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Atlas
of Genetics
and Cytogenetics
PTCH1 (patched
homolog 1 (Drosophila))
in Oncology and Haematology
Huret JL
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 2 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
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Atlas
of Genetics
and Cytogenetics
PTCH1 (patched
homolog 1 (Drosophila))
in Oncology and Haematology
Huret JL
OPEN ACCESS JOURNAL AT INIST-CNRS
Editor
Jean-Loup Huret
(Poitiers, France)
Volume 1, Number 1, May-September 1997
Table of contents
Gene Section
PTCH (patched homolog)
Jean-Loup Huret
1
TAL1 (T-cell acute leukemia 1)
Jean-Loup Huret, Marie-Claude Labastie
3
ALK (anaplastic lymphoma kinase)
Jean-Loup Huret
4
NF1 (neurofibromin 1)
Jean-Loup Huret
5
Leukaemia Section
Childhood myelodysplastic syndromes
Jean-Loup Huret, Claude Léonard
7
idic(X)(q13)
Franck Viguié
9
Polycythemia vera (PV)
Jean-Loup Huret, Nicole Smadja
11
+11 or trisomy 11 (solely)
François Desangles
12
Chronic lymphocytic leukaemia (CLL)
Hossein Mossafa, Jean-Loup Huret
13
dic(9;12)(p11-13;p11-12)
Jean-Loup Huret
15
t(1;3)(p36;q21)
Jean-Loup Huret
16
t(1;22)(p13;q13)
Jean-Loup Huret
17
t(3;5)(q25;q34)
Jean-Loup Huret
18
t(12;21)(p12;q22)
Jean-Loup Huret, Alain Bernheim
19
Atlas Genet Cytogenet Oncol Haematol. 1997; 1(1)
Atlas
of Genetics
and Cytogenetics
PTCH1 (patched
homolog 1 (Drosophila))
in Oncology and Haematology
Huret JL
OPEN ACCESS JOURNAL AT INIST-CNRS
+14 or trisomy 14 (solely)
Jean-Loup Huret
21
t(3;12)(q26;p13)
François Desangles
22
t(8;21)(q22;q22)
Jean-Loup Huret
23
t(9;22)(q34;q11) in ALL
Jean-Loup Huret
26
t(9;22)(q34;q11) in ANLL
Jean-Loup Huret
29
Solid Tumour Section
Bladder cancer
Jean-Loup Huret, Claude Léonard
32
Cancer Prone Disease Section
Naevoid basal cell carcinoma syndrome (NBCS)
Jean-Loup Huret
34
Neurofibromatosis type 1 (NF1)
Jean-Loup Huret
36
Neurofibromatosis type 2 (NF2)
Jean-Loup Huret
38
Atlas Genet Cytogenet Oncol Haematol. 1997; 1(1)
Atlas
of Genetics
and Cytogenetics
PTCH1 (patched
homolog 1 (Drosophila))
in Oncology and Haematology
Huret JL
OPEN ACCESS JOURNAL AT INIST-CNRS
Atlas Genet Cytogenet Oncol Haematol. 1997; 1(1)
Atlas
of Genetics
and Cytogenetics
PTCH1 (patched
homolog 1 (Drosophila))
in Oncology and Haematology
Huret JL
OPEN ACCESS JOURNAL AT INIST-CNRS
Gene Section
Short Communication
PTCH (patched homolog)
Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France
Published in Atlas Database: May 1997
Online version is available at: http://AtlasGeneticsOncology.org/Genes/PTCH100.html
DOI: 10.4267/2042/32018
This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence.
© 1997 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
Mutations
Other names: PTC, but this term was confusing with
PTC/PKA.
Location: 9q22.3
Local order: between FACC and XPAC.
Germinal
DNA/RNA
Somatic
Germ-line mutations lead to protein truncation in
naevoid basal cell carcinoma syndrome (NBCS)
patients (see below).
Mutation and allele loss events in basal cell carcinoma,
in NBCS and in sporadic basal cell carcinoma are, so
far, in accordance with the two-hit model for neoplasia,
as is found in retinoblastoma.
Description
23 exons, 2 of which are non-coding; 34 kb.
Transcription
Alternate splicing: 3 different 5' termini.
Implicated in
Protein
Naevoid basal cell carcinoma syndrome
(NBCS) or Gorlin syndrome
Description
Disease
Autosomal dominant condition; cancer prone disease
(multiple basal cell carcinomas); it is also a
chromosome instability syndrome.
Cytogenetics
Spontaneous and induced chromosome instability.
Glycoprotein; 12 transmembrane domains, 2 extra
cellular loops and intracellular N-term and C-term.
Localisation
Transmembrane protein.
Function
Sporadic basal cell carcinoma
Part of a signalling pathway; opposed by the hedgehog
gene's product; transmembrane protein, with a probable
cell to cell adhesion role; is thought to have a
repressive activity on cell proliferation; the recent
demonstration of NBCS syndrome (see below) as a
chromosome instability syndrome suggests that this
protein has a role in DNA maintenance, repair and/or
replication.
References
Tabata T, Eaton S, Kornberg TB. The Drosophila hedgehog
gene is expressed specifically in posterior compartment cells
and is a target of engrailed regulation. Genes Dev 1992
Dec;6(12B):2635-45.
Basler K, Struhl G. Compartment boundaries and the control of
Drosophila limb pattern by hedgehog protein. Nature 1994 Mar
17; 368(6468):208-14.
Capdevila J, Estrada MP, Sánchez-Herrero E, Guerrero I. The
Drosophila segment polarity gene patched interacts with
decapentaplegic in wing development. EMBO J 1994 Jan 1;
13(1):71-82.
Homology
Patched (drosophila segment polarity gene).
Atlas Genet Cytogenet Oncol Haematol. 1997; 1(1)
1
PTCH (patched homolog)
Huret JL
Gailani MR, Stǻhle-Bäckdahl M, Leffell DJ, Glynn M,
Zaphiropoulos PG, Pressman C, Undén AB, Dean M, Brash
DE, Bale AE, Toftgǻrd R. The role of the human homologue of
Drosophila patched in sporadic basal cell carcinomas. Nat
Genet 1996 Sep; 14(1):78-81.
Hahn H, Christiansen J, Wicking C, Zaphiropoulos PG,
Chidambaram A, Gerrard B, Vorechovsky I, Bale AE, Toftgard
R, Dean M, Wainwright B. A mammalian patched homolog is
expressed in target tissues of sonic hedgehog and maps to a
region associated with developmental abnormalities. J Biol
Chem 1996 May 24; 271(21):12125-8.
Hahn H, Wicking C, Zaphiropoulous PG, Gailani MR, Shanley
S, Chidambaram A, Vorechovsky I, Holmberg E, Unden
AB,Gillies S, Negus K, Smyth I, Pressman C, Leffell DJ,
Gerrard B, Goldstein AM, Dean M, Toftgard R, ChenevixTrench G, Wainwright B, Bale AE. Mutations of the human
homolog of Drosophila patched in the nevoid basal cell
carcinoma syndrome. Cell 1996 Jun 14; 85(6):841-51.
Johnson RL, Rothman AL, Xie J, Goodrich LV, Bare JW,
Bonifas JM, Quinn AG, Myers RM, Cox DR, Epstein EH Jr,
Scott MP. Human homolog of patched, a candidate gene for
Atlas Genet Cytogenet Oncol Haematol. 1997; 1(1)
the basal cell nevus syndrome. Science 1996 Jun 14;
272(5268):1668-71.
Wicking C, Shanley S, Smyth I, Gillies S, Negus K, Graham S,
Suthers G, Haites N, Edwards M, Wainwright B, ChenevixTrench G. Most germ-line mutations in the nevoid basal cell
carcinoma syndrome lead to a premature termination of the
PATCHED protein, and no genotype-phenotype correlations
are evident. Am J Hum Genet 1997 Jan; 60(1):21-6.
Shafei-Benaissa E, Savage JR, Babin P, Larregue M,
Papworth D, Tanzer J, Bonnetblanc JM, Huret JL. The naevoid
basal-cell carcinoma syndrome (Gorlin syndrome) is a
chromosomal instability syndrome. Mutat Res 1998 Feb 2;
397(2):287-92.
This article should be referenced as such:
Huret JL. PTCH (patched homolog). Atlas Genet Cytogenet
Oncol Haematol.1997;1(1):1-2.
2
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Gene Section
Short Communication
TAL1 (T-cell acute leukemia 1)
Jean-Loup Huret, Marie-Claude Labastie
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France
(JLH)
Institut d'Embryologie Cellulaire et Moléculaire-CNRS UPR 9064, Nogent-sur-Marne, France (MCL)
Published in Atlas Database: August 1997
Online version is available at: http://AtlasGeneticsOncology.org/Genes/TAL1.html
DOI: 10.4267/2042/32019
This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence.
© 1997 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
Implicated in
Other names: SCL (stem cell leukaemia), TCL5 (T
cell leukaemia 5).
Location: 1p32
t(1;14)(p32;q11)/T-ALL→ TAL1/TCRD
t(1;7)(p32;q34)/T-ALL→ TAL1/TCRB
T-ALL with normal karyotype,
DNA/RNA
1a 1b
TAL1
2b
2a
3
4
5
Deletions at the DNA level (in the 5’ region) with a
normal karyotype.
6
SIL
References
DNA diagram
Description
Bash RO, Crist WM, Shuster JJ, Link MP, Amylon M, Pullen J,
Carroll AJ, Buchanan GR, Smith RG, Baer R. Clinical features
and outcome of T-cell acute lymphoblastic leukemia in
childhood with respect to alterations at the TAL1 locus: a
Pediatric Oncology Group study. Blood 1993 Apr 15;
81(8):2110-7.
Wadman I, Li J, Bash RO, Forster A, Osada H, Rabbitts TH,
Baer R. Specific in vivo association between the bHLH and
LIM proteins implicated in human T cell leukemia. EMBO J
1994 Oct 17; 13(20):4831-9.
Osada H, Grutz G, Axelson H, Forster A, Rabbitts TH.
Association of erythroid transcription factors: complexes
involving the LIM protein RBTN2 and the zinc-finger protein
GATA1. Proc Natl Acad Sci USA 1995 Oct 10;92(21):9585-9.
Hofmann TJ, Cole MD. The TAL1/Scl basic helix-loop-helix
protein blocks myogenic differentiation and E-box dependent
transactivation. Oncogene 1996 Aug 1; 13(3):617-24.
Porcher C, Swat W, Rockwell K, Fujiwara Y, Alt FW, Orkin SH.
The T cell leukemia oncoprotein SCL/tal-1 is essential for
development of all hematopoietic lineages. Cell 1996 Jul 12;
86(1):47-57.
Ono Y, Fukuhara N, Yoshie O. Transcriptional activity of TAL1
in T cell acute lymphoblastic leukemia (T-ALL) requires RBTN1
or -2 and induces TALLA1, a highly specific tumor marker of TALL. J Biol Chem 1997 Feb 14; 272(7):4576-81.
8 exons; 16 kb.
Transcription
(Complex) alternate splicing of: 1A with 2A, or 3, or 5,
vs 1B, 2B, 3 and 5.
Protein
Description
331 amino acids and other; 42, 40, 34 kDa; domains:
prolin rich in N-term; basic Helix-Loop-Helix from the
exon 6.
Expression
In erythroblastes, megakaryoblastes, mastocytes,
basophils, and in the nervous system; role in
haematopoietic cell differentiation.
Function
Transcription factor; exhibits sequence-specific DNA
binding activity when in dimers with another bHLH
protein such as E2A.
This article should be referenced as such:
Huret JL, Labastie MC. TAL1 (T-cell acute leukemia 1). Atlas
Genet Cytogenet Oncol Haematol.1997;1(1):3.
Homology
- TAL2 in 9q32;
- LYL1 in 19p13.
Atlas Genet Cytogenet Oncol Haematol. 1997; 1(1)
3
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Gene Section
Short Communication
ALK (anaplastic lymphoma kinase)
Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France
Published in Atlas Database: September 1997
Online version is available at: http://AtlasGeneticsOncology.org/Genes/ALK.html
DOI: 10.4267/2042/32020
This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence.
© 1997 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Prognosis
Nonetheless, a 80% five yr survival may be associated
with this anomaly.
Cytogenetics
Additional anomalies are most often found.
Hybrid/Mutated Gene
5' NPM1-3' ALK on der(5).
Abnormal Protein
680 amino acids; N-term NPM1 is fused to the 563 Cterm aminoacids of ALK (i.e. the entire cytoplasmic
portion of ALK); no apparent expression of the
ALK/NPM1 counterpart; localisation: both in the
cytoplasm and in the nucleus.
Oncogenesis
Via the kinase function activated by oligomerization of
NPM1-ALK mediated by the NPM1 part.
