Pharmacol. 1997;40
Suppl:S3-8
Willman CL. The prognostic significance of the expression
and function of multidrug resistance transporter proteins in
acute myeloid leukemia: studies of the Southwest
Oncology Group Leukemia Research Program. Semin
Hematol. 1997 Oct;34(4 Suppl 5):25-33
References
Cole SP, Bhardwaj G, Gerlach JH, Mackie JE, Grant CE,
Almquist KC, Stewart AJ, Kurz EU, Duncan AM, Deeley
RG. Overexpression of a transporter gene in a multidrugresistant human lung cancer cell line. Science. 1992 Dec
4;258(5088):1650-4
This article should be referenced as such:
Viguié F. ABCC1 (ATP-binding cassette, sub-family C
(CFTR/MRP), member 1). Atlas Genet Cytogenet Oncol
Haematol. 1999; 3(1):11-12.
Burger H, Nooter K, Zaman GJ, Sonneveld P, van
Wingerden KE, Oostrum RG, Stoter G. Expression of the
Atlas Genet Cytogenet Oncol Haematol. 1999; 3(1)
Viguié F
12
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Gene Section
Mini Review
NBS1 (Nijmegen breakage syndrome 1)
Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers,
France (JLH)
Published in Atlas Database: November 1998
Online updated version : http://AtlasGeneticsOncology.org/Genes/NBS1ID160.html
DOI: 10.4267/2042/37477
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 1999 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
Mutations
Location: 8q21.3
Germinal
DNA/RNA
Transcription
Missense mutations in the BRCT domain or
truncating mutations downstream the BRCT are
found in Nijmegen breakage syndrome (see below);
most mutations are a 5 bases deletion at codon 218,
called 657del5, and should be due to a founder
effect.
4.4 and 2.6 kb (alternative polyadenylation); open
reading frame of 2265 nucleotides.
Implicated in
Protein
Nijmegen breakage syndrome
Description
Spans over 51 kb; 16 exons.
Disease
Nijmegen breakage syndrome is a chromosome
instability syndrome/cancer prone disease at risk of
non Hodgkin lymphomas (NHL).
Cytogenetics
Chromosome
rearrangements
involving
immunoglobulin superfamilly genes, in particular
inv(7)(p13q35).
Description
The protein is called nibrin; 754 amino acids; 85
kDa; contains in (the telomeric) N-term a forkhead
associated domain (amino acids 24-100) and a
breast cancer carboterminal domain (BRCT; amino
acids 105-190), both domains being found in the
various DNA damage responsive cell cycle
checkpoint proteins; 4 possible nuclear localization
domains in the half C-term.
References
Expression
Carney JP, Maser RS, Olivares H, Davis EM, Le Beau M,
Yates JR 3rd, Hays L, Morgan WF, Petrini JH. The
hMre11/hRad50 protein complex and Nijmegen breakage
syndrome: linkage of double-strand break repair to the
cellular DNA damage response. Cell. 1998 May
1;93(3):477-86
Wide; shorter transcript expressed at higher level in
the testis (may have a role in meiotic
recombination, as ATM does).
Function
Matsuura S, Tauchi H, Nakamura A, Kondo N, Sakamoto
S, Endo S, Smeets D, Solder B, Belohradsky BH, Der
Kaloustian VM, Oshimura M, Isomura M, Nakamura Y,
Komatsu K. Positional cloning of the gene for Nijmegen
breakage syndrome. Nat Genet. 1998 Jun;19(2):179-81
Member of the MRE/RAD50/nibrin double-strand
break repair complex of 1600 kDa.
Homology
No known homology.
Atlas Genet Cytogenet Oncol Haematol. 1999; 3(1)
13
NBS1 (Nijmegen breakage syndrome 1)
Huret JL
Varon R, Vissinga C, Platzer M, Cerosaletti KM,
Chrzanowska KH, Saar K, Beckmann G, Seemanová E,
Cooper PR, Nowak NJ, Stumm M, Weemaes CM, Gatti
RA, Wilson RK, Digweed M, Rosenthal A, Sperling K,
Concannon P, Reis A. Nibrin, a novel DNA double-strand
break repair protein, is mutated in Nijmegen breakage
syndrome. Cell. 1998 May 1;93(3):467-76
Atlas Genet Cytogenet Oncol Haematol. 1999; 3(1)
This article should be referenced as such:
Huret JL. NBS1 (Nijmegen breakage syndrome 1). Atlas
Genet Cytogenet Oncol Haematol. 1999; 3(1):13-14.
14
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Gene Section
Mini Review
NUP98 (nucleoporin 98 kDa)
Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers,
France (JLH)
Published in Atlas Database: November 1998
Online updated version : http://AtlasGeneticsOncology.org/Genes/NUP98.html
DOI: 10.4267/2042/37478
This article is an update of: Huret JL. NUP98 (nucleoporin 98 kDa). Atlas Genet Cytogenet Oncol Haematol.1998;2(1):7.
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 1999 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Prognosis
Mean survival: 15 months.
Cytogenetics
Sole anomaly most often.
Hybrid/Mutated gene
5' NUP98 - 3' HOXA9.
Abnormal protein
Fuses the GLFG repeat domains of NUP98 to the
HOXA9 homeobox.
Identity
Location : 11p15
DNA/RNA
Transcription
3.6, 6.5, 7.0 kb mRNA.
Protein
inv(11)(p15q22)/MDS or ANLL -->
NUP98/DDX10
Description
920 amino acids; 97 kDa; contains repeated motifs
(GLFG and FG) in N-term and a RNA binding
motif in C-term.
Disease
Therapy-related MDS and ANLL; de novo ANLL.
Hybrid/Mutated gene
5' NUP98 - 3' DDX10
Abnormal protein
Fuses the GLFG repeat domains of NUP98 to the
acidic domain of DDX11.
Expression
Wide.
Localisation
Nuclear membrane localisation.
Function
t(2;11)(q31;p15)/treatment-related
leukaemia --> NUP98/HOXD13
Nucleoporin: associated with the nuclear pore
complex; role in nucleocytoplasmic transport
processes.
Disease
So far, only 1 case of treatment related
myelodysplasia evolving towards M6 acute non
lymphocytic leukaemia.
Hybrid/Mutated gene
5' NUP98 - 3' HOXD13.
Abnormal protein
Fuses the GLFG repeat domains of NUP98 to the
HOXD13 homeodomain.
Homology
Member of the GLFG nucleoporins.
Implicated in
t(7;11)(p15;p15)/ANLL -->
NUP98/HOXA9
Disease
M2-M4 ANLL mostly; occasionally, CML-like
cases.
Atlas Genet Cytogenet Oncol Haematol. 1999; 3(1)
15
NUP98 (nucleoporin 98 kDa)
Huret JL
Powers MA, Forbes DJ, Dahlberg JE, Lund E. The
vertebrate GLFG nucleoporin, Nup98, is an essential
component of multiple RNA export pathways. J Cell Biol.
1997 Jan 27;136(2):241-50
References
Nakamura T, Largaespada DA, Lee MP, Johnson LA,
Ohyashiki K, Toyama K, Chen SJ, Willman CL, Chen IM,
Feinberg AP, Jenkins NA, Copeland NG, Shaughnessy JD
Jr. Fusion of the nucleoporin gene NUP98 to HOXA9 by
the chromosome translocation t(7;11)(p15;p15) in human
myeloid leukaemia. Nat Genet. 1996 Feb;12(2):154-8
Raza-Egilmez SZ, Jani-Sait SN, Grossi M, Higgins MJ,
Shows TB, Aplan PD. NUP98-HOXD13 gene fusion in
therapy-related acute myelogenous leukemia. Cancer Res.
1998 Oct 1;58(19):4269-73
Arai Y, Hosoda F, Kobayashi H, Arai K, Hayashi Y,
Kamada N, Kaneko Y, Ohki M. The inv(11)(p15q22)
chromosome translocation of de novo and therapy-related
myeloid malignancies results in fusion of the nucleoporin
gene, NUP98, with the putative RNA helicase gene,
DDX10. Blood. 1997 Jun 1;89(11):3936-44
Atlas Genet Cytogenet Oncol Haematol. 1999; 3(1)
This article should be referenced as such:
Huret JL. NUP98 (nucleoporin 98 kDa). Atlas Genet
Cytogenet Oncol Haematol. 1999; 3(1):15-16.
16
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Leukaemia Section
Short Communication
del(6q) in Multiple Myeloma
Christophe Brigaudeau
Laboratory of Hematology, University Hospital, 87000 Limoges, France
Published in Atlas Database: September 1998
Online updated version : http://AtlasGeneticsOncology.org/Anomalies/del6qMMID2060.html
DOI: 10.4267/2042/37479
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 1999 Atlas of Genetics and Cytogenetics in Oncology and Haematology
2- a pattern of either pseudodiploidy, hypodiploidy
or near-tetraploidy karyotypes; patients with the
latter pattern appear to have a worse prognosis than
patients with a hyperdiploid karyotype (med
survival of 1.5 yr vs 3 yrs; p<0.04). del(6q)
abnormalities were more frequent in the second
hypodiploid group.
Clinics and pathology
Disease
Multiple myeloma (MM) is a malignant plasma cell
proliferation
Phenotype/cell stem origin
Mature differentiated B-cell, but also with CD56
expression, which is not found in normal plasma
cell; CD38+, CD40+, CD138+.
Cytogenetics
Cytogenetics morphological
Epidemiology
del(6q) are mainly so-called terminal deletions,
with a variable breakpoint in q12, q15, q21, or q23;
overall, the break occurs predominantly in 6q21.
MM's annual incidence is 30/106; del(6q) is
observed in about 2 to 5% of MM cases (i.e.: 510% of cases with an abnormal karyotype).
Genes involved and
proteins
Clinics
Bone pain; susceptibility to infections; renal failure;
neurologic dysfunctions.
Note
del(6q) in MM cases encompass the 6q21 band:
loss of this band suggests that the critical gene(s)
might be a recessive tumour suppressor gene sitting
in 6q21, which remains to be identified
Pathology
MM staging:
- stage I: low tumour cell mass; normal Hb; low
serum calcium; no bone lesion; low monoclonal Ig
rate;
- stage II: fitting neither stage I nor stage II;
- stage III: high tumour cell mass; low Hb and/or
high serum calcium and/or advanced lytic bone
lesions and/or high monoclonal Ig rate.
References
Laï JL, Zandecki M, Mary JY, Bernardi F, Izydorczyk V,
Flactif M, Morel P, Jouet JP, Bauters F, Facon T. Improved
cytogenetics in multiple myeloma: a study of 151 patients
including 117 patients at diagnosis. Blood. 1995 May
1;85(9):2490-7
Evolution
Prognosis
Sawyer JR, Waldron JA, Jagannath S, Barlogie B.
Cytogenetic findings in 200 patients with multiple
myeloma. Cancer Genet Cytogenet. 1995 Jul 1;82(1):41-9
Prognosis (highly variable) is according to the
staging and other parameters, of which are now the
karyotypic findings: two distinct cytogenetic
pattern have been reported, according to the
chromosome number: 1- a hyperdiploid pattern, and
Brigaudeau C, Trimoreau F, Gachard N, Rouzier E,
Jaccard A, Bordessoule D, Praloran V. Cytogenetic study
of 30 patients with multiple myeloma: comparison of 3 and
6 day bone marrow cultures stimulated or not with
cytokines by using a miniaturized karyotypic method. Br J
Haematol. 1997 Mar;96(3):594-600
MM can evolve towards plasma cell leukemia.
Atlas Genet Cytogenet Oncol Haematol. 1999; 3(1)
17
del(6q) in Multiple Myeloma
Brigaudeau C
Calasanz MJ, Cigudosa JC, Odero MD, Ferreira C,
Ardanaz MT, Fraile A, Carrasco JL, Solé F, Cuesta B,
Gullón A. Cytogenetic analysis of 280 patients with
multiple myeloma and related disorders: primary
breakpoints and clinical correlations. Genes Chromosomes
Cancer. 1997 Feb;18(2):84-93
Smadja NV, Fruchart C, Isnard F, Louvet C, Dutel JL,
Cheron N, Grange MJ, Monconduit M, Bastard C.
Chromosomal analysis in multiple myeloma: cytogenetic
evidence of two different diseases. Leukemia. 1998
Jun;12(6):960-9
This article should be referenced as such:
Sawyer JR, Tricot G, Mattox S, Jagannath S, Barlogie B.
Jumping translocations of chromosome 1q in multiple
myeloma: evidence for a mechanism involving
decondensation of pericentromeric heterochromatin.
Blood. 1998 Mar 1;91(5):1732-41
Atlas Genet Cytogenet Oncol Haematol. 1999; 3(1)
Brigaudeau C. del(6q) in Multiple Myeloma. Atlas Genet
Cytogenet Oncol Haematol. 1999; 3(1):17-18.
18
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Leukaemia Section
Short Communication
Systemic mast cell disease (SMCD)
Lidia Larizza, Alessandro Beghini
Department of Biology and Genetics for Medical Sciences, Medical Faculty, University of Milan, Via
Viotti 3/5, 20133 Milan, Italy (LL, AB)
Published in Atlas Database: September 1998
Online updated version : http://AtlasGeneticsOncology.org/Anomalies/MastCellID2064.html
DOI: 10.4267/2042/37480
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 1999 Atlas of Genetics and Cytogenetics in Oncology and Haematology
- In mastocytosis with an associated hematological
disorder the urticaria pigmentosa symptoms are
accompanied by a variety of haematological
findings associated with mast cell infiltrates to bone
marrow, spleen, liver and lymph nodes.
