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Volume 1 - Number 1 May - September 1997
Volume 21 - Number 12 December 2017
The PDF version of the Atlas of Genetics and Cytogenetics in Oncology and Haematology is a reissue of the original articles published in collaboration with
the Institute for Scientific and Technical Information (INstitut de l’Information Scientifique et Technique - INIST) of the French National Center for Scientific
Research (CNRS) on its electronic publishing platform I-Revues.
Online and PDF versions of the Atlas of Genetics and Cytogenetics in Oncology and Haematology are hosted by INIST-CNRS.
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
INIST-CNRS
OPEN ACCESS JOURNAL
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 is made for and by: clinicians and researchers in cytogenetics, molecular biology, oncology, haematology, and pathology.
One main scope of the Atlas is to conjugate the scientific information provided by cytogenetics/molecular genetics to the
clinical setting (diagnostics, prognostics and therapeutic design), another is to provide an encyclopedic knowledge in cancer
genetics. The Atlas deals with cancer research and genomics. It is at the crossroads of research, virtual medical university
(university and post-university e-learning), and telemedicine. It contributes to "meta-medicine", this mediation, using
information technology, between the increasing amount of knowledge and the individual, having to use the information.
Towards a personalized medicine of cancer.
It presents structured review articles ("cards") on:
1- Genes,
2- Leukemias,
3- Solid tumors,
4- Cancer-prone diseases, and also
5- "Deep insights": more traditional review articles on the above subjects and on surrounding topics.
It also present
6- Case reports in hematology and
7- Educational items in the various related topics for students in Medicine and in Sciences.
The Atlas of Genetics and Cytogenetics in Oncology and Haematology does not publish research articles.
See also: http://documents.irevues.inist.fr/bitstream/handle/2042/56067/Scope.pdf
Editorial correspondance
Jean-Loup Huret, MD, PhD,
Genetics, Department of Medical Information,
University Hospital
F-86021 Poitiers, France
phone +33 5 49 44 45 46
jlhuret@AtlasGeneticsOncology.org
Editor, Editorial Board and Publisher See:http://documents.irevues.inist.fr/bitstream/handle/2042/48485/Editor-editorial-board-and-publisher.pdf
The Atlas of Genetics and Cytogenetics in Oncology and Haematology is published 12 times a year by ARMGHM, a non
profit organisation, and by the INstitute for Scientific and Technical Information of
the French National Center for Scientific Research (INIST-CNRS) since 2008.
The Atlas is hosted by INIST-CNRS (http://www.inist.fr)
Staff: Vanessa Le Berre
Philippe Dessen is the Database Directorof the on-line version (Gustave Roussy Institute – Villejuif – France).
Publisher Contact: INIST-CNRS
Mailing Address: Catherine Morel, 2,Allée du Parc de Brabois, CS 10130, 54519 Vandoeuvre-lès-Nancy France.
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© ATLAS - ISSN 1768-3262
Atlas Genet Cytogenet Oncol Haematol. 2017; 21(12)
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
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Editor-in-Chief Jean-Loup Huret (Poitiers, France) Lymphomas Section Editor Antonino Carbone (Aviano, Italy)
Myeloid Malignancies Section Editor Robert S. Ohgami (Stanford, California)
Bone Tumors Section Editor Judith Bovee (Leiden, Netherlands)
Head and Neck Tumors Section Editor Cécile Badoual (Paris, France)
Urinary Tumors Section Editor Paola Dal Cin (Boston, Massachusetts)
Pediatric Tumors Section Editor Frederic G. Barr (Bethesda, Maryland)
Cancer Prone Diseases Section Editor Gaia Roversi (Milano, Italy)
Cell Cycle Section Editor João Agostinho Machado-Neto (São Paulo, Brazil)
DNA Repair Section Editor Godefridus Peters (Amsterdam, Netherlands)
Hormones and Growth factors Section Editor Gajanan V. Sherbet (Newcastle upon Tyne, UK)
Mitosis Section Editor Patrizia Lavia (Rome, Italy)
WNT pathway Section Editor Alessandro Beghini (Milano, Italy)
B-cell activation Section Editors Anette Gjörloff Wingren and Barnabas Nyesiga (Malmö,
Sweden)
Oxidative stress Section Editor Thierry Soussi (Stockholm, Sweden/Paris, France)
Board Members
Sreeparna Banerjee Department of Biological Sciences, Middle East Technical University, Ankara, Turkey; banerjee@metu.edu.tr
Alessandro
Beghini Department of Health Sciences, University of Milan, Italy; alessandro.beghini@unimi.it
Judith Bovée 2300 RC Leiden, The Netherlands; j.v.m.g.bovee@lumc.nl
Antonio Cuneo Dipartimento di ScienzeMediche, Sezione di Ematologia e Reumatologia Via Aldo Moro 8, 44124 - Ferrara, Italy;
antonio.cuneo@unife.it
Paola Dal Cin Department of Pathology, Brigham, Women's Hospital, 75 Francis Street, Boston, MA 02115, USA; pdalcin@partners.org
François Desangles IRBA, Departement Effets Biologiques des Rayonnements, Laboratoire de Dosimetrie Biologique des Irradiations, Dewoitine C212,
91223 Bretigny-sur-Orge, France; francoisdesangles@hotmail.com
Enric Domingo Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, Roosevelt Dr. Oxford, OX37BN, UK
enric@well.ox.ac.uk
Ayse Elif Erson-
Bensan Department of Biological Sciences, Middle East Technical University, Ankara, Turkey; erson@metu.edu.tr
Ad Geurts van
Kessel
Department of Human Genetics, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, 6500 HB
Nijmegen, The Netherlands; ad.geurtsvankessel@radboudumc.nl
Oskar A. Haas Department of Pediatrics and Adolescent Medicine, St. Anna Children's Hospital, Medical University Vienna, Children's Cancer
Research Institute Vienna, Vienna, Austria. oskar.haas@stanna.at
Anne Hagemeijer Center for Human Genetics, University Hospital Leuven and KU Leuven, Leuven, Belgium; annemarie.hausman@kuleuven.be
Nyla Heerema Department of Pathology, The Ohio State University, 129 Hamilton Hall, 1645 Neil Ave, Columbus, OH 43210, USA;
nyla.heerema@osumc.edu
Sakari Knuutila Hartmann Institute and HUSLab, University of Helsinki, Department of Pathology, Helsinki, Finland; sakari.knuutila@helsinki.fi
Lidia Larizza Lab Centro di Ricerche e TecnologieBiomedicheIRCCS-IstitutoAuxologico Italiano Milano, Italy; l.larizza@auxologico
Roderick Mc Leod Department of Human, Animal Cell Lines, Leibniz-Institute DSMZ-German Collection of Microorganisms, Cell Cultures, Braunschweig,
Germany; roderick.macleod@dsmz.de
Cristina Mecucci Hematology University of Perugia, University Hospital S.Mariadella Misericordia, Perugia, Italy; cristina.mecucci@unipg.it
Fredrik Mertens Department of Clinical Genetics, University and Regional Laboratories, Lund University, SE-221 85 Lund, Sweden;
fredrik.mertens@med.lu.se
Konstantin Miller Institute of Human Genetics, Hannover Medical School, 30623 Hannover, Germany; miller.konstantin@mh-hannover.de
Felix Mitelman Department of Clinical Genetics, University and Regional Laboratories, Lund University, SE-221 85 Lund, Sweden;
felix.mitelman@med.lu.se
Hossain Mossafa Laboratoire CERBA, 95066 Cergy-Pontoise cedex 9, France; hmossafa@lab-cerba.com
Stefan Nagel Department of Human, Animal Cell Lines, Leibniz-Institute DSMZ-German Collection of Microorganisms, Cell Cultures, Braunschweig,
Germany; stefan.nagel@dsmz.de
Florence Pedeutour Laboratory of Solid Tumors Genetics, Nice University Hospital, CNRSUMR 7284/INSERMU1081, France; florence.pedeutour@unice.fr
Susana Raimondi Department of Pathology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Mail Stop 250, Memphis, Tennessee 38105-
3678, USA; susana.raimondi@stjude.org
Clelia Tiziana
Storlazzi Department of Biology, University of Bari, Bari, Italy; cleliatiziana.storlazzi@uniba.it
Sabine Strehl CCRI, Children's Cancer Research Institute, St. Anna Kinderkrebsforschunge.V., Vienna, Austria; sabine.strehl@ccri.at
Nancy Uhrhammer Laboratoire Diagnostic Génétique et Moléculaire, Centre Jean Perrin, Clermont-Ferrand, France; nancy.uhrhammer@cjp.fr
Dan L. Van Dyke Mayo Clinic Cytogenetics Laboratory, 200 First St SW, Rochester MN 55905, USA; vandyke.daniel@mayo.edu
Roberta Vanni Universita di Cagliari, Dipartimento di ScienzeBiomediche(DiSB), CittadellaUniversitaria, 09042 Monserrato (CA) - Italy;
vanni@unica.it
Franck Viguié Service d'Histologie-Embryologie-Cytogénétique, Unité de Cytogénétique Onco-Hématologique, Hôpital Universitaire Necker-Enfants
Malades, 75015 Paris, France; franck.viguie@aphp.fr
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
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Volume 21, Number 12, December 2017
Table of contents
Gene Section
CEBPE (CCAAT/enhancer binding protein epsilon) 438 Thomas Burmeister
MAPK4 (mitogen-activated protein kinase 4) 441 Simon Mathien, Sylvain Meloche
Leukaemia Section
del(18)(p11) 443 Lubomir Mitev, Lilya Grachlyova, Aselina Asenova
Early T-cell precursor acute lymphoblastic leukemia 447 Steven Richebourg
Multiple Myeloma 451 Matthew Ho Zhi Guang, Kenneth C. Anderson, Giada Bianchi
t(5;17)(p11;q11) and t(5;17)(q11-12;q11-12) 464 Adriana Zamecnikova, Soad al Bahar
t(5;17)(q35;q21) NPM1/RARA 466 Adriana Zamecnikova, Soad al Bahar
Solid Tumour Section
Nervous system: Astrocytoma with t(1;17)(p36;q21) SPOP/PRDM16 470 Jean-Loup Huret
Chromophobe renal cell carcinoma 472 Paola Dal Cin, Michelle S. Hirsch
Cancer Prone Disease Section
Ataxia telangiectasia (A-T) 475 Yossi Shiloh
Gene Section Short Communication
Atlas Genet Cytogenet Oncol Haematol. 2017; 21(12) 438
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
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CEBPE (CCAAT/enhancer binding protein epsilon) Thomas Burmeister
Charite, Med. Klinik fur Hamatologie, Onkologie und Tumorimmunologie, Hindenburgdamm 30,
12200 Berlin, Germany; thomas.burmeister@charite.de
Published in Atlas Database: March 2017
Online updated version : http://AtlasGeneticsOncology.org/Genes/CEBPEID42984ch14q11.html
Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/69005/03-2017-CEBPEID42984ch14q11.pdf DOI: 10.4267/2042/69005
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2017 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Abstract
Review on CEBPE, with data on DNA, on the
protein encoded, and where the gene is implicated.
Keywords
CEBPE; Transcription factor; Neutrophil specific
granule deficiency; Acute lymphoblastic leukemia;
Translocation.
Identity
Other names: CRP1
HGNC (Hugo): CEBPE
Location: 14q11.2
Location (base pair)
Starts at 23117306 and ends at 23119611 bp from
pter (according to GRCh38.p7 Annotation Release
108, May 5 2016)
DNA/RNA
Description
CEBPE is located on chromosome 14q11.2 in a
telomer-centromer orientation. Conflicting data
have been published on the gene structure of
CEBPE. According to the GRCh38.p7 assembly
annotation (2016/03/21) the gene consists of two
exons (1030 bp and 517 bp), which are partially
coding and separated by a 759 bp intron (Figure
1a).
This is in conflict with some previously published
papers. Yamanaka et al. (1997) described an
alternative 3-exon-organization of the human
CEBPE gene (Figure 1b). However, exon 1, as
described by Yamanaka et al. contains a frameshift
according to the GRCh38.p7 NCBI assembly.
Transcription
Various transcripts have been reported, resulting in
four protein isoforms (Lekstrom-Himes 2001,
Yamanaka 1997; Figure 1c). All transcripts share a
common 3' end.
Protein Description
CEBPE is a member of the CCAAT/enhancer-
binding protein (C/EBP) family, which also
includes CEBPA, CEBPB, CEBPG, CEBPD and
CEBPZ (Ramji & Foka; 2002). A common
structural feature of the C/EBP proteins is the
presence of a highly conserved 55-65 amino acid
sequence at the C-terminus which encodes a basic
leucine zipper motif (bZIP domain) that functions
as a dimerization domain. In the aminoterminal part
all C/EBP proteins possess a DNA-binding domain
with relative specificity for the CCAAT DNA
motif. C/EBP proteins exert their physiological
functions as either homo- or heterodimers. They
can also interact with other bZIP- and non-bZIP
transcription factors. Different protein domains
have been characterized. The full-length CEBPE
protein basically consists of an activation domain at
the aminoterminal end, a repression domain in the
center and the leucine zipper at the carboxyterminus
(Williamson et al. 1998).
CEBPE (CCAAT/enhancer binding protein epsilon) Burmeister T
Atlas Genet Cytogenet Oncol Haematol. 2017; 21(12) 439
Figure 1: Human CEBPE gene and mRNA transcript: a. according to the GRCh38.p7 assembly annotation (2016/03/21); b. according to Yamanaka et al. (1997); c. transcripts based on the Yamanaka exon organization
At least four different CEBPE protein isoforms of
32, 30, 27, and 14 kDa have been described, but
their functional significance is unclear (Lekstrom-
Hines et al. 2001, Figure 1c).
The CEBPE translation product can undergo a
number of post-translational modifications.
Phosphorylation of CEBPE on threonine 75,
located in the transactivation domain, is associated
with increased DNA binding capacity and
transcriptional activation (Williamson et al., 2005).
Sumoylation of lysine residues within the
repression domain has been found to modulate
CEBPE function (Kim et al., 2005). Acetylation of
lysine-121 and lysine-198 was found to be critical
for terminal neutrophil differentiation (Bartels et.
al., 2015).
Expression
CEBPE is predominantly expressed in cells of the
hematopoietic system and to a much lesser extent in
ovarian tissue (Yamanaka, et al., 1997). In normal
hematopoietic cells CEBPE is preferentially
expressed in myeloid-committed cells and the
protein is virtually only detectable in
metamyelocytes and myelocytes. The gene is also
expressed in more immature myeloid cells but
protein translation is repressed by miRNA-130a
(Larsen et al., 2014).
The expression of CEBPE protein induces growth
arrest, morphological differentiation, secondary
granule proteins and has proapoptotic effects
(Nakajima et al. 2006).
Localisation
Nuclear.
Function
CEBPE is a transcription factor, important for
monocyte and granulocyte development. The
transcription factor binds as a homodimer or
heterodimer (with CEBPD) to specific DNA
regulatory regions. Shorter CEBPE protein
isoforms are hypothetical attenuators of the
transcriptional activity of the long isoform.
Homozygous CEBPE knock-out (-/-) mice appear
healthy at birth but survive only 2-5 months after
birth, while heterozygous CEBPE knock-out mice
appear normal. CEBPE (-/-) mice showed a marked
increase in immature myeloid progenitors,
increased numbers of morphologically abnormal
neutrophils, that were functionally defect and
lacked an oxidative burst, and decreased numbers
of eosinophils. Thus it was concluded that CEBPE
is essential for a normal terminal differentiation of
committed granulocyte progenitor cells (Yamanaka,
et al., 1997).