Identity
Location: 2p23
DNA/RNA
Transcription
6.2 kb m RNA; coding sequence: 4.9 kb.
Protein
Description
1620 amino acids; 177 kDa; after glycosylation,
produces a 200 kDa mature glycoprotein.
Expression
Tissue specific; mainly in: brain, gut and testis; not in
the lymphocytes.
Localisation
References
Cell membrane.
t(2;5)(p23;q35)/CD30+ NHL →
NPM1/ALK
Morris SW, Kirstein MN, Valentine MB, Dittmer KG, Shapiro
DN, Saltman DL, Look AT. Fusion of a kinase gene, ALK, to a
nucleolar protein gene, NPM, in non-Hodgkin's lymphoma.
Science 1994 Mar 4; 263(5151):1281-4. Erratum in Science
1995 Jan 20; 267(5196):316-7.
Iwahara T, Fujimoto J, Wen D, Cupples R, Bucay N, Arakawa
T, Mori S, Ratzkin B, Yamamoto T. Molecular characterization
of ALK, a receptor tyrosine kinase expressed specifically in the
nervous system. Oncogene 1997 Jan 30; 14(4):439-49.
Morris SW, Naeve C, Mathew P, James PL, Kirstein MN, Cui
X, Witte DP. ALK, the chromosome 2 gene locus altered by the
t(2;5) in non-Hodgkin's lymphoma, encodes a novel neural
receptor tyrosine kinase that is highly related to leukocyte
tyrosine kinase. Oncogene 1997 May 8; 14(18):2175-88.
Erratum in Oncogene 1997 Dec 4; 15(23):2883.
Bischof D, Pulford K, Mason DY, Morris SW. Role of the
nucleophosmin (NPM) portion of the non-Hodgkin's lymphomaassociated NPM-anaplastic lymphoma kinase fusion protein in
oncogenesis. Mol Cell Biol 1997 Apr; 17(4):2312-25.
Disease
High grade NHL; most often: CD30+ anaplastic large
cell type.
This article should be referenced as such:
Huret JL. ALK (anaplastic lymphoma kinase). Atlas Genet
Cytogenet Oncol Haematol.1997;1(1):4.
Function
Membrane associated tyrosine kinase receptor;
probable role in nervous system development and
maintenance.
Homology
Homologies with the insulin receptor super family:
LTK (leucocyte tyrosine kinase), TRKA, ROS
(homolog of the drosophila Sevenless), IGF1-R and
IRbeta.
Implicated in
Atlas Genet Cytogenet Oncol Haematol. 1997; 1(1)
4
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Gene Section
Short Communication
NF1 (neurofibromin 1)
Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France
Published in Atlas Database: September 1997
Online version is available at: http://AtlasGeneticsOncology.org/Genes/NF1ID134.html
DOI: 10.4267/2042/32021
This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence.
© 1997 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Somatic
Identity
The second allele remains normal in benign tumours
and is often lost in malignant tumours another process
in tumourigenesis may involve RNA editing (for the
second allele), which gives rise to a truncated
neurofibromin having lost its GAP activity.
Location: 17q11.2
DNA/RNA
Description
Implicated in
60 exons; spans 350 kb; presence of 3 cryptic genes:
OMGP, EVI2A, and EVI2B ('overlapping genes'),
hidden within NF1 intron 27 with an opposite
transcription direction.
Neurofibromatosis type 1
Protein
Disease
Autosomal
dominant
cancer
prone
disease;
neurofibromatosis type 1 (NF1: the same symbol is
used for the disease neurofibromatosis type 1 and the
gene neurofibromin 1) is an hamartoneoplastic
syndrome.
Description
Watson syndrome
The protein has been called neurofibromin; 2839
amino acids.
Disease
Autosomal
dominant
disease
with
cardiac
malformations, and, as is found in von Recklinghausen
neurofibromatosis, low normal intelligence, café-aulait spots, and neurofibromas but to a lesser extend.
Oncogenesis
In accordance with the two-hit model for neoplasia, as
is found in retinoblastoma.
Transcription
At least 4 alternate splicings; 9.0 mRNA complete cds;
coding sequence: CDS 198..8717.
Expression
Is tissue and development stage specific.
Function
GTPase activating protein (GAP) interacting with
p21RAS →tumour suppressor.
Homology
References
Other (GAP); IRA1 and 2, the yeast inhibitors of
p21RAS.
Cawthon RM, Weiss R, Xu GF, Viskochil D, Culver M, Stevens
J, Robertson M, Dunn D, Gesteland R, O'Connell P, et al. A
major segment of the neurofibromatosis type 1 gene: cDNA
sequence, genomic structure, and point mutations. Cell 1990
Jul 13; 62(1):193-201. Erratum in Cell 1990 Aug 10; 62(3):608.
Gorlin RJ, Cohen MM, Levin LS. Syndromes of the head and
neck. Oxford Monogr Med Genet 1990; 19:392-399.
Viskochil D, Buchberg AM, Xu G, Cawthon RM, Stevens J,
Wolff RK, Culver M, Carey JC, Copeland NG, Jenkins NA, et
al. Deletions and a translocation interrupt a cloned gene at the
neurofibromatosis type 1 locus. Cell 1990 Jul 13; 62(1):187192.
Mutations
Germinal
Large deletions or insertions in 25% of cases,
translocations and point mutations; widely dispersed,
with no cluster: yielding difficulties in diagnosis;
truncating effect in 2/3 of cases.
Atlas Genet Cytogenet Oncol Haematol. 1997; 1(1)
5
NF1 (neurofibromin 1)
Huret JL
Wallace MR, Marchuk DA, Andersen LB, Letcher R, Odeh HM,
Saulino AM, Fountain JW, Brereton A, Nicholson J, Mitchell
AL, et al. Type 1 neurofibromatosis gene: identification of a
large transcript disrupted in three NF1 patients. Science 1990
Jul 13; 249(4965):181-186. Erratum in Science 1990 Dec 21;
250(4988):1749.
Allanson JE, Upadhyaya M, Watson GH, Partington M,
MacKenzie A, Lahey D, MacLeod H, Sarfarazi M, Broadhead
W, Harper PS, et al. Watson syndrome: is it a subtype of type
1 neurofibromatosis? J Med Genet 1991 Nov; 28(11):752-756.
Tassabehji M, Strachan T, Sharland M, Colley A, Donnai D,
Harris R, Thakker N. Tandem duplication within a
neurofibromatosis type 1 (NF1) gene exon in a family with
features of Watson syndrome and Noonan syndrome. Am J
Hum Genet 1993 Jul; 53(1):90-95.
Shannon KM, O'Connell P, Martin GA, Paderanga D, Olson K,
Dinndorf P, McCormick F. Loss of the normal NF1 allele from
the bone marrow of children with type 1 neurofibromatosis and
malignant myeloid disorders. N Engl J Med 1994 Mar 3;
330(9):597-601.
Henry I. Médecine-sciences 1995; 11:93. (Review). French.
Atlas Genet Cytogenet Oncol Haematol. 1997; 1(1)
Li Y, O'Connell P, Breidenbach HH, Cawthon R, Stevens J, Xu
G, Neil S, Robertson M, White R, Viskochil D. Genomic
organization of the neurofibromatosis 1 gene (NF1). Genomics
1995 Jan 1; 25(1):9-18.
Metheny LJ, Cappione AJ, Skuse GR. Genetic and epigenetic
mechanisms in the pathogenesis of neurofibromatosis type I. J
Neuropathol Exp Neurol 1995 Nov;54(6):753-760.
Cappione AJ, French BL, Skuse GR. A potential role for NF1
mRNA editing in the pathogenesis of NF1 tumors. Am J Hum
Genet 1997 Feb; 60(2):305-312.
Hoffmeyer S, Nürnberg P, Ritter H, Fahsold R, Leistner W,
Kaufmann D, Krone W. Nearby stop codons in exons of the
neurofibromatosis type 1 gene are disparate splice effectors.
Am J Hum Genet 1998 Feb; 62(2):269-77.
This article should be referenced as such:
Huret JL. NF1 (neurofibromin 1). Atlas Genet Cytogenet Oncol
Haematol.1997;1(1):5-6.
6
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Leukaemia Section
Mini Review
Childhood myelodysplastic syndromes
Jean-Loup Huret, Claude Léonard
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France
(JLH)
Cytogénétique, Laboratoire d'Anatomo Pathologie, CHU Bicêtre, 78 r Leclerc, F94270 Le Kremlin-Bicêtre,
France (CL)
Published in Atlas Database: July 1997
Online version is available at: http://AtlasGeneticsOncology.org/Anomalies/childMDS.html
DOI: 10.4267/2042/32022
This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence.
© 1997 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Epidemiology
10% of haematological malignancies in children;
median age: 2 to 5 yrs; sex ratio: balanced for some,
male predominance (in RAEB±T or CMML) for
others.
Prognosis
CR is obtained; however, median survival is about 3
yrs, while 1/3 of the cases may be considered as cured;
good prognostic features are: young age, female sex,
normal karyotype, and some of the genetic
predisposing factors; worse prognosis is found in
secondary MDS, RAEB and RAEBT, cases with +8,
+19, t(1;7).
Clinics and pathology
Disease
Very heterogeneous:
I.
idiopathic MDS
II. secondary MDS: to previous chemo- and/or
radio-therapy.
III. 'genetic MDS': cases associated with a
congenital genetic disease, such as:
- Neurofibromatosis type 1 (Von Recklinhausen)(MIM
16220): an hamartoneoplastic syndrome,
- Kostmann syndrome (MIM 20270): also called
congenital neutropenia,
- Bloom syndrome (MIM 21090): a chromosome
instability syndrome,
- Dubowitz syndrome (MIM 22337): mimicks
Bloom's, but without chromosome instability,
- Fanconi anaemia (MIM 22765): a chromosome
instability syndrome,
- Schwachman syndrome (MIM 26040): with
pancreatic insufficiency, and risk of leukaemia,
- Pearson disease (MIM 26056) and other
mitochondrial diseases: they often share pancreatic
insufficiency, bone marrow pancytopenia with
myelodysplastic features but maintained polyclonality,
muscular and other ubiquitous manifestations,
- Familial monosomy 7,
- Familial platelet storage pool deficiency,
- Unbalanced constitutional karyotypes, including
+21, +8, del(11q), del(21q) miscellaneous conditions.
Phenotype / cell stem origin
RA, RARS (very rare), RAEB, RAEBT, CMML,
'Juvenile CML', 'Infantile Monosomy 7', 'non
classifiable cases according to the FAB'; with variable
proportions according to the studies.
Atlas Genet Cytogenet Oncol Haematol. 1997; 1(1)
Cytogenetics
Cytogenetics, morphological
A normal karyotype or a monosomy 7 (intermediate
prognosis) are found in 30% -or more- of cases each;
others are: +8, +21, t(1;7), del(6q).
References
Creutzig U, Cantù-Rajnoldi A, Ritter J, Romitti L, Odenwald E,
Conter V, Riehm H, Masera G. Myelodysplastic syndromes in
childhood. Report of 21 patients from Italy and West Germany.
Am J Pediatr Hematol Oncol 1987; 9(4):324-30.
Brandwein JM, Horsman DE, Eaves AC, Eaves CJ, Massing
BG, Wadsworth LD, Rogers PC, Kalousek DK. Childhood
myelodysplasia: suggested classification as myelodysplastic
syndromes based on laboratory and clinical findings. Am J
Pediatr Hematol Oncol 1990; 12(1):63-70.
Tuncer MA, Pagliuca A, Hicsonmez G, Yetgin S, Ozsoylu S,
Mufti GJ. Primary myelodysplastic syndrome in children: the
clinical experience in 33 cases. Br J Haematol 1992 Oct;
82(2):347-53.
7
Childhood myelodysplastic syndromes
Huret JL, Léonard C
Hasle H, Jacobsen BB, Pedersen NT. Myelodysplastic
syndromes in childhood: a population based study of nine
cases. Br J Haematol 1992 Aug; 81(4):495-8.
Mansoor AM, Bharadwaj TP, Sethuraman S, Chandy M,
Pushpa V, Kamada N, Murthy PB. Analysis of karyotype, SCE,
and point mutation of RAS oncogene in Indian MDS patients.
Cancer Genet Cytogenet 1993 Jan; 65(1):12-20.
Hasle H. Myelodysplastic syndromes in childhood
classification, epidemiology, and treatment. Leuk Lymphoma
1994 Mar; 13(1-2):11-26. (Review).
Zipursky A, Thorner P, De Harven E, Christensen H, Doyle J.
Myelodysplasia and acute megakaryoblastic leukemia in
Down's syndrome. Leuk Res 1994 Mar; 18(3):163-71.