- Mast cell leukemia is characterized by
proliferation and infiltration of immature mast cells
in bone marrow, peripheral blood and various
extramedullary tissues.
- Aggressive mastocytosis is characterized by
aggressive involvement of several haematopoietic
organs.
Identity
Note
Mastocytosis is a heterogeneous clinical entity
which is classified into four categories:
1- indolent mastocytosis (the most common form),
2- mastocytosis with an associated hematologic
disorder,
3- mast cell leukemia and
4- aggressive mastocytosis.
Clinics and pathology
Pathology
Phenotype/cell stem origin
Accumulation of mast cells in various organs and
release of mast cell mediators which are responsible
for the different clinical signs.
Mast cell.
Etiology
Prognosis
Involvement of KIT/SCF has been demonstrated in
a few cases, but the diversity of the clinical pattern
has not yet been elucidated; increased soluble SCF
has been reported in the skin of patient with
indolent mastocytosis; c-KIT mutations have been
identified in mastocytosis with an associated
haematological disorder and in aggressive
mastocytosis.
Highly dependent on the form being severe, often
fatal, in all types with the exception of the indolent
form.
Genes involved and
proteins
Clinics
KIT
- Indolent mastocytosis involves the skin, bone
marrow and gastrointestinal tract; clinical features
range from a single cutaneous nodule to multiple
pigmented macules resulting from increased
epidermal melanin and papules (urticaria
pigmentosa) or diffuse cutaneous involvement;
bullae, vescicles and abnormal telangiectasia may
be seen; gastrointestinal involvement leads to
symptoms such as nausea, vomiting and abdominal
pain.
Location
4q12
DNA/RNA
21 exons.
Protein
Transmembrane SCF/MGF receptor with tyrosine
kinase activity; binding of ligand (SCF) induces
receptor dimerization, autophosphorylation and
signal transduction via molecules containing SH2domains.
Atlas Genet Cytogenet Oncol Haematol. 1999; 3(1)
19
Systemic mast cell disease (SMCD)
Larizza L, Beghini A
PCR in mast cell infiltrates in papulae from
mastocytosis patients.
Somatic mutations
Gly560Val, Asp816Val, Asp816Tyr, Asp820Gly:
- Asp816Val in peripheral blood lymphocytes
(mastocytosis with an associated hematological
disorder: AHD).
- Asp816Val in skin and spleen mast cells from
patients with aggressive mastocytosis.
- Asp816Tyr in blasts from a patient with AML-M2
with mast cell involvement.
- Asp820 Gly in blasts from a patient with
aggressive SMCD.
- Asp816Val and Gly560Val have been found in a
human mast cell leukemia cell line (HMC1).
All mutations with the exception of Gly560Val
cluster to c-kit exon 17. Direct or indirect evidence
has been provided that mutations affecting codon
816
promote
ligand-independent
autophosphorylation of the mutant receptor.
References
Furitsu T, Tsujimura T, Tono T, Ikeda H, Kitayama H,
Koshimizu U, Sugahara H, Butterfield JH, Ashman LK,
Kanayama Y. Identification of mutations in the coding
sequence of the proto-oncogene c-kit in a human mast cell
leukemia cell line causing ligand-independent activation of
c-kit product. J Clin Invest. 1993 Oct;92(4):1736-44
Longley BJ Jr, Morganroth GS, Tyrrell L, Ding TG,
Anderson DM, Williams DE, Halaban R. Altered
metabolism of mast-cell growth factor (c-kit ligand) in
cutaneous mastocytosis. N Engl J Med. 1993 May
6;328(18):1302-7
Nagata H, Worobec AS, Oh CK, Chowdhury BA,
Tannenbaum S, Suzuki Y, Metcalfe DD. Identification of a
point mutation in the catalytic domain of the
protooncogene c-kit in peripheral blood mononuclear cells
of patients who have mastocytosis with an associated
hematologic disorder. Proc Natl Acad Sci U S A. 1995 Nov
7;92(23):10560-4
SCF/MGF
Longley BJ, Tyrrell L, Lu SZ, Ma YS, Langley K, Ding TG,
Duffy T, Jacobs P, Tang LH, Modlin I. Somatic c-KIT
activating mutation in urticaria pigmentosa and aggressive
mastocytosis: establishment of clonality in a human mast
cell neoplasm. Nat Genet. 1996 Mar;12(3):312-4
Location
12q22
DNA/RNA
9 exons
Protein
- Soluble SCF: 248 amino acids containing a
proteolytic cleavage site encoded by exon 6
sequences, which is processed, giving rise to an
active form (soluble) of 165 amino acids;
membrane-bound SCF: 220 amino acids, results
from alternative splicing of exon 6.
- Note: increased soluble SCF has been detected in
the skin of patients with indolent mastocytosis;
SCF-specific transcripts are detected by in situ RTAtlas Genet Cytogenet Oncol Haematol. 1999; 3(1)
Pignon JM, Giraudier S, Duquesnoy P, Jouault H, Imbert
M, Vainchenker W, Vernant JP, Tulliez M. A new c-kit
mutation in a case of aggressive mast cell disease. Br J
Haematol. 1997 Feb;96(2):374-6
Beghini A, Cairoli R, Morra E, Larizza L. In vivo
differentiation of mast cells from acute myeloid leukemia
blasts carrying a novel activating ligand-independent C-kit
mutation. Blood Cells Mol Dis. 1998 Jun;24(2):262-70
This article should be referenced as such:
Larizza L, Beghini A. Systemic mast cell disease (SMCD).
Atlas Genet Cytogenet Oncol Haematol. 1999; 3(1):19-20.
20
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Leukaemia Section
Short Communication
t(1;5)(p32;q31)
Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers,
France (JLH)
Published in Atlas Database: September 1998
Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t0105ID1141.html
DOI: 10.4267/2042/37481
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 1999 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Clinics and pathology
Disease
Result of the chromosomal
anomaly
T cell acute lymphocytic leukaemia (T-ALL).
Hybrid gene
Clinics
Description
Breakpoint on TAL1 was found 10 kb upstream the
gene, as was found in the cases of t(1;3)(p32;p21),
while it is more 3', within the gene, in the
t(1;14)(p32;q11) and in TAL1 deletions.
Yet poorly known: only 1 case: a young adult male
patient with high WBC (common features in TALL); bone marrow transplantation; complete
remission: 43 mths +.
Genes involved and
proteins
Fusion protein
TAL1
References
Expression / Localisation
High nuclear expression.
Location
1p32
DNA/RNA
Complex alternate splicing.
Protein
Contains a basic Helix-Loop-Helix (DNA binding)
domain; forms heterodimers; transcription factor;
role in haematopoietic cell differentiation.
François S, Delabesse E, Baranger L, Dautel M, Foussard
C, Boasson M, Blanchet O, Bernard O, Macintyre EA, Ifrah
N. Deregulated expression of the TAL1 gene by
t(1;5)(p32;31) in patient with T-cell acute lymphoblastic
leukemia.
Genes
Chromosomes
Cancer.
1998
Sep;23(1):36-43
This article should be referenced as such:
Huret JL. t(1;5)(p32;q31). Atlas Genet Cytogenet Oncol
Haematol. 1999; 3(1):21.
Yet unknown gene
Location
5q31
Atlas Genet Cytogenet Oncol Haematol. 1999; 3(1)
21
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Leukaemia Section
Short Communication
t(11;14)(p13;q11), t(7;11)(q35;p13)
Chrystèle Bilhou-Nabera
Laboratoire d'Hématologie, Hôpital du Haut-Lévêque, CHU de Bordeaux, Avenue de Magellan,
33604 Pessac, France (CBN)
Published in Atlas Database: September 1998
Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t1114ID1070.html
DOI: 10.4267/2042/37482
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 1999 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
Genes involved and
proteins
Note
This t(11;14) must be not confused with the
t(11;14)(p15;q11) associated with an immature
immunophenotype (CD3-, CD4-, CD8-) and
involving respectively RTBN1 gene and TRD
locus.
RBTN2
Location
11p13
Protein
Cystein-rich protein with two tandemly arranged
zinc binding LIM-domain motifs: named Lom2;
Lmo2 directly interacts with the basic-loop-helix
protein Tal1/Scl and the GATA DNA protein Gata1; central role in adult hematopoietic pathway
regulation.
t(11;14)(p13;q11) G- banding (left) and R- banding (right) Courtesy Jean-Luc Lai and Alain Vanderhaegen.
TRA/D or TRB
Clinics and pathology
Location
14q11 and 7q35 respectively.
Disease
Epidemiology
Result of the chromosomal
anomaly
5-10% of childhood T-ALL.
Hybrid gene
Cytogenetics
Description
Chromosomal breakpoints occur 25 kb upstream
RBTN2 gene, in a presumed transcriptional start
site, inducing truncation of the promoter/control
region and leading to inappropriate Lmo2 level
especially
in
T-cells
(abnormal
T-cell
differentiation).
T-ALL
Additional anomalies
+17; to be noted that a Ph chromosome (m-BCR)
has been found in one case of T-ALL.
Variants
t(11;14)(p13;q11) and t(7;11)(q35;p13) are variant
translocations of each other.
Fusion protein
Oncogenesis
Lmo2 is activated after chromosomal translocation
by association with either the TRA/D or the TRB.
Atlas Genet Cytogenet Oncol Haematol. 1999; 3(1)
22
t(11;14)(p13;q11), t(7;11)(q35;p13)
Bilhou-Nabera C
Raimondi SC, Behm FG, Roberson PK, Pui CH, Rivera
GK, Murphy SB, Williams DL. Cytogenetics of childhood Tcell leukemia. Blood. 1988 Nov;72(5):1560-6
To be noted
Note
CELL LINE with t(11;14)(p13;q11): KOPT-K1;
the breakpoints occur: - on chromosome 11 in an
Alu-rich region, between two Alu sequences, 160
kb-closed from RTBN2; - on chromosome 14
within Jd1; RTBN2 is highly expressed in KOPTK1.
Boehm T, Foroni L, Kaneko Y, Perutz MF, Rabbitts TH.
The rhombotin family of cysteine-rich LIM-domain
oncogenes: distinct members are involved in T-cell
translocations to human chromosomes 11p15 and 11p13.
Proc Natl Acad Sci U S A. 1991 May 15;88(10):4367-71
Dong WF, Billia F, Atkins HL, Iscove NN, Minden MD.
Expression of rhombotin 2 in normal and leukaemic
haemopoietic cells. Br J Haematol. 1996 May;93(2):280-6
References
Wadman IA, Osada H, Grütz GG, Agulnick AD, Westphal
H, Forster A, Rabbitts TH. The LIM-only protein Lmo2 is a
bridging molecule assembling an erythroid, DNA-binding
complex which includes the TAL1, E47, GATA-1 and
Ldb1/NLI proteins. EMBO J. 1997 Jun 2;16(11):3145-57
Williams DL, Look AT, Melvin SL, Roberson PK, Dahl G,
Flake T, Stass S. New chromosomal translocations
correlate with specific immunophenotypes of childhood
acute lymphoblastic leukemia. Cell. 1984 Jan;36(1):101-9
This article should be referenced as such:
Lampert F, Harbott J, Ritterbach J, Ludwig WD, Fonatsch
C, Schwamborn D, Stier B, Gnekow A, Gerein V,
Stollmann B. T-cell acute childhood lymphoblastic
leukemia with chromosome 14 q 11 anomaly: a
morphologic, immunologic, and cytogenetic analysis of 10
patients. Blut. 1988 Mar;56(3):117-23
Atlas Genet Cytogenet Oncol Haematol. 1999; 3(1)
Bilhou-Nabera C. t(11;14)(p13;q11), t(7;11)(q35;p13).
Atlas Genet Cytogenet Oncol Haematol. 1999; 3(1):22-23.
23
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Leukaemia Section
Short Communication
B-cell prolymphocytic leukemia (B-PLL)
Lucienne Michaux
Department of Hematology and Center for Human Genetics Cliniques Universitaires Saint Luc
Avenue Hippocrate 10 1200 Brussels, Belgium (LM)
Published in Atlas Database: October 1998
Online updated version : http://AtlasGeneticsOncology.org/Anomalies/BPLL.html
DOI: 10.4267/2042/37483
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 1999 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Clinics and pathology
Cytogenetics
Disease
Cytogenetics morphological
Chronic lymphoproliferative disorder (CLD)
Few studies focused on B-PLL; the use of B-cell
mitogens might increase the detection rate of
cytogenetic changes; the most frequent aberrations
involve chromosomes 14, 6 and 1; 14q+ changes
are the most commonly observed and are often the
consequence of a translocation t(11;14)(q13;q32);
structural abnormalities of chromosome 6 are
primary or secondary; deletion 6q, as well as
translocation t(6;12)(q15;p13) are described;
structural aberrations of chromosome 1 involve
both p and q arms; trisomy 12 represents a
secondary change in this disease; finally,
i(17)(q10), as well as telomeric associations have
been reported; karyotypic evolution has been
documented in some cases and seems to be
associated with disease progression.
