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Atlas Genet Cytogenet Oncol Haematol. 2017; 21(10)




Editor-in-Chief Jean-Loup Huret (Poitiers, France) Lymphomas Section Editor Antonino Carbone (Aviano, Italy)

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Bensan Department of Biological Sciences, Middle East Technical University, Ankara, Turkey; [email protected]

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Kessel

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Cristina Mecucci Hematology University of Perugia, University Hospital S.Mariadella Misericordia, Perugia, Italy; [email protected]

Fredrik Mertens Department of Clinical Genetics, University and Regional Laboratories, Lund University, SE-221 85 Lund, Sweden;

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Stefan Nagel Department of Human, Animal Cell Lines, Leibniz-Institute DSMZ-German Collection of Microorganisms, Cell Cultures, Braunschweig,

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Florence Pedeutour Laboratory of Solid Tumors Genetics, Nice University Hospital, CNRSUMR 7284/INSERMU1081, France; [email protected]

Susana Raimondi Department of Pathology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Mail Stop 250, Memphis, Tennessee 38105-

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Clelia Tiziana

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Dan L. Van Dyke Mayo Clinic Cytogenetics Laboratory, 200 First St SW, Rochester MN 55905, USA; [email protected]

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Franck Viguié Service d'Histologie-Embryologie-Cytogénétique, Unité de Cytogénétique Onco-Hématologique, Hôpital Universitaire Necker-Enfants

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Volume 21, Number 10, October 2017

Table of contents

Gene Section

SPARC (secreted protein acidic and cysteine-rich) 351 Ana C. Pavanelli, Flávia Regina Mangone, Maria A. Nagai

PIMREG (PICALM interacting mitotic regulator) 358 Leticia Fröhlich Archangelo

Leukaemia Section

t(2;2)(p22;p22) LTBP1/BIRC6 / del(2)(p22p22) LTBP1/BIRC6 363 Jean-Loup Huret

Classification of Hodgkin lymphoma over years 365 Antonino Carbone, Annunziata Gloghini

t(5;14)(q35;q11) RANBP17 (or TLX3)/TRD 370 Hélène Bruyère

t(7;11)(p15;p15) NUP98/HOXA13 372 Aurelia M. Meloni-Ehrig

dic(5;17)(q11-14;p11-13) 375 Adriana Zamecnikova, Soad al Bahar

Solid Tumour Section

Kidney: Renal cell carcinoma with t(X;1)(p11;q21) PRCC/TFE3 380 Pedram Argani

Kidney: Renal cell carcinoma with t(X;17)(p11;q23) CLTC/TFE3 382 Pedram Argani, Marc Ladanyi

Case Report Section

Amplification of the MET/7q31 gene in a patient with myelodysplastic syndrome 385 Brandon S. Twardy, Deborah Schloff, Anwar N. Mohamed

Gene Section Review

Atlas Genet Cytogenet Oncol Haematol. 2017; 21(10) 351




SPARC (secreted protein acidic and cysteine-rich) Ana C. Pavanelli, Flávia Regina Mangone, Maria A. Nagai

Discipline of Oncology, Department of Radiology and Oncology, Faculty of Medicine, University of

São Paulo, 01246-903, São Paulo, and Laboratory of Molecular Genetics, Center for Translational

Research in Oncology, Cancer Institute of the State of São Paulo (ICESP), 01246-000, São Paulo,

Brazil; [email protected]

Published in Atlas Database: December 2016Online updated version : http://AtlasGeneticsOncology.org/Genes/SPARCID42369ch5q31.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/68736/12-2016-SPARCID42369ch5q31.pdf DOI: 10.4267/2042/68736

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 SPARC, with data on DNA, on the

protein encoded, and where the gene is implicated.

Keywords

SPARC; cChromosome 5; Matricellular

glycoprotein; Osteogenesis Imperfecta;

Osteoporosis; Pulmonary Fibrosis Cardiac Fibrosis;

Breast cancer.