Hasle H, Kerndrup G, Jacobsen BB. Childhood
myelodysplastic syndrome in Denmark: incidence and
predisposing conditions. Leukemia 1995 Sep; 9(9):1569-72.
Passmore SJ, Hann IM, Stiller CA, Ramani P, Swansbury GJ,
Gibbons B, Reeves BR, Chessells JM. Pediatric
Atlas Genet Cytogenet Oncol Haematol. 1997; 1(1)
myelodysplasia: a study of 68 children and a new prognostic
scoring system. Blood 1995 Apr 1; 85(7):1742-50.
Barnard DR, Kalousek DK, Wiersma SR, Lange BJ, Benjamin
DR, Arthur DC, Buckley JD, Kobrinsky N, Neudorf S, Sanders
J, Miller LP, Shina DC, Hammond GD, Woods WG.
Morphologic, immunologic, and cytogenetic classification of
acute myeloid leukemia and myelodysplastic syndrome in
childhood: a report from the Childrens Cancer Group.
Leukemia 1996 Jan; 10(1):5-12.
[No authors listed]. Forty-four cases of childhood
myelodysplasia with cytogenetics, documented by the Groupe
Français de Cytogénétique Hématologique. Leukemia 1997
Sep; 11(9):1478-85.
This article should be referenced as such:
Huret JL, Léonard C. Childhood myelodysplastic syndromes.
Atlas Genet Cytogenet Oncol Haematol.1997;1(1):7-8.
8
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Leukaemia Section
Short Communication
idic(X)(q13)
Franck Viguié
Laboratoire de Cytogénétique - Service d'Hématologie Biologique, Hôpital Hôtel-Dieu, 75181 Paris Cedex
04, France
Published in Atlas Database: July 1997
Online version is available at: http://AtlasGeneticsOncology.org/Anomalies/idicX.html
DOI: 10.4267/2042/32023
This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence.
© 1997 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
idic(X)(q13) G- banding and FISH; top - Courtesy Melanie Zenger and Claudia Haferlach; bottom - Courtesy Jean Luc Lai
Atlas Genet Cytogenet Oncol Haematol. 1997; 1(1)
9
Childhood myelodysplastic síndromes
Huret JL, Léonard C
Clinics and pathology
Cytogenetics
Disease
Cytogenetics, morphological
Acute non lymphocytic leukaemia (ANLL),
Myelodysplastic
syndromes
(MDS),
Chronic
myeloproliferative diseases (MPS).
Phenotype / cell stem origin
M1, M2, M4 ANLL, often with preceding MDS; MDS:
often RARS; an early progenitor cell is involved.
Epidemiology
Rare finding; only found in female patients aged 47-86
yrs; as one normal X chromosome seems to be needed,
it is not that surprising that male cases are not found.
Clinics
No history of toxic exposure.
Cytology
Bone marrow iron accumulation, ringed sideroblasts
are often found.
Prognosis
Variable.
Both the 2 centromeres appear to be active.
Cytogenetics, molecular
Breakpoint at or near the X inactivation center at Xq13.
The XIST (X inactive specific transcript) gene is
deleted. In 2 cases studied with BrDU, idic(X) was
late-replicating.
Additional anomalies
+ idic(X)(or more copies) in 2/3 of cases; other known
anomalies in MDS/ANLL; rings.
References
Dewald GW, Brecher M, Travis LB, Stupca PJ. Twenty-six
patients with hematologic disorders and X chromosome
abnormalities. Frequent idic(X)(q13) chromosomes and Xq13
anomalies associated with pathologic ringed sideroblasts.
Cancer Genet Cytogenet 1989; 42:173-185.
Rack KA, Chelly J, Gibbons RJ, Rider S, Benjamin D,
Lafreniére RG, Oscier D, Hendriks RW, Craig IW, Willard HF,
et al. Absence of the XIST gene from late-replicating
isodicentric X chromosomes in leukemia. Hum Mol Genet
1994; 3:1053-1059.
Dierlamm J, Michaux L, Criel A, Wlodarska I, Zeller W,
Louwagie A, Michaux JL, Mecucci C, Van den Berghe H.
Isodicentric (X)(q13) in haematological malignancies:
presentation of five new cases, application of fluorescence in
situ hybridization (FISH) and review of the literature. Br J
Haematol 1995; 91:885-891.
Genetics
Note: The gene(s) involved are unknown; breakpoint
located within a 450kb region proximal from XIST and
containing an inverted repeat.
This article should be referenced as such:
Viguié F. idic(X)(q13). Atlas Genet Cytogenet Oncol
Haematol.1997;1(1):9-10.
Atlas Genet Cytogenet Oncol Haematol. 1997; 1(1)
10
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Leukaemia Section
Short Communication
Polycythemia vera (PV)
Jean-Loup Huret, Nicole Smadja
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France
(JLH)
Laboratoire de Recherche en Cytogénétique Hématologique, Hôpital Saint Antoine, Paris, France (NS)
Published in Atlas Database: July 1997
Online version is available at: http://AtlasGeneticsOncology.org/Anomalies/PV.html
DOI: 10.4267/2042/32024
This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence.
© 1997 Atlas of Genetics and Cytogenetics in Oncology and Haematology
indicate progression of the disease, and may also occur
during evolution to MMM; finally, up to 100% of cases
with acute transformation have chromosome
anomalies; these are: del(20q), +8, +9 may be seen
solely or simultaneously in 20% of cases with
chromosome anomalies, del(13q) and a partial
duplication dup(1q)(sometimes in the form of
t(1;7)(q10;p10) in 10%, other anomalies in 30%; none
of them has prognostic significance; del(5q) and
del(7q), hypodiploidy are seen in cases evolving
towards therapy related ANLL: they confirm the
diagnosis and indicate an adverse prognosis.
Clinics and pathology
Disease
Chronic myeloproliferative syndrome
Phenotype / cell stem origin
Pluripotent -non lymphoid- stem cell is involved.
Epidemiology
Annual incidence: 10/106; sex ratio: 1M/1F; median
age 60 yrs.
Clinics
Asymptomatic for a long time, revealed by symptoms
related to blood hyperviscosity (headache, vertigo...),
or by asthenia, pruritus, skin erythrosis, or various
other symptoms; splenomegaly is frequent: 70%;
hepatomegaly in 40%; blood data: red cell mass of >
36 ml/kg in males, > 32 ml/kg in females; arterial
oxygen saturation > 92%; high haemoglobin; WBC
and platelets counts may be high.
Prognosis
Chronic disease, with, however, risks of thrombosis
and haemorrhages in various tissues, including central
nervous system; bone marrow evolution towards: 1myelofibrosis with myeloid metaplasia (MMM) in 20%
of cases; 2- acute leukaemia in 10%, either as an acute
transformation, or as a therapy related ANLL;
prognosis: median survival is 14 yrs with blood-letting,
12 yrs with 32P, less than 10 yrs with standard
chemotherapy.
Genes involved and Proteins
Note: genes involved are unkown.
References
Berlin NI. Diagnosis and classification of the polycythemias.
Semin Hematol 1975 Oct; 12(4):339-51.
Berk PD, Goldberg JD, Donovan PB, Fruchtman SM, Berlin NI,
Wasserman
LR.
Therapeutic
recommendations
in
polycythemia vera based on Polycythemia Vera Study Group
protocols. Semin Hematol 1986 Apr; 23(2):132-43.
Landaw SA. Acute leukemia in polycythemia vera. Semin
Hematol 1986 Apr; 23(2):156-65.
Rege-Cambrin G, Mecucci C, Tricot G, Michaux JL, Louwagie
A, Van Hove W, Francart H, Van den Berghe H. A
chromosomal profile of polycythemia vera. Cancer Genet
Cytogenet 1987; 25:233-45.
No authors listed. Cytogenetics of acutely transformed chronic
myeloproliferative
syndromes
without
a
Philadelphia
chromosome. A multicenter study of 55 patients. Groupe
Français de Cytogénétique Hématologique. Cancer Genet
Cytogenet 1988 Jun; 32(2):157-68.
Cytogenetics
Cytogenetics, morphological
This article should be referenced as such:
Huret JL, Smadja N. Polycythemia vera (PV). Atlas Genet
Cytogenet Oncol Haematol.1997;1(1):11.
Normal karyotype is found in > 80% of cases at
diagnosis, abnormal karyotype occurs with evolution,
but the appearance of a clonal anomaly does not
Atlas Genet Cytogenet Oncol Haematol. 1997; 1(1)
11
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
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Leukaemia Section
Short Communication
+11 or trisomy 11 (solely)
François Desangles
Laboratoire de Biologie, Hôpital du Val de Grâce, 75230 Paris, France
Published in Atlas Database: July 1997
Online version is available at: http://AtlasGeneticsOncology.org/Anomalies/tri11.html
DOI: 10.4267/2042/32025
This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence.
© 1997 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Protein
431 kDa; contains two DNA binding motifs (a AT
hook, and Zinc fingers), a DNA methyl transferase
motif, a bromodomain; wide expression; nuclear
localisation; transcriptional regulatory factor.
Clinics and pathology
Disease
Myeloid lineage: (ANLL, MDS)
Phenotype / cell stem origin
M1, M2, and M4 ANLL; therapy related ANLL; MDS
evolving towards ANLL; stem cell immunophenotype
(DR+, CD34+, and CD15, 33 and/or 13 positive);
trilineage dysplasia may be present.
To be noted that M1 and M2 subtypes of ANLL have
rarely been found associated with the classical MLL
rearrangements.
Epidemiology
Frequency: 1% of ANLL and MDS as well; balanced
sex ratio; found in adults; med age: 60 yrs.
Prognosis
Short CR; poor prognosis.
Results of the chromosomal
anomaly
Hybrid gene
Description
Exons 1 to 6 or 8 fused to a nearly entire MLL gene,
starting at exon 2 (i.e. the duplicated segment is E2 to
E6 or 8).
Fusion protein
Description
AT hook and DNA methyltransferase from MLL in Nterm fused to a quite entire MLL in C-term.
Expression localisation
Nuclear localisation.
Oncogenesis
Probable altered transcriptional regulation.
Cytogenetics
Cytogenetics, morphological
+11
To be noted
Cytogenetics, molecular
Partial tandem duplication (in situ) of MLL gene
located in 11q23.
Such a tandem duplication of MLL may also be found
in cases with a normal karyotype.
Probes
References
Oncor, Inc.
Additional anomalies
MLL
Ingram L, Raimondi SC, Mirro J Jr, Rivera GK, Ragsdale ST,
Behm F. Characteristics of trisomy 11 in childhood acute
leukemia with review of the literature. Leukemia 1989 Oct;
3(10):695-8. (Review).
Chichman SA, Canaani E, Croce CM. Self-fusion of the ALL1
gene. A new genetic mechanism for acute leukemia. JAMA
1995 Feb 15; 273(7):571-6. (Review).
Location: 11q23
DNA / RNA
21 exons, spanning over 100 kb; 13-15 kb mRNA.
This article should be referenced as such:
Desangles F. +11 or trisomy 11 (solely). Atlas Genet
Cytogenet Oncol Haematol.1997;1(1):12.
None (by that very fact).
Genes involved and Proteins
Atlas Genet Cytogenet Oncol Haematol. 1997; 1(1)
12
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Leukaemia Section
Mini Review
Chronic lymphocytic leukaemia (CLL)
Hossein Mossafa, Jean-Loup Huret
Laboratoire Pasteur-Cerba, 95066, Cergy-Pontoise, France (HM)
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France
(JLH)
Published in Atlas Database: August 1997
Online version is available at: http://AtlasGeneticsOncology.org/Anomalies/CLL.html
DOI: 10.4267/2042/32026
This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence.
© 1997 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Other: autoimmune hemolytic anaemia and
thrombocytopenia; transformation into Richter's
disease or into prolymphocytic leukaemia (in 10%).
Prognosis
According to the staging: A (less than 3 lymph nodes,
Hb < 10g/dl, platelets < 100 X 109/l): survival not
reduced compared to age matched population; B (3 or
more lymph nodes; Hb and platelets maintained):
median survival of 5 yrs; C (Hb < 10g/dl and/or
platelets < 100 X 109/l): median survival of 2 yrs;
according to the karyotype: survival is better in cases
with a normal karyotype (median: 15 yrs vs 8 yrs with
an abnormal karyotype), worse in the 10% of cases
where a complex karyotype is found (median: 6 yrs);
specific chromosome anomalies have specific
prognoses (see below).
Clinics and pathology
Disease
Chronic lymphoproliferation
Phenotype / cell stem origin
B-cell disease; the existence of rare cases of T-CLL
has been debated.
Epidemiology
Annual incidence 30/106; represents 70% of lymphoid
leukaemias, 1/4 of all leukaemias; median age: 60-80
yrs, 2M/1F.