Phenotype/cell stem origin
Disease affecting mature B-cells.
Immunophenotypically, B-PLL is characterized by
reactivity with pan B-cell markers CD19, CD20 and
CD24.
B-PLL cells are distinct from B-CLL cells in that
they express bright surface immunoglobulin,
unfrequently express CD5, fail to form rosettes with
mouse erythrocytes and react strongly with FMC7.
Expression of CD22 is often observed whereas
CD23 is usually not expressed.
Epidemiology
Rare disease; slight male predominance with
median age of 69 years.
Genes involved and
proteins
Clinics
Patients often present with advanced stage disease.
B-PLL is characterized by high white blood cell
counts and splenomegaly without adenopathy.
Bone marrow infiltration pattern is either diffuse or
mixed.
Blood data: elevated white blood cell counts with
prolymphocytes representing more than 55% of the
circulating lymphoid cells.
Anemia and thrombocytopenia may be observed.
Note
Little is known about underlying genetic
mechanisms in B-PLL.
Immunoglobulin gene rearrangements are always
observed.
BCL-1 gene is involved in some cases bearing
t(11;14)(q13;q32), with breakpoints located
centrometric to the major translocation cluster.
Overall, abnormalities of P53 occur in 75% cases,
representing the highest reported frequency in Bcell malignancies.
Prognosis
Evolution: this disease is always progressive.
Prognosis: poor response to therapy is often
observed; median survival is 3 years.
Atlas Genet Cytogenet Oncol Haematol. 1999; 3(1)
24
B-cell prolymphocytic leukemia (B-PLL)
Michaux L
No CDKNL-2 or RB1 gene involvement has been
documented so far.
C-MYC rearrangement has been described in PLL.
Howell RT, Kitchen C, Standen GR. Telomeric
associations in a patient with B-cell prolymphocytic
leukaemia.
Genes
Chromosomes
Cancer.
1993
Jun;7(2):116-8
To be noted
Brennscheidt U, Eick D, Kunzmann R, Martens U,
Kiehntopf M, Mertelsmann R, Herrmann F. Burkitt-like
mutations in the c-myc gene locus in prolymphocytic
leukemia. Leukemia. 1994 May;8(5):897-902
Note
T-cell prolymphocytic leukaemia also exists and
account for 1/4 of cases of PLL.
Döhner H, Pilz T, Fischer K, Cabot G, Diehl D, Fink T,
Stilgenbauer S, Bentz M, Lichter P. Molecular cytogenetic
analysis of RB-1 deletions in chronic B-cell leukemias.
Leuk Lymphoma. 1994 Dec;16(1-2):97-103
References
Galiègue-Zouitina S, Collyn-d'Hooghe M, Denis C,
Mainardi A, Hildebrand MP, Tilly H, Bastard C, Kerckaert
JP. Molecular cloning of a t(11;14)(q13;q32) translocation
breakpoint centromeric to the BCL1-MTC. Genes
Chromosomes Cancer. 1994 Dec;11(4):246-55
Pittman S, Catovsky D. Chromosome abnormalities in Bcell prolymphocytic leukemia: a study of nine cases.
Cancer Genet Cytogenet. 1983 Aug;9(4):355-65
Sadamori N, Han T, Minowada J, Bloom ML, Henderson
ES, Sandberg AA. Possible specific chromosome change
in prolymphocytic leukemia. Blood. 1983 Oct;62(4):729-36
Schröder M, Mathieu U, Dreyling MH, Bohlander SK,
Hagemeijer A, Beverloo BH, Olopade OI, Stilgenbauer S,
Fischer K, Bentz M. CDKN2 gene deletion is not found in
chronic lymphoid leukaemias of B- and T-cell origin but is
frequent in acute lymphoblastic leukaemia. Br J Haematol.
1995 Dec;91(4):865-70
Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton
DA, Gralnick HR, Sultan C. Proposals for the classification
of chronic (mature) B and T lymphoid leukaemias. FrenchAmerican-British (FAB) Cooperative Group. J Clin Pathol.
1989 Jun;42(6):567-84
Lens D, De Schouwer PJ, Hamoudi RA, Abdul-Rauf M,
Farahat N, Matutes E, Crook T, Dyer MJ, Catovsky D. p53
abnormalities in B-cell prolymphocytic leukemia. Blood.
1997 Mar 15;89(6):2015-23
Brito-Babapulle V, Catovsky D. Inversions and tandem
translocations involving chromosome 14q11 and 14q32 in
T-prolymphocytic leukemia and T-cell leukemias in
patients with ataxia telangiectasia. Cancer Genet
Cytogenet. 1991 Aug;55(1):1-9
This article should be referenced as such:
Michaux L. B-cell prolymphocytic leukemia (B-PLL). Atlas
Genet Cytogenet Oncol Haematol. 1999; 3(1):24-25.
Brito-Babapulle V, Ellis J, Matutes E, Oscier D, Khokhar T,
MacLennan
K,
Catovsky
D.
Translocation
t(11;14)(q13;q32) in chronic lymphoid disorders. Genes
Chromosomes Cancer. 1992 Sep;5(2):158-65
Atlas Genet Cytogenet Oncol Haematol. 1999; 3(1)
25
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Leukaemia Section
Short Communication
Splenic lymphoma with villous lymphocytes
Jean-Loup Huret, Hossain Mossafa
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers,
France (JLH), Laboratoire Pasteur-Cerba, 95066, Cergy-Pontoise, France (HM)
Published in Atlas Database: October 1998
Online updated version : http://AtlasGeneticsOncology.org/Anomalies/splenvillousID2063.html
DOI: 10.4267/2042/37484
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 1999 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Clinics and pathology
Genes involved and
proteins
Epidemiology
Occurs in the elderly (med 70 years); sex ratio
2M/1F.
Note
BCL1 in 11q13 and IgH in 14q32 are involved in
20% of cases, with or without a visible t(11;14);
BCL1 encodes the cyclin D1; role in the cell cycle
control (G1 progression and G1/S transition); 5'
BCL1 translocated on chromosome 14 near JH,
resulting
in
promoter
exchange;
the
immunoglobulin gene enhancer stimulates the
expression of BCL1, and overexpression of BCL1
which accelerates passage through the G1 phase;
microdeletion in the RB1 region in half cases.
Clinics
Splenomegaly without hepatomegaly nor enlarged
lymph nodes; peripheral blood lymphocytes with
villous projections; monoclonal Ig in half cases.
Cytology
B-cells expressing CD19+,
CD24+ and DBA44+.
CD20+,
CD22+,
Treatment
References
Splenectomy.
Prognosis
Oscier DG, Matutes E, Gardiner A, Glide S, Mould S, BritoMulligan SP, Matutes E, Dearden C, Catovsky D. Splenic
lymphoma with villous lymphocytes: natural history and
response to therapy in 50 cases. Br J Haematol 1991
Jun;78(2):206-9
5-year survival: 80%; adverse prognostic factors:
WBC above 30 x 109/l, low lymphocyte count;
cases treated with chemotherapy have shorter
survival.
Wong KF, Chu YC, Hui PK. Splenic lymphoma with villous
lymphocytes showing del(7) and inv(10). Cancer Genet
Cytogenet 1998 Apr 15;102(2):145-7. (Review)
Cytogenetics
Oscier DG, Matutes E, Gardiner A, Glide S, Mould S, BritoBabapulle V, Ellis J, Catovsky D. Cytogenetic studies in
splenic lymphoma with villous lymphocytes. Br J Haematol
1993 Nov;85(3):487-491
Cytogenetics morphological
The karyotype is often abnormal:
- del(7q) and translocations involving 7q (20% of
cases),
- t(11;14)(q13;q32) (15%),
- other anomalies, in particular i(17q), 2p11
translocations.
Atlas Genet Cytogenet Oncol Haematol. 1999; 3(1)
Matutes E, Morilla R, Owusu-Ankomah K, Houlihan A,
Catovsky D. The immunophenotype of splenic lymphoma
with villous lymphocytes and its relevance to the
differential diagnosis with other B-cell disorders. Blood
1994 Mar 15;83(6):1558-62
26
Splenic lymphoma with villous lymphocytes
Huret JL, Mossafa H
Troussard X, Valensi F, Duchayne E, Garand R, Felman
P, Tulliez M, Henry-Amar M, Bryon PA, Flandrin G. Splenic
lymphoma with villous lymphocytes: clinical presentation,
biology and prognostic factors in a series of 100 patients.
Groupe Français d'Hématologie Cellulaire (GFHC). Br J
Haematol 1996 Jun;93(3):731-736
allelic imbalance of the RB1 gene but not the D13S25
locus on chromosome 13q14. Cancer Res 1998 Apr
15;58(8):1736-1740
This article should be referenced as such:
Huret JL, Mossafa H. Splenic lymphoma with villous
lymphocytes. Atlas Genet Cytogenet Oncol Haematol.
1999; 3(1):26-27.
García-Marco JA, Nouel A, Navarro B, Matutes E, Oscier
D, Price CM, Catovsky D. Molecular cytogenetic analysis
in splenic lymphoma with villous lymphocytes: frequent
Atlas Genet Cytogenet Oncol Haematol. 1999; 3(1)
27
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Leukaemia Section
Short Communication
+8 or trisomy 8
Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers,
France (JLH)
Published in Atlas Database: November 1998
Online updated version : http://AtlasGeneticsOncology.org/Anomalies/tri8ID1017.html
DOI: 10.4267/2042/37486
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 1999 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Clinics and pathology
Prognosis
No prognostic significance.
Disease
Disease
Chronic myelogenous leukaemia (CML)
Epidemiology
+8 is one of the major anomalies additional to the
t(9;22), with i(17q), + der(22), before +19; found as
a unique additional anomaly in 10%, with other in
25% of CML cases with clonal evolution; these
additional anomalies may be present at the
diagnosis of CML (in 10%, possibly with
unfavourable significance), or may appear during
course of the disease, they do not indicate the
imminence of a blast crisis, although they also
frequently emerge at the time of acute
transformation; +8 is more often found in the
myeloid than in the lymphoid blast crisis.
Prognosis
+8 has apparently no prognostic significance in
CML.
Myelodysplastic syndromes (MDS): refractory
anaemia (RA), refractory anaemia with ring
sideroblasts (RARS), refractory anaemia with
excess of blasts ± in transformation (RAEB±T),
chronic myelomonocytic leukaemia (CMML).
Note
The present (unpublished) review of about 250
ANLL cases with +8 is a review of literature cases
and may therefore be biased, although the
percentages herein given are in accordance with
those of large series.
Epidemiology
+8 is found in 15-20% of MDS; 5-10% of MDS
with +8 are treatment-related MDS; +8 is present in
each FAB subgroup: up to 30% of RARS cases
have +8; 15-20% of other subgroups have +8.
+8 is: the sole anomaly in 55%, found with simple
karyopypic changes in 20%, and part of a complex
karyotype in the remaining 25% of cases.
Altogether, sex ratio is 1.5M/1F (1.8/1 in cases
RAEB±T and CMML, 1/1 in RA or RARS).
- 15% of +8/MDS are found with -5/del(5q), often
in complex karyotypes.
4%
of
+8/MDS
are
found
with
t(1;7)(q10;p10)(and 20% of t(1;7)/MDS-ANLL also
associate +8).
- 4% as well are found with del(20q), mainly in
simple karyotypes.
- +8 is strickingly found in independant subclones,
with other subclones carrying other anomalies, in
particular del(5q) or t(1;7) (e.g.: 46, XY,
del(5q)/47, XY, +8).
Disease
Other
chronic
myeloproliferative
diseases:
polycytemia
vera
(PV),
and
idiopathic
myelofibrosis (but not found in essential
thrombocythemia).
Epidemiology
+8 is found in 20% of PV cases with an abnormal
karyotype, mostly as the sole anomaly, may be
accompanied with +9 (abnormal karyotypes in PV
occur mainly with evolution, but the appearance of
a clonal anomaly does not indicate progression of
the disease); +8 is found in 10% of myelofibrosis
cases with chromosome anomalies, sometimes with
+9.
Atlas Genet Cytogenet Oncol Haematol. 1999; 3(1)
28
+8 or trisomy 8
Huret JL
Prognosis
Median survival would near 2 years.
- 1% of +8/ANLL are found with t(1;7)(q10;p10),
but as far as 20% of t(1;7) also associate +8.
- 15% of Down syndrome patients with
MDS/ANLL have +8 in their leukaemic cells.
Clinics
From 2 studies on ANLL in adults with +8 solely:
no specific FAB subgroup; median age was 60
years (vs 50 years in cases of +8 accompanying
t(8;21), t(15;17) or inv(16)); no gross
organomegaly; moderate WBC.
Prognosis
Of ANLL in adults with +8 solely: complete
remission in 60-70% (vs 90% in cases
accompanying t(8;21), t(15;17) or inv(16)); median
survival was 13 months in one study, 20 months in
another; taking all +8 cases, solely or not, median
survival would be of about a year; +8 does not seem
to alter the relatively good prognosis of t(8;21),
t(15;17) or inv(16), while the (numerous) cases
with a complex karyotype exhibit a poor outcome;
age is an adverse feature.
Disease
Acute non lymphocytic leukaemias (ANLL)
Note
The present (unpublished) review of more than 500
ANLL cases with +8 is a review of literature cases
and may therefore be biased, although the
percentages herein given are in accordance with
those of large series; we also add 39 unpublished
t(11;19) to 101 published cases.