Identity

Other names: BM-40; ON, OI17

HGNC (Hugo): SPARC

Location: 5q31.3-q32

Location (base pair)

Start: 151,661,096bp from pter End: 151,687,165bp

from pter (GRCh38.5 - 22/09/2015); Size: 26,070

bases; Orientation: Minus strand

DNA/RNA

Description

DNA size: 26,070 kb; Exon count: 10; mRNA size:

3604 bp NM_003118. A CPG-rich sequence has

been identified at the 5' region of the SPARC gene,

characterizing the presence of CpG island spanning

from exon 1 to intron 1 (Yang et al., 2007).

Transcription

Three transcript variants encoding different

isoforms have been found for this gene.

NM_003118.3 - Homo sapiens secreted protein

acidic and cysteine-rich (SPARC), transcript variant

1, mRNA: NP_003109.1. Transcript size: 3604 bp.

Variant 1 encodes the predominant isoform.

NM_001309443.1 - Homo sapiens secreted protein

acidic and cysteine-rich (SPARC), transcript variant

2, mRNA: NP_001296372.1. Transcript size: 3601

bp. Variant 2 uses an alternate in-frame splice

junction at the 5' end of an exon compared to

variant 1. The resulting isoform has the same N-

and C-termini but is 1 aa shorter compared to

isoform 1. NM_001309444.1 - Homo sapiens

secreted protein acidic and cysteine-rich (SPARC),

transcript variant 3, mRNA: NP_001296373.1 .

Transcript size: 3602 bp. Variant 3 uses an alternate

splice junction at the 5' end of the last exon

compared to variant 1 that causes a frameshift. The

resulting isoform has a longer and distinct C-

terminus compared to isoform 1.

Protein

Note

SPARC encodes a cysteine-rich acidic matrix-

associated protein that belongs to a family of

SPARC-related proteins composed of others six

members, that include SPOCK1, SPOCK2,

SPOCK3, SPARCL1, SMOC1, SMOC2 (testican-1,

-2, -3, SPARC-like 1 (or hevin, Mast9), and

SPARC-related modular calcium binding (SMOC)-

1, and -2). All members of this protein family share

the three similar domains (Bradshaw and Sage,

2001; Brekken and Sage, 2000). SPARC protein is

SPARC (secreted protein acidic and cysteine-rich) Pavanelli AC, et al.


required for the collagen in the bone to become

calcified. SPARC is also involved in extracellular

matrix synthesis and remodeling being associated

with the promotion of changes in cell shape.

SPARC protein has been associated with tumor

suppression but has also been correlated with

metastasis based on changes to cell shape which

can promote tumor cell invasion (GeneCard

RefSeq). Molecular weight: 303aa, 43 kDa;

Isoelectric point: 4.4719. Although, after cleavage

of the signal sequence, SPARC is a 32-kDa protein

(Mason et al. 1986), the secreted form is identified

as a 43 kDa protein on SDS-PAGE, which is due to

the addition of carbohydrate (Sage et al. 1984).

NP_003109.1: molecular weight: 303 aa;

NP_001296372.1: molecular weight: 302 aa;

NP_001296373.1: molecular weight: 341 aa

Description

SPARC is a 43kDa protein, composed of 303

aminoacids. The first 17 amino acids containing the

signaling peptide sequence is removed during

protein processing. SPARC protein has three

structural domains: N-terminal domain (NT; aa 3-

51) encoded by exons 3 and 4, follistatin-like

domain (FS; 53-137 aa) encoded by exons 5 and 6,

the Extra Cellular domain (EC; aa 138-286)

encoded by exons 7 to 9. It has eleven collagen- and

six high-affinity Ca2+ binding residues. Also, the

protein presents cleavage sites for cathepsin and

members of the metalloproteinases family (Brekken

and Sage, 2000; figure 1). The NT domain binds

hydroxyapatite and calcium ions. The FS domain

contains several internal disulfide bonds that

stabilize two weakly interacting modules. The N-

terminus region of the FS domain has a very

twisted-hairpin structure that is linked by disulfide

bonds at cysteines 1-3, and 2-4. This distribution of

disulfide bonds makes the FS-domain structurally

homologous to epidermal growth factor (EGF)-like

domain of factor IX, a coagulation factor. At the

other end of the FS-domain, its C-terminus region

has structural similarity to Kazal family of serine

proteases. It has antiparallel alpha-helices

connected to small three-stranded antiparallel

alpha-sheets with disulfide bonds linking cysteines

5-9, 6-8, 7-10. The EC domain contains two E-F

hand motifs that bind calcium with high affinity,

and comprise almost entirely of alpha-helices

(Hohenester et al., 1997).