Clinics
Diagnosis is often delayed, due to the lack of
symptoms (therefore, median survival from the
begining of the disease may be much more than med.
surv. from diagnosis); enlarged lymph nodes;
splenomegaly; blood data: lymphocytosis > 4 X 109/l;
hypogammaglobulinemia in 60%.
Cytology
Typically, proliferation of mature small lymphocytes
of normal morphology; lymphocytes with more
abundant cytoplasm can be present; prolymphocytes
must represent less than 10% of the lymphocytes
(otherwise, the diagnosis of 'chronic lymphocytic
leukaemia-prolymphocytic leukaemia' should be
made); expression of sIg with monotypy
(monoclonality); CD19+, CD20+, and CD5+ most
often.
Treatment
None in early stage; chemotherapy afterwards.
Cytogenetics
Cytogenetics, morphological
Clonal anomaly is found in about 50% of cases;
complex karyotypes are found in 10%; unrelated
clones demonstrating the existence of cells
subpopulations are frequent findings in this disease.
+12: is found in 15-20% of cases, depending on the use
of interphase cytogenetics methods (FISH) and the cell
morphology of the cases under study (trisomy 12 is
typically found in atypical lymphocyte morphology
and CD5- cases, often with an increased number of
prolymphocytes, in advanced stages, and is associated
with disease progression); trisomy 12 is an adverse
prognostic factor (median survival: 5 yrs); found either
as the sole anomaly, as an anomaly accompanied by
others, or even as an accompanying (secondary)
anomaly; present only in a subset of the malignant cell
population; region q13-q22 might be of particular
pathogenetic importance;
Evolution
Unrelated causes and disease-related infections are the
2 major causes of death.
Atlas Genet Cytogenet Oncol Haematol. 1997; 1(1)
13
Chronic lymphocytic leukaemia (CLL)
Mossafa H, Huret JL
Fluorescent in situ hybridization and cytogenetic studies of
trisomy 12 in chronic lymphocytic leukemia. Blood 1993 May
15; 81(10):2702-2707.
Que TH, Marco JG, Ellis J, Matutes E, Babapulle VB, Boyle S,
Catovsky D Trisomy 12 in chronic lymphocytic leukemia
detected by fluorescence in situ hybridization: analysis by
stage, immunophenotype, and morphology. Blood. 1993 ; 82
(2) : 571-575.
Criel A, Wlodarska I, Meeus P, Stul M, Louwagie A, Van Hoof
A, Hidajat M, Mecucci C, Van den Berghe H. Trisomy 12 is
uncommon in typical chronic lymphocytic leukemias. Br J
Haematol 1994 Jul; 87(3):523-528.
Matutes E. Trisomy 12 in chronic lymphocytic leukemia. Leuk
Res 1996 May; 20(5):375-377.
Matutes E, Oscier D, Garcia-Marco J, Ellis J, Copplestone A,
Gillingham R, Hamblin T, Lens D, Swansbury GJ, Catovsky D.
Trisomy 12 defines a group of CLL with atypical morphology:
correlation between cytogenetic, clinical and laboratory
features in 544 patients. Br J Haematol 1996 Feb; 92(2):382388.
Woessner S, Solé F, Pérez-Losada A, Florensa L, Vilá RM.
Trisomy 12 is a rare cytogenetic finding in typical chronic
lymphocytic leukemia. Leuk Res 1996 May;20(5):369-374.
Crossen PE. Genes and chromosomes in chronic B-cell
leukemia. Cancer Genet Cytogenet 1997 Mar; 94(1):44-51.
(Review).
Dierlamm J, Michaux L, Criel A, Wlodarska I, Van den Berghe
H, Hossfeld DK. Genetic abnormalities in chronic lymphocytic
leukemia and their clinical and prognostic implications. Cancer
Genet Cytogenet 1997 Mar; 94(1):27-35. (Review).
Garcia-Marco JA, Price CM, Catovsky D. Interphase
cytogenetics in chronic lymphocytic leukemia. Cancer Genet
Cytogenet 1997 Mar; 94(1):52-58.
del(13q) and t(13;Var): found in 10-20% of cases;
q14 and Rb gene and also DNA sequences telomeric
and centromeric to Rb are often involved; deletion may
be hetero- or homozygous; good prognostic feature
(median survival > 15 yrs);
14q32 involvement: is frequent in CLL, as in other Bcell
chronic
leukaemias
or
lymphomas;
t(11;14)(q13;q32), typical of mantle cell lymphoma,
with BCL1/IgH rearrangement, may occasionally be
found in CLL;
t(14;19)(q32;q13), with BCL3/IgH rearrangement,
may
be
associated
with
short
survival;
t(2;14)(p13;q32), exceptional;
Other t(14; var) have been found;
del(6q), del(11q), +3, +18: are the most frequent other
anomalies.
Genes involved and Proteins
Note: Genes involved as a primary event are still
unknown. P53 has been found mutated in 10-15% of
cases; adverse prognostic indicator.
References
[No authors listed]. Prognostic and therapeutic advances in
CLL management: the experience of the French Cooperative
Group. French Cooperative Group on Chronic Lymphocytic
Leukemia. Semin Hematol 1987 Oct; 24(4):275-90.
Huret JL, Mossafa H, Brizard A, Dreyfus B, Guilhot F, Xue XQ,
Babin P, Tanzer J. Karyotypes of 33 patients with clonal
aberrations in chronic lymphocytic leukemia. Review of 216
abnormal karyotypes in chronic lymphocytic leukemia. Ann
Genet 1989; 32(3):155-159.
Escudier SM, Pereira-Leahy JM, Drach JW, Weier HU,
Goodacre AM, Cork MA, Trujillo JM, Keating MJ, Andreeff M.
Atlas Genet Cytogenet Oncol Haematol. 1997; 1(1)
This article should be referenced as such:
Mossafa H, Huret JL. Chronic lymphocytic leukaemia (CLL).
Atlas Genet Cytogenet Oncol Haematol.1997;1(1):13-14.
14
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Leukaemia Section
Short Communication
dic(9;12)(p11-13;p11-12)
Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France
Published in Atlas Database: August 1997
Online version is available at: http://AtlasGeneticsOncology.org/Anomalies/dic0912.html
DOI: 10.4267/2042/32027
This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence.
© 1997 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Clinics
Moderate organomegaly; bood data: moderate WBC.
Treatment
No BMT; no high risk protocol.
Prognosis
CR in all cases; 5 yrs survival > 95%.
Identity
Note: dic(9;12) is mainly found in ALL, and that is the
clinical entity which is described below.
Cytogenetics
Cytogenetics, morphological
Dicentric with loss of parts of 9p and 12p → ploidy:
45 chromosomes.
Additional anomalies
+8, +21.
To be noted
Bone marrow transplantation should not be performed,
as the prognosis of the dic(9;12)/ALL is excellent.
References
Mahmoud H, Carroll AJ, Behm F, Raimondi SC, Schuster J,
Borowitz M, Land V, Pullen DJ, Vietti TJ, Crist W. The nonrandom dic(9;12) translocation in acute lymphoblastic leukemia
is associated with B-progenitor phenotype and an excellent
prognosis. Leukemia 1992; 6:703-707.
Behrendt H, Charrin C, Gibbons B, Harrison CJ, Hawkins JM,
Heerema NA, Horschler-Bötel B, Huret JL, Laï JL, Lampert F,
et al. Dicentric (9; 12) in acute lymphocytic leukemia and other
hematological malignancies: report from a dic(9;12) study
group. Leukemia 1995; 9:102-106.
Clinics and pathology
Disease
ALL most often; rarely: CML in blast crisis, T-cell
leukaemia or lymphoma.
Phenotype / cell stem origin
Of dic(9;12)/ALL: L1/L2 CD10+ most often, may be
CIg+ ALL.
Epidemiology
1% of paediatric ALL; sex ratio: 2M/1F; children and
young adults (> 1 yr, < 25 yrs); no infant case.
Atlas Genet Cytogenet Oncol Haematol. 1997; 1(1)
This article should be referenced as such:
Huret JL. dic(9;12)(p11-13;p11-12). Atlas Genet Cytogenet
Oncol Haematol.1997;1(1):15.
15
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
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Leukaemia Section
Short Communication
t(1;3)(p36;q21)
Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France
Published in Atlas Database: August 1997
Online version is available at: http://AtlasGeneticsOncology.org/Anomalies/t0103.html
DOI: 10.4267/2042/32028
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© 1997 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Clinics and pathology
Cytogenetics
Disease
Additional anomalies
Myeloid lineage (MDS, ANLL, therapy related ANLL,
BC-CML)
Phenotype / cell stem origin
MDS (RA: 3 cases; RAEB: 4 cases; CMML: 2 cases;
RAEBT: 1 case); ANLL (M1, M4...), often (13/16
cases) with preceding MDS, according to cases herein
reviewed; seem to involve a myeloid stem cell, t(1;3)
being absent from B or T lymphocytes; may be
secondary to toxic exposure.
Epidemiology
Median age: 49 yrs; sex ratio: 7M/9F.
Clinics
Blood data: frequent thrombocytosis.
Cytology
Dysmegakaryocytopoiesis.
Prognosis
Very poor so far: median survival is 6 mths in ANLL,
20 mths in MDS.
del (5q) in 3 of 16 cases.
Atlas Genet Cytogenet Oncol Haematol. 1997; 1(1)
To be noted
This translocation share commun features with
inv(3)(q21q26), t(3;3)(q21;q26), and t(3;5)(q2125;q31-35).
References
Welborn JL, Lewis JP, Jenks H, Walling P. Diagnostic and
prognostic significance of t(1;3)(p36;q21) in the disorders of
hematopoiesis. Cancer Genet Cytogenet 1987; 28:277-285.
Grigg AP, Gascoyne RD, Phillips GL, Horsman DE. Clinical,
haematological and cytogenetic features in 24 patients with
structural rearrangements of the Q arm of chromosome 3. Br J
Haematol 1993; 83:158-165.
This article should be referenced as such:
Huret JL. t(1;3)(p36;q21). Atlas Genet Cytogenet Oncol
Haematol.1997;1(1):16.
16
Atlas of Genetics and Cytogenetics
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Leukaemia Section
Short Communication
t(1;22)(p13;q13)
Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France
Published in Atlas Database: August 1997
Online version is available at: http://AtlasGeneticsOncology.org/Anomalies/t0122.html
DOI: 10.4267/2042/32029
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© 1997 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Epidemiology
30% of paediatric M7; 70 to 100% of infants M7; age:
infants (17/18); sex ratio: 5M/13F herein reviewed.
Clinics
Organomegaly; bood data: moderate WBC;
Thrombocytopenia; myelofibrosis.
Prognosis
CR: 11/18; poor survival is probable.
Identity
Cytogenetics
Additional anomalies
Often none; otherwise: +der(1), +19, +6…
References
Lion T, Haas OA, Harbott J, Bannier E, Ritterbach J, Jankovic
M, Fink FM, Stojimirovic A, Herrmann J, Riehm HJ, et al. The
translocation t(1;22)(p13;q13) is a nonrandom marker
specifically associated with acute megakaryocytic leukemia in
young children. Blood 1992 Jun 15; 79(12):3325-30.
Lion T, Haas OA. Acute megakaryocytic leukemia with the
t(1;22)(p13;q13). Leuk Lymphoma 1993 Sep; 11(1-2):15-20.
(Review).
t(1;22)(p13;q13) G- and R- banding
Clinics and pathology
Disease
Only found so far in M7 ANLL (acute megakaryocytic
leukaemia); not found in Down syndrome (DS), and
yet, DS is a disease with highly elevated risk of M7.
Phenotype / cell stem origin
M7 (CD 41).
Atlas Genet Cytogenet Oncol Haematol. 1997; 1(1)
This article should be referenced as such:
Huret JL. t(1;22)(p13;q13). Atlas Genet Cytogenet Oncol
Haematol.1997;1(1):17.
17
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
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Leukaemia Section
Short Communication
t(3;5)(q25;q34)
Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France
Published in Atlas Database: August 1997
Online version is available at: http://AtlasGeneticsOncology.org/Anomalies/t0305.html
DOI: 10.4267/2042/32030
This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence.
© 1997 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Clinics and pathology
Results of the chromosomal
anomaly
Disease
ANLL; may be preceded by MDS; BC-CML
Phenotype / cell stem origin
M2, M4, M6 (although a rare subtype) ANLL;
trilineage involvement.
Epidemiology
Med. age: 35 yrs; balanced sex ratio.
Prognosis
CR: 8/12, but median survival is less than 1 yr.
Hybrid gene
Description
5' NPM-3' MLF1 on der(5).
Fusion protein
Expression localisation
54 kDa with the 175 N-term amino acids from NPM;
localization: nucleus, mainly in the nucleolus.