Epidemiology
+8 is found in 10-15% of ANLL; 10% of ANLL
with +8 are treatment-related ANLL; +8 is present
in each FAB subgroup (from M1 to M7) in a
grossly equivalent percentage (but in M5a where
the percentage is higher), in contrast to what has
been previously claimed; cases may present with a
preceeding myelodysplasia.
+8 is: the sole anomaly in 40%, found with simple
karyopypic changes in 35%, and part of a complex
karyotype in the remaining 25% of cases.
altogether, sex ratio is 1.2/1 (1.6/1 in cases with a
complex karyotype, 1/1 otherwise).
- 5-10% of +8/ANLL are found with 5/del(5q)and/or -7/del(7q), often associated, and
nearly always in complex karyotypes.
- 5-10% also are found in t(15;17)/M3 cases,
mostly as a single additional anomaly, while 1/3 of
t(15;17) are accompanied with +8.
- 5-10% are found with inv(16), mainly in simple
karyotypes (and 15% of inv(16) cases also carry
+8).
- 5% are associated with +21, often parts of a
complex karyotype.
- 5% also are found in 11q23 ANLL, mostly in
t(9;11)(p22;q23) cases (and 20% of t(9;11) also
carry +8, while 15% of t(11;19)(q23;p13.3)/ANLL
or ALL (91 cases, 25 unpublished), 10% of
t(6;11)(q27;q23)/ANLL, t(10;11)(p12;q23)/ANLL,
and t(11;19)(q23;p13.1)/ANLL (49 cases, 14
unpublished) as well, and only 3% of
t(4;11)(q21;q23)/ALL, have an additional 8
chromosome.
- Less than 5% are found with t(8;21)(q21;q21)
often in simple karyotypes, and 10% of t(8;21)
associate +8.
- Less than 5% also are associated with
t(9;22)(q34;q11)/ANLL, mostly in complex
karyotypes.
- 2% are associated with +9, either in simple or in
complex karyotypes.
Atlas Genet Cytogenet Oncol Haematol. 1999; 3(1)
Disease
Acute lymphocytic leukaemia (ALL)
Phenotype/cell stem origin
+8 is more often found in B-cell than in T-cell
cases.
Epidemiology
- +8 is a rare anomaly in lymphoid malignancies
(90% of +8 occur in myeloid malignancies); found
in about 5% of ALL.
- Rarely found as a sole anomaly (5-10%), may be
part of hyperploid karyotypes (>50 chromosomes
mainly) without structural anomalies (20% of
cases), mostly found in complex karyotypes with
structural anomalies (2/3 of cases), these complex
karyotypes being often hyperploid as well.
- Sex ratio: 1.5/1.
- Accompany (mostly in complex karyotypes):
t(9;22)(q34;q11)/ALL, t(4;11) (see above) and
other 11q23, del(6q), t(1;19)(q23;p13), dic(9;12)
and other known primary anomalies.
Disease
Non-Hodgkin lymphomas
Epidemiology
+8 is exceptional; has been found associated with
t(14;18)(q32; q21), t(8;14)(q24;q32), and other
known or unknown anomalies.
Disease
Chronic lymphoproliferative diseases
Epidemiology
Very rare anomaly (to be noted that +8 is
29
+8 or trisomy 8
Huret JL
Danesino C, Pasquali F. Constitutional trisomy 8 as first
mutation in multistep carcinogenesis: clinical, cytogenetic,
and molecular data on three cases. Genes Chromosomes
Cancer. 1996 Oct;17(2):94-101
exceptional in T-prolymphocytic leukaemia, in
contrast with the freqency of i(8q), which occurs by
completely different mechanisms, but gives, for
parts, very similar genetic imbalances).
Pedersen B. MDS and AML with trisomy 8 as the sole
chromosome aberration show different sex ratios and
prognostic profiles: a study of 115 published cases. Am J
Hematol. 1997 Dec;56(4):224-9
Genetics
Note
Genes (possibly) involved are unknown.
Schoch C, Haase D, Fonatsch C, Haferlach T, Löffler H,
Schlegelberger B, Hossfeld DK, Becher R, Sauerland MC,
Heinecke A, Wörmann B, Büchner T, Hiddemann W. The
significance of trisomy 8 in de novo acute myeloid
leukaemia: the accompanying chromosome aberrations
determine the prognosis. German AML Cooperative Study
Group. Br J Haematol. 1997 Dec;99(3):605-11
To be noted
Note
Karyotypes with +8 may be misinterpreted with a
possible overlooked constitutional trisomy 8, a
syndrome associating mild to moderate mental
delay and (sometimes mild as well) bone
anomalies; furthermore constitutional trisomy 8 has
been said to be at increased rirk of cancers,
haematological malignancies in particular.
Byrd JC, Lawrence D, Arthur DC, Pettenati MJ, Tantravahi
R, Qumsiyeh M, Stamberg J, Davey FR, Schiffer CA,
Bloomfield CD. Patients with isolated trisomy 8 in acute
myeloid leukemia are not cured with cytarabine-based
chemotherapy: results from Cancer and Leukemia Group
B 8461. Clin Cancer Res. 1998 May;4(5):1235-41
This article should be referenced as such:
References
Huret JL. +8 or trisomy 8. Atlas Genet Cytogenet Oncol
Haematol. 1999; 3(1):28-30.
Seghezzi L, Maserati E, Minelli A, Dellavecchia C, Addis P,
Locatelli F, Angioni A, Balloni P, Miano C, Cavalli P,
Atlas Genet Cytogenet Oncol Haematol. 1999; 3(1)
30
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Leukaemia Section
Short Communication
t(1;7)(q10;p10)
Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers,
France (JLH)
Published in Atlas Database: November 1998
Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t0107ID1003.html
DOI: 10.4267/2042/37485
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 1999 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
der(7)t(1;7)(q10;p10) G- (left) and R- (right) bandings - top: Courtesy Jean-Luc Lai; middle and bottom: - Courtesy Diane H.
Norback, Eric B. Johnson, and Sara Morrison-Delap, UW Cytogenetic Services.
leukaemia (ANLL); ANLL in 30%, frequently with
preceeding MDS; these MDS or ANLL are therapyrelated (secondary to toxic exposure) in half cases;
myeloproliferative diseases (MPD) represent the
remaining 10% of cases.
Clinics and pathology
Disease
Myelodysplasic syndromes (MDS) in 60% of cases,
often evolving towards acute non lymphoblastic
Atlas Genet Cytogenet Oncol Haematol. 1999; 3(1)
31
t(1;7)(q10;p10)
Huret JL
Phenotype/cell stem origin
Additional anomalies
MDS cases: often RAEB±T or RA; ANLL: M4 or
M1; MPD cases: myelofibrosis.
Sole anomaly in half; hyperploidy in 1/3 of cases;
+8 (20%); +21 (10%); +9; additional structural
abnormalities in 15%.
Epidemiology
References
Represent 3-7% of secondary leukaemias, 0.5% and
2% of de novo ANLL and MDS respectively; adults
mostly (median 60 yrs; only a very few children
cases); male predominance (3M/2F), but secondary
leukaemias cases are more frequently female cases
(presence of uncovered environmental genotoxic
factors in male cases?).
Geraedts JP, den Ottolander GJ, Ploem JE, Muntinghe
OG. An identical translocation between chromosome 1 and
7 in three patients with myelofibrosis and myeloid
metaplasia. Br J Haematol. 1980 Apr;44(4):569-75
Willem P, Pinto M, Bernstein R. Translocation t(1;7)
revisited. Report of three further cases and review. Cancer
Genet Cytogenet. 1988 Nov;36(1):45-54
Prognosis
Horiike S, Taniwaki M, Misawa S, Nishigaki H, Okuda T,
Yokota S, Kashima K, Inazawa J, Abe T. The unbalanced
1;7 translocation in de novo myelodysplastic syndrome
and its clinical implication. Cancer. 1990 Mar
15;65(6):1350-4
Poor prognosis; median survival was reviewed in
1992 and was found to be of 11 mths; male sex, a
low haemoglobin level may be adverse prognostic
features; prognosis is better, obviously in case of a
MPD.
Johansson B, Mertens F, Heim S, Kristoffersson U,
Mitelman F. Cytogenetics of secondary myelodysplasia
(sMDS) and acute nonlymphocytic leukemia (sANLL). Eur
J Haematol. 1991 Jul;47(1):17-27
Cytogenetics
Cytogenetics morphological
Pedersen B. Survival of patients with t(1;7)(p11;p11).
Report of two cases and review of the literature. Cancer
Genet Cytogenet. 1992 May;60(1):53-9
Whole-arm translocation of 7p with 1q; most often
unbalanced (-7, +t(1;7)) --> trisomy for
1q/monosomy for 7q; may therefore represent an
equivalent to del(7q).
This article should be referenced as such:
Huret JL. t(1;7)(q10;p10). Atlas Genet Cytogenet Oncol
Haematol. 1999; 3(1):31-32.
Probes
Centromeric probes.
Atlas Genet Cytogenet Oncol Haematol. 1999; 3(1)
32
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Leukaemia Section
Short Communication
del(6q) abnormalities in lymphoid malignancies
Christophe Brigaudeau, Chrystele Bilhou-Nabera
Laboratory of Hematology, University Hospital, 87000 Limoges, France (CB); Laboratoire
d'Hématologie, Hôpital du Haut-Lévêque, CHU de Bordeaux, Avenue de Magellan, 33604 Pessac,
France (CBN)
Published in Atlas Database: December 1998
Online updated version : http://AtlasGeneticsOncology.org/Anomalies/del6qID1148.html
DOI: 10.4267/2042/37487
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 1999 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
Phenotype/cell stem origin
Lack
of
specificity
for
a
particular
immunophenotype.
Epidemiology
Found in 5-15% of patients after conventional
cytogenetic analysis, in 30% after FISH analysis, in
5 to 25% of cases in loss of heterozygosity studies.
Prognosis
Not significantly different from patients lacking a
6q rearrangement.
Note
Deletion of the long arm of chromosome 6 (del(6q))
is more frequently described in lymphoid
proliferations than in other hematological
malignancies; del(6q) is observed in acute
lymphoblastic leukemia (ALL), in chronic
lymphocytic leukemia (CLL), in prolymphocytic
leukemia and in non-Hodgkin lymphomas (NHL)
(15%
cases,
sometimes
associated
with
t(14;18)(q32;q21)); these deletions are mainly
reported to be terminal, but also interstitial.
Disease
Childhood T-cell acute lymphoblastic leukemia (TALL)
Epidemiology
del(6q) is one of the most frequent cytogenetic
aberration occurring in 10-20% of cases and often
associated with 14q11 or del(9p) abnormalities.
Prognosis
Outcome similar to cases with normal diploid
karyotypes.
Disease
Adult acute lymphoblastic leukemia
Phenotype/cell stem origin
T-cell phenotype found in 50% of cases (ALL).
Epidemiology
del(6q) in adult-ALL occur with a lower frequency
(5%) than in children and is reported predominantly
in young adult (15 to 40 years aged).
Prognosis
Patients with a 6q change tented to have longer
event free survival (EFS) (median: 11 months; 3
del(6q) - Courtesy Diane H. Norback, Eric B. Johnson, Sara
Morrison-Delap Cytogenetics at theWaisman Center; Rbanding (right) – Editor.
Clinics and pathology
Disease
Childhood B-cell acute lymphoblastic leukemia (BALL)
Atlas Genet Cytogenet Oncol Haematol. 1999; 3(1)
33
del(6q) abnormalities in lymphoid malignancies
Brigaudeau C, Bilhou-Nabera C
years EFS: 47%) than did patients without 6q
changes (median EFS: 7 month; 3 years EFS: 20%).
Genes involved and
proteins
Disease
B-cell small lymphocytic lymphoma
Epidemiology
del(6)(q21q23) is the most common recurrent
cytogenetic abnormality in this disease.
Clinics
In cases with del(6q), a morphological appearance
of peripheral blood large prolymphocytes, a mature
B-cell phenotype and a typical clinical course of
other well-differentiated lymphocytic neoplams are
described.
Multiple myeloma
Phenotype/cell stem origin
Multiple myeloma (MM) is a malignant plasma cell
proliferation of mature differentiated B-cell.
Epidemiology
del (6q) in multiple myeloma represent 15% of
cases of MM.
Prognosis
del(6q) are more frequent in the hypodiploid group
of multiple myeloma, bearing a worse prognosis
(med survival of 1.5 yr).
Note
6q21 band loss suggests the presence of a recessive
tumour suppressor gene whose absence might
contribute to malignant transformation and
development of both T and precursor B-ALLs; the
lack
of
specificity
for
a
particular
immunophenotype may imply that the gene or
genes affected by 6q abnormalities are broadly
active in the multistep process of lymphoid
leukemogenesis.
Putative tumour suppressor gene(s) on chromosome
arm 6q remains to be identified; to demonstrate this
loss of heterozygosity of informative markers
(LOH) was analysed using PCR amplification of
polymorphic microsatellite sequences; using
polymorphic markers located from the 6q14-15 to
telomere, LOH was detected in 5 to 25% of
childhood ALL cases.