Expression

The evaluation of the expression pattern of SPARC

protein and mRNA during human embryonic and

fetal development revealed that it is usually

expressed in tissues undergoing rapid proliferation

(Mundlos et al., 1992). These authors also showed

that earlier developmental stages showed a more

general distribution, changing to more

heterogeneity expression pattern in later stages.

SPARC expression was observed in bone, cartilage,

teeth, kidney, gonads, adrenal gland, lung, eye,

vessels (Mundlos et al., 1992). In adults SPARC is

expressed in different tissues and organs, including

bone marrow, whole blood, lymph node, thymus,

brain, cerebellum, retina, heart, smooth muscle,

skeletal muscle, spinal cord, intestine, colon,

adipocyte, kidney, liver, pancreas, thyroid, salivary

gland, skin, ovary, uterus, placenta, cervix and

prostate (Wang et al, 2014).

Figure 1 - Schematic representation of the 303 aa human SPARC protein with its functional and structural domains. Box represents the three functional domains: acidic domain (18-52aa), follistatin-like (53-137aa), extracellular Ca2+-binding (138-

286aa). The first seventeen amino acids correspond to the signaling peptide. Stars and triangles represent some of the structural domains: yellow and green stars represent collagen-binding and high-affinity Ca2+-binding residues, respectively. Triangles

represent cleavage sites for cathepsin (blue), MMP2, MMP3, MMP7, MMP9, and MMP13 (red), and MMP3 (purple). (based on Brekken and Sage, 2001; Chlenski and Cohn, 2010)



It is also described that SPARC is expressed by

different cell types including active osteoblasts,

bone marrow progenitor cells, odontoblasts

endothelial cells, fibroblasts, pericytes, astrocytes

and macrophages (McCurdy et al. 2010; Rosseta

and Bradshaw, 2016). In cancer, according to

PrognoScan database, SPARC expression was

observed in bladder, blood, brain, breast, colorectal,

eye tumors, glioma, head and neck cancer, lung,

esophagus, ovarian, and skin cancer tissues (Wang

et al., 2014). There are evidences that SPARC

expression is transcriptionally regulated by

methylation in different types of neoplasia such as

ovarian cancer (Socha et al, 2009), pancreatic

cancer (Vaz et al, 2015), hepatocellular carcinoma

(Zhang et al, 2012) colorectal (Cheetham et al.,

2008) and breast (Matteucci et al, 2016). Loss of

heterozygosity (LOH) at 5q has been demonstrated

in pancreatic cancer (Hahn et al., 1995), in

pulmonary fibrosis (Demopoulos et al., 2002) and

myelodysplastic syndromes (Giagounidis et al.,

2014).

Localisation

SPARC is a secreted glycoprotein found mainly in

the extracellular compartment.

However, it has also been described to be localized

both to cell nucleus and to cytoplasm (Hudson et

al., 2005; Baldini et al. 2008).

Function

SPARC is an evolutionarily conserved matricellular

glycoprotein that is involved in diverse biological

processes, including tissue remodeling, wound

repair, morphogenesis, cell differentiation,

proliferation, migration, and angiogenesis.

Matricellular glycoprotein proteins are a family of

proteins that can be associated with structural

elements and mediates cell-matrix interaction rather

than functions as extracellular matrix (ECM)

structural elements (Bornstein, 1995).

SPARC was first described in skeletal tissue as a

bone-specific protein that binds selectively to both

hydroxyapatite and collagen (Termine et al., 1981).