To be noted
Cytogenetics
Specific comments: this translocation share some (but
not all) common features with t(1;3)(p36;q21),
inv(3)(q21q26)..., although the genes involved on
chromosome 3 are different.
Cytogenetics, morphological
Location of breakpoints is difficult to ascertain.
Additional anomalies
Most often none; +8.
References
Genes involved and Proteins
De Braekeleer M, Vekemans M. A t(3;5) in blastic phase of a
Philadelphia chromosome-negative chronic myeloid leukemia.
Cancer Genet Cytogenet 1989 Feb; 37(2):163-8. (Review).
Grigg AP, Gascoyne RD, Phillips GL, Horsman DE. Clinical,
haematological and cytogenetic features in 24 patients with
structural rearrangements of the Q arm of chromosome 3. Br J
Haematol 1993; 83:158-65.
Yoneda-Kato N, Look AT, Kirstein MN, Valentine MB,
Raimondi SC, Cohen KJ, Carroll AJ, Morris SW. The
t(3;5)(q25.1;q34) of myelodysplastic syndrome and acute
myeloid leukemia produces a novel fusion gene, NPM-MLF1.
Oncogene 1996; 12:265-275.
MLF1
Location: 3q25
Protein
31 kDa; do not contain known functional motifs;
widely expressed; cytoplasmic localisation.
NPM1
Location: 5q34
Protein
Nuclear localisation; binds to single and double strand
nucleic acids; phosphoprotein that may transport
ribonucleoproteins; may also have a role in DNA
replication.
Atlas Genet Cytogenet Oncol Haematol. 1997; 1(1)
This article should be referenced as such:
Huret JL. t(3;5)(q25;q34). Atlas Genet Cytogenet Oncol
Haematol.1997;1(1):18.
18
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Leukaemia Section
Short Communication
t(12;21)(p12;q22)
Jean-Loup Huret, Alain Bernheim
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France
(JLH);
Laboratoire de Cytogénétique, UMR 1599 CNRS, Institut Gustave Roussy, 94805 Villejuif, France (AB)
Published in Atlas Database: August 1997
Online version is available at: http://AtlasGeneticsOncology.org/Anomalies/t1221.html
DOI: 10.4267/2042/32031
This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence.
© 1997 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Clinics and pathology
Genes involved and Proteins
Disease
ETV6
B cell ALL
Phenotype / cell stem origin
L1 and L2, CD10+.
Epidemiology
15 to 35% of paediatric B-lineage ALL: so far the most
frequent translocation in this group; rare or absent in
adults and in infants; age: children; no case > 20 yrs so
far; male and female equally represented.
Clinics
Standard ALL.
Prognosis
CR in all cases; prognosis seems good.
Location: 12p13
DNA / RNA
9 exons; alternate splicing.
Protein
Contains a HLH domain and a ETS-DNA binding
domain; wide expression; nuclear localisation; ETSrelated transcription factor.
AML1
Location: 21q22
DNA / RNA
Transcription is from telomere to centromere.
Protein
Contains a Runt domain and, in the C-term, a
transactivation domain; forms heterodimers; widely
expressed; nuclear localisation; transcription factor
(activator) for various hematopoietic-specific genes.
Cytogenetics
Cytogenetics, morphological
t(12;21) often remained undetected.
Easily detected by chromosomes 12 and 21 painting or
specific probes.
Results of the chromosomal
anomaly
Additional anomalies
Hybrid gene
Frequent del(12)(p12) on the other chromosome; in
rare cases duplication of der(21)t(12;21); looks like a
+21.
Description
TEL-AML1 chimaeric gene; 5' centromere to 3'
telomere orientation.
Transcript
The fusion transcript on chromosome 21 TEL-AML1
is the crucial one; the AML1-TEL transcript is absent
in some cases; the other TEL allele is often deleted.
Cytogenetics, molecular
Variants
t(6;12;21), t(3;12;21)
Atlas Genet Cytogenet Oncol Haematol. 1997; 1(1)
19
t(12;21)(p12;q22)
Huret JL, Bernheim A
Romana SP, Poirel H, Leconiat M, Flexor MA, Mauchauffé M,
Jonveaux P, Macintyre EA, Berger R, Bernard OA. High
frequency of t(12;21) in childhood B-lineage acute
lymphoblastic leukemia. Blood 1995 Dec 1; 86(11):4263-9.
Raynaud S, Cave H, Baens M, Bastard C, Cacheux V,
Grosgeorge J, Guidal-Giroux C, Guo C, Vilmer E, Marynen P,
Grandchamp B. The 12; 21 translocation involving TEL and
deletion of the other TEL allele: two frequently associated
alterations found in childhood acute lymphoblastic leukemia.
Blood 1996 Apr 1; 87(7):2891-9.
Detection protocol
RT-PCR of the fusion transcript.
Fusion protein
Description
Helix loop helix of TEL fused to the nearly entire
AML1 protein, comprising the Runt domain and the
transactivation domain.
References
This article should be referenced as such:
Huret JL, Bernheim A. t(12;21)(p12;q22).
Cytogenet Oncol Haematol.1997;1(1):19-20.
Golub TR, Barker GF, Lovett M, Gilliland DG. Fusion of PDGF
receptor beta to a novel ets-like gene, tel, in chronic
myelomonocytic
leukemia
with
t(5;12)
chromosomal
translocation. Cell 1994 Apr 22; 77(2):307-16.
Atlas Genet Cytogenet Oncol Haematol. 1997; 1(1)
20
Atlas
Genet
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Leukaemia Section
Short Communication
+14 or trisomy 14 (solely)
Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France
Published in Atlas Database: August 1997
Online version is available at: http://AtlasGeneticsOncology.org/Anomalies/tri_14.html
DOI: 10.4267/2042/32032
This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence.
© 1997 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Clinics and pathology
Cytogenetics, molecular
Disease
Chromosome painting (although
attempts are, so far, not relevant).
Myeloid disorders: MDS in more than half cases,
ANLL in 1/4 of cases, chronic myeloproliferative
syndrome
(atypical
CML);
exceptionally:
lymphoproliferations; therefore, only trisomy 14 solely
in myeloid malignancies is herein described.
Phenotype / cell stem origin
MDS: RA, RAEB±T mainly; ANLL: M1, M2, M4;
atypical CML: with dysplastic features.
Epidemiology
Median age 60-65 yrs (range: 4-89 yrs); sex ratio:
4M/3F.
Clinics
No history of carcinogen exposure of note; blood data:
platelets count: 130 X 109/l; monocytosis in half cases.
Cytology
All FAB subtypes of MDS can be found; atypical CML
cases present with dysplastic features; non-lobulated
megakaryocytes are often found.
Prognosis
Survival < 2 yrs in most cases; +14 do not seem to bear
a distinct prognosis.
detection
Additional anomalies
None, at least in the sub-clone with '+14 solely', by that
very fact; most often none in karyotype follow-up.
Variants
May be found as i(14q).
Genes involved and Proteins
Note: genes involved are unknown.
References
Brizard A, Guilhot F, Babin P, Burucoa C, Tanzer J, Huret JL.
Four additional cases of trisomy 14 as the sole anomaly in
various haematological malignancies. Leuk Res 1992;
16(5):537-40. (Review).
Toze CL, Barnett MJ, Naiman SC, Horsman DE. Trisomy 14 is
a non-random karyotypic abnormality associated with myeloi
malignancies. Br J Haematol 1997 Jul;98(1):177-85.
This article should be referenced as such:
Huret JL. +14 or trisomy 14 (solely). Atlas Genet Cytogenet
Oncol Haematol.1997;1(1):21.
Cytogenetics
Cytogenetics, morphological
Most often (90% of cases) in mosaic with normal cells.
Atlas Genet Cytogenet Oncol Haematol. 1997; 1(1)
+14
21
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Leukaemia Section
Short Communication
t(3;12)(q26;p13)
François Desangles
Laboratoire de Biologie, Hôpital du Val de Grâce, 75230 Paris, France
Published in Atlas Database: September 1997
Online version is available at: http://AtlasGeneticsOncology.org/Anomalies/t0312.html
DOI: 10.4267/2042/32033
This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence.
© 1997 Atlas of Genetics and Cytogenetics in Oncology and Haematology
- TEL: cDNA c50F4, c163E7, c148B6 Lawrence
Livermore National Laboratories, Livermore, CA.
Identity
Additional anomalies
del(7q) or -7.
Genes involved and Proteins
MDS1
EVI1
Location: 3q26
t(3;12)(q26;p13) G-banding - Courtesy Jean-Luc Lai and Alain
Vanderhaegen.
ETV6
Location: 12p13
DNA / RNA
9 exons; alternate splicing.
Protein
Contains a Helix-Loop-Helix and ETS DNA binding
domains; wide expression; nuclear localisation; ETSrelated transcription factor.
Clinics and pathology
Disease
Myeloid lineage: MDS in transformation, ANLL, BCCML.
Phenotype / cell stem origin
Multilineage involvement; RAEB → M2, M7 and
others ANLL subtypes.
Epidemiology
Only 8 cases described so far; sex ratio: 3M/1F; age: 387 yrs (med: 40 yrs).
Cytology
Megakaryocytes dysplasia
Prognosis
Very poor; survival often below 1 yr.
References
Golub TR, Barker GF, Lovett M, Gilliland DG. Fusion of PDGF
receptor beta to a novel ets-like gene, tel, in chronic
myelomonocytic
leukemia
with
t(5;12)
chromosomal
translocation. Cell 1994 Apr 22; 77(2):307-16.
Secker-Walker LM, Mehta A, Bain B. Abnormalities of 3q21
and 3q26 in myeloid malignancy: a United Kingdom Cancer
Cytogenetic Group study. Br J Haematol 1995 Oct; 91(2):490501.
Raynaud SD, Baens M, Grosgeorge J, Rodgers K, Reid CD,
Dainton M, Dyer M, Fuzibet JG, Gratecos N, Taillan B, Ayraud
N, Marynen P. Fluorescence in situ hybridization analysis of
t(3; 12)(q26; p13): a recurring chromosomal abnormality
involving the TEL gene (ETV6) in myelodysplastic syndromes.
Blood 1996 Jul 15; 88(2):682-9.
Cytogenetics
Cytogenetics, molecular
Heterogenous breakpoints.
Probes
- EVI1: ly2 and l3 E Parganas, St Jude Children's
Reseach Hospital, Memphis, TN;
- MDS1: P856 G Nucifora, Univ. of Chicago, IL;
- TEL: YAC 958b8 CEPHII Mega-YAC library
Paris, France;
Atlas Genet Cytogenet Oncol Haematol. 1997; 1(1)
This article should be referenced as such:
Desangles F. t(3;12)(q26;p13). Atlas Genet Cytogenet Oncol
Haematol.1997;1(1):22.
22
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Leukaemia Section
Mini Review
t(8;21)(q22;q22)
Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France
Published in Atlas Database: September 1997
Online version is available at: http://AtlasGeneticsOncology.org/Anomalies/t0821.html
DOI: 10.4267/2042/32034
This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence.
© 1997 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
t(8;21)(q22;q22) G-banding (left) - Courtesy Jean-Luc Lai and Alain Vanderhaegen (top) and Diane H. Norback, Eric B. Johnson, Sara
Morrison-Delap Cytogenetics at the Waisman Center (middle and below); R-banding (right) - above: Editor; 2nd row: - Courtesy
Christiane Charrin; 3rd and 4th row: - Courtesy Roland Berger.
Phenotype / cell stem origin
M2 mostly, rarely: M1 or M4.
Epidemiology
Annual incidence: 1/106; 10% of ANLL, 40% of M2
Clinics and pathology
Disease
ANLL
Atlas Genet Cytogenet Oncol Haematol. 1997; 1(1)
23
t(8;21)(q22;q22)
Huret JL
ANLL; the most frequent anomaly in chilhood ANLL;
Seen in children and adults: mean age 30 yrs, rare in
elderly patients; male excess (4M/3F) is much less than
sometimes claimed.
Clinics
Chloromas
Cytology
Numerous and thin Auer rods; eosinophilia of the bone
marrow; CD19 (early B) and CD56 (natural killer) may
be expressed: the cell involved may be an early
progenitor.
Prognosis
CR in most cases (90%); but relapse is frequent, and
median survival -1.5 yrs (adults) to 2 yrs (children)- in
the range with other ANLL in some series, relatively
long median survival, especially in the adults for
others; no adverse effect of additional chromosome
anomalies.
Cytogenetics
Cytogenetics, molecular
Cases with cryptic molecular translocation have been
detected (similar to Ph negative CML with positive
BCR-ABL) → FISH use may be relevant.