Regarding LOH results, two distinct regions were
identified:
- first region flanked by D6S283 and D6S302 loci
at 6q21-22
- second region flanked by D6S275 and D6S283
loci at 6q21.
Using LOH analysis on several cases, the authors
demonstrated an identical 6q21-22 structure at
diagnosis and at relapse, suggesting that 6q deletion
may be an initial event in leukemogenesis and may
occur less frequently during progression of the
disease.
Cytogenetics
References
Cytogenetics morphological
Hayashi Y, Raimondi SC, Look AT, Behm FG,
Kitchingman GR, Pui CH, Rivera GK, Williams DL.
Abnormalities of the long arm of chromosome 6 in
childhood acute lymphoblastic leukemia. Blood. 1990 Oct
15;76(8):1626-30
Disease
Atypical chronic lymphocytic leukemia
Prognosis
Complex karyotypes with +12, del(13)(q14),
del(11q), del(6)(q21q23) and possible 4q or 10q
anomalies are associated with a poor prognosis.
Disease
The frequency of the deletions is difficult to
estimate by conventional cytogenetic analysis
because small interstitial deletions are beyond the
sensitivity of the technique; furthermore, many
studies have reported conflicting data on the
putative region of overlap and the number of region
involved; the break occurs predominantly in 6q21,
but 6q15 is also often described; overall, del(6q)
cases encompassed the 6q21 band.
in acute lymphoblastic leukemia (ALL), del(6q) is
the sole anomaly in about 30% of cases, or
associated with other structural abnormalities such
as del(12p) (early pre-B ALL), del(9p) (B and Tcell immunophenotype), specific aberrations, such
as t(4;11), t(1;19), t(9;22), t(12;21) or with random
chromosomal changes.
Atlas Genet Cytogenet Oncol Haematol. 1999; 3(1)
Offit K, Louie DC, Parsa NZ, Filippa D, Gangi M, Siebert R,
Chaganti RS. Clinical and morphologic features of B-cell
small lymphocytic lymphoma with del(6)(q21q23). Blood.
1994 May 1;83(9):2611-8
Cytogenetic abnormalities in adult acute lymphoblastic
leukemia: correlations with hematologic findings outcome.
A Collaborative Study of the Group Français de
Cytogénétique
Hématologique. Blood.
1996
Apr
15;87(8):3135-42
Cavé H, Guidal C, Elion J, Vilmer E, Grandchamp B. A low
rate of loss of heterozygosity is found at many different loci
in childhood B-lineage acute lymphocytic leukemia.
Leukemia. 1996 Sep;10(9):1486-91
34
del(6q) abnormalities in lymphoid malignancies
Brigaudeau C, Bilhou-Nabera C
Bigoni R, Cuneo A, Roberti MG, Bardi A, Rigolin GM, Piva
N, Scapoli G, Spanedda R, Negrini M, Bullrich F, Veronese
ML, Croce CM, Castoldi G. Chromosome aberrations in
atypical chronic lymphocytic leukemia: a cytogenetic and
interphase
cytogenetic
study.
Leukemia.
1997
Nov;11(11):1933-40
from the Children's Cancer Group. J Clin Oncol. 1998
Apr;16(4):1270-8
Merup M, Moreno TC, Heyman M, Rönnberg K, Grandér
D, Detlofsson R, Rasool O, Liu Y, Söderhäll S, Juliusson
G, Gahrton G, Einhorn S. 6q deletions in acute
lymphoblastic leukemia and non-Hodgkin's lymphomas.
Blood. 1998 May 1;91(9):3397-400
Gérard B, Cavé H, Guidal C, Dastugue N, Vilmer E,
Grandchamp B. Delineation of a 6 cM commonly deleted
region in childhood acute lymphoblastic leukemia on the
6q chromosomal arm. Leukemia. 1997 Feb;11(2):228-32
Takeuchi S, Koike M, Seriu T, Bartram CR, Schrappe M,
Reiter A, Park S, Taub HE, Kubonishi I, Miyoshi I, Koeffler
HP. Frequent loss of heterozygosity on the long arm of
chromosome 6: identification of two distinct regions of
deletion in childhood acute lymphoblastic leukemia.
Cancer Res. 1998 Jun 15;58(12):2618-23
Secker-Walker LM, Prentice HG, Durrant J, Richards S,
Hall E, Harrison G. Cytogenetics adds independent
prognostic information in adults with acute lymphoblastic
leukaemia on MRC trial UKALL XA. MRC Adult Leukaemia
Working Party. Br J Haematol. 1997 Mar;96(3):601-10
This article should be referenced as such:
Heerema NA, Sather HN, Sensel MG, Kraft P, Nachman
JB, Steinherz PG, Lange BJ, Hutchinson RS, Reaman GH,
Trigg ME, Arthur DC, Gaynon PS, Uckun FM. Frequency
and clinical significance of cytogenetic abnormalities in
pediatric T-lineage acute lymphoblastic leukemia: a report
Atlas Genet Cytogenet Oncol Haematol. 1999; 3(1)
Brigaudeau C, Bilhou-Nabera C. del(6q) abnormalities in
lymphoid malignancies. Atlas Genet Cytogenet Oncol
Haematol. 1999; 3(1):33-35.
35
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Leukaemia Section
Short Communication
t(8;16)(p11;p13)
Christine Pérot, Jean-Loup Huret
Laboratoire de Cytogénétique, Hopital Saint-Antoine, Paris, France (CP); Genetics, Dept Medical
Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France (JLH)
Published in Atlas Database: December 1998
Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t0816.html
DOI: 10.4267/2042/37488
This article is an update of: Pérot C, Huret JL. t(8;16)(p11;p13). Atlas Genet Cytogenet Oncol Haematol.1997;1(2):79-80.
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 1999 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
t(8;16)(p11;p13) G- banding (left) - Courtesy Jean-Luc Lai (top left) and Charles D. Bangs (middle and bottom left), R- banding
(top right) - Courtesy Jean-Luc Lai, and ideogram (bottom right) - Courtesy Charles D. Bangs.
Clinics and pathology
Epidemiology
Disease
Rare disease (<1% of ANLL); found in children
(including infants) and young adults of both sexes.
ANLL; t-ANLL
Clinics
Phenotype/cell stem origin
Disseminated intra vascular coagulation may be
present; extramedullary infiltration; 20% of the
cases could be therapy-related.
M4, M5a, M5b; possible involvement of a granulomonocytic precursor; no preceeding MDS.
Atlas Genet Cytogenet Oncol Haematol. 1999; 3(1)
36
t(8;16)(p11;p13)
Pérot C, Huret JL
The t(8;16) has been cloned and shown to fuse the MOZ (monocytic leukemia zinc finger) gene at 8p11.2 to the CBP (CREB
binding protein) gene at 16p13.3. The MOZ gene has also been found to be involved in variant translocations t(8;19)(p11;q13)
and t(8;22)(p11;q13) and inv(8)(p11q13) translocations associated with M5/M4 AML.This translocation is associated with AML
M5/M4. In the majority of cases it is associated with features of hemophagocytosis by leukemic cells, particularly
erythrophagocytosis - Courtesy Georges Flandrin, CD-ROM AML/MDS G.Flandrin/ICG. TRIBVN.
translocation would therefore be an equivalent (not
identical), and not a simple variant with hidden
16p13 involvement.
Cytology
Erythrophagocytosis,
esterase activities.
strong
peroxidase
and
Genes involved and
proteins
Prognosis
Poor: remission may be obtained in half cases;
infections, bleeding; survival is often less than 1
year but spontaneous remission has occurred (at
least) once.
MOZ
Location
8p11
Cytogenetics
CBP
Additional anomalies
Location
16p13
In half cases; +8, various; complex karyotype may
be found.
Result of the chromosomal
anomaly
Variants
Complex t(8;16;Var) involving a (variable) third
chromosome have been described; 8p11 breakpoint
with another partner as well, of which is the
recurrent t(8;22)(p11;q13), which may involve
P300 on 22q13 in the place of CBP: this
Atlas Genet Cytogenet Oncol Haematol. 1999; 3(1)
Hybrid gene
Description
5' MOZ - 3' CBP
37
t(8;16)(p11;p13)
Pérot C, Huret JL
t(8:19)(p11:q13)--case report and review of the literature.
Leuk Res. 1995 Jun;19(6):367-79
Fusion protein
Description
N-term MOZ fused to most of CBP; 3722 amino
acids; 415 kDa; combines the MOZ finger motifs
(DNA binding) and acetyl transferase with the
transcriptional coactivator from CBP; the reciprocal
CBP-MOZ has no role (as it is out of frame).
Borrow J, Stanton VP Jr, Andresen JM, Becher R, Behm
FG, Chaganti RS, Civin CI, Disteche C, Dubé I, Frischauf
AM, Horsman D, Mitelman F, Volinia S, Watmore AE,
Housman DE. The translocation t(8;16)(p11;p13) of acute
myeloid leukaemia fuses a putative acetyltransferase to
the CREB-binding protein. Nat Genet. 1996 Sep;14(1):3341
References
Velloso ER, Mecucci C, Michaux L, Van Orshoven A, Stul
M, Boogaerts M, Bosly A, Cassiman JJ, Van Den Berghe
H. Translocation t(8;16)(p11;p13) in acute non-lymphocytic
leukemia: report on two new cases and review of the
literature. Leuk Lymphoma. 1996 Mar;21(1-2):137-42
Brizard A, Guilhot F, Huret JL, Benz-Lemoine E, Tanzer J.
The 8p11 anomaly in "monoblastic" leukaemia. Leuk Res.
1988;12(8):693-7
Quesnel B, Kantarjian H, Bjergaard JP, Brault P, Estey E,
Lai JL, Tilly H, Stoppa AM, Archimbaud E, Harousseau JL.
Therapy-related acute myeloid leukemia with t(8;21),
inv(16), and t(8;16): a report on 25 cases and review of the
literature. J Clin Oncol. 1993 Dec;11(12):2370-9
Dinulos JG, Hawkins DS, Clark BS, Francis JS.
Spontaneous remission of congenital leukemia. J Pediatr.
1997 Aug;131(2):300-3
Stark B, Resnitzky P, Jeison M, Luria D, Blau O, Avigad S,
Shaft D, Kodman Y, Gobuzov R, Ash S. A distinct subtype
of M4/M5 acute myeloblastic leukemia (AML) associated
with t(8:16)(p11:p13), in a patient with the variant
Pérot C, Huret JL. t(8;16)(p11;p13). Atlas Genet Cytogenet
Oncol Haematol. 1999; 3(1):36-38.
Atlas Genet Cytogenet Oncol Haematol. 1999; 3(1)
This article should be referenced as such:
38
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Solid Tumour Section
Mini Review
Bone: Chordoma
Monica Miozzo
Dipartimento di Medicina Ospedale San Paolo Lab di Genetica Umana, Via di Rudini 8, 20142 Milan,
Italy (MM)
Published in Atlas Database: September 1998
Online updated version : http://AtlasGeneticsOncology.org/Tumors/chordomaID5028.html
DOI: 10.4267/2042/37490
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 1999 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Pathology
Identity
Microscopically, it resembles normal fetal
notochord in its different stages of development; it
is composed of extremly large cells (know as
physaliferous) and other small tumour cells; areas
of cartilage and bone may be present.
Note
Chordoma is a malignant tumour derived from
remnants of the fetal notochord; it occurs along the
spinal axis, predominantly in the sphenooccipital
(35%), vertebral (15%) and sacrococcygeal (50%)
regions.
Cytogenetics
Clinics and pathology
Cytogenetics Morphological
Etiology
In eight sporadic sacral chordomas with abnormal
karyotype, a tumour-specific rearrangement has not
been identified; the karyotypes, characterized by a
hypo-or near-diploid chromosome number, showed
complex
rearrangements
affecting
several
chromosomes, among them chromosome 1 was
frequently involved in losses and translocations
with different partners; no FISH experiments to
clarify the complex cytogenetic picture have been
performed so far.
Although most chordomas are sporadics, five
families with chordoma occurrence have been
reported, two of them displaying an autosomal
dominant transmission with incomplete penetrance
(MIM. *215400); preliminary linkage data in a
three generation family suggest that the disease
locus might be assigned to chromosomes 1,17 or
19.
Epidemiology
References
Chordomas accounts for 1-4% of all primary bone
tumours; the sacrococcygeal lesions are more
common in the fifth decade of life, whereas the
sphenooccipital tumours occur predominantly in
children.
FOOTE RF, ABLIN G, HALL WW. Chordoma in siblings.
Calif Med. 1958 May;88(5):383-6
Krengel B. Letter: Findings in pellagrin patients. S Afr Med
J. 1975 Mar 15;49(11):383
Clinics
Chetty R, Levin CV, Kalan MR. Chordoma: a 20-year
clinicopathologic review of the experience at Groote
Schuur Hospital, Cape Town. J Surg Oncol. 1991
Apr;46(4):261-4
Chordoma
is
a
slowly-growing
tumour,
characterized by local destruction of bone and
rarely distant metastatic spread.
The differential diagnosis includes renal tumours,
chondrosarcomas
and
myxo-papillary
ependymoma.