Posteriorly, it was shown that this protein is broadly

expressed both in mineralized and non-mineralized

tissues being associated to ECM, regulating cell-

matrix interactions and cellular functions, than

contributing to ECM organization (Bornstein, 2000;

Bradshaw, 2012).

SPARC has also been shown to regulate the activity

of matrix metalloproteinases (MMP), a family of

enzymes capable of breaking down proteins, such

as collagen, normally found in ECM and considered

to be the mediators of ECM proteolysis and

turnover. Angiogenesis, healing and metastasis,

processes that require ECM restructuring are

associated with higher SPARC production.

The influence of SPARC on MMP-1, MMP-3, and

MMP-9 activity was first described by Tremble et

al., 1993. Further studies were carried out in

transformed cells and tumor, and it was

demonstrated that SPARC could increase MMP-2

activity in glioma cells and breast cancer cells but

not in melanoma cells (McClung et al., 2007,

Nischt et al., 2001, Gilles et al., 1998).

Homology

The human SPARC gene shows 92% and 31%

identity with the mouse and nematode homologs,

respectively. SPARC is conserved in a wide variety

of evolutionarily diverse organisms (e.g., C.

elegans, Drosophila, brine shrimp, trout, chicken,

mice, and humans), suggesting that it plays an

important function in multicellular biology

(Bradshaw and Sage, 2001).

Implicated in

Osteogenesis Imperfecta, Type XVII

SPARC gene mutations have been correlated with a

severe disease known as osteogenesis imperfecta, a

connective tissue disorder characterized by low

bone mass, bone fragility and susceptibility to

fractures after minimal trauma. Whole-exome

sequencing was carried out in 2 unrelated girls

carrying osteogenesis imperfecta (OI17; 616507)

leading to the identification of two different

homozygous missense mutations, R166H

(VAR_075142) and E263K (VAR_075143)

(Mendoza-Londono et al., 2015). Previous studies

described diminished expression of SPARC in

osteoblasts from patients with osteogenesis

imperfecta (Muriel et al., 1991) and in osteoblasts

obtained from the fro/fro mouse, an animal with

fragile bones (Vetter et al., 1991)

Osteoporosis

The involvement of SPARC in bone remodeling

has been described, and its expression is observed

in osteoblasts express (Kelm et al., 1992). SPARC-

null mice were reported to have decreased numbers

of osteoblasts and osteoclasts, indicating decreased

bone turnover, resulting in low turnover

osteoporosis-like phenotype affecting trabecular

bone (Delany, et al., 2000). Also, in osteonectin-

null mice, osteonectin levels have been shown to

play a role in modulating the balance of bone

formation and resorption in response to PTH

treatment (Machado do Reis et al., 2008).

Pulmonary and Cardiac Fibrosis

Fibrosis is characterized by excessive deposition of

extracellular matrix, resulting in tissue remodeling

and thus interfering with normal tissue architecture

and function.



SPARC expression and up-regulation have been

reported in multiple types of fibrosis both human

and animal fibrotic models. It has been shown that

SPARC can influence TGFB1 (TGF-beta), a known

regulator of fibrosis. Thus it is suggested that

SPARC may regulate TGF-beta activity in fibrotic

tissues (Trombetta and Bradshaw, 2012).

Cardiac disease

SPARC expression was reported in cardiac disease.

It is highly expressed in fibroblasts and endothelial

cells and less expressed in cardiac myocytes. By

screening analysis, SPARC was found as

differentially expressed and potentially associated

with myocardial infarction and transverse aortic

constriction (Wang et al., 2015). Also, SPARC

demonstrated to have potential therapeutic

applications in inhibiting cardiac dilatation and

dysfunction after myocardial infarction (Schelling

et al., 2009).

Cancer

SPARC protein modulates different cell functions

like as adhesion, proliferation, angiogenesis, cell

survival, and has been associated with tumor

development and progression (Arnold and Brekken,

2009; Nagaraju et al., 2014).