CEBPE (CCAAT/enhancer binding protein epsilon) Burmeister T
Atlas Genet Cytogenet Oncol Haematol. 2017; 21(12) 440
Implicated in
Neutrophil specific granule deficiency (SGD)
Some, but not all of the very few known patients
with SGD harboured CEBPE mutations which led
to loss of the dimerization domain; phenotypically,
SGD patients show bilobed nuclei, impaired
chemotaxis and bactericidal activity with
susceptibility to severe bacterial infections
(Gombart & Koeffler 2002).
Acute lymphoblastic leukemia (ALL)
The CEBPE single nucleotide polymorphism
rs2239633 has been implicated as a susceptibility
factor for the development of B lineage ALL in
children and adults. The relative risk (odds ratio)
conferred is 1.1-1.6 (Papaemmanuil et al., 2009;
Burmeister et al. 2014).
t(14;14)(q11;q32) CEBPE/IGH and inv(14)(q11q32) CEBPE/IGH
CEBPE is found recurrently translocated to the
immunoglobulin heavy chain locus ( IGH) on
14q32 in acute lymphoblastic leukemia patients
with inv(14)(q11q32)/t(14;14)(q11;q32). The
translocation leads to an overexpression of CEBPE
under the control of the immunoglobulin heavy
chain gene promoters. At least five cases have been
described (Akasaka et al. 2007).
References Akasaka T, Balasas T, Russell LJ, Sugimoto KJ, Majid A, Walewska R, Karran EL, Brown DG, Cain K, Harder L, Gesk S, Martin-Subero JI, Atherton MG, Brüggemann M, Calasanz MJ, Davies T, Haas OA, Hagemeijer A, Kempski H, Lessard M, Lillington DM, Moore S, Nguyen-Khac F, Radford-Weiss I, Schoch C, Struski S, Talley P, Welham MJ, Worley H, Strefford JC, Harrison CJ, Siebert R, Dyer MJ. Five members of the CEBP transcription factor family are targeted by recurrent IGH translocations in B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Blood. 2007 Apr 15;109(8):3451-61
Bartels M, Govers AM, Fleskens V, Lourenço AR, Pals CE, Vervoort SJ, van Gent R, Brenkman AB, Bierings MB, Ackerman SJ, van Loosdregt J, Coffer PJ. Acetylation of C/EBPε is a prerequisite for terminal neutrophil differentiation. Blood. 2015 Mar 12;125(11):1782-92
Burmeister T, Bartels G, Gröger D, Trautmann H, Schwartz S, Lenz K, Tietze-Bürger C, Viardot A, Wäsch R, Horst HA, Reinhardt R, Gökbuget N, Hoelzer D, Kneba M, Brüggemann M. Germline variants in IKZF1, ARID5B, and CEBPE as risk factors for adult-onset acute lymphoblastic leukemia: an analysis from the GMALL study group.
Haematologica. 2014 Feb;99(2):e23-5
Gombart AF, Koeffler HP. Neutrophil specific granule deficiency and mutations in the gene encoding transcription factor C/EBP(epsilon). Curr Opin Hematol. 2002 Jan;9(1):36-42
Han Y, Xue Y, Zhang J, Wu Y, Pan J, Wang Y, Shen J, Dai H, Bai S. Translocation (14;14)(q11;q32) with simultaneous involvement of the IGH and CEBPE genes in B-lineage acute lymphoblastic leukemia. Cancer Genet Cytogenet. 2008 Dec;187(2):125-9
Kim J, Sharma S, Li Y, Cobos E, Palvimo JJ, Williams SC. Repression and coactivation of CCAAT/enhancer-binding protein epsilon by sumoylation and protein inhibitor of activated STATx proteins. J Biol Chem. 2005 Apr 1;280(13):12246-54
Larsen MT, Häger M, Glenthøj A, Asmar F, Clemmensen SN, Mora-Jensen H, Borregaard N, Cowland JB. miRNA-130a regulates C/EBP-ε expression during granulopoiesis. Blood. 2014 Feb 13;123(7):1079-89
Lekstrom-Himes JA. The role of C/EBP(epsilon) in the terminal stages of granulocyte differentiation Stem Cells 2001;19(2):125-33
Nakajima H, Watanabe N, Shibata F, Kitamura T, Ikeda Y, Handa M. N-terminal region of CCAAT/enhancer-binding protein epsilon is critical for cell cycle arrest, apoptosis, and functional maturation during myeloid differentiation J Biol Chem 2006 May 19;281(20):14494-502
Papaemmanuil E, Hosking FJ, Vijayakrishnan J, Price A, Olver B, Sheridan E, Kinsey SE, Lightfoot T, Roman E, Irving JA, Allan JM, Tomlinson IP, Taylor M, Greaves M, Houlston RS. Loci on 7p12 2, 10q21 2 and 14q11
Prasad RB, Hosking FJ, Vijayakrishnan J, Papaemmanuil E, Koehler R, Greaves M, Sheridan E, Gast A, Kinsey SE, Lightfoot T, Roman E, Taylor M, Pritchard-Jones K, Stanulla M, Schrappe M, Bartram CR, Houlston RS, Kumar R, Hemminki K. Verification of the susceptibility loci on 7p12 2, 10q21 2, and 14q11
Ramji DP, Foka P. CCAAT/enhancer-binding proteins: structure, function and regulation Biochem J 2002 Aug 1;365(Pt 3):561-75
Williamson EA, Williamson IK, Chumakov AM, Friedman AD, Koeffler HP. CCAAT/enhancer binding protein epsilon: changes in function upon phosphorylation by p38 MAP kinase Blood 2005 May 15;105(10):3841-7
Yamanaka R, Kim GD, Radomska HS, Lekstrom-Himes J, Smith LT, Antonson P, Tenen DG, Xanthopoulos KG. CCAAT/enhancer binding protein epsilon is preferentially up-regulated during granulocytic differentiation and its functional versatility is determined by alternative use of promoters and differential splicing Proc Natl Acad Sci U S A 1997 Jun 10;94(12):6462-7
This article should be referenced as such:
Burmeister T. CEBPE (CCAAT/enhancer binding protein epsilon). Atlas Genet Cytogenet Oncol Haematol. 2017; 21(12):438-440.
Gene Section Short Communication
Atlas Genet Cytogenet Oncol Haematol. 2017; 21(12) 441
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
INIST-CNRS OPEN ACCESS JOURNAL
MAPK4 (mitogen-activated protein kinase 4) Simon Mathien, Sylvain Meloche
Institute of Research in Immunology and Cancer, Université de Montréal, Montreal, Quebec H3C 3J7,
Canada; simon.mathien@umontreal.ca; sylvain.meloche@umontreal.ca
Published in Atlas Database: March 2017
Online updated version : http://AtlasGeneticsOncology.org/Genes/MAPK4ID41293ch18q21.html
Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/69006/03-2017-MAPK4ID41293ch18q21.pdf DOI: 10.4267/2042/69006
This article is an update of : MAPK4 (mitogen-activated protein kinase 4). Atlas Genet Cytogenet Oncol Haematol 2017;21(12) Meloche S. MAPK4 (mitogen-activated protein kinase 4). Atlas Genet Cytogenet Oncol Haematol 2009;13(1)
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2017 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Abstract
Review on MAPK4, with data on DNA, on the
protein encoded, and where the gene is implicated.
Keywords
MAPK4; ERK4; Kinase; signaling pathway; RAS-
RAF-MAPK pathway
Identity
HGNC (Hugo): MAPK4
Location: 18q21.1
Other names: ERK4, PRKM4, pP63mapk
Local order: The MAPK4 gene is located between
the genes SKA1 (C18orf24) and MRO on
chromosome 18
DNA/RNA
Description
The MAPK4 gene spans 171.7 kb on the long arm
of chromosome 18 and is transcribed in the
centromere-to-telomere orientation.
The gene is composed of 6 exons with the
translation initiation codon located in exon 2. The
first two exons are separated by a long intron of
102.8 kb.
Transcription The MAPK4 transcribed mRNA has 4,736 bp. No
splice variants have been reported.
Pseudogene None.
Protein Description
Extracellular signal-regulated kinase 4 (ERK4) is
an atypical member of the mitogen-activated
protein (MAP) kinase family of serine/threonine
kinases. The human ERK4 protein is made of 587
amino acids and contains a typical kinase domain
located at the N-terminal extremity. Another region
with homology to the MAP kinase ERK3 (C34
domain) has been identified after the kinase
domain. The function of the C34 domain is
unknown.
Figure 1. Genomic organization of the MAPK4 gene on chromosome 18.
MAPK4 (mitogen-activated protein kinase 4) Mathien S, Meloche S
Atlas Genet Cytogenet Oncol Haematol. 2017; 21(12) 442
Figure 2. Schematic representation of the ERK4 protein structure. Kinase, catalytic kinase domain; C34 conserved region in ERK3 and ERK4; SEG, activation loop motif containing the regulatory phosphorylation residue Ser186.
Expression
MAPK4 mRNA is expressed to the highest level in
the brain. Other sites of expression include the
heart, lung, kidney, intestine, pancreas, parathyroid
gland, prostate, thymus, ovary, eye and ear.
Localisation
ERK4 localizes to the cytoplasm and nucleus of a
variety of cultured cells.
Function
Little is known about the regulation and functions
of ERK4. The only known substrate of ERK4 is the
protein kinase MAPKAPK5 (MK5).
Homology
ERK4 display 73% amino acid identity with ERK3
in the kinase domain. ERK4 and ERK3 define a
distinct subfamily of MAP kinases.
Mutations The R114C/H mutation has been reported in several
types of cancer (colorectal adenocarcinoma, diffuse
glioma, non-small cell lung cancer, cutaneous
melanoma, stomach adenocarcinoma, uterine
carcinosarcoma). The functional impact of this
mutation on the expression or activity of ERK4 is
not known.
Implicated in
Cancer
Analysis of copy number alterations (CNAs) from
TCGA datasets show that MAPK4 gene is deleted
in several adenocarcinomas, includingprostate,
esophageal, stomach and lung adenocarcinomas.
Also, a chromosomal subregion containing the
MAPK4 gene is deleted with high frequency (23%)
in pancreatic adenocarcinoma. On the other hand,
MAPK4 is amplified with low frequency in
neuroendocrine prostate cancer, diffuse large B-cell
lymphoma and sarcomas.
Interrogation of the Oncomine database reveals that
expression of MAPK4 mRNA is downregulated in
breast and prostate cancer.
Consistent with CNA analysis, MAPK4 mRNA is
upregulated in diffuse large B-cell lymphoma.
References Aberg E, Perander M, Johansen B, Julien C, Meloche S, Keyse SM, Seternes OM. Regulation of MAPK-activated protein kinase 5 activity and subcellular localization by the atypical MAPK ERK4/MAPK4. J Biol Chem. 2006 Nov 17;281(46):35499-510
Coulombe P, Meloche S. Atypical mitogen-activated protein kinases: structure, regulation and functions. Biochim Biophys Acta. 2007 Aug;1773(8):1376-87
Gonzalez FA, Raden DL, Rigby MR, Davis RJ. Heterogeneous expression of four MAP kinase isoforms in human tissues. FEBS Lett. 1992 Jun 15;304(2-3):170-8
Kant S, Schumacher S, Singh MK, Kispert A, Kotlyarov A, Gaestel M. Characterization of the atypical MAPK ERK4 and its activation of the MAPK-activated protein kinase MK5. J Biol Chem. 2006 Nov 17;281(46):35511-9
Nowak NJ, Gaile D, Conroy JM, McQuaid D, Cowell J, Carter R, Goggins MG, Hruban RH, Maitra A. Genome-wide aberrations in pancreatic adenocarcinoma. Cancer Genet Cytogenet. 2005 Aug;161(1):36-50
Turgeon B, Lang BF, Meloche S. The protein kinase ERK3 is encoded by a single functional gene: genomic analysis of the ERK3 gene family. Genomics. 2002 Dec;80(6):673-80
This article should be referenced as such:
Mathien S, Meloche S. MAPK4 (mitogen-activated protein kinase 4). Atlas Genet Cytogenet Oncol Haematol. 2017; 21(12):441-442.
Leukaemia Section Short Communication
Atlas Genet Cytogenet Oncol Haematol. 2017; 21(12) 443
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
INIST-CNRS OPEN ACCESS JOURNAL
del(18)(p11) Lubomir Mitev, Lilya Grachlyova, Aselina Asenova
Military Medical Academy, Department of Cytogenetics and Molecular Biology, Sofia, Bulgaria,
cytogen.vma@abv.bg
Published in Atlas Database: February 2017
Online updated version : http://AtlasGeneticsOncology.org/Anomalies/del18p11ID1314.html
Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/69007/02-2017-del18p11ID1314.pdf DOI: 10.4267/2042/69007
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2017 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Abstract Review on del(18)(p11) in haematological
malignancies, with data on the genes possibly
involved.
Keywords
Chromosome 18; Chronic myeloid leukemia;
Myelodysplastic syndromes; Acute myeloid
leukemia; Acute lymphoblastic leukemia; Follicular
lymphoma
Clinics and pathology del(18)(p11) is a very rare structural anomaly found
only in 24 cases with onco-hematological disorders.
This deletion has been observed in both myeloid
(14 cases) and lymphoid (10 cases) malignancies
and has been predominantly associated with a
complex karyotype. In all cases 18p- is presented as
a single copy in the karyotype. The anomaly was
determined by conventional cytogenetic as terminal
deletion with sub-band location of the breakpoint in
18p11.2. Microarray comparative genome
hybridization (aCGH) studies in patients with acute
myeloid leukemia have demonstrated that the
deleted segment in 18p could be also interstitial and
variable in size as has been proven in other tumor
associated deletions. Three submicroscopic deleted
regions have been identified - 18p11.32-p11.31,
18p11.23 and 18p11.22-p11.21 (Itzhar et al, 2011).
Disease
Acute Myeloid Leukemia (AML)
Epidemiology
del(18)(p11) is found in 9 cases ( 0.1% of all AML
cases with an abnormal karyotype) (Alimena et al.,
1981; Brodeur et al., 1983; GFCH, 1990; Lawler et
al., 1990; Mohamed et al., 1993; Davey et al., 1995;
Krauter et al., 1998; Babicka et al., 2007; Kasyan et
al., 2010) - 1 case with M1 French-American-
British (FAB) phenotype, 2 cases with M2, 1 case
with M3, 1 case with M4, 1 case with M6 and 3
with AML, NOS (one diagnosed as therapy related
AML).
The sex ratio is significantly unbalanced, near
M:F=3.5:1.
The age is documented in 5 cases: 6 and 35 (M2),
59 (M3), 42 (M4) and 61 (M6).
Cytogenetics
In 5 cases del(18)(p11) is found in complex
karyotypes and in one as a sole anomaly. Three
cases are with -5/del(5q), two with +8 and one case
of each of the following well known
rearrangements: -7; del(17p); t(8;21)(q22;q22);
t(17;20)(q21;q11) in a M3 ( RARA not checked). In
one case both arms of chromosome 18 are affected-
der(18)del(18)(p11)del(18)(q21). In 3 cases 18p- is
associated with sex chromosome abnormalities - 2
with a loss of Y chromosome and one with
del(X)(q26).
Disease
Other Myeloproliferative Disorders
Epidemiology
del(18)(p11) is described in 2 cases (one male and
one female) with chronic myeloid leukemia (CML)
(Ohyashiki et al., 1997; Sun et al,. 2011), 2 cases
(males) with a myelodysplastic syndrome (Cerretini
et al., 2002; Volkert et al., 2014) and one case
(female) with primary myelofibrosis (PMF)
involving a lymph node (Hu et al., 2009).
del(18)(p11) Mitev L, et al.