Additional anomalies
Sole anomaly in only 20%; additional anomalies:
numerical in 2/3, structural in 1/3; loss of Y or X
chromosome in half cases (1 X must be present),
del(7q) or -7, +8, del(9q): 10% each.
Variants
Complex t(8;21;Var) involving a (variable) third
chromosome have been described in 3%; part from
chromosome 21 goes on der(8), part of the 8 on der
(Var), and part of Var on der(21); therefore, the crucial
event lies on der(8).
Translocation t(8;21) is found in 5-12% of AML. Among the non-random chromosomal aberrations observed in AML, t(8;21)(q22;q22) is
one of the best known and usually correlates with AML M2, with well defined and specific morphological features. The common
morphological features include the presence of large blast cells with abundant basophilic cytoplasm, often containing numerous
azurophilic granulations; few blasts in some cases show very large granules (pseudo-Chediak-Higashi granules), suggesting abnormal
fusion. Auer rods are frequently found. In addition to the large blast cells, there are also some smaller blasts, predominantly found in the
peripheral blood. Promyelocytes, myelocytes and mature granulocytes with variable dysplasia are seen in the bone marrow. These cells
may show abnormal nuclear segmentation and/or cytoplasmic staining defects including homogeneous pink colored cytoplasm Courtesy Georges Flandrin, CD-ROM AML/MDS G. Flandrin/ICG. TRIBVN.
Atlas Genet Cytogenet Oncol Haematol. 1997; 1(1)
24
t(8;21)(q22;q22)
Huret JL
t(8;21)(q22;q22): cohybridization experiments using dJ155L8 (ETO) and dJ1107L6 (AML1); note the splitting of AML1 and colocalization
on der(8) with ETO - Courtesy Mariano Rocchi, Resources for Molecular Cytogenetics. Laboratories willing to validate the probes are
welcome: contact M Rocchi.
Fusion protein
Genes involved and Proteins
Description
The N-term runt domain from AML1 is fused to the
577 C-term residues from ETO; reciprocal product not
detected; probable DNA binding role; the fusion
protein retains the ability to recognize the AML1
concensus binding site → negative dominant
competitor with the normal AML1) and to dimerize
with the CBFb subunit.
Oncogenesis
Probable altered transcriptional regulation of normal
AML1 target genes.
ETO
Location: 8q22
DNA / RNA
Transcription is from telomere to centromere.
Protein
3 proline rich domains, 2 Zn fingers, and in C-term, a
PEST region; tissue restricted expression; nuclear
localisation; putative transcription factor.
AML1
Location: 21q22
DNA / RNA
Transcription is from telomere to centromere.
Protein
Contains a Runt domain and, in the C-term, a
transactivation domain; forms heterodimers; widely
expressed; nuclear localisation; transcription factor
(activator) for various hematopoietic-specific genes.
References
Berger R, Bernheim A, Daniel MT, Valensi F, Sigaux F,
Flandrin G. Cytologic characterization and significance of
normal karyotypes in t(8;21) acute myeloblastic leukemia.
Blood 1982 Jan; 59(1):171-8.
[No authors listed]. Acute myelogenous leukemia with an 8;21
translocation. A report on 148 cases from the Groupe Français
de Cytogénétique Hématologique. Cancer Genet Cytogenet
1990 Feb; 44(2):169-79.
Maseki N, Miyoshi H, Shimizu K, Homma C, Ohki M, Sakurai
M, Kaneko Y. The 8;21 chromosome translocation in acute
myeloid leukemia is always detectable by molecular analysis
using AML1. Blood 1993 Mar 15; 81(6):1573-9.
Ohki M. Molecular basis of the t(8;21) translocation in acute
myeloidleukemia. Semin Cancer Biol 1993 Dec; 4(6):369-75.
(Review).
Nucifora G, Rowley JD. AML1 and the 8;21 and 3;21
translocations in acute and chronic myeloid leukemia. Blood
1995 Jul 1; 86(1):1-14. (Review).
Results of the chromosomal
anomaly
Hybrid gene
Description
5' AML1 - 3' ETO; breakpoints: at the very 5' end of
ETO, between exons 5 and 6 in AML1.
Detection protocol
RT-PCR in cases: 1- of typical cell morphology, but
apparently without the t(8;21); 2- for minimal residual
disease detection.
Atlas Genet Cytogenet Oncol Haematol. 1997; 1(1)
This article should be referenced as such:
Huret JL. t(8;21)(q22;q22). Atlas Genet Cytogenet Oncol
Haematol.1997;1(1):23-25.
25
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Leukaemia Section
Mini Review
t(9;22)(q34;q11) in ALL
Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France
Published in Atlas Database: September 1997
Online version is available at: http://AtlasGeneticsOncology.org/Anomalies/t0922ALL.html
DOI: 10.4267/2042/32035
This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence.
© 1997 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
Note: Although the same hybrid genes issued from ABL and BCR are the hallmark of the t(9;22) translocation, this
translocation may be seen in the following diseases: CML, ANLL, and ALL, and will therefore be described in the 3
different situations: t(9;22)(q34;q11) in CML, t(9;22)(q34;q11) in ALL, t(9;22)(q34;q11) in ANLL.
t(9;22)(q34;q11) in ALL is herein described.
t(9;22)(q34;q11) G-banding (left) - Courtesy Jean-Luc Lai and Alain Vanderhaegen (3 top) and Diane H. Norback, Eric B. Johnson, and
Sara Morrison-Delap, UW Cytogenetic Services (2 bottom); R-banding (right) top: Editor; 2 others Courtesy Jean-Luc Lai and Alain
Vanderhaegen); diagram and breakpoints (Editor).
Atlas Genet Cytogenet Oncol Haematol. 1997; 1(1)
26
t(9;22)(q34;q11) in ALL
Huret JL
Clinics and Pathology
Genes involved and Proteins
Disease
ABL
ALL
Phenotype / cell stem origin
L1 or L2 ALL; most often with B-cell phenotype, rare
T-cell cases; heterogeneity of lineage involvement:
may either be a multipotent stem cell, or a lymphoidcommitted progenitor.
Epidemiology
20% of adult ALL, 2-5% of children ALL.
Clinics
Frequent CNS involvement, even at diagnosis; blood
data: high WBC (50-150 X 109/l).
Cytology
CD10+ in most cases, sometimes CD19+ CD10-.
Treatment
BMT is indicated.
Prognosis
Is very poor, especially in lymphoid-committed
progenitor cases; the breakpoint in M-bcr or in m-bcr
(see below) does not seem to have impact on
prognosis.
Location: 9q34
DNA / RNA
Alternate splicing (1a and 1b) in 5'.
Protein
Giving rise to 2 proteins of 145 kDa; contains SH
(SRC homology) domains; N-term SH3 and SH2 - SH1
(tyrosine kinase) - DNA binding motif - actin binding
domain C-term; widely expressed; localisation is
mainly nuclear; inhibits cell growth.
BCR
Location: 22q11
DNA / RNA
Various splicings.
Protein
Main form: 160 kDa; N-term Serine-Threonine kinase
domain, SH2 binding, and C-term domain which
functions as a GTPase activating protein for p21rac;
widely expressed; cytoplasmic localisation; protein
kinase; probable role in signal transduction.
Cytogenetics
Results of the chromosomal
anomaly
Cytogenetics, morphological
Hybrid gene
The chromosomal anomaly disappears during
remission, in contrast with BC-CML cases when
treated with conventional therapies.
Description
The crucial event lies on der(22), id est 5' BCR/3' ABL
hybrid gene is pathogenic, while ABL/BCR may or
may not be expressed;
- breakpoint in ABL is variable over a region of 200
kb, often between the two alternative exons 1b and 1a,
sometimes 5' of 1b, or 3' of 1a, but always 5' of exon 2;
- breakpoint in BCR is either:
1- in the same region as in CML, called M-bcr (for
major breakpoint cluster region), a cluster of 5.8 kb,
between exons 12 and 16, also called b1 to b5 of Mbcr; most breakpoints being either between b2 and b3,
or between b3 and b4; transcript is 8.5 kb long; this
results in a 210 kDa chimeric protein (P210), with the
first 902 or 927 amino acids from BCR;
2- in a 35 kb region between exons 1 and 2, called mbcr (minor breakpoint cluster region), → 7 kb mRNA,
resulting in a 190 kDa protein (P190), with the 427 Nterminal amino acids from BCR.
Transcript
7 or 8.5 kb.
Cytogenetics, molecular
Is useful to uncover a 'masked Philadelphia'
chromosome, where chromosomes 9 and 22 all appear
to be normal, but where cryptic insertion of 3' ABL
within a chromosome 22 can be demonstrated.
Additional anomalies
Found in 50 to 80% of cases: +der(22), -7, del(7q) most
often, +8, but not an i(17q), in contrast with CML and
ANLL cases; complex karyotypes, often hyperploid,
are frequent.
Variants
t(9;22;V) and apparent t(V;22) or t(9;V), where V is a
variable chromosome, may be found, as in CML.
Atlas Genet Cytogenet Oncol Haematol. 1997; 1(1)
27
t(9;22)(q34;q11) in ALL
Huret JL
Fusion protein
To be noted
Description
190 or 210 kDa (see diagram);
BCR/ABL has a cytoplasmic localization, in contrast
with ABL, mostly nuclear; this may have a
carcinogenetic role.
The hybrid protein has an increased protein kinase
activity compared to ABL: 3BP1 (binding protein)
binds normal ABL on SH3 domain, which prevents
SH1 activation; with BCR/ABL, the first (N-terminal)
exon of BCR binds to SH2, hidding SH3 which, as a
consequence, cannot be bound to 3BP1; thereof, SH1 is
activated.
Oncogenesis
1-Proliferation is induced: there is activation by
BCR/ABL of Ras signal transduction pathway via it's
linkage to son-of-sevenless (SOS), a Ras activator;
PI3-K (phosphatidyl inositol 3' kinase) pathway is also
activated; MYC as well;
2-BCR/ABL inhibits apoptosis;
3-BCR/ABL provokes cell adhesive abnormalities:
impaired adherence to bone marrow stroma cells,
which allows unregulated proliferation of leukaemic
progenitors.
Atlas Genet Cytogenet Oncol Haematol. 1997; 1(1)
Blast crisis is sometimes at the first onset of CML, and
those cases may be undistinguishable from true ALL
with t(9;22) and P210 BCR/ABL hybrid.
References
Heisterkamp N, Groffen J. Molecular insights into the
Philadelphia translocation. Hematol Pathol 1991; 5(1):1-10.
(Review).
Kurzrock R, Talpaz M. The molecular pathology of chronic
myelogenous leukemia. Br J Haematol 1991 Oct; 79 Suppl
1:34-7. (Review).
Secker-Walker LM, Craig JM. Prognostic implications of
breakpoint and lineage heterogeneity in Philadelphia-positive
acute lymphoblastic leukemia: a review. Leukemia 1993 Feb;
7(2):147-51. (Review).
Gotoh A, Broxmeyer HE. The function of BCR/ABL and related
proto-oncogenes. Curr Opin Hematol 1997 Jan; 4(1):3-11.
(Review).
This article should be referenced as such:
Huret JL. t(9;22)(q34;q11) in ALL. Atlas Genet Cytogenet
Oncol Haematol.1997;1(1):26-28.
28
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Leukaemia Section
Mini Review
t(9;22)(q34;q11) in ANLL
Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France
Published in Atlas Database: September 1997
Online version is available at: http://AtlasGeneticsOncology.org/Anomalies/t0922ANL.html
DOI: 10.4267/2042/32036
This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence.
© 1997 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
Note: Although the same hybrid genes issued from ABL and BCR are the hallmark of the t(9;22) translocation, this
translocation may be seen in the following diseases: CML, ANLL, and ALL, and will therefore be described in the 3
different situations: t(9;22)(q34;q11) in CML, t(9;22)(q34;q11) in ALL, t(9;22)(q34;q11) in ANLL.
t(9;22)(q34;q11) in ANLL is herein described.
t(9;22)(q34;q11) G-banding (left) - Courtesy Jean-Luc Lai and Alain Vanderhaegen (3 top) and Diane H. Norback, Eric B. Johnson, and
Sara Morrison-Delap, UW Cytogenetic Services (2 bottom); R-banding (right) top: Editor; 2 others Courtesy Jean-Luc Lai and Alain
Vanderhaegen); diagram and breakpoints (Editor).
Atlas Genet Cytogenet Oncol Haematol. 1997; 1(1)
29
t(9;22)(q34;q11) in ANLL
Huret JL
DNA / RNA
Various splicings.
Protein
Main form: 160 kDa; N-term Serine-Treonine kinase
domain, SH2 binding, and C-term domain which
functions as a GTPase activating protein for p21rac;
widely expressed; cytoplasmic localisation;
Protein kinase; probable role in signal transduction.