Atlas Genet Cytogenet Oncol Haematol. 1999; 3(1)
Mertens F, Kreicbergs A, Rydholm A, Willén H, Carlén B,
Mitelman F, Mandahl N. Clonal chromosome aberrations in
three sacral chordomas. Cancer Genet Cytogenet. 1994
Apr;73(2):147-51
39
Bone: Chordoma
Miozzo M
Butler MG, Dahir GA, Hedges LK, Juliao SF, Sciadini MF,
Schwartz HS. Cytogenetic, telomere, and telomerase
studies in five surgically managed lumbosacral chordomas.
Cancer Genet Cytogenet. 1995 Nov;85(1):51-7
Stepanek J, Cataldo SA, Ebersold MJ, Lindor NM, Jenkins
RB, Unni K, Weinshenker BG, Rubenstein RL. Familial
chordoma with probable autosomal dominant inheritance.
Am J Med Genet. 1998 Jan 23;75(3):335-6
Korczak JF, Kelley MJ, Allikian KA, Shah AA, Goldstein
AM, Parry DM. Genomic screening for linkage in a family
with autosomal dominant chordoma Am J Hum Genet.
1997;61:A400.
This article should be referenced as such:
Atlas Genet Cytogenet Oncol Haematol. 1999; 3(1)
Miozzo M. Bone: Chordoma. Atlas Genet Cytogenet Oncol
Haematol. 1999; 3(1):39-40.
40
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Solid Tumour Section
Mini Review
Kidney: Nephroblastoma (Wilms tumor)
Monica Miozzo
Dipartimento di Medicina Ospedale San Paolo Lab di Genetica Umana, Via di Rudini 8, 20142 Milan,
Italy (MM)
Published in Atlas Database: November 1998
Online updated version : http://AtlasGeneticsOncology.org/Tumors/WilmsID5034.html
DOI: 10.4267/2042/37491
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 1999 Atlas of Genetics and Cytogenetics in Oncology and Haematology
neoplastic,
raising
the
possibility
that
undifferentiated blastema cells are precursors of the
stromal and heterologous elements.
Identity
Alias: Wilms tumour
Treatment
Clinics and pathology
Stage 1 and 2 are treated with nephrectomy and
chemotherapy, radiation therapy is added to
tumours of higher staging.
Etiology
- Wilms tumours are either sporadic or familial (12%); it may be associated with hemihypertrophia or
genitourinary malformations (10%) and part of a
recognized syndrome (2%).
- The syndromes predisposing to Wilms tumours
are: WAGR (Wilms tumour, aniridia, genitourinary
abnormalities and mental retardation), DDS
(Denys-Drash syndrome: mesangial sclerosis, male
pseudohermaphrodism and Wilms tumours), BWS
(Beckwith-Weideman: exomphalos, macroglossia,
gigantism) and SGBS (Simpson Golabi Behmel
syndrome: overgrowth, mental impairment,
craniofacial anomalies).
Prognosis
The overall cure rate for unilateral Wilms tumours
is 80%; anaplastic tumours (4%) have an
unfavorable prognosis.
Genetics
Note
This entity is heterogenous at the genetic level.
Cytogenetics
Cytogenetics Morphological
Epidemiology
The observed heterogeneity reflects the complexity
of the genetic changes; structural changes at 11p13,
11p15, 1p, 1q and 7p are the most frequently
reported, as well as trisomies 8, 12, and 18; 11p
deletions occur in 20% of cases, trisomy 12 in 25%,
del(16q) in 20%; the der(16)t(1;16), also described
in a wide range of tumours, is considered a marker
of tumour progression.
The most common paediatric cancer of the kidney,
affecting 10/105 children; 50% of cases occurs
before the age of 3 years and 90% before 6 years.
Clinics
The localization is primarily the kidney; the
incidence of bilateral involvement is 5-10%.
Pathology
Genes involved and
proteins
Wilms tumours show a mimicry of nephrogenesis
as the tumour comprises undifferentiated blastemal
cells, differentiated epithelial cells and stromal
cells; ectopic components, particularly skeletal
muscle, are observed in 5-10% of tumours; the
presence of identical deletions of WT1 in all
components of some sporadic Wilms tumours
suggests that the stromal components are
Atlas Genet Cytogenet Oncol Haematol. 1999; 3(1)
Note
- 11p13: constitutional deletion of one copy of the
WT1 gene (11p13) is responsible for predisposition
to Wilms tumours and for genitourinary
malformations in WAGR patients; constitutional
41
Kidney: Nephroblastoma (Wilms tumor)
Miozzo M
heterozygous intragenic mutations have been
described in DDS; WT1 is somatically involved in
10% of the sporadic cases.
- 11p15: BWS, an overgrowth syndrome, is caused
by alterations of 11p15, a region subject to genomic
imprinting: loss of of imprinting of IGF2 is the
most common defect found; WT1 is rarely
implicated solely in sporadic Wilms tumours, but
maternal alleles often displays a loss of
heterozygosity (LOH) at 11p15, which suggests the
existence of a second locus WT2.
- 7p, 17q, 19q: a third locus WT3, at least, is likely,
on the grounds of the existence of familial cases of
Wilms tumour without 11p13 nor 11p15
involvement; one locus has been identified in 17q
in one large Wilms tumours family, and another
one in 19q13 in five families; another predisposing
gene to Wilms tumours maps to 7p, where
constitutional translocations and somatic deletions
have been described; in tumours, loss of
heterozygosity for 16q has been reported for two
different loci: 16q13 and 16q21.
- Xq26: the gene of SGBS, an overgrowth
syndrome, has been cloned at Xq26.
- Mutations of P53 occur in 5% of Wilms tumours
and are associated with tumour progression.
IGF2 and PDGFA; the WT1-KTS isoforms
associate and synergize with SF-1 (steroidogenic
factor 1) to promote AMH (anti mullerian hormone
or MIS, mullerian inhibiting substance).
Germinal mutations
Missense mutations of exons 8 and 9 in DDS; in the
proximal part of the gene leading to truncated
proteins in WAGR, genitourinary malformations
and WT; in the donor splice site of intron 9 in
Frasier
syndrome
(pseudohermaphroditism,
glomerulopathy, not associated WT).
Somatic mutations
Stop and frameshift mutations in about 10% of WT.
References
Austruy E, Candon S, Henry I, Gyapay G, Tournade MF,
Mannens M, Callen D, Junien C, Jeanpierre C.
Characterization of regions of chromosomes 12 and 16
involved in nephroblastoma tumorigenesis. Genes
Chromosomes Cancer. 1995 Dec;14(4):285-94
Little M, Wells C. A clinical overview of WT1 gene
mutations. Hum Mutat. 1997;9(3):209-25
Soukup S, Gotwals B, Blough R, Lampkin B. Wilms tumor:
summary of 54 cytogenetic analyses. Cancer Genet
Cytogenet. 1997 Sep;97(2):169-71
Zhuang Z, Merino MJ, Vortmeyer AO, Bryant B, Lash AE,
Wang C, Deavers MT, Shelton WF, Kapur S, Chandra RS.
Identical genetic changes in different histologic
components of Wilms' tumors. J Natl Cancer Inst. 1997
Aug 6;89(15):1148-52
WT1
Location
11p13
DNA / RNA
50 kb, 10 exons.
Protein
Protein tumour zing finger transcription factor
expressed during renal and gonadal development;
exons 1-6 encode a proline/glutamine rich
transcriptional regulation region; exons 7-10
encode the four zinc fingers; two alternative
splicing regions allow synthesis of four isoforms
showing different binding specificity; WT1
regulates transcription of several genes, including
Atlas Genet Cytogenet Oncol Haematol. 1999; 3(1)
Jeanpierre C, Béroud C, Niaudet P, Junien C. Software
and database for the analysis of mutations in the human
WT1 gene. Nucleic Acids Res. 1998 Jan 1;26(1):271-4
McDonald JM, Douglass EC, Fisher R, Geiser CF, Krill CE,
Strong LC, Virshup D, Huff V. Linkage of familial Wilms'
tumor predisposition to chromosome 19 and a two-locus
model for the etiology of familial tumors. Cancer Res. 1998
Apr 1;58(7):1387-90
This article should be referenced as such:
Miozzo M. Kidney: Nephroblastoma (Wilms tumor). Atlas
Genet Cytogenet Oncol Haematol. 1999; 3(1):41-42.
42
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Cancer Prone Disease Section
Mini Review
Familial gastrointestinal stromal tumors (GISTs)
Lidia Larizza, Alessandro Beghini
Department of Biology and Genetics for Medical Sciences, Medical Faculty, University of Milan, Via
Viotti 3/5, 20133 Milan, Italy (LL, AB)
Published in Atlas Database: September 1998
Online updated version : http://AtlasGeneticsOncology.org/Kprones/GastroISTID10029.html
DOI: 10.4267/2042/37492
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 1999 Atlas of Genetics and Cytogenetics in Oncology and Haematology
DNA/RNA
Description: 21 exons
Protein
Description: Transmembrane SCF/MGF receptor
with tyrosine kinase activity; binding of ligand
(SCF)
induces
receptor
dimerization,
autophosphorylation and signal transduction via
molecules containing SH2- domains.
Mutations
Germinal: Small deletion of one of two consecutive
valine residues (codon 559 or 560, GTTGTT).
Somatic: In frame deletions (550del27, 551del15,
559del6) and missense mutations (Lys 550Ile and
Val559Asp); all mutations, clustered in exon 11,
lead to constitutive phosphorylation and kinase
activation.
Identity
Note
A recently described familial cancer syndrome
characterized by development of multiple GISTs in
different family members.
Inheritance
Autosomal dominant.
Clinics
Phenotype and clinics
Symptoms are attributable to development of
benign and malignant GISTs.
Hyperpigmentation and mast-cell disease may be
associated.
- Etiology: GISTs originate from the CD34+/KIT+
interstitial cells of Cajal (ICCs) which development
depends
on
the
SCF/KIT
interaction;
germline/somatic KIT mutations in familial/solitary
GISTs.
- Pathology: mesenchymal tumours developped in
the gastrointestinal wall mainly characterized by
positivity for both KIT and CD34; precursor
tumour cells are likely ICCs that are located in and
near the circular muscle layer of the stomach, small
intestine and large intestine.
References
Hirota S, Isozaki K, Moriyama Y, Hashimoto K, Nishida T,
Ishiguro S, Kawano K, Hanada M, Kurata A, Takeda M,
Muhammad Tunio G, Matsuzawa Y, Kanakura Y,
Shinomura Y, Kitamura Y. Gain-of-function mutations of ckit in human gastrointestinal stromal tumors. Science.
1998 Jan 23;279(5350):577-80
Nishida T, Hirota S, Taniguchi M, Hashimoto K, Isozaki K,
Nakamura H, Kanakura Y, Tanaka T, Takabayashi A,
Matsuda H, Kitamura Y. Familial gastrointestinal stromal
tumours with germline mutation of the KIT gene. Nat
Genet. 1998 Aug;19(4):323-4
Genes involved and
proteins
This article should be referenced as such:
Larizza L, Beghini A. Familial gastrointestinal stromal
tumors (GISTs). Atlas Genet Cytogenet Oncol Haematol.
1999; 3(1):43.
KIT
Location
4q12
Atlas Genet Cytogenet Oncol Haematol. 1999; 3(1)
43
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Cancer Prone Disease Section
Mini Review
Piebaldism
Lidia Larizza, Alessandro Beghini
Department of Biology and Genetics for Medical Sciences, Medical Faculty, University of Milan, Via
Viotti 3/5, 20133 Milan, Italy (LL, AB)
Published in Atlas Database: September 1998
Online updated version : http://AtlasGeneticsOncology.org/Kprones/piebaldID10030.html
DOI: 10.4267/2042/37494
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 1999 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Prognosis
Identity
In contrast to vitiligo, piebaldism is both congenital
and non-progressive.
Note
Defect in melanocyte development; one of the first
genetic disorders for which a pedigree was
presented in 1786.
Inheritance
Autosomal dominant; frequency is about 2.5/105
newborns.
Cytogenetics
Inborn conditions
A few patients with interstitial deletions of
chromosome 4q12-q21.1 have been identified; they
are charaterized by multiple congenital anomalies,
short stature and mental retardation.
Clinics
Genes involved and
proteins
Phenotype and clinics
Congenital patches of white skin and white hair,
principally located on the scalp, forehead, chest and
abdomen and on the limbs; several patients report
lifelong severe constipation; a hierarchical
correlation has been elaborated between severe or
mild phenotypic traits and the associated KIT
mutations; in a few patients with interstitial
deletions, mental retardation and congenital
anomalies
have
been
also
described.
Etiology: defective melanoblasts proliferation,
survival and migration from the neural crest during
development and defective migration of entericplexus ganglion cells from the neural crest to the
gut.
Pathology: white spotting in human piebaldism
results from the absence of melanocytes from the
nonpigmented patches of skin and from hairbulbs in
the white patches of hair; occasionally, individuals
lack ganglion cells of the intestinal enteric neural
plexus, which, like melanoblasts, are derived from
the neural crest.
KIT
Location
4q12
DNA/RNA
Description: 21 exons
Protein
Description: Transmembrane SCF/MGF receptor
with tyrosine kinase activity; binding of ligand
(SCF)
induces
receptor
dimerization,
autophosphorylation and signal transduction via
molecules containing SH2- domains.
Mutations
Germinal: Loss of function mutations resulting in
haploinsufficiency of the receptor; different kinds
of point mutations have been identified (diagram).