Atlas Genet Cytogenet Oncol Haematol. 2017; 21(12) 444
Cytogenetics
In 2 cases with MDS and one case with CML
del(18)(p11) is associated with a complex
karyotype, in one case with CML it is a second
event and in one case (with PMF) it is a sole
anomaly.
In the two cases with CML 18p- anomaly is present
in additional deviating sub-clones (sidelines) and in
one case with MDS in two clones with
dic(17;20)(p11-12;q11) and dic(18;18)(p11;p11).
Disease
Acute Lymphoblastic Leukemia (ALL)
Epidemiology
del(18)(p11) is found in 8 cases with ALL (0.08%
of all ALL cases with an abnormal karyotype)
(Oshimura et al., 1977; Kanerva et al., 2002; van
der Burg et al., 2002; Soulier et al., 2003; Karst et
al., 2006; Shin et al., 2011; Schmiegelow et al.,
2012; Lundin et al., 2014).
The sex ratio is significantly unbalanced, near
M:F=1.7:1.
The anomaly has been observed in young, as well
as older patients (average age 22.6 years; range 5-
65).
Cytogenetics
In 5 cases del(18)(p11) is found in complex
karyotypes and in 3 cases it is accompanied with
second anomalies - der(21) in two cases and
dup(18q)(q11q11) in one (unrelated clone). In 4 of
the 5 cases with complex karyotypes 18p- is
associated with one or more deletions including 6p-
, 9p-, 11q- and 12p- and in two cases with
t(7;14)(p13;q32) and t(14;18)(q32;q21) (Shin et al.,
2011), respectively.
Disease
Follicular lymphoma (FL)
Cytogenetics
del(18)(p11) is reported in 2 cases with FL (Bosga-
Bouwer et al., 2003; Horsman et al., 2003). Both
have hyperdiplpoid, highly complex karyotypes.
Genetics A tumor suppressor gene(s) (TSG) important to the
described hematological malignances may be is
involved in the molecular pathogenesis of
del(18)(p11).
A number of TSG candidates are mapped in the
deleted segment 18p11.2->18pter including PTPN2
(18p11.21), LDLRAD4 (C18orf1) (18p11.21),
RALBP1 (18p11.22), PPP4R1 (18p11.22), PTPRM
(18p11.23), EPB41L3 (18p11.31), L3MBTL4
(18p11.31), TGIF1 (18p11.31), ZEP161 (18p11.31)
and SMCHD1 (18p11.32).
Almost all are implicated in the pathogenesis of a
variety of solid tumors, but there are several lines of
data suggesting that four of them (PTPN2, PTPRM,
TGIF1 and SMCHD1) could also have a role in
leukogenesis and respectively may act as TSG in
the hematopoietic system.
Genes involved and proteins
PTPN2 (protein tyrosine phosphatase, non-receptor type 2)
Location
18p11.21
Protein
PTPN2 (Tyrosine-protein phosphatase non-receptor
type2) is a negative regulator of multiple signaling
pathways, including IL2 (interleukin 2) mediated
JAK2/STAT cascade and is inactivated by nonsense
mutation in 5% and deleted in 6% of the cases with
adult acute T-cell lymphoblastic leukemia (Kleppe
et al., 2010).
PTPRM (protein tyrosine phosphatase, receptor type M)
Location
18p11.23
Protein
PTPRM (Tyrosine-protein phosphatase, receptor
type M) is targeted by aCGH within the deleted
region 18p11.23 found in 17 cases with AML.
The protein encoded by this gene is involved in
cell-cell adhesion through hemophilic interactions.
Hypermethylation of PTPRM in cases with ALL
(Stevenson et al, 2013) and submicroscopic
deletion of PTPRM in cases of adult T cell
leukemia/lymphoma have been observed (Kataoka
et al 2015).
TGIF1 (TGFB induced factor homeobox 1)
Location
18p11.31
Protein
TGiF1 (TG-interacting factor 1) is targeted by
aCGH within the deleted region 18p11.32p11.31
found in 14 cases with AML.
The protein encoded by this gene plays an essential
role in the regulation of hematopoiesis inhibiting
the signaling pathways of RA (retinoic acid) and
TGFB1 (transforming growth factor beta) by
transcriptional repression of SMAD2.
It has been demonstrated that TGIF1 is a negative
regulator of KMT2A (MLL)-rearranged AML
(Willer et al, 2014).
del(18)(p11) Mitev L, et al.
Atlas Genet Cytogenet Oncol Haematol. 2017; 21(12) 445
SMCHD1 (structural maintenance of chromosomes flexible hinge domain containing 1)
Location
18p11.32
Protein
SMCHD1 (Structural maintenance of chromosome
flexible hinge domain containing 1) is also targeted
by aCGH within the region 18p11.32p11.31.
This gene encodes a protein required for the
maintenance of an X chromosome inactivation in
females. It has been reported that SMCHD1 is
associated with increased tumorigenesis in a mouse
model.
Global gene expressing profiling revealed that
SMCHD1 normally repress genes activated by
MLL- chimeric fusion proteins in leukemia (Leong
et al, 2012).
These data have suggested that the loss of
SMCHD1 may cause hematological malignances of
both cell lineage - myeloid and lymphoid.
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This article should be referenced as such:
Mitev L, Grachlyova L, Asenova A. del(18)(p11). Atlas Genet Cytogenet Oncol Haematol. 2017; 21(12):443-446.
Leukaemia Section Short Communication
Atlas Genet Cytogenet Oncol Haematol. 2017; 21(12) 447
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
INIST-CNRS OPEN ACCESS JOURNAL
Early T-cell precursor acute lymphoblastic leukemia Steven Richebourg
Laboratoire de cytogénétique onco-hématologique, Département de pathologie, Hôpital du Saint
Sacrement, CHU de Québec Université Laval, 1050, Chemin Sainte Foy, Département de Médecine
Moléculaire, Faculté de médecine, Université Laval, Québec, G1S4L8 Québec, Qc, Canada;
steven.richebourg.cha@ssss.gouv.qc.ca
Published in Atlas Database: February 2017
Online updated version : http://AtlasGeneticsOncology.org/Anomalies/EarlyTcellALLID1667.html
Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/69008/02-2017-EarlyTcellALLID1667.pdf DOI: 10.4267/2042/69008
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2017 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Abstract Review on early T-cell precursor acute
lymphoblastic leukemia, with data on clinics and
the genes possibly involved.
Keywords
T-cell; acute lymphoblastic leukemia
Identity
Other names
Early T-cell precursor lymphoblastic
leukemia/ETP-ALL/ETP T-ALL
Clinics and pathology
Note
Identified in 2009 from gene expression profiling
data, Early T cell Precursor Acute Lymphoblastic
Leukemia (ETP-ALL) represents a subset of T-
ALL sharing transcriptional and immunophenotypic
similarities with early T-cell precursors (Coustan-
Smith et al., 2009).
ETP-ALL is currently defined by a distinctive
phenotype characterized by a lack of expression of
the T-lineage cell surface markers CD1a and CD8,
weak or absent expression of CD5 and aberrant
expression of one or more myeloid or stem cell
markers (Coustan-Smith et al., 2009).
Since the description, genetic alterations and
prognostic data have been reported in literature
improving our understanding of this subgroup.
Therefore, ETP-ALL has been included as a
provisional entity in the 2016 revision of the WHO
classification of Acute Leukemias (Arber et al.,
2016).
Disease
Phenotype/cell stem origin
Early T-cell precursors (ETPs) are immature
progenitors that have recently immigrated from the
bone marrow to the thymus and which retain a
multilineage differentiation potential (T-lymphoid,
natural killer, dendritic and myeloid cell
differentiation potential). Animal model based
studies of ETPs demonstrate similarities with
immature myeloid progenitors and hematopoietic
stem cells (Bell and Bandhoola, 2008; Wada et al.,
2008). Because gene expression profiling is not part
of routine laboratory investigations, ETP-ALL
cases are currently identified through the phenotype
of blast cells : CD1a-, CD8-, CD5- /weak, and
positivity for one or more stem cell and/or myeloid
antigens (CD117, CD34, HLA-DR, CD13, CD33,
CD11b, and/or CD65) (Coustan-Smith et al., 2009;
Chopra et al., 2014). ETP-ALL typically also
express CD2, CD7 and cytoplasmic CD3 and may
express CD4.
Epidemiology
Initially described from children ALL cohorts,
ETP-ALL have also been identified in adults.
Frequency of ETP-ALL varies among studies
around 10-15% of T ALL.
Early T-cell precursor acute lymphoblastic leukemia Richebourg S
Atlas Genet Cytogenet Oncol Haematol. 2017; 21(12) 448
Courtesy Linda Boulay and Frédéric Barabé, Flow Cytometry Laboratory, Hôpital du Saint Sacrement, CHU de Québec Université Laval
In children, ETP-ALL has been reported in 11% to
16% of T-ALL (Coustan-Smith et al., 2009; Patrick
et al., 2014).
In adults, ETP-ALL frequency ranges from 7,4%
(Neumann et al., 2012) to 17% of T-ALL (Jain et
al., 2016).
Based on gene expression profiling, some authors
suggest that there is an immature signature related
to ETPs (called "near ETP' or "close to ETP")
which may be more prevalent (Van Vlierberghe et
al., 2013; Haydu and Ferrando, 2013).
Clinics
Most studies report no significant association
between ETP-ALL signature and clinical features
including sex, age, white blood cell count, and
central nervous system involvement (Coustan-
Smith et al., 2009; Inukai et al., 2012; Neumann et
al., 2012).
Though, two no recurrent features were identified :
an older age in paediatric population (Coustan-
Smith et al., 2009) and a lower frequency of
mediastinal mass at diagnosis in adult population
(Neumann et al., 2012).
Cytology
No specific morphologic features have been
reported to date.
Treatment
Since there is no consensus on the prognosis (see
below), no specific protocol is recommended.
Because of the trend to negative impact on
prognosis, some authors suggest that new
therapeutic strategies are needed to improve the
outcomes of ETP-ALL (Jain et al., 2016; Neumann
et al., 2013), including the use myeloid-targeted
therapies such as tyrosine kinase inhibitors
(Neumann et al., 2012; Neumann et al., 2013;
Zhang et al., 2012)
Prognosis
There is currently no consensus on the prognosis of
ETP-ALL.
Initial prognostic studies between 2009 and 2012
reported a negative prognostic impact on response
rate and survival (Coustan-Smith et al., 2009,
Inukai et al., 2012; Ma et al., 2012) and a higher
risk of relapse (Allen and al., 2013).
These data were not confirmed in more recent
studies with larger cohorts (Brent et al., 2014;
Patrick et al., 2014; Zuurbier et al., 2014).
However, in 2016, a MD Anderson study reported
again a negative prognostic impact on the response
rate and the overall survival of patients with ETP-
ALL (Jain et al., 2016).
Early T-cell precursor acute lymphoblastic leukemia Richebourg S
Atlas Genet Cytogenet Oncol Haematol. 2017; 21(12) 449
Cytogenetics No specific cytogenetic abnormality is associated
with ETP-ALL subtype.
In most studies, ETP-ALL patients present highly
variable karyotypes with remarkably a lower
frequency of classic recurrent rearrangements
associated with T-ALL (Patrick et al., 2014).
Coustan Smith and al reported a higher frequency
of deletion 13q (Coustan-Smith et al., 2009) and
Patrick et al a higher frequency of KMT2A
rearrangements (Patrick et al., 2014).
SNP analysis demonstrated a higher frequency of
copy number alterations in ETP-ALL vs non ETP-
ALL (Coustan-Smith et al., 2009).
Genes involved and proteins
ETP-ALL subgroup is characterized by a high
genetic heterogeneity and present a distinct
genomic profile defined by a lower incidence of
typical mutations associated with T ALL such as
NOTCH1 or FBXW7 and a high frequency of
myeloid associated gene mutations ( FLT3, RAS
mutations, DNMT3A, IDH1 / IDH2 mutations)
(Neumann et al., 2013; Van Vlierberghe et al.,
2011; Zhang et al., 2012).
Whole exome and whole genome sequencing
approaches identified mutations in multiple
pathways including mutations in genes activating
cytokine receptor and RAS signalling ( NRAS ,
KRAS, FLT3, IL7R, JAK3, JAK1, SH2B3 and
BRAF), inactivating haematopoietic transcription
factors ( GATA3, ETV6, RUNX1, IKZF1 and
EP300) and in epigenetic regulators (EZH2, EED,
SUZ12, SETD2 and EP300) (Zhang et al., 2012)
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Richebourg S. Early T-cell precursor acute lymphoblastic leukemia. Atlas Genet Cytogenet Oncol Haematol. 2017; 21(12):447-450.
Leukaemia Section Review
Atlas Genet Cytogenet Oncol Haematol. 2017; 21(12) 451
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
INIST-CNRS OPEN ACCESS JOURNAL
Multiple Myeloma Matthew Ho Zhi Guang, Kenneth C. Anderson, Giada Bianchi
LeBow Institute for Myeloma Therapeutics and Jerome Lipper Multiple Myeloma Center, Department
of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, 02115.
matthew_ho@dfci.harvard.edu; kenneth_anderson@dfci.harvard.edu;
giada_bianchi@dfci.harvard.edu
Published in Atlas Database: January 2017
Online updated version : http://AtlasGeneticsOncology.org/Anomalies/MultipleMyelomaID1776.html
Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/69009/01-2017-MultipleMyelomaID1776.pdf DOI: 10.4267/2042/69009
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2017 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Abstract
Multiple Myeloma (MM) is a cancer of plasma
cells resulting from the abnormal proliferation of
malignant plasma cells within the bone marrow
(BM) microenvironment. MM accounts for 1.3% of
all malignancies and 12% of hematologic cancers,
and is the second most commonly diagnosed blood
cancer after non-Hodgkin lymphoma. The hallmark
characteristics of MM include: high levels of intact
monoclonal immunoglobulin or its fragment (free
light chain) in serum or urine, and excess
monotypic plasma cells in the bone marrow in
conjunction with evidence of end organ damage
related to MM: (1) hypercalcemia, (2) renal failure,
(3) anemia, and (4) osteolytic bone lesions or severe
osteopenia, known as CRAB criteria. Even though
novel agents targeting MM cells in the context of
the BM microenvironment such as proteasome
inhibitors, immunomodulatory drugs (IMiDs), and
monoclonal antibodies have significantly prolonged
survival in MM patients, the disease remains
incurable. A deeper understanding of the molecular
mechanisms of MM growth, survival, and
resistance to therapy, such as genomic instability,
clonal heterogeneity and evolution, as well as MM-
BM microenvironmental host immune and other
factors, will provide the framework for
development of novel therapies to further improve
patient outcome.
Keywords
multiple myeloma, bone marrow
microenvironment, monoclonal gammopathy of
undetermined significance
Identity
Other names
Plasma cell myeloma, Myelomatosis, Kahler's
disease
Note
This paper is an update of Multiple myeloma in
2004.
Clinics and pathology
Disease
MM is a plasma cell cancer which is preceded by
an asymptomatic, premalignant condition called
monoclonal gammopathy of undetermined
significance (MGUS) which then progresses to MM
or related malignancies with a rate of about 1% per
year (Zingone and Kuehl 2011).
Phenotype/cell stem origin
Antigen-selected, post-germinal center, terminally
differentiated plasma cell (Anderson and Carrasco
2011)
Multiple Myeloma Ho M, et al.
Atlas Genet Cytogenet Oncol Haematol. 2017; 21(12) 452
Top: Normal Bone Marrow; Bottom: Multiple Myeloma Bone Marrow (note: ≥ 10% clonal bone marrow plasma cells). Image taken from: http://www.thrombocyte.com/causes-of-multiple-myeloma-cancer/
Etiology
Etiology not known. No confirmed predisposing
factors.