SPARC is differentially expressed in different types

of cancer, and its ability to inhibit or promote tumor

progression is dependent on the cellular type,

tumoral stage and the type of established

interactions among the different components of

cellular microenvironment (Arnold and Brekken,

2009).

The pleiotropic effects of SPARC reflect the

complexity of actions of this protein, which can act

as an oncogene or tumor suppressor (Podhajcer et

al.,2008; Arnold and Brekken, 2009). Hence, the

role of SPARC in the process of tumorigenesis and

as a tumor biomarker is still controversial. Higher

levels of SPARC were observed in malignant

tumors, including breast, esophagus, brain, prostate,

glioma, and melanoma, suggesting that increased

SPARC expression is associated with tumor

progression (Framson and Sage, 2004; Bos et

al.,2004; Watkins et al.,2005; Koblinski et

al.,2005). On the other hands, other studies have

suggested that SPARC may act as a tumor

suppressor, promoting apoptosis in ovarian cancer

cells and presenting an anti-tumoral effect in

pancreatic and breast cancers (Chlenski and Cohn,

2010; Nagai et al.,2011).

Tumor with high metastatic potentials such as

glioblastomas, melanoma, breast and prostate

cancer, express higher levels of SPARC while less

metastatic tumor-like ovarian, pancreatic and

colorectal tumors, expresses lower or undetectable

SPARC (Feng and Tang, 2014).

The diversity of SPARC expression effects has

been observed in different types of cancers. SPARC

has been associated with tumor development in

melanoma, esophagus cancer, gastric cancer and

glioma, and data suggests that higher expression is

correlated with a more aggressive phenotype such

as tumor size, metastasis and poor prognosis

(Yamashita K et al., 2003; Bos et al.,2004; Framson

and Sage, 2004; Wang et al., 2004; Koblinsk et

al.,2005; Zhao et al., 2010; Fenouille et al., 2011;

Liu et al., 2011; Rocco et al., 2011; McClung et al.,

2012; Kim et al., 2013)

The expression of SPARC does not seem to directly

influence cellular transformation since SPARC

knockout mice do not develop tumors. However,

SPARC might significantly influence tumor-stroma

interactions contributing to tumor progression and

therapy response (Said et al., 2013).

In different tumor types such as prostatic

carcinoma, neuroblastoma, pulmonary carcinoma,

leukemia, pancreatic and colorectal cancer, it was

described that SPARC inhibits tumor growth and

reverts drug resistance increasing chemotherapy

response. (Brekken et al., 2003; Sato et al., 2003;

Puolakkainen et al., 2004; Said and Motamed,

2005; Tai et al., 2005; DiMartino et al., 2006; Tai

and Tang, 2007; Cheetam et al., 2008; Pan et al.,

2008; Wong et al., 2008; Socha et al., 2009;

Bhoopathi et al., 2011; Davids and Steensma, 2010;

Chew et al., 2011; Rahman et al., 2011).

Cheetham et al., 2008, showed that the

demethylating agent 5-Aza-2'deoxycytidine (5-Aza)

leads to the expression of SPARC and increased

chemosensitivity in colon cancer cells. In

irinotecan-resistant cancer cells, endogenous or

exogenous SPARC exposure triggers senescence

associated with increased levels of p16 and TP53

phosphorylation (Chan et al., 2010). Also, in vitro

and in vivo studies have demonstrated that over-

expression of the NT-domain of SPARC leads to a

significantly greater sensitivity to chemotherapy

and tumor regression that involves an interplay

between the NT-domain, BCL2 and CASP8

(caspase 8), which increases apoptosis and confers

greater chemosensitivity (Rahman et al., 2011).

More recently, Fan et al., demonstrated that over-

expression of SPARC increased gemcitabine-

induced apoptosis in pancreatic cancer cells via up-

regulation of the expression of apoptosis-related

proteins. These findings provide insight on the role

played by SPARC in drug sensitivity and that its re-

expression has a potential to restore

chemosensitivity.