Clinics and pathology
Disease
ANLL
Phenotype / cell stem origin
Mostly M1 or M2 ANLL.
Epidemiology
3% of ANLL; 1% in childhood ANLL.
Prognosis
Is very poor.
Results of the chromosomal
anomaly
Cytogenetics
Hybrid gene
Description
The crucial event lies on der(22), id est 5' BCR/3' ABL
hybrid gene is pathogenic, while ABL/BCR may or
may not be expressed;
Breakpoint in ABL is variable over a region of 200 kb,
often between the two alternative exons 1b and 1a,
sometimes 5' of 1b, or 3' of 1a, but always 5' of exon 2;
Breakpoint in BCR is either (as in ALL cases):
1- in the same region as in CML, called M-bcr (for
major breakpoint cluster region), a cluster of 5.8 kb,
between exons 12 and 16, also called b1 to b5 of Mbcr; most breakpoints being either between b2 and b3,
or between b3 and b4; transcript is 8.5 kb long; this
results in a 210 kDa chimeric protein (P210), with the
first 902 or 927 amino acids from BCR;
2- in a 35 kb region between exons 1 and 2, called mbcr (minor breakpoint cluster region), → 7 kb mRNA,
resulting in a 190 kDa protein (P190), with the 427 Nterminal amino acids from BCR.
Transcript
7 or 8.5 kb
Cytogenetics, morphological
The chromosomal anomaly disappears during
remission, in contrast with BC-CML cases when
treated with conventional therapies.
Genes involved and Proteins
ABL
Location: 9q34
DNA / RNA
Alternate splicing (1a and 1b) in 5'.
Protein
Giving rise to 2 proteins of 145 kDa; contains SH
(SRC homology) domains; N-term SH3 and SH2 - SH1
(tyrosine kinase) - DNA binding motif - actin binding
domain C-term; widely expressed; localisation is
mainly nuclear; inhibits cell growth.
BCR
Location: 22q11
Atlas Genet Cytogenet Oncol Haematol. 1997; 1(1)
30
t(9;22)(q34;q11) in ANLL
Huret JL
which allows unregulated proliferation of leukaemic
progenitors.
Fusion protein
Description
190 or 210 kDa (see diagram); BCR/ABL has a
cytoplasmic localization, in contrast with ABL, mostly
nuclear; this may have a carcinogenetic role. The
hybrid protein has an increased protein kinase activity
compared to ABL: 3BP1 (binding protein) binds
normal ABL on SH3 domain, which prevents SH1
activation; with BCR/ABL, the first (N-terminal) exon
of BCR binds to SH2, hidding SH3 which, as a
consequence, cannot be bound to 3BP1; thereof, SH1 is
activated.
Oncogenesis
1-Proliferation is induced: there is activation by
BCR/ABL of Ras signal transduction pathway via it's
linkage to son-of-sevenless (SOS), a Ras activator;
PI3-K (phosphatidyl inositol 3' kinase) pathway is also
activated; MYC as well;
2-BCR/ABL inhibits apoptosis;
3-BCR/ABL provokes cell adhesive abnormalities:
impaired adherence to bone marrow stroma cells,
Atlas Genet Cytogenet Oncol Haematol. 1997; 1(1)
To be noted
Blast crisis is sometimes at the first onset of CML, and
those cases may be undistinguishable from true ANLL
with t(9;22) and P210 BCR/ABL hybrid.
References
Heisterkamp N, Groffen J. Molecular insights into the
Philadelphia translocation. Hematol Pathol 1991; 5(1):1-10.
(Review).
Kurzrock R, Talpaz M. The molecular pathology of chronic
myelogenous leukemia. Br J Haematol 1991 Oct; 79 Suppl
1:34-7. (Review).
Gotoh A, Broxmeyer HE. The function of BCR/ABL and related
proto-oncogenes. Curr Opin Hematol 1997 Jan; 4(1):3-11.
(Review).
This article should be referenced as such:
Huret JL. t(9;22)(q34;q11) in ANLL. Atlas Genet Cytogenet
Oncol Haematol.1997;1(1):29-31.
31
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Solid Tumour Section
Mini Review
Bladder cancer
Jean-Loup Huret, Claude Léonard
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France
(JLH)
Cytogénétique, Laboratoire d'Anatomo Pathologie, CHU Bicêtre, 78 r Leclerc, F94270 Le Kremlin-Bicêtre,
France (CL)
Published in Atlas Database: August 1997
Online version is available at: http://AtlasGeneticsOncology.org/Tumours/blad5001.html
DOI: 10.4267/2042/32037
This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence.
© 1997 Atlas of Genetics and Cytogenetics in Oncology and Haematology
- graded by the degree of cellular atypia (G0→ G3),
and;
- staged: pTIS carcinoma in situ (but high grade), and
pTa papillary carcinoma, both mucosally confined;
pT1 lamina propria invasive; pT2 infiltrates the
superficial muscle, and pT3a, the deep muscle; pT3b
invasion into perivesical fat; pT4 extends into
neighbouring structures and organs.
Treatment
Resection (more or less extensive: electrofulguration
→ cystectomy); chemo and/or radiotherapy, BCGtherapy.
Evolution
Recurrence is highly frequent.
Prognosis
According to the stage and the grade; pTa is of good
prognosis (> 90% are cured); prognosis is uncertain in
pT1 and G2 tumours, where cytogenetic findings may
be relevant prognostic indicators. 20% survival at 1 yr
(stable at 3 yrs) is found in T4 cases; however,
identification of individual patient's prognosis is often
difficult, although of major concern for treatment
decision and for follow up.
Classification
Existence of different histologic types.
Very rare types are:
- Squamous cell carcinoma (5%);
- Adenocarcinoma (2%);
- The most frequent, representing 90-95 % of cases is
transitional cell carcinoma of the bladder, herein
described.
Clinics and pathology
Disease
Cancer of the urothelium
Epidemiology
Annual incidence: 250/106, 2% of cancers, the fourth
cancer in males, the seventh in females, 3M/1F; occurs
mainly in the 6th-8th decades of life; risk factors:
cigarette smoking and occupational exposure (aniline,
benzidine, naphtylamine); 20 to 30 yrs latency after
exposure.
Clinics
Hematuria, irritation.
Pathology
Grading and staging: tumours are:
Atlas Genet Cytogenet Oncol Haematol. 1997; 1(1)
32
Bladder cancer
Huret JL, Léonard C
paints/comparative genomic hybridization (CGH)
should prove useful tools; flow cytometry for DNA
index measurement has often been used, but appears to
be a ‘blind’ method.
Cytogenetics
Cytogenetics, morphological
Highly complex and diverse, but non-random.
-9: monosomy 9 is frequent (about 50% of cases, and
can be the only anomaly; found also in early stages; not
associated with tumour progression; loss of
heterozygocity (LOH): critical deletion segments are in
9p21 and somewhere in 9q; gensolin could be
implicated.
-11 or del(11p): are frequent; associated with high
stages and tumour progression.
del(17p) and LOH at 17p: also frequent; mainly found
in pT2 to pT4; also found in a subset of pTIS, which
might be a relevant indicator for these tumours with
variable but often poor prognostic; the deletion involve
P53.
del(13q) and Rb loss are corrrelated with the stage.
+7: often found, but the same occurs in a number of
cancers of various origin; may have no pertinence,
inasmuch as +7 has also been found in normal (i.e. non
tumoural) cells!
Mar, aneuploidy, polyploidy, complex karyotypes:
are bad prognostic features.
del(3p), del(5q) and i(5p), del(6q), del(8p), del(14q)
and del(18q) are also consistantly found; these LOH
point to probable tumour suppression genes, which
could be implicated in tumour progression.
Genes involved and Proteins
Note: as the process is multistep, genes involved in
transitional cell carcinoma of the bladder should be
numerous; most are still unknown; some are quoted
above.
References
Sandberg AA, Berger CS. Review of chromosome studies in
urological tumors. II. Cytogenetics and molecular genetics of
bladder cancer. J Urol 1994; 151:545-560.
Sauter G, Moch H, Wagner U, Novotna H, Gasser TC,
Mattarelli G, Mihatsch MJ, Waldman FM. Y chromosome loss
detected by FISH in bladder cancer. Cancer Genet Cytogenet
1995; 82:163-169.
Voorter C, Joos S, Bringuier PP, Vallinga M, Poddighe P,
Schalken J, du Manoir S, Ramaekers F, Lichter P, Hopman A.
Detection of chromosomal imbalances in transitional cell
carcinoma of the bladder by comparative genomic
hybridization. Am J Pathol 1995; 146:1341-1354.
Gibas Z, Gibas L. Cytogenetics of bladder cancer. Cancer
Genet Cytogenet 1997; 95:108-115.
This article should be referenced as such:
Huret JL, Léonard C. Bladder cancer. Atlas Genet Cytogenet
Oncol Haematol.1997;1(1):32-33.
Cytogenetics, molecular
Interphase cytogenetics using whole chromosome
Atlas Genet Cytogenet Oncol Haematol. 1997; 1(1)
33
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Cancer Prone Disease Section
Mini Review
Naevoid basal cell carcinoma syndrome (NBCS)
Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France
Published in Atlas Database: September 1997
Online version is available at: http://AtlasGeneticsOncology.org/Kprones/NBC10005.html
DOI: 10.4267/2042/32038
This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence.
© 1997 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Evolution
Extensive number of basal cell carcinomas.
Prognosis
According to the tumours (basal cell carcinomas are
not life threatening, but may be devastating).
Identity
Other names: Gorlin syndrome; Gorlin-Goltz
syndrome; Multiple basal cell nevi, odontogenic
keratocysts, skeletal anomalies; Fifth phacomatosis;
Hydrocephalus, costovertebral dysplasia, sprengel
anomaly.
Inheritance: autosomal dominant with complete
penetrance, but variable expressivity; 40% are de novo
mutations; frequency is about 2/105 newborns.
Cytogenetics
Inborn condition
Spontaneous and induced chromosome instability.
Delay in the cell cycle.
NBCS is therefore a chromosome instability syndrome.
Clinics
NBCS is a hamartoneoplastic syndrome; it is also a
chromosome instability syndrome; hamartomas are
localized
tissue
proliferations
with
faulty
differenciation and mixture of component tissues; they
are heritable malformations that have a potential
towards neoplasia.
Phenotype and clinics
Multiple basal cell carcinomas, appearing as early as
15 yrs;
Jaw keratocysts;
Dyskeratotic palmar/plantar pits;
Skeletal malformations (of ribs, spina bifida occulta...);
Soft tissue calcifications (falx cerebri, ovarian fibroma,
diaphragma sellae...);
Facial dysmorphia.
Neoplastic risk
Mainly multiple basal cell carcinomas;
Other proliferations (see below) in 60% of patients;
Other malignancies: medulloblastoma, ovarian
fibrosarcoma;
Benign proliferations: ovarian fibroma, meningioma,
rhabdomyoma, cardiac fibroma.
Treatment
Tumour exereses.
Atlas Genet Cytogenet Oncol Haematol. 1997; 1(1)
Cancer cytogenetics
Poorly documented.
Genes involved and Proteins
Complementation groups
None so far.
PTCH
Location: in 9q22.3 (between FACC and XPAC!!)
Protein
Description: glycoprotein with transmembrane
domains, extra cellular loops and intracellular domains.
Localisation: transmembrane protein.
Function: part of a signalling pathway; probable cell
to cell adhesion role; may have a repressive activity on
cell proliferation; as NBCS syndrome is a chromosome
instability syndrome, this protein may have a role in
DNA maintenance, repair and/or replication.
Mutations
Germinal: most germ-line mutations in NBCS patients
lead to protein truncation, which suggests that
developmental anomalies seen in NBCS may be due to
haplo-insufficiency; no obvious genotype-phenotype
correlations.
34
Naevoid basal cell carcinoma syndrome (NBCS)
Huret JL
Hahn H, Christiansen J, Wicking C, Zaphiropoulos PG,
Chidambaram A, Gerrard B, Vorechovsky I, Bale AE, Toftgard
R, WainwrightB, Dean M. A mammalian patched homolog is
expressed in target tissues of sonic hedgehog and maps to a
region associated with developmental abnormalities. J Biol
Chem 1996; 271:12125-12128.
Hahn H, Wicking C, Zaphiropoulos PG, Gailani MA, Shanley S,
Chidambaram A, Vorechovsky I, Holmberg E, Unden AB,
Gillies S, Negus K, Smyth I, Pressman C, Leffel DJ, Gerrard B,
Goldstein AM, Dean M, Toftgard R, Chenevix-Trench G,
Wainwright B, Bale AE. Mutations of the human homolog of
Drosophila patched in the nevoid basal cell carcinoma
syndrome. Cell 1996; 85:841-851.