Possible (unconfirmed and controversial) risk
factors include (Sundar Jagannath et al 2016):
Environmental factors such as radiation exposure,
occupational exposure (agricultural, chemical,
metallurgical, rubber plant, pulp, wood, paper), and
chemical exposure (formaldehyde, epichlorohydrin,
Agent orange, hair dyes, paint sprays, asbestos)
Viral infection: Herpesvirus 8 infection noted in
some patients with MM
Genetic predisposition
The transformation of normal plasma cells into
myeloma cells is thought to result from one of two
primary genetic events: either (1) hyperdiploidy or
(2) aberrant class switch recombination (CSR),
likely occurring in the germinal center, leading to
MGUS. Secondary cytogenetic abnormalities result
in the progression of MGUS to SMM, MM, and
plasma cell leukemia (PCL) (see below:
Cytogenetics). MM cells are dependent upon the
BM microenvironment for growth, survival, and
drug resistance, due both to tumor cell adhesion to
BM accessory cells and release of growth factors
and cytokines including (1) interleukin-6 ( IL6), (2)
vascular endothelial growth factor ( VEGFA), (3)
insulin-like growth factor 1 ( IGF1), (4) members
of the superfamily of tumor necrosis factor, (5)
transforming growth factor beta1 (TGFB1), and (6)
interleukin-10 ( IL10) (Palumbo and Anderson
2011). Coupled with various genetic changes, these
abnormal microenvironmental interactions between
MM cells and BM cells contribute to aberrant
angiogenesis and MM disease progression
(Palumbo and Anderson 2011).
Epidemiology
See table below.
Clinics
The most common presenting symptoms of MM are
fatigue and bone or back pain. Multiple myeloma
cells typically grow within the BM of the spine,
skull, ribs, sternum, pelvis, humeri, and femora,
causing pain, osteopenia, and frequently
pathological fractures (Palumbo and Anderson
2011).
Myeloma cells typically secrete an excess of a
monoclonal immunoglobulin or its fragments (free
light chain), which can then be detected in the
patient's serum and/or urine via protein
electrophoresis and serum free light chain (sFLC)
testing, respectively. Immunofixation shows the
myeloma (M) protein to be monoclonal in nature
and identifies heavy (IgG/IgA/IgM/IgD, in order of
frequency) and light chain ( κ/λ) specific isotype.
Multiple Myeloma Ho M, et al.
Atlas Genet Cytogenet Oncol Haematol. 2017; 21(12) 453
Rarely, MM may be non-secretory and neither a
monoclonal Ig nor an excess sFLC can be
identified. The diagnosis of MM is made based on
the percentage of bone marrow involvement by
clonal MM cells, size of M protein spike, and
presence/absence of end-organ damage (CRAB) or
myeloma-defining biomarkers (Rajkumar,
Dimopoulos et al. 2014).
CRAB criteria:
Hypercalemia -> (C) Up to 20% of newly diagnosed patients have
hypercalcemia due to bone destruction.
Hypercalcemia is associated with high tumor
burden and requires prompt treatment with
aggressive hydration and loop diuretic therapy,
bisphosphonates, calcitonin, and anti-myeloma
therapy for disease control.
Renal Failure -> (R) Renal dysfunction (anuria or oliguria) resulting
from direct tubular damage by free light chain
tubular or glomerular deposition, hypercalcemia,
dehydration, and nephrotoxic medications (NSAIDs
for pain control, IV radiographic contrast,
bisphosphonates) is present in 20 to 40% of newly
diagnosed patients.
Light-chain cast nephropathy is the most common
cause of renal failure in MM. Other causes include
amyloidosis and light-chain deposition disease.
Anemia-> (A) At diagnosis, symptomatic normocytic,
normochromic anemia (typically secondary to
myelophthisis and hyporegenerative BM) is present
in approximately 73% of patients. Mean
corpuscular volume (MCV) may be macrocytic; an
artifact related to rouleaux formation.
Bone Disease -> (B) Up to 58% of patients report bone pain (especially
from compression fractures of vertebrae or ribs),
and up to 80% of newly diagnosed patients have
bony lesions.
The characteristic "punched-out" osteolytic lesions
result from lytic bone destruction that is uncoupled
from reactive bone formation. MM cells increase
the activity of osteoclasts by upregulating osteoclast
inducers (i.e. TNFSF11 (RANKL, TRANCE),
CCL3 and CCL4 (MIP-1 alpha /beta), CXCL12
(SDF-1 alpha), IL1B (IL-1 beta), TNF (TNF-
alpha), IL6,) and downregulating TNFRSF11B
(OPG, decoy receptor for RANKL).
Simultaneously, MM cells suppress osteoblast
differentiation and function (by producing DKK1)
resulting in an imbalance favouring bone resorption
(osteoclast activation) over bone formation
(osteoblast suppression) (Sezer 2009).
Revised International Staging System (R-ISS) (Palumbo, Avet-Loiseau et al. 2015)*Standard-risk: No high-risk chromosomal abnormality. High-risk: Presence of del(17p) and/or translocation t(4;14) and/or translocation t(14;16)
Multiple Myeloma Ho M, et al.
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Multiple Myeloma Ho M, et al.
Atlas Genet Cytogenet Oncol Haematol. 2017; 21(12) 455
International Myeloma Working Group (IMWG) diagnostic criteria (Rajkumar, Dimopoulos et al. 2014)
Multiple Myeloma Ho M, et al.
Atlas Genet Cytogenet Oncol Haematol. 2017; 21(12) 456
M-protein Left: Serum protein electrophoresis showing characteristic "M-protein" spike. Image taken from:
http://bestpractice.bmj.com/best-practice/images/bp/en-gb/179-5-iline_default.gif and http://www.aafp.org/afp/1999/0401/p1885.html; Right: Urine protein electrophoresis showing gamma-globulin peak
corresponding to Bence-Jones proteinuria. Image taken from: https://ahdc.vet.cornell.edu/sects/clinpath/test/immun/electro.cfm
Pathology
MM is characterized by the presence of ≥10%
malignant plasma cells in the bone marrow. MM
can be divided into (1/>= secretory MM, (2)
oligosecretory MM (aka light chain MM), and (3)
non-secretory MM based on whether M-protein is
secreted and detectable (Lonial and Kaufman
2013). Non-secretory MM accounts for <5% of
cases and can be further divided into producer (i.e.
patients who have detectable M-protein within MM
cells but do not secrete M-protein) and non-
producer MM (patients who do not have detectable
M-protein even within MM cells) (Lonial and
Kaufman 2013). The presence of Bence-Jones
protein (BJP) in the urine indicates the excessive
production of monoclonal light-chain proteins that
exceeds the re-absorptive ability of the proximal
tubules. These filtered light-chains are, in their
various forms (free, tubular casts, amyloid),
nephrotoxic and are responsible for the most
common cause of renal failure in patients with MM.
Another hallmark feature of MM is the presence of
osteolytic bone lesions that results from an
imbalance favoring bone resorption over bone
formation due to increased osteoclast activity and
reduced osteoblast differentiation and function,
secondary to secreted factors from MM cells (Sezer
2009). Associated with bone destruction are
complications such as bone pain, pathological
fractures, and hypercalcemia. Anemia is another
frequent finding in patients with MM that results
from multiple mechanisms including anemia of
chronic disease, EPO deficiency (secondary to renal
impairment), myelosuppression from
chemotherapy, and bone marrow infiltration by
plasma cells.
Osteolytic bone lesions (a-d) X-rays showing characteristic osteolytic bone lesions typical sites such as the (a) skull, (b) tibia, (c) femur, and (d) pelvis. Image taken from: http://orthoinfo.aaos.org/topic.cfm?topic=A00086 ; (e) Sagittal CT showing multiple
osteolytic bone lesions of the vertebral column. Image taken from: https://radiopaedia.org/cases/multiple-myeloma-skeletal-survey
Multiple Myeloma Ho M, et al.
Atlas Genet Cytogenet Oncol Haematol. 2017; 21(12) 457
MM kidney disease Left: Normal kidney biopsy; Right: Monoclonal protein-containing casts surrounded by histiocytes and giant cells. Note the presence of acute tubular injury and interstitial nephritis which are commonly seen in MM kidney disease. Images
taken from: https://ajkdblog.org/2012/06/14/test-your-knowledge-myeloma-and-the-kidney/#prettyPhoto (courtesy of Dr. Tibor Nadasdy)
Natural History of MM Monoclonal Gammopathy of Undetermined Significance (MGUS; premalignant; asymptomatic) -> Smoldering Multiple Myeloma (SMM; pre-malignant; asymptomatic) -> Multiple Myeloma (MM; malignant; symptomatic) -> Plasma cell Leukemia (PCL), extramedullary disease. MM remains incurable in the long-term as most patients inevitably, yet
unpredictably, develop refractory relapse disease (i.e. disease that fails to respond to induction or salvage therapy, or progresses within 60 days of last therapy). Images taken from: Kyle et al, NEJM, Volume 356:2582-2590 (Kyle, Remstein et al. 2007) and
Roman Hajek, Intech open, DOI: 10.5772/55366 (Hajek 2013)
Multiple Myeloma Ho M, et al.
Atlas Genet Cytogenet Oncol Haematol. 2017; 21(12) 458
Multiple Myeloma Ho M, et al.
Atlas Genet Cytogenet Oncol Haematol. 2017; 21(12) 459
Treatment
See tables
(NCCN guidelines version 3.2017) and IMWG
RESPONSE CRITERIA (Kumar, Paiva et al. 2016)
Prognosis
Varies greatly depending on:
-Stage of disease (see above: ISS)
-Cytogenetics (see below: cytogenetics)
-LDH levels (high levels associated with
extramedullary disease, plasma cell leukemia,
plasmablastic disease, plasma cell hypoploidy, drug
resistance, and poor outcomes)
-Plasma cell labeling index
-C-reactive protein (high levels associated with
poor outcomes)
-Plasmablastic histology
-Extramedullary disease
-Age
Type of treatment available
- Conventional therapy: OS ~3 years; EFS <2 years
- High-dose chemotherapy and stem-cell
transplantation: 5-year OS >50%
In general, poor prognosticators include:
-Large tumor burden
- Hypercalcemia
- High LDH
- Bence-Jones proteinuria
- Renal impairment
- IgA subtype
- Extramedullary disease at presentation
Genetics See figure below.
Cytogenetics
Cytogenetics morphological
See figures below.
Genes involved and proteins
FGFR3 (Fibroblast Growth Factor Receptor 3)
Location
4p16.3
Note
Involved in t(4;14)(p16;q32)
Both FGFR3 and WHSC1 (MMSET) are
implicated in the translocation with IGH
Incidence: 6-12%
NSD2 (MMSET)
Location
4p16.3
Note
Involved in t(4;14)(p16;q32)
CCND1 (B-cell leukemia/lymphoma 1)
Location
11q13.3
Note
Involved in t(11;14)(q13;q32)
Incidence: 15-20%
Multiple Myeloma Ho M, et al.
Atlas Genet Cytogenet Oncol Haematol. 2017; 21(12) 460
Genetics
Multiple Myeloma Ho M, et al.
Atlas Genet Cytogenet Oncol Haematol. 2017; 21(12) 461
Primary Cytogenetic Abnormalities (Normal plasma cell --> MGUS/SMM). Ref : Rajan and Rajkumar (2015)
Multiple Myeloma Ho M, et al.
Atlas Genet Cytogenet Oncol Haematol. 2017; 21(12) 462
Secondary Cytogenetic Abnormalities (MGUS/SMM --> MM --> RR MM, PCL) Ref : Morgan, Walker et al. (2012).
CCND3 (cyclin D3)
Location
6p21.1
Note
Involved in t(6;14)(p21;q32)
Incidence: 5%
MAF (v-maf musculoaponeurotic fibrosarcoma oncogene homolog (avian))
Location
16q23.2
Note
Involved in t(14;16)(q32;q23)
Incidence: 4-10%
IRF4 (interferon regulatory factor 4)
Location
6p25.3
Note
Involved in t(6;14)(p25;q32)
Incidence: 5%
MYC v-myc myelocytomatosis viral oncogene homolog (avian)
Location
8q24.21
Note
Involved in t(8;14)(q24;q32)
Incidence: <10%
MAFB (v-maf avian musculoaponeurotic fibrosarcoma oncogene homolog B)
Location
20q12
Note
Involved in t(14;20)(q32;q11)
Incidence: 1 - 5%
BCL9 (B-cell CLL/lymphoma 9)
Location
1q21.2
Note
Incidence: Frequent
Both BCL9, IL6R, and MCL1 can be deleted
Multiple Myeloma Ho M, et al.
Atlas Genet Cytogenet Oncol Haematol. 2017; 21(12) 463
IL6R (interleukin 6 receptor)
Location
1q21.3
Note
Incidence: Frequent
MCL1 (MCL1, BCL2 family apoptosis regulator)
Location
1q21.2
Note
Incidence: Frequent
References Anderson KC, Carrasco RD. Pathogenesis of myeloma. Annu Rev Pathol. 2011;6:249-74
Becker N. Epidemiology of multiple myeloma. Recent Results Cancer Res. 2011;183:25-35
Hajek, R.. Multiple Myeloma - A Quick Reflection on the Fast Progress
Huang SY, Yao M, Tang JL, Lee WC, Tsay W, Cheng AL, Wang CH, Chen YC, Shen MC, Tien HF. Epidemiology of multiple myeloma in Taiwan: increasing incidence for the
past 25 years and higher prevalence of extramedullary myeloma in patients younger than 55 years Cancer 2007 Aug 15;110(4):896-905
Kyle RA, Remstein ED, Therneau TM, Dispenzieri A, Kurtin PJ, Hodnefield JM, Larson DR, Plevak MF, Jelinek DF, Fonseca R, Melton LJ 3rd, Rajkumar SV. Clinical course and prognosis of smoldering (asymptomatic) multiple myeloma N Engl J Med 2007 Jun 21;356(25):2582-90
Lonial S, Kaufman JL. Non-secretory myeloma: a clinician's guide Oncology (Williston Park) 2013
Sep;27(9):924-8, 930
Morgan GJ, Walker BA, Davies FE. The genetic architecture of multiple myeloma Nat Rev Cancer 2012 Apr 12;12(5):335-48
Palumbo A, Avet-Loiseau H, Oliva S, Lokhorst HM, Goldschmidt H, Rosinol L, Richardson P, Caltagirone S, Lahuerta JJ, Facon T, Bringhen S, Gay F, Attal M, Passera R, Spencer A, Offidani M, Kumar S, Musto P, Lonial S, Petrucci MT, Orlowski RZ, Zamagni E, Morgan G, Dimopoulos MA, Durie BG, Anderson KC, Sonneveld P, San Miguel J, Cavo M, Rajkumar SV, Moreau P. Revised International Staging System for Multiple Myeloma: A Report From International Myeloma Working Group J Clin
Oncol 2015 Sep 10;33(26):2863-9
Rajan AM, Rajkumar SV. Interpretation of cytogenetic results in multiple myeloma for clinical practice Blood Cancer J 2015 Oct 30;5:e365
Rajkumar SV, Dimopoulos MA, Palumbo A, Blade J, Merlini G, Mateos MV, Kumar S, Hillengass J, Kastritis E, Richardson P, Landgren O, Paiva B, Dispenzieri A, Weiss B, LeLeu X, Zweegman S, Lonial S, Rosinol L, Zamagni E, Jagannath S, Sezer O, Kristinsson SY, Caers J, Usmani SZ, Lahuerta JJ, Johnsen HE, Beksac M, Cavo M, Goldschmidt H, Terpos E, Kyle RA, Anderson KC, Durie BG, Miguel JF. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma Lancet Oncol 2014 Nov;15(12):e538-48
Sezer O. Myeloma bone disease: recent advances in biology, diagnosis, and treatment Oncologist 2009 Mar;14(3):276-83
Sundar Jagannath, Paul G. Richardson, Nikhil C. Munshi. Multiple Myeloma and Other Plasma Cell Dyscrasias Cancer Network
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Ho M, Anderson KC, Bianchi G. Multiple Myeloma. Atlas Genet Cytogenet Oncol Haematol. 2017; 21(12):451-463.