- Missense substitutions (Glu583Lys; Phe584Leu;
Ala621Thr; His650Pro; Gly664Arg; Gly791Arg;
Val812Gly; Glu861Ala) and small deletions
(641del2; 892del12) in the intracellular tyrosine
kinase domain; correlate with severe piebald
Neoplastic risk
An increased risk of epithelioma has been reported.
Atlas Genet Cytogenet Oncol Haematol. 1999; 3(1)
44
Piebaldism
Larizza L, Beghini A
phenotypes,
because
of
dominant-negative
inhibition of the KIT receptor via formation of
impaired receptor heterodimers between a normal
and a mutant KIT monomer, and a 75% decrease of
KIT- dependent signal transduction.
- Proximal frameshifts (84del1; 249del4);
Trp557Term; and missense mutations (Cys136Arg;
Ala178Thr; Met318Gly) associated with a mild
piebald
phenotype,
the
result
of pure
haploinsufficiency due to a 50% decrease of KITdependent signal transduction.
- Distal frameshifts: 630insA; and splice junction
mutations (IVS1+4G-A; IVS12+1G-A), located
near the intracellular TK domain associated with
variable phenotypes, as the truncated polypeptides
via incorporation into nonfunctional receptor
heterodimers would decrease KIT-dependent signal
transduction by 50-75%, depending on their
stability.
- Complete deletions of the entire KIT gene (null
mutations) result in a mild-intermediate phenotype.
SCF/MGF
Location
12q22
Note
No alteration of this gene has been so far identified
in typical patients; at difference with the mouse
system, where steel mice bearing SCF mutations
show the white spotting phenotype likewise W
mice bearing kit mutations; however, as mutations
of KIT could not be detected in a consistent fraction
of these patients, involvement of SCF is still an
open question.
References
Ezoe K, Holmes SA, Ho L, Bennett CP, Bolognia JL,
Brueton L, Burn J, Falabella R, Gatto EM, Ishii N. Novel
mutations and deletions of the KIT (steel factor receptor)
gene in human piebaldism. Am J Hum Genet. 1995
Jan;56(1):58-66
Riva P, Milani N, Gandolfi P, Larizza L. A 12-bp deletion
(7818del12) in the c-kit protooncogene in a large Italian
kindred with piebaldism. Hum Mutat. 1995;6(4):343-5
PDGFRA
Fleischman RA, Gallardo T, Mi X. Mutations in the ligandbinding domain of the kit receptor: an uncommon site in
human
piebaldism.
J
Invest
Dermatol.
1996
Nov;107(5):703-6
Location
4q12
Note
PDGFRA is also deleted in patients with interstitial
cytogenetic deletions (contiguous gene syndrome).
Atlas Genet Cytogenet Oncol Haematol. 1999; 3(1)
This article should be referenced as such:
Larizza L, Beghini A. Piebaldism. Atlas Genet Cytogenet
Oncol Haematol. 1999; 3(1):44-45.
45
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Cancer Prone Disease Section
Mini Review
Nijmegen breakage syndrome
Jérôme Couturier
Department of Pathology, Institut Curie, Paris, France (JC)
Published in Atlas Database: October 1998
Online updated version : http://AtlasGeneticsOncology.org/Kprones/NijmegenID10020.html
DOI: 10.4267/2042/37495
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 1999 Atlas of Genetics and Cytogenetics in Oncology and Haematology
is absent; alphafoetoprotein levels are normal, in
contrast to AT patients.
- Craniofacial dysmorphy: progressive and severe
microcephaly, "bird-like" face with prominent
midface, long nose and receding mandible.
- Immunodeficiency: severe combined deficiency
with agammaglobulinemia, IgA, IgG2 and IgG4
deficiencies, decreased CD3+ and CD4+
lymphocytes, and decreased CD4+/CD8+ ratio;
these disturbances are responsible of frequent
respiratory, gastrointestinal and urinary infections.
Identity
Alias
Ataxia-telangiectasia, variant VI; Seemanova
syndrome II; Microcephaly with normal
intelligence, immunodeficiency, lymphoreticular
malignancies; Immunodeficiency, microcephaly,
chromosomal instability
Note
Belongs to the group of inherited chromosomal
instability syndromes including Bloom's syndrome,
Fanconi's disease, and ataxia telangiectasia (AT).
Inheritance
Autosomal recessive disease; since the recognition
of the Nijmegen breakage syndrome (NBS) in
1981, about 50 patients are included in the NBS
Registry in Nijmegen; the disease appears to have
originated in central Europe, in the Slavic
population, and to have spread through a founder
effect.
Neoplastic risk
High frequency and early development of
lymphomas, more often involving B-cells, in
contrast with those found in AT.
Other forms of cancer may also be at higher risk.
Cytogenetics
Inborn conditions
- Lymphocyte cultures often show low mitotic
index.
- Structural chromosome aberrations are observed
in 10-30% of metaphases; most of the
rearrangements occur in or between chromosomes 7
and 14, at bands 7p13, 7q35, 14q11, and 14q32, as
in AT; these bands contain immunoglobulin and Tcell receptor genes; the most frequent
rearrangement is the inv(7)(p13q35).
Clinics
Note
The condition is characterised by growth and
mental retardation, craniofacial dysmorphy, ovarian
failure, immunodeficiency, chromosome instability,
predisposition to lymphoid malignancies, and
radiosensitivity.
Phenotype and clinics
Other findings
- Growth and mental development: 30% of children
have low birth weight and short stature, and 75% a
head circumference at birth below the 3rd
percentile; all patients develop a severe
microcephaly during the first months of life; mental
development is normal in 35% of the patients,
moderately retarded in the others; cerebellar ataxia
Atlas Genet Cytogenet Oncol Haematol. 1999; 3(1)
Note
Radiosensitivity: increased sensitivity of both
lymphocytes and fibroblasts to ionising radiations
and radiomimetics, radio-resistant DNA synthesis.
46
Nijmegen breakage syndrome
Couturier J
Genes involved and
proteins
References
van der Burgt I, Chrzanowska KH, Smeets D, Weemaes C.
Nijmegen breakage syndrome. J Med Genet. 1996
Feb;33(2):153-6
NBS1
Shiloh Y. Ataxia-telangiectasia and the Nijmegen breakage
syndrome: related disorders but genes apart. Annu Rev
Genet. 1997;31:635-62
Location
8q21
DNA/RNA
Description: 16 exons
Protein
Function: The product of NBS1, the nibrin, should
have a role in the control of double-strand DNA
breaks involved, for example, in VDJ joining in
immunoglobulin and T-cell receptor genes
recombination process, in meiotic recombination,
and in radio-induced DNA lesions; this suggests
that nibrin and the product of ATM could act in a
common pathway of detection or repair of doublestrand breaks.
Mutations
Germinal: All Nijmegen patients show truncating
mutations.
Matsuura S, Tauchi H, Nakamura A, Kondo N, Sakamoto
S, Endo S, Smeets D, Solder B, Belohradsky BH, Der
Kaloustian VM, Oshimura M, Isomura M, Nakamura Y,
Komatsu K. Positional cloning of the gene for Nijmegen
breakage syndrome. Nat Genet. 1998 Jun;19(2):179-81
Varon R, Vissinga C, Platzer M, Cerosaletti KM,
Chrzanowska KH, Saar K, Beckmann G, Seemanová E,
Cooper PR, Nowak NJ, Stumm M, Weemaes CM, Gatti
RA, Wilson RK, Digweed M, Rosenthal A, Sperling K,
Concannon P, Reis A. Nibrin, a novel DNA double-strand
break repair protein, is mutated in Nijmegen breakage
syndrome. Cell. 1998 May 1;93(3):467-76
Yamazaki
V,
Wegner
RD,
Kirchgessner
CU.
Characterization of cell cycle checkpoint responses after
ionizing radiation in Nijmegen breakage syndrome cells.
Cancer Res. 1998 Jun 1;58(11):2316-22
This article should be referenced as such:
Couturier J. Nijmegen breakage syndrome. Atlas Genet
Cytogenet Oncol Haematol. 1999; 3(1):46-47.
Atlas Genet Cytogenet Oncol Haematol. 1999; 3(1)
47
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Cancer Prone Disease Section
Mini Review
Retinoblastoma
Dietmar R Lohmann
Institut fuer Humangenetik, Hufelandstr. 55, D-45122 Essen, Germany (DRL)
Published in Atlas Database: October 1998
Online updated version : http://AtlasGeneticsOncology.org/Kprones/RbKprID10031.html
DOI: 10.4267/2042/37496
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 1999 Atlas of Genetics and Cytogenetics in Oncology and Haematology
- brain tumours (pinealoma in particular some
patients also show multiple benign tumours of
adipose tissue (lipoma).
Identity
Inheritance
Predisposition to retinoblastoma is transmitted as an
autosomal dominant trait; it is caused by mutations
in the RB1 gene; penetrance and expressivity
depend on the nature of the predisposing mutational
change; there is also a non-hereditary form of
retinoblastoma (mostly in children with isolated
unilateral retinoblastoma) that is caused by RB1mutations confined to somatic cells.
Treatment
Clinics
Retinoblastomas can be cured by (depending on
size and location): local therapy (photocoagulation,
cryotherapy, radiation), combined systemic and
local therapy, or enucleation of the eye;
surveillance:
following
the
diagnosis
of
retinoblastoma, repeated examinations under
general anesthesia are required for early diagnosis
of new tumour foci; up to now, no screening for
second primary neoplasms.
Phenotype and clinics
Prognosis
Retinoblastoma in early childhood: white reflexes
in one or both eyes or strabismus usually are the
first signs indicating this malignant eye tumour; in
most children with the hereditary retinoblastoma,
both eyes are affected by multiple tumour foci
(bilateral multifocal retinoblastoma).
Adults (most often relatives of patients with
retinoblastoma) may show retinal scars indicating
regressed retinoblastomas or retinomas (nonprogressive tumours).
In addition to retinoblastoma, children with
cytogenetic deletions involving 13q14 may show
developmental delay and dysmorphic signs.
Most often, treatment of retinoblastoma is very
effective and, therefore, death from retinoblastoma
is rare; however, life span in patients that develop
second primary neoplasms is reduced (cumulative
mortality at age 40: 6.4% in bilateral patients
without radiotherapy, 1.5% in patients with
unilateral retinoblastoma).
Neoplastic risk
Location: 13q14
DNA/RNA
Genes involved and
proteins
RB1 (retinoblastoma susceptibility
gene)
Early childhood: formation of retinoblastomas (see
genotype-phenotype correlation).
Adolescence and adulthood: tumours outside the
eye (second primary neoplasms):
- osteosarcoma,
- melanoma,
c-RB1 at 13q14 in normal cells: PAC 825K21 - Courtesy
Mariano Rocchi.
Atlas Genet Cytogenet Oncol Haematol. 1999; 3(1)
48
Retinoblastoma
Lohmann DR
Musarella MA, Gallie BL. A simplified scheme for genetic
counseling in retinoblastoma. J Pediatr Ophthalmol
Strabismus. 1987 May-Jun;24(3):124-5
Description: 180 kb genomic DNA containing 27
exons.
Transcription: 4.7 kb mRNA with 2.7 kb open
reading frame.
Protein
Description: 928 aa nuclear phosphoprotein.
Localisation: Nucleus.
Function: Involved in cell cycle regulation.
Mutations
Note: Mutations predisposing to retinoblastoma are
one allele mutations; in retinoblastoma, both copies
of the RB1 gene are mutated (two-step inactivation
mechanism typical of tumor suppressor genes).
Nature and localization of individual mutations are
heterogeneous regarding their nature: 20% deletions
larger 1kb; 30% small deletions or insertions; 45%
point mutations.
And location: mutations have been found in 25 of
the 27 coding exons and in promoter elements.
Genotype-phenotype correlation: most mutant RB1alleles show premature termination codons;
typically, these mutant alleles are associated with
almost complete penetrance (>95%) and high
expressivity (more than 6 individual retinoblastoma
foci per individual and, therefore, most often
involvement of both eyes); some rare mutant alleles
that code for proteins with retention of parts of the
functions of the wild-type prote in or that result in
diminished amounts of wild-type transcript are
associated with incomplete penetrance (<75%) and
low expressivity (mean of less than 2 tumor foci).
Sakai T, Ohtani N, McGee TL, Robbins PD, Dryja TP.
Oncogenic germ-line mutations in Sp1 and ATF sites in the
human retinoblastoma gene. Nature. 1991 Sep
5;353(6339):83-6
Dryja TP, Rapaport J, McGee TL, Nork TM, Schwartz TL.
Molecular etiology of low-penetrance retinoblastoma in two
pedigrees. Am J Hum Genet. 1993 Jun;52(6):1122-8
Eng C, Li FP, Abramson DH, Ellsworth RM, Wong FL,
Goldman MB, Seddon J, Tarbell N, Boice JD Jr. Mortality
from second tumors among long-term survivors of
retinoblastoma. J Natl Cancer Inst. 1993 Jul
21;85(14):1121-8
Toguchida J, McGee TL, Paterson JC, Eagle JR, Tucker
S, Yandell DW, Dryja TP. Complete genomic sequence of
the human retinoblastoma susceptibility gene. Genomics.
1993 Sep;17(3):535-43
Fleischman RA, Gallardo T, Mi X. Mutations in the ligandbinding domain of the kit receptor: an uncommon site in
human
piebaldism.
