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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



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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; [email protected]

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


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


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





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; [email protected]; [email protected]

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)


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


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


Mathien S, Meloche S. MAPK4 (mitogen-activated protein kinase 4). Atlas Genet Cytogenet Oncol Haematol. 2017; 21(12):441-442.

Leukaemia Section Short Communication





del(18)(p11) Lubomir Mitev, Lilya Grachlyova, Aselina Asenova

Military Medical Academy, Department of Cytogenetics and Molecular Biology, Sofia, Bulgaria,

[email protected]

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


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.


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).



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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Mitev L, Grachlyova L, Asenova A. del(18)(p11). Atlas Genet Cytogenet Oncol Haematol. 2017; 21(12):443-446.






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;

[email protected]

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


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


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).



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).


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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D, Espy S, Bobba KC, Song G, Pei D, Cheng C, Roberts S, Barbato MI, Campana D, Coustan-Smith E, Shurtleff SA, Raimondi SC, Kleppe M, Cools J, Shimano KA, Hermiston ML, Doulatov S, Eppert K, Laurenti E, Notta F, Dick JE, Basso G, Hunger SP, Loh ML, Devidas M, Wood B, Winter S, Dunsmore KP, Fulton RS, Fulton LL, Hong X, Harris CC, Dooling DJ, Ochoa K, Johnson KJ, Obenauer JC, Evans WE, Pui CH, Naeve CW, Ley TJ, Mardis ER, Wilson RK, Downing JR, Mullighan CG. The genetic basis of early T-cell precursor acute lymphoblastic leukaemia Nature 2012 Jan 11;481(7380):157-63

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Gevaert AO, de Rooi J, Li Y, Smits WK, Buijs-Gladdines JG, Sonneveld E, Look AT, Horstmann M, Pieters R, Meijerink JP. Immature MEF2C-dysregulated T-cell leukemia patients have an early T-cell precursor acute lymphoblastic leukemia gene signature and typically have non-rearranged T-cell receptors Haematologica 2014 Jan;99(1):94-102


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Leukaemia Section Review





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.

[email protected]; [email protected];

[email protected]

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


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.


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).


Antigen-selected, post-germinal center, terminally

differentiated plasma cell (Anderson and Carrasco

2011)

Multiple Myeloma Ho M, et al.


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.

http://www.thrombocyte.com/causes-of-multiple-myeloma-cancer/



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)



International Myeloma Working Group (IMWG) diagnostic criteria (Rajkumar, Dimopoulos et al. 2014)



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

https://radiopaedia.org/cases/multiple-myeloma-skeletal-survey

https://radiopaedia.org/cases/multiple-myeloma-skeletal-survey



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)



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.


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


CCND1 (B-cell leukemia/lymphoma 1)

Location

11q13.3

Note

Involved in t(11;14)(q13;q32)

Incidence: 15-20%



Genetics



Primary Cytogenetic Abnormalities (Normal plasma cell --> MGUS/SMM). Ref : Rajan and Rajkumar (2015)



Secondary Cytogenetic Abnormalities (MGUS/SMM --> MM --> RR MM, PCL) Ref : Morgan, Walker et al. (2012).

CCND3 (cyclin D3)

Location

6p21.1

Note


Incidence: 5%

MAF (v-maf musculoaponeurotic fibrosarcoma oncogene homolog (avian))

Location

16q23.2

Note


Incidence: 4-10%

IRF4 (interferon regulatory factor 4)

Location

6p25.3

Note


Incidence: 5%

MYC v-myc myelocytomatosis viral oncogene homolog (avian)

Location

8q24.21

Note


Incidence: <10%

MAFB (v-maf avian musculoaponeurotic fibrosarcoma oncogene homolog B)

Location

20q12

Note


Incidence: 1 - 5%

BCL9 (B-cell CLL/lymphoma 9)

Location

1q21.2

Note

Incidence: Frequent

Both BCL9, IL6R, and MCL1 can be deleted



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


Ho M, Anderson KC, Bianchi G. Multiple Myeloma. Atlas Genet Cytogenet Oncol Haematol. 2017; 21(12):451-463.






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 [email protected]


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


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


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


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


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.






t(5;17)(q35;q21) NPM1/RARA Adriana Zamecnikova, Soad al Bahar

Kuwait Cancer Control Center, Department of Hematology [email protected]


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)


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


Disease

Acute myeloid leukemia (AML)


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


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)



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).


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



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


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





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. [email protected]

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


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


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.


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


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


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





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)


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.


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


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


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

References Eble J, Delahunt B, Moch H, Martignoni G, Amin MB, Srigley JR, Argani P, Tan PH, Cheville J, Tickoo SK. Papillary adenoma. In: World Health Organization Classification of Tumours: Pathology and Genetics of Tumours of the Urinary System and Male Genital Organs. Moch, H., Humphrey, P.A., Ulbright, T.M., Reuter, V.E. eds; IARC Press, Lyon 2016, 42-43.

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.

ICGC Breast Cancer Consortium. Alexandrov LB, Nik-Zainal S, Wedge DC, Aparicio SA, Behjati S, Biankin AV, Bignell GR, Bolli N, Borg A, Børresen-Dale AL, Boyault S, Burkhardt B, Butler AP, Caldas C, Davies HR, Desmedt C, Eils R, Eyfjörd JE, Foekens JA, Greaves M, Hosoda F, Hutter B, Ilicic T, Imbeaud S, Imielinski M, Jäger N, Jones DT, Jones D, Knappskog S, Kool M, Lakhani SR, López-Otín C, Martin S, Munshi NC, Nakamura H, Northcott PA, Pajic M, Papaemmanuil E, Paradiso A, Pearson JV, Puente XS, Raine K, Ramakrishna M, Richardson AL, Richter J, Rosenstiel P, Schlesner M, Schumacher TN, Span PN, Teague JW, Totoki Y, Tutt AN, Valdés-Mas R, van Buuren MM, van 't Veer L, Vincent-Salomon A, Waddell N, Yates LR; Australian Pancreatic Cancer Genome Initiative; ICGC MMML-Seq Consortium ; ICGC PedBrain

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


Dal Cin P, Hirsch MS. Chromophobe renal cell carcinoma. Atlas Genet Cytogenet Oncol Haematol. 2017; 21(12):472-474.

Cancer Prone Disease Section Review





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;

[email protected]

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.


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


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%



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.



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.


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.



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.



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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Shiloh Y. Ataxia telangiectasia (A-T). Atlas Genet Cytogenet Oncol Haematol. 2017; 21(12):475-487.



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