Leukaemia Section Short Communication
Atlas Genet Cytogenet Oncol Haematol. 2017; 21(12) 464
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
INIST-CNRS OPEN ACCESS JOURNAL
t(5;17)(p11;q11) and t(5;17)(q11-12;q11-12) Adriana Zamecnikova, Soad al Bahar
Kuwait Cancer Control Center, Department of Hematology annaadria@yahoo.com
Published in Atlas Database: January 2017
Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t0517p11q11ID1772.html
Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/69010/01-2017-t0517p11q11ID1772.pdf DOI: 10.4267/2042/69010
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2017 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Abstract
Review on t(5;17)(p11;q11) and t(5;17)(q11-
12;q11-12), with data on clinics.
Keywords
Chromosome 5; chromosome 17; Acute myeloid
leukaemia
Clinics and pathology
Disease
Acute myeloid leukemia (AML)
Epidemiology
Described in 2 male and 3 female patients aged 28
to 70 years; Acute myeloblastic leukemia with
maturation (FAB type M2) in 3 (Huebner et al.,
2000; Paietta et al., 1988; Arnaud et al., 2005) and
AML-NOS in 2 patients (Suciu et al., 1993;
Kerndrup and Kjeldsen., 2001) (Table 1).
Prognosis
May represent an unfavorable cytogenetic
prognostic category in association with monosomy
7 and/or complex karyotypes.
Figure 1. (A) Partial karyotypes showing the t(5;17)(p11;q11). (B) Fluorescence in situ hybridization with LSI TP53/CEP17 probe (Vysis, Abott Moleculars, US) showing the chromosome 17 centromere (green) and the p53 gene (red) on der(17) chromosome containing the short arms of chromosomes 5 and 17. (C) Hybridization with LSI CSF1R/D5S23/D5S721 hybridizing on 5p13.2 (green) and 5q33 (red) showing the signal for 5p (green) on der(17) and the signal for 5q33 (red) on der(5) chromosome. (D)
Simultaneous hybridization with LSI TP53/CEP17 and LSI CSF1R/D5S23/D5S721 probes demonstrating the presence of TP53/CEP17 and 5p13 signals on der(17) and the 5q33 signal on der(5) chromosome containing the long arm of chromosome
17.
t(5;17)(p11;q11) and t(5;17)(q11-12;q11-12) Zamecnikova A, al Bahar S
Atlas Genet Cytogenet Oncol Haematol. 2017; 21(12) 465
Table 1. Reported patients with t(5;17)(p11-12-q11;q11-12). Abbreviations: M, male; F, female; AML-M2, Acute myeloblastic leukemia with maturation (FAB type M2), AML, Acute myeloid leukemia, NOS. 1. Huebner et al., 2000; 2. Paietta et al., 1988; 3.
Suciu et al., 1993; 4. Kerndrup & Kjeldsen., 2001; 5. Arnaud et al., 2005.
Cytogenetics
Additional anomalies
Complex chromosome rearrangements in all the 5
described patients, found in association with
monosomy 7 in 2 (Huebner et al., 2000; Arnaud et
al., 2005) and trisomy 8 in 3 patients (Paietta et al.,
1988; Suciu et al., 1993; Kerndrup and Kjeldsen.,
2001).
Result of the chromosomal anomaly
Fusion protein
Oncogenesis
The reciprocal, apparently balanced t(5;17)(p11-
q11;q11) is a rare but non-random anomaly in
acute myeloid leukemia, that may be particularly
associated with acute myeloblastic leukemia with
maturation (AML-M2). The key mechanism of
oncogenesis is unknown; however as it presents in
association with known anomalies such as
monosomy 7 or trisomy 8 in all the described cases,
it is likely that it represents a secondary anomaly
that developed during the multistep process of
leukemogenesis.
References Huebner G, Karthaus M, Pethig K, Freund M, Ganser A. Myelodysplastic syndrome and acute myelogenous leukemia secondary to heart transplantation. Transplantation. 2000 Aug 27;70(4):688-90
Kerndrup GB, Kjeldsen E. Acute leukemia cytogenetics: an evaluation of combining G-band karyotyping with multi-color spectral karyotyping. Cancer Genet Cytogenet. 2001 Jan 1;124(1):7-11
Paietta E, Papenhausen P, Gucalp R, Wiernik PH. Translocation t(12;19)(q13;q13.3). A new recurrent abnormality in acute nonlymphocytic leukemia with atypical erythropoiesis. Cancer Genet Cytogenet. 1988 Aug;34(1):19-23
Suciu S, Zeller W, Weh HJ, Hossfeld DK. Immunophenotype of mitotic cells with clonal chromosome abnormalities demonstrating multilineage involvement in acute myeloid leukemia. Cancer Genet Cytogenet. 1993 Oct 1;70(1):1-5
This article should be referenced as such:
Zamecnikova A, al Bahar S. t(5;17)(p11;q11) and t(5;17)(q11-12;q11-12). Atlas Genet Cytogenet Oncol Haematol. 2017; 21(12):464-465.
Leukaemia Section Short Communication
Atlas Genet Cytogenet Oncol Haematol. 2017; 21(12) 466
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
INIST-CNRS OPEN ACCESS JOURNAL
t(5;17)(q35;q21) NPM1/RARA Adriana Zamecnikova, Soad al Bahar
Kuwait Cancer Control Center, Department of Hematology annaadria@yahoo.com
Published in Atlas Database: January 2017
Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t517ID1081.html
Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/69011/01-2017-t517ID1081.pdf DOI:10.4267/2042/69011
This article is an update of : Viguié F. t(5;17)(q35;q21). Atlas Genet Cytogenet Oncol Haematol 2000;4(2)
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2017 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Abstract
Acute promyelocytic leukemia (APL) is
characterized by distinct clinical and biological
features and by the reciprocal translocation
t(15;17)(q22;q21) in the majority of patients. The
translocation generates the fusion of the
promyelocytic leukemia (PML) gene to the gene for
retinoic acid receptor alpha (RARA) and these
patients are responsive to differentiation treatment
with all-trans retinoic acid (ATRA). Rare cases of
patients with a morphological diagnosis of APL
have variant chromosome translocations, which
fuse RARA gene with partner genes other than
PML, such as in the variant translocation
t(5;17)(q35;q21) that fuses the N-terminus of
nucleophosmin (NPM1) gene at 5q35 to the retinoic
acid receptor alpha at 17q21.
Keywords
Chromosome 5; chromosome 17; Acute myeloid
leukaemia; Acute promyelocytic leukemia; RARA;
NPM1
Clinics and pathology
Disease
Acute myeloid leukemia (AML)
Phenotype/cell stem origin
Acute promyelocytic leukemia (AML-M3
according to the FAB classification)
Etiology
Exceptional; only 7 cases with balanced
t(5;17)(q35;q12-21) translocation and the
underlying NPM1/RARA fusion have been
identified (5 males and 2 females, aged 2.5 to 52
years).
There were 2 adult males, aged 29 and 52 years and
4 patients were pediatric cases, among them 2 were
12-year-old males and 2 were 2.5 and 9-year-old
females (Table 1).
Clinics
Disseminated intravascular coagulation was present
at diagnosis in one case; remission obtained with
chemotherapy and/or ATRA; first relapse at 7 and 5
months in 2 cases (Corey et al., 1994 ; Hummel et
al., 1999). The 6-month-old boy described by
Otsubo et al., presented with cutaneous
mastocytosis and aleukemic leukemia cutis that
regressed without any therapy within 6 months.
Both adult patients also presented with myeloid
sarcoma, therefore it is likely that it may occur
frequently in NPM1/RARA associated APL (Nicci
et., 2005; Kikuma et al.,2015).
Cytology
Hypergranular and hypogranular bilobed
promyelocytes; absence of Auer rods; typical
microspeckeled pattern with anti-RARa antibodies;
terminal differentiation of blasts and promyelocytes
in vitro with ATRA.
t(15;17)(q22;q21) NPM1/RARA Zamecnikova A, al Bahar S
Atlas Genet Cytogenet Oncol Haematol. 2017; 21(12) 467
Table 1. Reported cases with t(5;17)(q35;q12-21) and confirmed NPM1-RARA fusion. Abbreviations: M, male; F, female; ATRA; all-trans-retinoic acid. 1. Corey et al., 1994 and Redner et al., 1996. 2. Hummel et al., 1999; 3. Grimwade et al., 2000; 4.
Xu et al., 2001; 5. Nicci et al., 2005; 6. Otsubo et al., 2012; Kikuma et al., 2015.
Prognosis
The 2.5 years-old child (Corey et al., 1994; Redner
et al., 1996) was treated with ATRA while in partial
remission and relapsed shortly after ATRA
cessation. One of the 12-years old males (Hummel
et al., 1999) received chemotherapy in induction
and consolidation and relapsed after 5 months;
remission was obtained with Ara-C and ATRA
therapy followed by allogenic BM transplantation,
but relapsed with therapy refractoriness. The second
12-years old male who presented with severe DIC
died of cerebral hemorrhage after 5 days of ATRA
treatment (Xu et al., 2001). The 9-year-old female
was treated with ATRA as a part of induction
therapy and was alive in first CR at 29 months
(Grimwade et al 2000). The last pediatric patient
presented with aleukemic leukemia cutis and
t(5;17)(q35;q12) NPM1/RARA fusion at the age of
6-month-old (Kanegane et al., 2009; Otsubo et al.,
2012). He showed no sign of leukemia without any
therapy after 12 months, except for the presence of
NPM1-RARA transcript in the bone marrow, but
developed APL at the age of 4 years with complete
remission to ATRA. Both adult patients received
ATRA as part of induction therapy, resulting in
cytogenetic but not a molecular remission in 1
patient who relapsed at 22 months after diagnosis
(Nicci et al., 2005), and in complete hematological
and molecular remission in the other case (Kikuma
et al., 2015).
From these data, the response to ATRA is difficult
to assess since it was not part of induction treatment
in some cases and due to the limited number of
patients. However, patients with NPM1/RARA
fusion appear to be sensitive to ATRA (Hummel et
al., 1999; Grimwade et al., 2000; Kikuma et al.,
2015) and cells bearing the t(5;17) terminally
differentiate in its response (Redner et al., 1996),
indicating that ATRA can be used to treat
NPM1/RARA-positive APL patients. It is also
possible that the presence of the additional/complex
karyotypic abnormalities may be related to the
prognosis in this group of patients.
Cytogenetics Additional anomalies
Sole anomaly in both adult patients (Nicci et al.,
2005; Kikuma et al., 2015) and associated with
additional anomalies in pediatric patients: del(12p)
in 1 (Xu et al., 2001), i(21)(q10) in 1 (Otsubo et al.,
2012) and complex anomalies in 2 cases (Hummel
et al., 1999; Grimwade et al., 2000).
Variants
Variant chromosome translocations, which fuse
RARA with 1 of the partner genes: PML
(promyelocytic leukemia protein) in
t(15;17)(q22;q21) that is found in the majority of
APL patients; ZBTB16 (zinc finger and BTB
domain containing 16, previously known as PLZF)
t(15;17)(q22;q21) NPM1/RARA Zamecnikova A, al Bahar S
Atlas Genet Cytogenet Oncol Haematol. 2017; 21(12) 468
in t(11;17)(q23;q21) (De Braekeleer et al., 2014);
NUMA1 (nuclear matrix-mitotic apparatus protein
1 gene) in t(11;17)(q13;q21) (Wells et al., 1997);
STAT5B (signal transducer and activator of
transcription 5 beta) in dup(17)(q21.3q23) (Chen et
al., 2012); PRKAR1A (protein kinase, cAMP-
dependent, regulatory, type I, alpha) in
t(17;17)(q21;q24)/del(17)(q21q24) (Catalano et al.,
2007); FIP1L1 (factor interacting with PAP 1-like
1) in t(4;17)(q12;q21) (Buijs et al., 2007); NABP1
(OBFC2A: oligonucleotide/oligosaccharide-binding
fold containing 2A) in der(2)t(2;17)(q32;q21) (Won
et al., 2013); TBL1XR1 (TBLR1, GenBank
KF589333) in a complex t(3;17)(q26;q21),
t(7;17)(q11.2;q21) (Chen et al., 2014); BCOR
(BCL6 corepressor gene) in t(X;17)(p11.4;q21)
(Ichikawa et l., 2015) and the recently described
new RARA partner IRF2BP2 (interferon regulatory
factor 2 binding protein 2) in t(1;17)(q42.3; q21)
(Yin et al., 2015).
Genes involved and proteins
NPM1 (nucleophosmin)
Location
5q35.1
Protein
Gene for the nucleolar phosphoprotein
nucleophosmin; would participate in ribosome
assembly.
RARA (Retinoic acid receptor, alpha)
Location
17q21.2
Protein
Gene for the retinoic acid receptor alpha. Ligand-
dependent transcription factor specifically involved
in hematopoietic cells differentiation and
maturation. Receptor for all-trans retinoic acid
(ATRA) and 9-cis RA. After linking with ATRA,
RARA binds with RXR (retinoid X receptor
protein) to the RARE domain (retinoic acid
response elements), a DNA sequence common to a
number of genes. The breakpoint lies within the
second intron of the gene, as in t(15;17) and
t(11;17) translocations.
Result of the chromosomal anomaly
Hybrid gene
Description
Two reciprocal fusion genes are generated: 5'-
NPM1 + 3'- RARA on der(5) and 5'-RARa + 3'-
NPM on der(17); both fusion genes are transcribed,
the crucial one is NPM1/RARA; two NPM1/RARA
chimeric cDNAs are generated, one short and one
long differing from 129 bp, with corresponding
transcripts of 2.3 and 2.4 kb (alternatively spliced
transcripts); in one case, only the short
NPM1/RARA isoform could be detected; the 5' end
of NPM1/RARA cDNAs contains the first 442 bp
of the NPM1 cDNA; the 3' end contains RARA
sequences of exon 3 through the 3' end of RARA; a
reciprocal RARA/NPM1 transcript is detected:
RARA exons 1 and 2 are fused to 3' NPM1
downstream bp 443.
Detection
Nested RT-PCR.
Fusion protein
Description
Two NPM1/RARA proteins, of 563 and 520 amino
acids, are encoded (MW 62 and 57 kDa);
NPM1/RARA fusion protein acts as a retinoic acid-
responsive transcriptional activator: increase of
activity in a concentration dependant manner.