J
Invest
Dermatol.
1996
Nov;107(5):703-6
Fleischman RA, Gallardo T, Mi X. Mutations in the ligandbinding domain of the kit receptor: an uncommon site in
human
piebaldism.
J
Invest
Dermatol.
1996
Nov;107(5):703-6
Gallie BL, Budning A, DeBoer G, Thiessen JJ, Koren G,
Verjee Z, Ling V, Chan HS. Chemotherapy with focal
therapy can cure intraocular retinoblastoma without
radiotherapy. Arch Ophthalmol. 1996 Nov;114(11):1321-8
Abramson DH, Frank CM. Second nonocular tumors in
survivors of bilateral retinoblastoma: a possible age effect
on
radiation-related
risk.
Ophthalmology.
1998
Apr;105(4):573-9; discussion 579-80
References
Abramson DH, Frank CM, Susman M, Whalen MP, Dunkel
IJ, Boyd NW 3rd. Presenting signs of retinoblastoma. J
Pediatr. 1998 Mar;132(3 Pt 1):505-8
Gallie BL, Ellsworth RM, Abramson DH, Phillips RA.
Retinoma: spontaneous regression of retinoblastoma or
benign manifestation of the mutation? Br J Cancer. 1982
Apr;45(4):513-21
Sippel KC, Fraioli RE, Smith GD, Schalkoff ME, Sutherland
J, Gallie BL, Dryja TP. Frequency of somatic and germ-line
mosaicism in retinoblastoma: implications for genetic
counseling. Am J Hum Genet. 1998 Mar;62(3):610-9
Friend SH, Bernards R, Rogelj S, Weinberg RA, Rapaport
JM, Albert DM, Dryja TP. A human DNA segment with
properties of the gene that predisposes to retinoblastoma
and
osteosarcoma.
Nature.
1986
Oct
1622;323(6089):643-6
This article should be referenced as such:
Atlas Genet Cytogenet Oncol Haematol. 1999; 3(1)
Lohmann DR. Retinoblastoma. Atlas Genet Cytogenet
Oncol Haematol. 1999; 3(1):48-49.
49
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Cancer Prone Disease Section
Mini Review
Rothmund-Thomson syndrome (RTS)
Lidia Larizza
Department of Biology and Genetics for Medical Sciences, Medical Faculty, University of Milan, Via
Viotti 3/5, 20133 Milan, Italy (LL)
Published in Atlas Database: October 1998
Online updated version : http://AtlasGeneticsOncology.org/Kprones/RothmundID10021.html
DOI: 10.4267/2042/37497
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 1999 Atlas of Genetics and Cytogenetics in Oncology and Haematology
- premature aging.
Diagnosis: the diagnosis is difficult before the
development of the erythema.
Identity
Alias: Poikiloderma atrophicans and cataract
Note
RTS is a chromosomal instability syndrome with an
increased risk of cancers.
Inheritance
Autosomal recessive; rare geno-dermatosis with
increased frequency in females; more than 200
cases reviewed in the medical literature.
Differential Diagnosis
Differential diagnosis with: Werner syndrome,
dyskeratosis congenita, Cockayne syndrome,
Anhidrotic ectodermal dysplasia, Bloom syndrome,
Fanconi anaemia.
Neoplastic risk
There are more than 30 documented cases of
malignancies in RTS patients, predominantly
affecting skin (squamous cell carcinoma, basal cell
carcinoma) and bone (osteosarcoma).
Etiology is unknown; a DNA repair deficiency has
been postulated to account for cancer proneness,
but no conclusive results have so far been achieved.
Clinics
Phenotype and clinics
Clinical expression highly variable.
Main features include:
- growth retardation,
- skin defects appearing within the first year of life
(90%):
atrophic
dermatosis,
poikiloderma,
hyperpigmentation, teleangiectasia,
- sparse hair which may progress to partial or total
alopecia; dystrophic nails,
- photosensitivity,
- congenital skeletal defects: hypoplasia or absence
of the radii and thumbs, osteopenia, cystic or
sclerotic changes of the long bones (in more than
50%); bone age lower than chronological age,
- juvenile cataract, corneal dystrophy (50%),
- hypodontia,
- hypogonadism (25%),
- proportionate short stature,
Atlas Genet Cytogenet Oncol Haematol. 1999; 3(1)
Treatment
Only protection against sunlight is possible;
dermatologic therapies; surgical correction of
skeletal malformations and cataracts; regular and
careful work-up of signs and symptoms of both
cutaneous and internal malignancy; caution is
warranted in administering chemotherapy to
affected individuals due to their sensitivity to
chemotherapeutic agents.
Evolution
The disease tends to progress during the first years
of life, but becomes static so that patients may have
a normal lifespan; the mortality from neoplastic
disease during the second or third decade is very
significantly increased.
50
Rothmund-Thomson syndrome (RTS)
Larizza L
Cytogenetics
homozygosity mapping have been performed due to
the few reported families.
Inborn conditions
References
Spontaneous/induced chromatid breaks were found
increased in only a very few studies; In contrast
with (mainly negative) chromatid results, consistent
clonal/non
clonal
structural
chromosomal
abnormalities were evidenced in most studies, often
involving chromosome 8, in cultured lymphocytes
and in fibroblasts; low frequency trisomy 8
mosaicism has been reported in both lymphocyte
and primary fibroblast cultures as well as in
uncultured blood and buccal smears, indicating this
characteristic chromosomal abnormality is present
in vivo; a propensity to centromere misdivision
with
development
of
clones
carrying
isochromosomes, such as i(8q), is peculiar of RTS.
Smith PJ, Paterson MC. Enhanced radiosensitivity and
defective DNA repair in cultured fibroblasts derived from
Rothmund Thomson syndrome patients. Mutat Res. 1982
May;94(1):213-28
Der Kaloustian VM, McGill JJ, Vekemans M, Kopelman
HR. Clonal lines of aneuploid cells in Rothmund-Thomson
syndrome. Am J Med Genet. 1990 Nov;37(3):336-9
Ying KL, Oizumi J, Curry CJ. Rothmund-Thomson
syndrome associated with trisomy 8 mosaicism. J Med
Genet. 1990 Apr;27(4):258-60
Vennos EM, Collins M, James WD. Rothmund-Thomson
syndrome: review of the world literature. J Am Acad
Dermatol. 1992 Nov;27(5 Pt 1):750-62
Shinya A, Nishigori C, Moriwaki S, Takebe H, Kubota M,
Ogino A, Imamura S. A case of Rothmund-Thomson
syndrome with reduced DNA repair capacity. Arch
Dermatol. 1993 Mar;129(3):332-6
Cytogenetics of cancer
Marked chromosomal instability has been detected
in mesenchymal tumours developed by RTS sibs.
Orstavik KH, McFadden N, Hagelsteen J, Ormerod E, van
der Hagen CB. Instability of lymphocyte chromosomes in a
girl with Rothmund-Thomson syndrome. J Med Genet.
1994 Jul;31(7):570-2
Other findings
Note
Reduced unscheduled DNA synthesis, 37% of
normal after exposure to ultraviolet C or gamma
irradiation.
Lindor NM, Devries EM, Michels VV, Schad CR, Jalal SM,
Donovan KM, Smithson WA, Kvols LK, Thibodeau SN,
Dewald GW. Rothmund-Thomson syndrome in siblings:
evidence for acquired in vivo mosaicism. Clin Genet. 1996
Mar;49(3):124-9
Genes involved and
proteins
Miozzo M, Castorina P, Riva P, Dalprà L, Fuhrman Conti
AM, Volpi L, Hoe TS, Khoo A, Wiegant J, Rosenberg C,
Larizza L. Chromosomal instability in fibroblasts and
mesenchymal tumors from 2 sibs with Rothmund-Thomson
syndrome. Int J Cancer. 1998 Aug 12;77(4):504-10
Note
The gene has not been mapped; it has been
provisionally assigned to chromosome 8 on the
basis of trisomy 8 mosaicism in affected
individuals; no linkage studies exploiting
Atlas Genet Cytogenet Oncol Haematol. 1999; 3(1)
This article should be referenced as such:
Larizza L. Rothmund-Thomson syndrome (RTS). Atlas
Genet Cytogenet Oncol Haematol. 1999; 3(1):50-51.
51
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Cancer Prone Disease Section
Mini Review
Bannayan-Riley-Ruvalcaba syndrome
Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers,
France (JLH)
Published in Atlas Database: November 1998
Online updated version : http://AtlasGeneticsOncology.org/Kprones/BannayanID10044.html
DOI: 10.4267/2042/37498
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 1999 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Neoplastic risk
Identity
- Multiple lipomas (75% of cases).
- Hemangiomas (40%).
- Hamartomatous polyps (ileus and colon; 45%).
- Lymphangiomas (10%).
Alias
Bannayan-Zonana
syndrome;
Riley-Smith
syndrome; Ruvalcaba-Myhre-Smith syndrome;
Macrocephaly,
pseudopapilledema,
multiple
hemangiomata; Macrocephaly, multiple lipomas,
hemangiomata
Inheritance
autosomal dominant; existence of sporadic cases.
Genes involved and
proteins
PTEN
Clinics
Location
10q23
Protein
Description: 403 amino acids.
Function: Protein tyrosine phosphatase; tumour
suppressor gene.
Mutations
Germinal: May be not all Bannayan-RileyRuvalcaba syndrome cases are due to PTEN
mutations; germ-line mutations have also been
described in Cowden disease and in some cases
with juvenile polyposis syndrome.
Somatic: PTEN is mutated in a large number of
cancer types.
Note
Bannayan-Riley-Ruvalcaba syndrome is an
overgrowth syndrome/hamartomatous polyposis
condition with an increased risk of benign and
malignant tumours; other overgrowth syndromes at
(known) risk of tumourigenesis are:
- Beckwith-Weideman syndrome,
- Sotos syndrome (cerebral gigantism),
- Hemihyperplasia (hemihypertrophy), and
- Simpson Golabi Behemel syndrome.
Phenotype and clinics
Onset in chilhood (in contrast with Cowden disease,
although an allelic disorder, see below); more often
found in male patients (lower penetrance in female
patients).
- Overgrowth at birth (postnatal growth
decelerates).
- Macrocephaly.
- Hypotonia and mental deficiency.
- Subcutaneous and visceral lipomas and
hemangiomas, and intestinal juvenile polyposis.
- Myopathy of the proximal type in 2/3 of cases.
- Pigmentation spots of the male genitalia.
Atlas Genet Cytogenet Oncol Haematol. 1999; 3(1)
References
Riley HD Jr and Smith WR. Macrocephaly,
pseudopapilledema and multiple hemangiomata: a
previously
undescribed
heredofamilial
syndrome.
Pediatrics. 1960;26:293-300.
Bannayan
GA.
Lipomatosis,
angiomatosis,
and
macrencephalia. A previously undescribed congenital
syndrome. Arch Pathol. 1971 Jul;92(1):1-5
Ruvalcaba RH, Myhre S, Smith DW. Sotos syndrome with
intestinal polyposis and pigmentary changes of the
genitalia. Clin Genet. 1980 Dec;18(6):413-6
52
Bannayan-Riley-Ruvalcaba syndrome
Huret JL
Arch EM, Goodman BK, Van Wesep RA, Liaw D, Clarke K,
Parsons R, McKusick VA, Geraghty MT. Deletion of PTEN
in a patient with Bannayan-Riley-Ruvalcaba syndrome
suggests allelism with Cowden disease. Am J Med Genet.
1997 Sep 5;71(4):489-93
DiLiberti
JH.
Inherited
macrocephaly-hamartoma
syndromes. Am J Med Genet. 1998 Oct 2;79(4):284-90
Marsh DJ, Coulon V, Lunetta KL, Rocca-Serra P, Dahia
PL, Zheng Z, Liaw D, Caron S, Duboué B, Lin AY,
Richardson AL, Bonnetblanc JM, Bressieux JM, CabarrotMoreau A, Chompret A, Demange L, Eeles RA, Yahanda
AM, Fearon ER, Fricker JP, Gorlin RJ, Hodgson SV,
Huson S, Lacombe D, Eng C. Mutation spectrum and
genotype-phenotype analyses in Cowden disease and
Bannayan-Zonana syndrome, two hamartoma syndromes
with germline PTEN mutation. Hum Mol Genet. 1998
Mar;7(3):507-15
Marsh DJ, Dahia PL, Zheng Z, Liaw D, Parsons R, Gorlin
RJ, Eng C. Germline mutations in PTEN are present in
Bannayan-Zonana
syndrome.
Nat
Genet.
1997
Aug;16(4):333-4
Carethers JM, Furnari FB, Zigman AF, Lavine JE, Jones
MC, Graham GE, Teebi AS, Huang HJ, Ha HT, Chauhan
DP, Chang CL, Cavenee WK, Boland CR. Absence of
PTEN/MMAC1 germ-line mutations in sporadic BannayanRiley-Ruvalcaba syndrome. Cancer Res. 1998 Jul
1;58(13):2724-6
Atlas Genet Cytogenet Oncol Haematol. 1999; 3(1)
This article should be referenced as such:
Huret JL. Bannayan-Riley-Ruvalcaba syndrome. Atlas
Genet Cytogenet Oncol Haematol. 1999; 3(1):52-53.
53
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
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