Johnson R. Human homolog of patched, a candidate gene for
the basal cell nevus syndrome. Science 1996; 272:1668-1671.
Wicking C, Shanley S, Smyth I, Gillies S, Negus K, Graham S,
Suthers G, Haites N, Edwards M, Wainwright B, ChenevixTrench G. Most germ-line mutations in the nevoid basal cell
carcinoma syndrome lead to a premature tremination of the
patched protein, and no genotype-phenotype correlations are
evident. Am Hum Genet 1997; 60:21-26.
Shafei-Benaissa E, Savage JRK, Babin P, Larrègue M,
Papworth D, Tanzer J, Bonnetblanc JM, Huret JL. The naevoid
basal-cell carcinoma syndrome (Gorlin syndrome) is a
chromosomal instability syndrome. Mutat Res 1998 Feb 2;
397(2):287-92.
Somatic: mutation and allele loss events in basal cell
carcinoma, in NBCS and in sporadic basal cell
carcinoma are, so far, in accordance with the two-hit
model for neoplasia, as is found in retinoblastoma.
References
Gorlin RJ, Cohen MM, Levin LS. Syndromes of the head and
neck. Oxford Monogr Med Genet 1990; 19:372-380.
Tabata T, Eaton SE, Kornberg TB. The Drosophila hedgehog
gene is expressed specifically in posterior compartment cells
and is a target of engrailed regulation. Gene Dev 1992;
6:2635-2645.
Evans DGR, Ladusans EJ, Rimmer S, Brunell LD, Thakker N,
Farndon PA. Complications of the naevoid basal cell
carcinoma syndrome : results of a population based study. J
Med Genet 1993; 30:460-464.
Basler K, Struhl G. Compartment boundaries and the control of
Drosophila limb pattern by hedgehog protein. Nature 1994;
368:208-214.
Capdevila J, Estrada MP, Sánchez-Herrero E, Guerrero I. The
drosophila segment polarity gene patched interacts with
decapenta plegic in wing development. EMBO J 1994; 13:7182.
Gailani MR, Stǻhle-Bäckdahl M, Leffell DJ, Glynn M,
Zaphiropoulos PG, Pressman C, Undén AB, Dean M,Brash
DE, Bale AE, Toftgǻrd R. The role of the human homologue of
Drosophila patched in sporadic basal cell carcinomas. Nature
Genetics 1996; 14:78-81.
Atlas Genet Cytogenet Oncol Haematol. 1997; 1(1)
This article should be referenced as such:
Huret JL. Naevoid basal cell carcinoma syndrome (NBCS).
Atlas Genet Cytogenet Oncol Haematol.1997;1(1):34-35.
35
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Cancer Prone Disease Section
Mini Review
Neurofibromatosis type 1 (NF1)
Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France
Published in Atlas Database: September 1997
Online version is available at: http://AtlasGeneticsOncology.org/Kprones/NF1ID10006.html
DOI: 10.4267/2042/32039
This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence.
© 1997 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Mental retardation in 10 %; learning diabilities in half
patients;
Sexual precocity and other endocrine anomalies;
Hypertension (renal artery stenosis).
Neoplastic risk
5% of NF1 patients experience a malignant neoplasm
Neurofibromas, especially the plexiform variety;
polyclonal (benign) proliferation; may be present at
birth or appear later, may be a few or thousands, small
or enormous, occur in the skin and in various tissus and
organs; neurofibromas localized to the spine are
extremely difficult to manage.
Neurofibrosarcomatous transformation (malignant) of
these in 5-10 %.
Schwannomas (optic nerve, see above), meningiomas,
astrocytomas, ependymomas.
Childhood MDS (myelodysplasia) and ANLL, often
with monosomy 7 (monosomy 7 syndrome, 'juvenile
myelomonocytic leukaemia'): risk, increased by X 200
to 500, is still low, as childhood MDS is rare; M > F;
most often before the age of 5 yrs; no increased risk of
leukaemia in the adult.
Pheochromocytomas.
Various
other
neoplasias,
of
which
are
rhabdomyosarcomas.
Identity
Other names: Von Recklinghausen neurofibromatosis;
Peripheral neurofibromatosis
Inheritance: autosomal dominant with almost
complete penetrance; frequency is 30/105 newborns
(and 1 of 200 mentally handicapped persons): one of
the most frequent genetically inheritable disease;
neomutation in 50%, mostly from the paternal allele;
highly variable expressivity, from very mild to very
severe; expressivity is also age-related.
Clinics
NF1 is a hamartoneoplastic syndrome; hamartomas are
localized
tissue
proliferations
with
faulty
differentiation and mixture of component tissues; they
are heritable malformations that have a potential
towards neoplasia.
The embryonic origin of dysgenetic tissues involved in
NF1 is ectoblastic.
Phenotype and clinics
Diagnosis is made on the ground of at least 2 of the
following:
Café-au-lait spots (6 or more, over 0.5 cm of diameter
(in pre-puberty));
2 or more neurofibromas or 1 plexiform neurofibromas
(mainly cutaneous);
2 or more Lisch nodules (melanocytic hamartomas of
the iris);
Freckling in the axillary/inguinal region (Crowe's
sign);
Glioma of the optic nerve;
Distinctive bone anomalies (scoliosis, pseudoarthroses,
bony defects (orbital wall)...);
Positive family history.
Other features:
Macrocephaly;
Epilepsy;
Atlas Genet Cytogenet Oncol Haematol. 1997; 1(1)
Treatment
Early diagnosis, lifetime monitoring and surgery are
essential.
Cytogenetics
Inborn condition
No special feature.
Cancer cytogenetics
According to the cancer type in most cases.
Myelodysplasia and ANLL: monosomy 7.
36
Neurofibromatosis type 1 (NF1)
Huret JL
Genes involved and Proteins
References
NF1
NIH Consensus Development Conference. Arch Neurol 1988;
45: 575.
Huson SM, Compston DA, Clark P, Harper PS. A genetic study
of von Recklinghausen neurofibromatosis in south east Wales.
I. Prevalence, fitness, mutation rate, and effect of parental
transmission on severity. J Med Genet 1989 Nov;26(11):704711.
Kaneko Y, Maseki N, Sakurai M, Shibuya A, Shinohara T,
Fujimoto T, Kanno H, Nishikawa A. Chromosome pattern in
juvenile chronic myelogenous leukemia, myelodysplastic
syndrome,
and
acute
leukemia
associated
with
neurofibromatosis. Leukemia 1989 Jan; 3(1):36-41.
Gorlin RJ, Cohen MM, Levin LS. Syndromes of the head and
neck. Oxford Monogr Med Genet 1990;19:392-399.
Henry I. médecine/sciences 1995; 11: 93.
Metheny LJ, Cappione AJ, Skuse GR. Genetic and epigenetic
mechanisms in the pathogenesis of neurofibromatosis type I. J
Neuropathol Exp Neurol 1995 Nov;54(6):753-760.
Gutmann DH, Aylsworth A, Carey JC, Korf B, Marks J, Pyeritz
RE, Rubenstein A, Viskochil D. The diagnostic evaluation and
multidisciplinary management of neurofibromatosis 1 and
neurofibromatosis 2. JAMA 1997 Jul 2; 278(1):51-57.
Location: 17q11.2
Protein
Description: the protein has been called
neurofibromin; GTPase activating protein; tumour
suppressor.
Mutations
Germinal: nucleotide substitutions, small deletions or
insertions on one allele.
Somatic: the second allele remains normal in the
benign tumours and is often lost in the malignant
tumours.
To be noted
Beside neurofibromatoses 1 and 2 (NF2), other types
of neurofibromatoses are numbered and named 3 to 9,
some of them being known to involve other loci.
This article should be referenced as such:
Huret JL. Neurofibromatosis type 1 (NF1). Atlas Genet
Cytogenet Oncol Haematol.1997;1(1):36-37.
Atlas Genet Cytogenet Oncol Haematol. 1997; 1(1)
37
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Cancer Prone Disease Section
Mini Review
Neurofibromatosis type 2 (NF2)
Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France
Published in Atlas Database: September 1997
Online version is available at: http://AtlasGeneticsOncology.org/Kprones/NF2Kpr10007.html
DOI: 10.4267/2042/32040
This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence.
© 1997 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
Cytogenetics
Other names: Central neurofibromatosis; Bilateral
acoustic
neurofibromatosis;
Bilateral
acoustic
neurinoma; Bilateral acoustic schwannomas
Inheritance: autosomal dominant with almost
complete penetrance; frequency is 3/105 newborns;
neomutation represent 50% of cases; variable
expressivity from mild disease through life (Gardner
type) to severe condition at young age (Wishart type:
with more than 3 tumours).
Inborn condition
Normal.
Cancer cytogenetics
Chromosome 22 loss is very frequent both in sporadic
and in NF2 schwannomas and meningiomas.
Genes involved and Proteins
SCH
Clinics
Location: 22q12.1-12.2 junction, (incidentally not far
from EWS (Ewing tumour))
DNA/RNA
Description: 16 exons; 120 kb.
Transcription: alternate splicing after exon 15.
Protein
Protein has been called schwannomin or SCH.
Description: 590 or 595 amino acids; 66 kDa;
domains: NH2 -- membrane binding -- a helix binding
to actin of the cytoskeleton -- COOH.
Expression: in lung, kidney, ovary, breast, placenta,
neuroblasts.
Function: membrane-cytoskeleton anchor (as APC
also appears to be); has characteristics of a tumour
suppressor, as has been found in sporadic as well as
NF2 induced schwannomas and meningiomas
(accordingly to the Rb model).
Homology ezrin, radixin, moesin, members of the
erythrocytes band 4.1 family, especially so in the Nterm.
Mutations
Germinal: (inborn condition of NF2 patients): protein
truncations due to various frameshift deletions or
insertions or nonsense mutations; splice-site or
missense mutations are also found; phenotypegenotype correlations are observed (i.e. that severe
NF2 is an hamartoneoplastic syndrome; hamartomas
are localized tissue proliferations with faulty
differenciation and mixture of component tissues; they
are heritable malformations that have a potential
towards neoplasia.
Phenotype and clinics
Bilateral vestibular (8th cranial pair) schwannomas;
other central or peripheral nerve schwannomas;
meningiomas; ependymomas.
Hearing loss (average age 20 yrs), tinnitus, imbalance,
headache, cataract in 50%, facial paralysis.
Café-au-lait spots and cutaneous and peripheral
neurofibromas may be present, but far less extensively
than in neurofibromatosis type 1.
Neoplastic risk
NF2 cases represent about 5 % of schwannomas and
meningiomas (i.e. risk increased by 2000), appearing at
the age of 20, while they are found in the general
population at the age of 50 and over.
Prognosis
These tumours are usually benign, but their location
within the central nervous system gives them a grave
prognosis; patients with the Wishart severe form
usually do not survive past 50 yrs.
Atlas Genet Cytogenet Oncol Haematol. 1997; 1(1)
38
Neurofibromatosis type 2 (NF2)
Huret JL
Marineau C, Mérel P, Rouleau GA, Thomas G. Le gène de la
neurofibromatose de type 2. Médecine/sciences 1995; 11:3542. (Review). French.
Parry DM, MacCollin MM, Kaiser-Kupfer MI, Pulaski K,
Nicholson HS, Bolesta M, Eldridge R, Gusella JF. Germ-line
mutations in the neurofibromatosis 2 gene: correlations with
disease severity and retinal abnormalities. Am J Hum Genet
1996 Sep; 59(3):529-39.
Ruttledge MH, Andermann AA, Phelan CM, Claudio JO, Han
FY, Chretien N, Rangaratnam S, MacCollin M, Short P, Parry
D, Michels V, Riccardi VM, Weksberg R, Kitamura K, Bradburn
JM, Hall BD, Propping P, Rouleau GA. Type of mutation in the
neurofibromatosis type 2 gene (NF2) frequently determines
severity of disease. Am J Hum Genet 1996 Aug; 59(2):331-42.
phenotypes are found in cases with protein truncations
rather than those with amino acid substitution).
Somatic: tumourigenesis in NF2 patients.
References
Neurofibromatosis. Conference statement. National Institutes
of Health Consensus Development Conference. Arch Neurol
1988 May; 45(5):575-8.
Gorlin RJ, Cohen MM, Levin LS. Syndromes of the head and
neck. Oxford Monogr Med Genet 1990;19:392-399.
Rouleau GA, Merel P, Lutchman M, Sanson M, Zucman J,
Marineau C, Hoang-Xuan K, Demczuk S, Desmaze C,
Plougastel B, et al. Alteration in a new gene encoding a
putative membrane-organizing protein causes neurofibromatosis type 2. Nature 1993 Jun 10; 363(6429):515-21.
Parry DM, Eldridge R, Kaiser-Kupfer MI, Bouzas EA, Pikus A,
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