References Brunel V, Lafage-Pochitaloff M, Alcalay M, Pelicci PG, Birg F. Variant and masked translocations in acute promyelocytic leukemia. Leuk Lymphoma. 1996 Jul;22(3-4):221-8
Buijs A, Bruin M. Fusion of FIP1L1 and RARA as a result of a novel t(4;17)(q12;q21) in a case of juvenile myelomonocytic leukemia. Leukemia. 2007 May;21(5):1104-8
Chen H, Pan J, Yao L, Wu L, Zhu J, Wang W, Liu C, Han Q, Du G, Cen J, Xue Y, Wu D, Sun M, Chen S. Acute promyelocytic leukemia with a STAT5b-RARα fusion transcript defined by array-CGH, FISH, and RT-PCR. Cancer Genet. 2012 Jun;205(6):327-31
Chen Y, Li S, Zhou C, Li C, Ru K, Rao Q, Xing H, Tian Z, Tang K, Mi Y, Wang B, Wang M, Wang J. TBLR1 fuses to retinoid acid receptor α in a variant t(3;17)(q26;q21) translocation of acute promyelocytic leukemia. Blood. 2014 Aug 7;124(6):936-45
Cheng GX, Zhu XH, Men XQ, Wang L, Huang QH, Jin XL, Xiong SM, Zhu J, Guo WM, Chen JQ, Xu SF, So E, Chan LC, Waxman S, Zelent A, Chen GQ, Dong S, Liu JX, Chen SJ. Distinct leukemia phenotypes in transgenic mice and different corepressor interactions generated by promyelocytic leukemia variant fusion genes PLZF-RARalpha and NPM-RARalpha. Proc Natl Acad Sci U S A. 1999 May 25;96(11):6318-23
Corey SJ, Locker J, Oliveri DR, Shekhter-Levin S, Redner RL, Penchansky L, Gollin SM. A non-classical translocation involving 17q12 (retinoic acid receptor alpha) in acute promyelocytic leukemia (APML) with atypical features. Leukemia. 1994 Aug;8(8):1350-3
De Braekeleer E, Douet-Guilbert N, De Braekeleer M. RARA fusion genes in acute promyelocytic leukemia: a review. Expert Rev Hematol. 2014 Jun;7(3):347-57
Grimwade D. The pathogenesis of acute promyelocytic leukaemia: evaluation of the role of molecular diagnosis and monitoring in the management of the disease. Br J
t(15;17)(q22;q21) NPM1/RARA Zamecnikova A, al Bahar S
Atlas Genet Cytogenet Oncol Haematol. 2017; 21(12) 469
Haematol. 1999 Sep;106(3):591-613
Hummel JL, Wells RA, Dubé ID, Licht JD, Kamel-Reid S. Deregulation of NPM and PLZF in a variant t(5;17) case of acute promyelocytic leukemia. Oncogene. 1999 Jan 21;18(3):633-41
Ichikawa S, Ichikawa S, Ishikawa I, Takahashi T, Fujiwara T, Harigae H. Successful treatment of acute promyelocytic leukemia with a t(X;17)(p11.4;q21) and BCOR-RARA fusion gene. Cancer Genet. 2015 Apr;208(4):162-3
Kanegane H, Nomura K, Abe A, Makino T, Ishizawa S, Shimizu T, Naoe T, Miyawaki T. Spontaneous regression of aleukemic leukemia cutis harboring a NPM/RARA fusion gene in an infant with cutaneous mastocytosis. Int J Hematol. 2009 Jan;89(1):86-90
Kikuma T, Nakamachi Y, Noguchi Y, Okazaki Y, Shimomura D, Yakushijin K, Yamamoto K, Matsuoka H, Minami H, Itoh T, Kawano S. A new transcriptional variant and small azurophilic granules in an acute promyelocytic leukemia case with NPM1/RARA fusion gene. Int J Hematol. 2015 Dec;102(6):713-8
Otsubo K, Horie S, Nomura K, Miyawaki T, Abe A, Kanegane H. Acute promyelocytic leukemia following aleukemic leukemia cutis harboring NPM/RARA fusion gene. Pediatr Blood Cancer. 2012 Nov;59(5):959-60
Pandolfi PP. PML, PLZF and NPM genes in the molecular pathogenesis of acute promyelocytic leukemia. Haematologica. 1996 Sep-Oct;81(5):472-82
Redner RL, Corey SJ, Rush EA. Differentiation of t(5;17) variant acute promyelocytic leukemic blasts by all-trans retinoic acid. Leukemia. 1997 Jul;11(7):1014-6
Redner RL, Rush EA, Faas S, Rudert WA, Corey SJ. The t(5;17) variant of acute promyelocytic leukemia expresses a nucleophosmin-retinoic acid receptor fusion. Blood. 1996 Feb 1;87(3):882-6
Won D, Shin SY, Park CJ, Jang S, Chi HS, Lee KH, Lee JO, Seo EJ. OBFC2A/RARA: a novel fusion gene in variant acute promyelocytic leukemia. Blood. 2013 Feb 21;121(8):1432-5
Yin CC, Jain N, Mehrotra M, Zhagn J, Protopopov A, Zuo Z, Pemmaraju N, DiNardo C, Hirsch-Ginsberg C, Wang SA, Medeiros LJ, Chin L, Patel KP, Ravandi F, Futreal A, Bueso-Ramos CE. Identification of a novel fusion gene, IRF2BP2-RARA, in acute promyelocytic leukemia. J Natl Compr Canc Netw. 2015 Jan;13(1):19-22
This article should be referenced as such:
Zamecnikova A, al Bahar S. t(5;17)(q35;q21) NPM1/RARA. Atlas Genet Cytogenet Oncol Haematol. 2017; 21(12):466-469.
Solid Tumour Section Short Communication
Atlas Genet Cytogenet Oncol Haematol. 2017; 21(12) 470
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
INIST-CNRS OPEN ACCESS JOURNAL
Nervous system: Astrocytoma with t(1;17)(p36;q21) SPOP/PRDM16 Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers,
France. jean-loup.huret@chu-poitiers.fr
Published in Atlas Database: September 2016
Online updated version : http://AtlasGeneticsOncology.org/Tumors/t0117p36q21ID5447.html
Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/69012/09-2016-t0117p36q21ID5447.pdf DOI: 10.4267/2042/69012
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2017 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Abstract
Review on t(1;17)(p36;q21) SPOP/PRDM16
translocation in astrocytic tumor, with data on the
genes involved.
Keywords
chromosome 1; chromosome 17; t(1;17)(p36;q21);
SPOP; PRDM16, Astrocytic tumor
Clinics and pathology
Disease
A t(1;17)(p36;q21) was found in a case of
astrocytoma grade I-II, but no further data is
available (Yoshihara et al 2015).
Clinics
Grade I astrocytomas are pilocytic astrocytoma and
subependymal giant cell astrocytoma, the latter
being the most common central nervous system
neoplasm in tuberous sclerosis; they are slow
growing tumors; they typically occur during the
first two decades of life. Grade II astrocytomas are
pilomyxoid astrocytoma occurring most often in
infants and very young children, diffuse
astrocytoma, seen at any age, but often between
ages 30-40, and pleomorphic xanthoastrocytoma,
typically developing in children and young adults.
Genes involved and proteins
PRDM16 (PR domain containing 16)
Location
1p36.32
DNA / RNA
11 splice variants
Protein
1276 amino acids and smaller proteins. Contains a
N-term PR domain; 7 Zinc fingers, a proline-rich
domain, and 3 Zinc fingers in the C-term. Binds
DNA.
Transcription activator; PRDM16 has an intrinsic
histone methyltransferase activity. PRDM16 forms
a transcriptional complex with CEBPB. PRDM16
plays a downstream regulatory role in mediating
TGFB signaling (Bjork et al., 2010).
PRDM16 induces brown fat determination and
differentiation. PRDM16 is expressed selectively in
the earliest stem and progenitor hematopoietic cells,
and is required for the maintenance of the
hematopoietic stem cell pool during development.
PRDM16 is also required for survival, cell-cycle
regulation and self-renewal in neural stem cells
(Chuikov et al., 2010; Kajimura et al., 2010; Aguilo
et al., 2011; Chi and Cohen, 2016).
SPOP (speckle type BTB/POZ protein)
Location
17q21.33
DNA / RNA
24 splice variants
Nervous system: Astrocytoma with t(1;17)(p36;q21) SPOP/PRDM16
Huret JL
Atlas Genet Cytogenet Oncol Haematol. 2017; 21(12) 471
Protein
374 amino acids SPOP comprises a N-term MATH
domain (Meprin And TRAF Homology; substrate
recognition and binding), a BTB/POZ domain
(Bric-a-brac, Tramtrack and Broad complex/ Pox
virus and Zinc finger; connects to the CUL3 -
RBX1 (Cullin 3-RING box 1) scaffold protein), a
3-box domain (facilitating CUL3 binding and
resembling to F-/SOCS-boxes) and a C-terminal
nuclear localization sequence. SPOP is a E3
ubiquitin ligase adaptor protein that participates in
the degradation of various substrates. AR (androgen
receptor), DAXX, BMI1, BRMS1 and PDX1 are
targets of SPOP. SPOP is critically involved in
SETD2 (a tumor suppressor) stability. SPOP
enables homology-directed DNA repair of double
strand breaks, and mutant SPOP promotes genomic
rearrangements within chromosomes. SPOP
suppresses gastric tumorigenesis through inhibiting
hedgehog/ GLI2 signaling pathway. SPOP is
frequently mutated in prostate and endometrial
cancers. TMPRSS2 - ERG fusions, frequently seen
in prostate carcinoma, encode N-terminal-truncated
ERG proteins that are resistant to the SPOP-
mediated degradation. Decreased expression of
SPOP is associated with poor prognosis in glioma.
On the other hand, SPOP is highly expressed in
clear cell renal cell carcinoma (Zhuang et al., 2009;
Mani, 2014; Zeng et al., 2014; Karnes et al., 2015;
Ding et al., 2015; Rider and Cramer, 2015).
References Aguilo F, Avagyan S, Labar A, Sevilla A, Lee DF, Kumar P, Lemischka IR, Zhou BY, Snoeck HW. Prdm16 is a physiologic regulator of hematopoietic stem cells. Blood. 2011 May 12;117(19):5057-66
An J, Ren S, Murphy SJ, Dalangood S, Chang C, Pang X,
Cui Y, Wang L, Pan Y, Zhang X, Zhu Y, Wang C, Halling GC, Cheng L, Sukov WR, Karnes RJ, Vasmatzis G, Zhang Q, Zhang J, Cheville JC, Yan J, Sun Y, Huang H. Truncated ERG Oncoproteins from TMPRSS2-ERG
Fusions Are Resistant to SPOP-Mediated Proteasome Degradation. Mol Cell. 2015 Sep 17;59(6):904-16
Bjork BC, Turbe-Doan A, Prysak M, Herron BJ, Beier DR. Prdm16 is required for normal palatogenesis in mice. Hum Mol Genet. 2010 Mar 1;19(5):774-89
Chi J, Cohen P. The Multifaceted Roles of PRDM16: Adipose Biology and Beyond. Trends Endocrinol Metab. 2016 Jan;27(1):11-23
Chuikov S, Levi BP, Smith ML, Morrison SJ. Prdm16 promotes stem cell maintenance in multiple tissues, partly by regulating oxidative stress. Nat Cell Biol. 2010 Oct;12(10):999-1006
Ding D, Song T, Jun W, Tan Z, Fang J. Decreased expression of the SPOP gene is associated with poor prognosis in glioma. Int J Oncol. 2015 Jan;46(1):333-41
Kajimura S, Seale P, Kubota K, Lunsford E, Frangioni JV, Gygi SP, Spiegelman BM. Initiation of myoblast to brown fat switch by a PRDM16-C/EBP-beta transcriptional complex. Nature. 2009 Aug 27;460(7259):1154-8
Mani RS. The emerging role of speckle-type POZ protein (SPOP) in cancer development. Drug Discov Today. 2014 Sep;19(9):1498-502
Rider L, Cramer SD. SPOP the mutation. Elife. 2015 Oct 27;4
Yoshihara K, Wang Q, Torres-Garcia W, Zheng S, Vegesna R, Kim H, Verhaak RG. The landscape and therapeutic relevance of cancer-associated transcript fusions. Oncogene. 2015 Sep 10;34(37):4845-54
Zeng C, Wang Y, Lu Q, Chen J, Zhang J, Liu T, Lv N, Luo S. SPOP suppresses tumorigenesis by regulating Hedgehog/Gli2 signaling pathway in gastric cancer. J Exp Clin Cancer Res. 2014 Sep 11;33:75
Zhuang M, Calabrese MF, Liu J, Waddell MB, Nourse A, Hammel M, Miller DJ, Walden H, Duda DM, Seyedin SN, Hoggard T, Harper JW, White KP, Schulman BA. Structures of SPOP-substrate complexes: insights into molecular architectures of BTB-Cul3 ubiquitin ligases. Mol Cell. 2009 Oct 9;36(1):39-50
This article should be referenced as such:
Nervous system: Astrocytoma with t(1;17)(p36;q21) SPOP/PRDM16. Nervous system: Astrocytoma with t(1;17)(p36;q21) SPOP/PRDM16. Atlas Genet Cytogenet Oncol Haematol. 2017; 21(12):470-471.
Solid Tumour Section Short Communication
Atlas Genet Cytogenet Oncol Haematol. 2017; 21(12) 472
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
INIST-CNRS OPEN ACCESS JOURNAL
Chromophobe renal cell carcinoma Paola Dal Cin, Michelle S. Hirsch
Department of Pathology, Brigham, Women's Hospital, 75 Francis Street, Boston, MA 02115, USA
Published in Atlas Database: November 2016
Online updated version : http://AtlasGeneticsOncology.org/Tumors/ChromophobeRenalID5124.html
Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/69013/11-2016-ChromophobeRenalID5124.pdf DOI: 10.4267/2042/69013
This article is an update of: Dal Cin P. Kidney: Chromophobe renal cell carcinoma. Atlas Genet Cytogenet Oncol Haematol 2002;6(1)
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2017 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Abstract
Review on chromophobe renal cell carcinoma, with
data on clinics and cytogenetics.
Classification
Chromophobe renal cell carcinoma (ChRCC) is a
distinct subtype of renal cell carcinoma, possibly
originating from the the distal nephron.
Clinics and pathology
Epidemiology
ChRCC comprise ~5% of all renal cell carcinomas.
Most tumors are sporadic, with a slight male
predilection.
Pathology
ChRCC tumors can vary in size and have a tan to
brown cut surface. The growth pattern is often solid
with sheets of cells divided by vascular septae,
some of which may have perivascular hyalinized
stroma. ChRCC tumor cells have pale cytoplasm
and distinct cell membranes. Small eosinophilic
cells with granular appearance may be present.
Nuclei may appear atypical, but are usually small
with wrinkled nuclear membranes and
multinucleation (Fig1A). ChRCC grading is
complicated by the nuclear atypia, and Fuhrman
nuclear grading should not be used. Prognosis is
generally favorable with low grade, low stage
tumors; but increased cytologic atypia, increased
mitotic activity, necrosis, and vascular invasion are
poor prognostic indicators. Sarcomatoid
differentiation and high tumor stage are also
predictors of poor outcome.
Special stains and immunohistochemistry can be
used to distinguish ChRCC from other renal
epithelial neoplasms. The presence of Hale's
colloidal iron in the cytoplasm of tumor cells is
supportive of ChRCC (an apical staining pattern is
more supportive of oncocytoma) (Fig.1B).
Immunohistochemical expression of CK7 (patchy
to diffuse) combined with the absence of S100A1,
HNF1beta (nuclear), and CD10 is consistent with a
ChRCC.
Occasionally composite oncocytic tumors with
features of both oncocytoma and ChRCC tumors
have been described, and are most commonly seen
in patients with Birt-Hogg-Dube' syndrome and/or
oncocytosis.
Fig. 1A: ChRCC (H&E stain) is comprised of sheets of tumor cells with well-defined cell borders, round to
raisonoid nuclei, and perinuclear halos. Long linear, parallel vessels are common in ChRCC.
Chromophobe renal cell carcinoma Dal Cin P, Hirsch MS
Atlas Genet Cytogenet Oncol Haematol. 2017; 21(12) 473
Fig 1B: A Hale's colloidal iron stain is positive (blue) in the
cytoplasm of ChRCC tumor cells.
Cytogenetics
Cytogenetics Morphological
Chromophobe RCCs generally have a tendency to
grow very slowly in vitro in comparison to all other
type of renal tumors. This may be a reason why
cytogenetic reports are scarce and usually few
metaphases of poor quality were available for
investigation. A low chromosome number ranging
between 32-39, without discernible structural
changes was the most frequent cytogenetic finding.
Chromosomes 1, 2, 6, 10, 13, 17 and 21 were most
frequently lost (Fig.2). Endoreduplication of the
cells with hypodiploid karyotype has been
observed. It is of interest, the presence of an
hypodiploid clone can be disclosed by a DNA index
of 0.86. The low chromosome number has been
confirmed by other techniques such as flow
cytometry, comparative genomic hybridization
(CGH), restriction fragment length polymorphism
(RFLP) analysis, and polymorphic microsatellite
markers.
Genes involved and Proteins
Note
High resolution DNA-microarray analysis excluded
the occurrence of small specific alteration
confirming that this combination of monosomies
occurs exclusively in chromophobe subtype of
RCC. The most commonly mutated genes in
chRCC are TP53 and PTEN, combined with
chromosome 17 and 10 deletions (Haake et al
2016).
Whole genomes sequencing identified a number of
genomic rearrangements in the TERT promoter
region, these same tumors displayed elevated TERT
gene expression, suggesting a functional role for
these gene fusions.
TERT (telomerase reverse transcriptase)
Location 5p15.33
Note Structural rearrangements in the TERT promoter
region and TERT upregulation are found in a subset
of chromophobe RCCs.
Protein Telomerase encodes a catalytic subunit of the
telomerase enzyme, which functions to maintain
telomere ends. Telomerase is upregulated in a
variety of tumors and plays a role tumor cell
immortalization.
PTEN (Phosphatase and Tensin homolog deleted on chromosome Ten) Location 10q23.31
Note PTEN mutations are found in approximately 20%
of chromophobe RCCs1.
Protein PTEN mutations frequently co-occur with loss of
chromosome 10 resulting in complete loss of
function. PTEN is a tumor suppressor that functions
as a protein and lipid phosphatase and negatively
regulates the PI3K-AKT/PKB signaling pathway.
TP53 (Tumour protein p53 (Li-Fraumeni syndrome)) Location 17p13.1
Note Approximately 32% of chromophobe RCCs have a
TP53 mutation.
Protein TP53 encodes a tumor suppressor protein, which
plays a regulatory role in many cellular processes
including DNA repair, growth arrest, apoptosis,
senescence and metabolism. Mutations in TP53 are
found in a broad range of tumor types.
Chromophobe renal cell carcinoma Dal Cin P, Hirsch MS
Atlas Genet Cytogenet Oncol Haematol. 2017; 21(12) 474
Fig.2. GTG-banded karyotype showing combination of monosomies 1, 2, 6, 8, 10, 13, 15, 17 and 22, and loss of the Y-chromosome
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Moch, H., Humphrey, P.A., Ulbright, T.M., Reuter, V.E.World Health Organization Classification of Tumours of the Urinary Systems and Male Genital Organs eds (4th edition); IARC Press, Lyon 2016; 11-76.
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Haake SM, Weyandt JD, Rathmell WK. Insights into the Genetic Basis of the Renal Cell Carcinomas from The Cancer Genome Atlas. Mol Cancer Res 2016 Jul;14(7):589-98
Hirsch MS, Signoretti S, Dal Cin P. Adult Renal Cell Carcinoma: A Review of Established Entities from Morphology to Molecular Genetics. Surg Pathol Clin 2015 Dec;8(4):587-621
Iqbal MA, Akhtar M, Ulmer C, Al-Dayel F, Paterson MC. FISH analysis in chromophobe renal-cell carcinoma. Diagn
Cytopathol 2000 Jan;22(1):3-6
Kovacs A, Kovacs G. Low chromosome number in chromophobe renal cell carcinomas. Genes Chromosomes Cancer 1992 Apr;4(3):267-8
Kovacs G, Soudah B, Hoene E. Binucleated cells in a human renal cell carcinoma with 34 chromosomes. Cancer Genet Cytogenet 1988 Apr;31(2):211-5
Speicher MR, Schoell B, du Manoir S, Schröck E, Ried T, Cremer T, Störkel S, Kovacs A, Kovacs G. Specific loss of chromosomes 1, 2, 6, 10, 13, 17, and 21 in chromophobe renal cell carcinomas revealed by comparative genomic hybridization. Am J Pathol 1994 Aug;145(2):356-64
Srigley JR, Delahunt B, Eble JN, Egevad L, Epstein JI, Grignon D, Hes O, Moch H, Montironi R, Tickoo SK, Zhou M, Argani P; ISUP Renal Tumor Panel
The International Society of Urological Pathology (ISUP) Vancouver Classification of Renal Neoplasia Am J Surg Pathol
Störkel S, Steart PV, Drenckhahn D, Thoenes W. The human chromophobe cell renal carcinoma: its probable relation to intercalated cells of the collecting ductVirchows Arch B Cell Pathol Incl Mol Pathol 1989;56(4):237-45
Tan PH, Cheng L, Rioux-Leclercq N, Merino MJ, Netto G, Reuter VE, Shen SS, Grignon DJ, Montironi R, Egevad L, Srigley JR, Delahunt B, Moch H; ISUP Renal Tumor PanelRenal tumors: diagnostic and prognostic biomarkers Am J Surg Pathol
Tickoo SK, Amin MB, Zarbo R. Colloidal iron staining in renal epithelial neoplasms, including chromophobe renal cell carcinoma: emphasis on technique and patterns of staining. Am J Surg Pathol 1998 Apr;22(4):419-24
This article should be referenced as such:
Dal Cin P, Hirsch MS. Chromophobe renal cell carcinoma. Atlas Genet Cytogenet Oncol Haematol. 2017; 21(12):472-474.
Cancer Prone Disease Section Review
Atlas Genet Cytogenet Oncol Haematol. 2017; 21(12) 475
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
INIST-CNRS OPEN ACCESS JOURNAL
Ataxia telangiectasia (A-T) Yossi Shiloh
The David and Inez Myers Chair in Cancer Research, Department of Human Molecular Genetics and
Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel;
yossih@post.tau.ac.il
Published in Atlas Database: October 2016
Online updated version : http://AtlasGeneticsOncology.org/Kprones/ataxiaID10003.html
Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/69014/10-2016-ataxiaID10003.pdf DOI: 10.4267/2042/69014
This article is an update of : Huret, JL. Ataxia telangiectasia. Atlas Genet Cytogenet Oncol Haematol. 1998;2(4):153-154. Uhrhammer, N ; Bay, JO ; Gatti, RA. Ataxia telangiectasia. Atlas Genet Cytogenet Oncol Haematol. 1999;3(4):209-211. Uhrhammer, N ; Bay, JO ; Gatti, RA. Ataxia telangiectasia. Atlas Genet Cytogenet Oncol Haematol. 2003;7(1):52-54.
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2017 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Abstract
Review on Ataxia telangiectasia, with data on
clinics, and the gene involved.
Keywords
Review on Ataxia telangiectasia, with data on
clinics, and the gene involved.
Identity
Other names
Louis-Bar syndrome
Note
See also, in Deep Insight section: Ataxia-
Telangiectasia and variants.
Inheritance
Autosomal recessive disease. Genome instability
syndrome found worldwide with incidence of .0.5.
to 2.5/105 newborns in different human populations.
A founder effect is found in some isolated
population. Heterozygotes are estimated to be 1%
of the general population. The clinical phenotype of
A-T ranges from severe to milder variants of the
disease, but is usually portrayed by its classical,
severe form (Perlman SL et al., 2012; Lavin MF,
2008; Crawford TO, 1998; Chun HH et al., 2004;
Nissenkorn A et al., 2016). However, awareness is
growing of the broad clinical variability associated
with the causative mutations (Taylor AM et al.,
2015).
The primary cause of all variants of the disease is
mutations in the autosomal gene ATM (A-T,
mutated) at 11q22-23 (Gatti RA et al., 1988;
Savitsky K et al., 1995a), which encodes the ATM
protein (Savitsky K et al., 1995b; Ziv Y et al.,
1997) a multi-functional protein kinase (Shiloh Y et
al., 2013; Shiloh Y, 2014; Guleria A et al., 2016;
Ditch S et al., 2012).
Clinics Ataxia telangiectasia is a chromosome instability
syndrome (Perlman SL et al., 2012; Lavin MF,
2008; Crawford TO, 1998; Chun HH et al., 2004;
Taylor AM et al., 1982; Taylor AM et al., 2015;
Taylor AM, 1978; Butterworth SV et al., 1986;
Kennaugh AA et al., 1986) with cerebellar
degeneration, immunodeficiency, and an increased
risk of cancers; A-T cells are defective in
recognizing double-strand DNA damage to signal
for repair.
The cellular phenotype of A-T represents genome
instability, deficient DNA damage response (DDR),
and elevated oxidative stress, in addition to a
premature senescence component (Shiloh Y et al.,
1982). A-T patients show a striking sensitivity to
the cytotoxic effect of ionizing radiation (Gotoff SP
et al., 1967; Morgan JL et al., 1968). Cells from A-
T patients exhibit marked chromosomal instability
and sensitivity to ionizing radiations and
radiomimetic chemicals (Taylor AM, 1978; Taylor
AM et al., 1975; Taylor AM et al., 1979; Shiloh Y
Ataxia telangiectasia (A-T) Shiloh Y
Atlas Genet Cytogenet Oncol Haematol. 2017; 21(12) 476
et al., 1982; Shiloh Y et al., 1983; Djuzenova CS et
al., 1999). This acute sensitivity results from a
profound defect in the cellular response to DNA
double-strand breaks (DSBs), whose chief
mobilizer is the ATM protein. It is important to
note, however, that A-T cells are also moderately
sensitive to a wide array of other DNA damaging
agents suggesting that these cells cope less
efficiently with many other DNA lesions besides
DSBs.
Phenotype and clinics
Onset of the disease is often noted during the
second year of life: there is progressive cerebellar
ataxia (initially truncal, with further peripheral
extension); ataxia is a constant feature in this
disease; oculomotor apraxia, dysarthria, and
dystonia; leading to muscular atrophia.
Cerebellar ataxia. The prominent symptom of
classical A-T is progressive cerebellar ataxia that
develops into a general motor dysfunction,
eventually confining most patients to a wheelchair
around the end of their first decade (Crawford TO,
1998; Chun HH et al., 2004; Nissenkorn A et al.,
2016; Boder E et al., 1958; Sedgwick RP et al.,
1960; Boder E, 1985; Crawford TO et al., 2000;
Gatti RA, 1995; Verhagen MM et al., 2012). The
main underlying pathology appears to be
progressive cerebellar cortical degeneration that
primarily affects Purkinje and granule neurons, but
also basket cells (Vinters HV et al., 1985; Gatti RA
et al., 1985).
Impairment of the extrapyramidal movement
system is common in A-T, as are oculomotor
abnormalities such as apraxia, strabismus and
nystagmus. Swallowing and articulation of speech
are often abnormal, and facial expression is limited.
Dysfunctional swallowing is often associated with a
general nutritional problem as well as clinically
unapparent aspiration, which is thought to play a
role in the increasing frequency of lower respiratory
tract infections in many patients (Lefton-Greif MA
et al., 2000; Bhatt JM et al., 2015). An absence of
deep reflexes and peripheral neuropathy are
common in A-T, but usually develop relatively later
than other neurological impairments (Nissenkorn A
et al., 2016).
Oculocutaneous telangiectasia (dilated blood
vessels) appear at various ages, usually in the eyes
(conjunctiva) and sometimes on the ears and facial
skin exposed to sunlight, (Perlman SL et al., 2012;
Greenberger S et al., 2013). Finally, telangiectasia
appear in the brain and other internal organs of
young adults with A-T, a peculiar finding seen in
people without A-T only as a late effect of
treatment with ionizing radiation for cancer therapy
(Lin DD et al., 2014).
Combined Immunodeficiency (in 70 %) is
another hallmark of A-T. Typically, IgA, IgE and
various IgG subclasses are reduced; a diminished
lymphocyte count is common, affecting B and T
but not natural killer cells, and many have impaired
antibody responses to vaccines (Gatti RA, 1995),
(Nowak-Wegrzyn A et al., 2004; Gatti RA et al.,
1982; Weaver M et al., 1985; Härtlova A et al.,
2015). The thymus is typically vestigial, as are the
gonads.
Growth/Puberty. Many children with A-T grow at
a diminished rate, and puberty is often delayed; this
growth retardation was suggested to result from a
primary endocrine defect (Ehlayel M et al., 2014;
Voss S et al., 2014; Pommerening H et al., 2015;
Ehlayel M et al., 2014), or a primary growth defect
(Nissenkorn A et al., 2016), but is probably also a
function of swallowing problems making eating an
inefficient and exhausting task.
Dyslipidemia and diabetes. There was also an
increased incidence of dyslipidemia (10/52 = 19%)
and diabetes (2/52 = 4%; Nissenkorn A et al.,
2016). These abnormalities together with elevated
levels of C-reactive protein suggest a diagnosis of
metabolic syndrome in a substantial number of
young A-T patients. Insulin-resistant diabetes is an
important endocrine abnormality in some patients
(Nissenkorn A et al., 2016; Schalch DS et al., 1970;
Morrell D et al., 1986; Blevins LS Jr et al., 1996).
Osteoporosis is common because of a lack of
weight bearing, nutritional deficiencies, and early
gonadal failure in females. Incapacitating fatigue
affects a majority of A-T patients over the age of
30. The etiology of this problem is likely to be
multifactorial, with contributions from the extra
effort required to function with neurodegeneration,
and central nervous system effects of elevated
levels of pro-inflammatory cytokines including IL-
6 and IL-8 (McGrath-Morrow SA et al., 2016) and
chronic, elevated levels of Type I interferons
(Härtlova A et al., 2015).
SenescenceA-T has recently emerged as a
premature aging disease. The broad immune system
defects in A-T have been regarded as a reflection of
premature ageing of this system in these patients
(Exley AR et al., 2011; Carney EF et al., 2012).
Finding striking similarities between the immune
system phenotypes of A-T patients and the elderly
(Carney EF et al., 2012), it was concluded that the
immune system of A-T patients is congenitally
aged, and A-T could be viewed as a model of
immune ageing (Exley AR et al., 2011). Similarly,
the resemblance between ageing-associated decline
of brain functionality and neurodegeneration
associated with genome instability has recently
been highlighted (Barzilai A et al., 2016).
Adolescents and young adults with A-T exhibit an
array of health problems that are typically not seen
until late middle age or later. Among 53 A-T
patients with mean age of 14.6 years (range 5.9 -
26.1), 43% had elevated serum transaminases, 39%
Ataxia telangiectasia (A-T) Shiloh Y
Atlas Genet Cytogenet Oncol Haematol. 2017; 21(12) 477
of those patients had fatty liver detected by
ultrasound, and 33% of the latter group developed
steatohepatitis , fibrosis or cirrhosis (Weiss B et al.,
2016). Progeric features of skin include premature
greying and thinning of hair, thinning of skin, and
vitiligo (Reed WB et al., 1966).
Neoplastic risk
Another prominent clinical hallmark of A-T is
cancer predisposition; risk of cancers is X 100,
consisting mainly of T- cell malignancies (a 70-fold
and 250-fold increased risks of leukemia of both B
cell and T cell origin, and 250-fold increased risks
of non-Hodgkin's lymphoma and Hodgkin's
lymphoma), but not myeloid leukemia (Loeb DM et
al., 2000; Murphy RC et al., 1999; Olsen JH et al.,
2001; Taylor AM et al., 1982). There is a striking
incidence of gammopathy in A-T (Sadighi Akha
AA et al., 1999), another abnormality that is rarely
seen in people < 30 years old.
The most common malignancies in A-T patients of
all ages are of lymphocytic origin. However, among
those from 18-40 years old with cancer, 11/21
(52%) had cancers of solid organs (stomach,
esophagus,liver,parotid gland, thyroid, skin,breast
and lung) that are rarely seen in that age group
among people without A-T (HM Lederman, L
Chessa, unpublished observations).
Cancer treatment is complicated by radiation- and
chemo-sensitivity.
Evolution
Progressive cerebellar degeneration: patients are
usually in a wheelchair by the age of ten.
Prognosis
Respiratory infection is the common cause of death,
with cancer being the second most common.
Survival is often into fourth decade today where
optimal medical care is available.
Cytogenetics
Difficulty to grow cells with phytohemaglutinin:
karyotypes should be performed with interleukine 2
in 4 days cultures.
Lymphocyte cultures from A-T patients often
contain clonal translocations that mainly involve
the loci of the T-cell receptor and immunoglobulin
heavy-chain genes (Butterworth SV et al., 1986;
Kennaugh AA et al., 1986; Taylor AM et al., 1986;
Heppell A et al., 1988; Kojis TL et al., 1991),
pointing to a defect in the maturation of these genes
via V(D)J and class-switch recombination in the
adaptive immune system. Such clones usually
herald the onset of malignancy and expand as
malignancy progresses. Cultured A-T cell strains
exhibit elevated rates of chromosome end
associations and reduced telomere length (Pandita
TK et al., 1995; Smilenov LB et al., 1999; Wood
LD et al., 2001; Metcalfe JA et al., 1996; Vaziri H,
1997). A-T fibroblast strains exhibit similar growth
properties to wild-type cells at early passage levels
but senesce prematurely (Shiloh Y et al., 1982).
Inborn conditions
Spontaneous chromatid/chromosome breaks,
triradials, quadriradials (less prominent
phenomenon than in Fanconi anaemia); telomeric
associations.
The best diagnosis test is on the (pathognomonic)
highly elevated level (10% of mitoses) of
inv(7)(p14q35), t(14;14)(q11;q32), and other non
clonal stable chromosome rearrangements
involving 2p12, 7p14, 7q 35, 14q11, 14q32, and
22q11 (illegitimate recombinations between
immunoglobulin superfamilly genes Ig and TCR);
normal level of those rearrangements are: 1/500
(inv(14)), 1/200 (t(7;14)), 1/10 000 (inv(7)).
Clonal rearrangements further occur in 10% of
patients, but without manifestation of malignancy:
t(14;14), inv(14), or t(X;14).
Cytogenetics of cancer
Clonal rearrangements in T-cell ALL and T-PLL
(prolymphocytic leukaemia) in AT patients are
complex, with the frequent involvement of
t(14;14)(q11;q32)(q11;q32), or t(X;14)(q28;q11),
implicating the genes TCL1 or MTCP1
respectively, as is found in T-Pro Lymphocytic
Leukemia in non-AT patients.
Other findings
High sensitivity to ionizing radiations and to
radiomimetic drugs (diagnostic may in part be
based on the hypersensitivity of AT lymphocytes to
killing by gamma irradiation); cell irradiation does
not inhibit S phase (DNA synthesis): this is quite
pathognomonic of AT, and shows that G1
checkpoint is deficient; there is a lack of TP53,
GADD45 and CDKN1A (P21) induction, and a fall
in radiation-induced apoptosis; TP53
phosphorylation at ser15 is deficient.
Telomeres. The observation of accelerated
telomere shortening and telomere fusions in
peripheral blood lymphocytes (Metcalfe JA et al.,
1996) and cultured fibroblasts (Xia SJ et al., 1996;
Smilenov LB et al., 1997) from A-T patients and
cell lines expressing dominant-negative ATM
fragments (Smilenov LB et al., 1997) exposed an
important possible contributor to premature
senescence of ATM-deficient cells. The wealth of
information currently available on telomere
maintenance and the role of the DDR in telomere
dynamics (reviewed in (Webb CJ et al., 2013;
Doksani Y et al., 2014; Arnoult N et al., 2015) has
tightly linked ATM to telomere homeostasis and
added an important component to the ageing aspect
of A-T.
Ataxia telangiectasia (A-T) Shiloh Y
Atlas Genet Cytogenet Oncol Haematol. 2017; 21(12) 478
Sporadic (rows 1 and 2) and clonal (row 3) rearrangements in ataxia telangiectasia (R- banding). Row 1, from left to right: inv(7)(p14q35), t(7;7)(p14;q35), t(14;14)(q11;q32), inv(14)(q11q32); Row 2:, from left to right: t(7;14)(p14;q11), t(7;14)(q35;q11), t(7;14)(p14;q32), t(7;14)(q35;q32); Row 3, from left to right: inv(14)(q11;q32), t(X;14)(q28;q11) (note the late replicating X on the
left ), t(14;14)(q11;q32) - Courtesy Alain Aurias (modified figure reprinted from Médecine/Sciences 1986; 2: 298-303., by permission of the publisher Masson).
Lenthening of the cell cycle.
Oxidative stress. Increasing numbers of reports
have described elevated readouts of oxidative stress
in plasma of A-T patients (Reichenbach J et al.,
2002), in cultured A-T fibroblasts (Gatei M et al.,
2001; Lee SA et al., 2001) and lymphocytes
(Ludwig LB et al., 2013), and in tissues and
cultured cells from Atm-deficient mice (Barlow C
et al., 1999; Kamsler A et al., 2001; Gage BM et
al., 2001; Ziv S et al., 2005; Chen P et al., 2003;
Reliene R et al., 2004; Reliene R et al., 2007; Liu N
et al., 2005; McDonald CJ et al., 2011). Notably,
the response of A-T fibroblast strains to induced
oxidative stress was found defective (Yi M et al.,
1990; Ward AJ et al., 1994). These observations
were later linked to the role of ATM in regulating
cellular oxidative stress.
Alpha fetoprotein/serum carcinoembryonic
antigen Notable laboratory findings are elevation
of serum alpha fetoprotein and serum
carcinoembryonic antigen. Further aspects of A-T,
which entail segmental premature ageing.
Genes involved and proteins
Gene
ATM (ataxia telangiectasia mutated)
Location
11q22.3
DNA/RNA
Description
66 exons spanning 184 kb of genomic DNA.
Transcription
Northern blot analysis shows two transcript: the
first-one, TRIM37a of about 4.5-kb and the second-
one, TRIM37b of approximately 3.9 kb.
Protein
Description
3056 amino acids; 350 kDa; contains a Pl 3-kinase-
like domain.
Ataxia telangiectasia (A-T) Shiloh Y
Atlas Genet Cytogenet Oncol Haematol. 2017; 21(12) 479
Localisation
Mostly in the nucleus in replicating cells, cytoplasm
in differentiating cells.
Function
Homeostatic protein kinase involved in many
cellular circuits. A primary role in the DNA damage
response. Activated vigorously by DNA double-
strand breaks and activates a broad network of
responses. ATM initiates cell cycle checkpoints in
response to double-strand DNA breaks by
phosphorylating TP53, BRCA1, H2AFX ID:
40783,
Double strand breaks. The most widely
documented function of ATM, and the one
associated with its most vigorous activation, is the
mobilization of the complex signaling network that
responds to DSBs in the DNA (Shiloh Y et al.,
2013; Cremona CA et al., 2014; Awasthi P et al.,
2016; Thompson LH, 2012; McKinnon PJ, 2012).
DSBs are induced by exogenous DNA breaking
agents or endogenous reactive oxygen species
(Schieber M et al., 2014), and are an integral part of
physiological processes including meiotic
recombination (Borde V et al., 2013; Lange J et al.,
2011) and the rearrangement of antigen receptor
genes in the adaptive immune system (Alt FW et
al., 2013). DSBs are repaired via nonhomologous
end-joining (NHEJ), or homologous recombination
repair (HRR; Shibata A et al., 2014; Chapman JR et
al., 2012; Jasin M et al., 2013; Radhakrishnan SK et
al., 2014). Once ATM mobilizes the vast DDR
network in response to a DSB (McKinnon PJ, 2012;
Shiloh Y et al., 2013; Bhatti S et al., 2011), its
protein kinase activity is rapidly enhanced. ATM
subsequently phosphorylates key players in various
arms of the DSB response network (Shiloh Y et al.,
2013; Bensimon A et al., 2010; Matsuoka S et al.,
2007; Mu JJ et al., 2007; Bensimon A et al., 2011),
including other protein kinases that in turn
phosphorylate still other targets (Bensimon A et al.,
2011).
Single-strand break repair and base excision
repair. A broader, overarching role for ATM in
maintaining genome stability was recently
suggested in addition to mobilizing the DSB
response (Shiloh Y, 2014). According to this
conjecture, ATM supports other DNA repair
pathways that respond to various genotoxic
stresses, among them single-strand break repair
(SSBR; Khoronenkova SV et al., 2015) and base
excision repair (BER) - a cardinal pathway in
dealing with the daily nuclear and mitochondrial
DNA damage caused by endogenous agents
(Wallace SS, 2014; Bauer NC et al., 2015). ATM's
involvement in these processes is based on its
ability to phosphorylate proteins that function in
these pathways.
This ongoing role of ATM is its routine function in
the daily maintenance of genome stability, while its
powerful role in the DSB response is reserved for
when this harmful lesion interferes with the daily
life of a cell. Thus, when ATM is missing, not only
is there markedly reduced response to DSBs, the
ongoing modulation of numerous pathways in
response to occasional stresses becomes
suboptimal. All of these lesions are part of the daily
wear and tear on the genome that contributes to
ageing.
An additional role for ATM in genome dynamics
was proposed following evidence that ATM is
involved in shaping the epigenome in neurons by
regulating the localization of the histone
deacetylase 4 (HDAC4; Li J et al., 2012; Herrup K
et al., 2013; Herrup K, 2013), targeting the EZH2
component of the polycomb repressive complex 2
(Li J et al., 2013), and regulating the levels of 5-
hydroxymethylcytosine in Purkinje cells (Jiang D et
al., 2015).
Oxidative stress/Cellular homeostasis. Cytoplasmic fraction of ATM. ATM's role in
cellular homeostasis is further expanded by its
cytoplasmic fraction. Specifically, cytoplasmic
ATM was found to be associated with peroxisomes
(Watters D et al., 1999; Tripathi DN et al., 2016;
Zhang J et al., 2015) and mitochondria (Valentin-
Vega YA et al., 2012). In view of the evidence of
increased oxidative stress in ATM-deficient cells, it
has long been suspected that ATM senses and
responds to oxidative stress (Gatei M et al., 2001;
Rotman G et al., 1997; Rotman G et al., 1997;
Barzilai A et al., 2002; Watters DJ, 2003; Takao N
et al., 2000; Alexander A et al., 2010). This
conjecture was validated by work from the Paull lab
(Guo Z et al., 2010a), which identified an MRN-
independent mode of ATM activation,
differentiating it from DSB-induced activation,
stimulated by reactive oxygen species (ROS) and
leading to ATM oxidation (Paull TT, 2015; Guo Z
et al., 2010a; Guo Z et al., 2010b; Lee JH et al.,
2014).
Mitochondrial fraction of ATM. Still another
arm of the ATM-mediated response to oxidative
stress operates in the mitochondrial fraction of
ATM. ATM is thus emerging also as a regulator of
mitochondrial homeostasis. Evidence is
accumulating of its involvement in mitochondrial
function, mitophagy, and the integrity of
mitochondrial DNA (Valentin-Vega YA et al.,
2012; Ambrose M et al., 2007; Eaton JS et al.,
2007; Fu X et al., 2008; Valentin-Vega YA et al.,
2012; D'Souza AD et al., 2013; Sharma NK et al.,
2014) and further work is needed to identify its
substrates in mitochondria and the mechanistic
aspects of its action in this arena.
Ataxia telangiectasia (A-T) Shiloh Y
Atlas Genet Cytogenet Oncol Haematol. 2017; 21(12) 480
Links between ATM and the SASP (senescence-
associated secretory phenotype). Several
laboratories recently described direct links between
ATM and the SASP - a cardinal feature of cell
senescence. Work from the Gamble lab (Chen H et
al., 2015) showed that the histone variant
macroH2A.1 is required for full transcriptional
activation of SASP-promoting genes, driving a
positive feedback loop that enhances cell
senescence. This response is countered by a
negative feedback loop that involves ATM
activation by endoplasmic reticulum stress, elevated
ROS levels or DNA damage. ATM's activity is
required for the removal of macroH2A.1 from sites
of SASP genes, thus leading to SASP gene
repression.
Insulin response and lipoprotein metabolism. IGF-1 receptor. Another pathway by which ATM
may impact on cellular senescence is the
dependence of IGF1R (IGF-1 receptor) expression
on ATM (Peretz S et al., 2001; Goetz EM et al.,
2011; Ching JK et al., 2013).
Beta-adrenergic receptor. Another series of
observations assigned ATM a protective role in
cardiac myocyte apoptosis stimulated by β-
adrenergic receptor and myocardial remodeling.
Mutations
Germinal
Various types of mutations, dispersed throughout
the gene, and therefore most patients are compound
heterozygotes; however, most mutations appear to
inactivate the ATM protein by truncation, large
deletions, or annulation of initiation or termination.
Missense mutations have been described in breast
cancer patients, but do not seem to contribute to
ataxia-telangiectasia.
Patients with the severe form of A-T are
homozygous or compound heterozygous for null
ATM alleles. The corresponding mutations usually
lead to truncation of the ATM protein and
subsequently to its loss due to instability of the
truncated derivatives; a smaller portion of the
mutations create amino acid substitutions that
abolish ATM's catalytic activity (Taylor AM et al.,
2015; Gilad S et al., 1996; Sandoval N et al., 1999;
Barone G et al., 2009) (see also
http://chromium.liacs.nl/LOVD2/home.php?select_
db=ATM).
Careful inspection of the neurological symptoms of
A-T patients reveals variability in their age of onset
and rate of progression among patients with
different combinations of null ATM alleles (Taylor
AM et al., 2015; Crawford TO et al., 2000;
Alterman N et al., 2007). Thus, despite the identical
outcome in terms of ATM function, additional
genes may affect the most cardinal symptom of A-
T. Other, milder types of ATM mutations further
extend this variability, and account for forms of the
disease with extremely variable severity and age of
onset of symptoms.
The corresponding ATM genotypes are
combinations of hypomorphic alleles or
combinations of null and hypomorphic ones. Many
of the latter are leaky splicing mutations and others
are missense mutations, eventually yielding low
amounts of active ATM (Taylor AM et al., 2015;
Alterman N et al., 2007; Soresina A et al., 2008;
Verhagen MM et al., 2009; Silvestri G et al., 2010;
Saunders-Pullman R et al., 2012; Verhagen MM et
al., 2012; Worth PF et al., 2013; Claes K et al.,
2013; Méneret A et al., 2014; Nakamura K et al.,
2014; Gilad S et al., 1998).
To be noted Heterozygote cancer risk: the relative risk of breast
cancer in A-T heterozygote women has been
estimated through epidemiological studies to be 3.9
(CI 2.1-7.1), and through haplotype analysis to be
3.32 (CI 1.75-6.38); since the A-T heterozygote
frequency is about 1 %, 2-4 % of breast cancer
cases may be due to ATM heterozygosity; the risk
of other types of cancer in A-T heterozygotes is
low.
The A-T variant Nijmegen breakage syndrome does
not involve the same gene, but, instead, NBN or
RAD50, involved in the MRE11/RAD50/NBN
double-strand break repair complex.
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