Breast cancer

In breast cancer, SPARC is expressed in more

invasive but not in non-invasive cell lines (Giles et

al., 1998).



In normal mammary tissue, SPARC expression was

undetectable or slightly detectable and in benign

mammary lesions the expression was weakly

positive. However, the stromal cell of 75% of in

situ and invasive breast cancer samples was

strongly positive for SPARC (Bellahcène and

Castronovo, 1995; Barth et al., 2005; Matteucci et

al., 2016).

As previous described, the role of SPARC in breast

cancer is also controversial. SPARC expression is

not detected in MCF-7 breast cancer cell line,

however, in response to c-Jun overexpression,

SPARC expression is highly induced being

associated to increased invasive and migration

potential (Briggs et al., 2002). Instead, in the

tumorigenic model of breast cancer cells, MDA-

MD-231, SPARC expression inhibited invasion and

metastasis (Koblinski et al., 2005).

In breast tumors increased SPARC expression was

associated with tumor progression and

aggressiveness phenotype (Watkins et al., 2005 and

Helleman et al. 2008). On the other hand, the

reduction of SPARC protein expression was

associated with poor prognosis of breast cancer

patients (Hsiao et al., 2010 e Nagai et al., 2011). In

breast cancer brain metastasis SPARC expression

was down-regulated in comparison to primary

tumors, apart from the tumoral subtype. However,

among the primary tumors evaluated, triple

negative subtype expressed the higher protein level

(Wikman et al., 2014). Previous data of our group,

have already shown that association between

SPARC and triple negative tumors, and positivity to

SPARC was a marker of good prognosis in

comparison to those patients with reduced SPARC

level (Nagai et al., 2011).

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This article should be referenced as such:

Pavanelli AC, Mangone FR, Nagai MA. SPARC (secreted protein acidic and cysteine-rich). Atlas Genet Cytogenet Oncol Haematol. 2017; 21(10):351-357.

Gene Section Review





PIMREG (PICALM interacting mitotic regulator) Leticia Fröhlich Archangelo

Department of Cellular and Molecular Biology and Pathogenic Bioagents, Ribeirão Preto Medical

School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil. [email protected]

Published in Atlas Database: January 2017

Online updated version : http://AtlasGeneticsOncology.org/Genes/PIMREGID54310ch17p13.html

Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/68737/01-2017-PIMREGID54310ch17p13.pdf DOI: 10.4267/2042/68737


Abstract PIMREG (FAM64) was initially identified as

CATS, the CALM (PICALM) interacting protein

expressed in thymus and spleen. Mounting

evidence suggests the involvement of FAM64A in

tumorigenesis. Through interaction with PICALM,

FAM64 was able to influence the subcellular

localization of the leukemic fusion protein

PICALM/MTT10 (CALM/AF10). FAM64A is

highly expressed in leukemia, lymphoma and tumor

cell lines and its levels are strongly correlated with

cellular proliferation in both malignant and normal

cells. FAM64A is a mitotic regulator that controls

chromosome segregation during cell division, and

its transcripts covariate with that of cell cycle

regulation genes in tumorigenesis. Nevertheless, a

precise role of FAM64A in tumorigenesis is yet to

be defined.

Keywords:

PIMREG; FAM64; chromosome 17; proliferation;

tumorigeneses; metaphase-anaphase transition; cell-

cycle control; PICALM/MTT10

Identity

Other names: FAM64A, FLJ10156, FLJ10491,

CATS, RCS1

HGNC (Hugo): PIMREG

Location: 17q13.2

Location (base pair): Starts at 6444415 and ends

at 6451469 bp from pter (according to hg38 -

Dec2013)

DNA/RNA

Description

PIMREG (FAM64) is located on chromosome 17

band p13.2, 6.29 megabase pairs from the telomere

of the short arm (chromosome 17 genomic contig

NT_010718). The genomic locus spans 7 Kb and

contains 6 exons with a non-coding first exon.

Transcription

Two alternatively spliced transcripts of 1.5 Kb are

formed (NM_019013 and NM_001195228) and

code for two protein isoforms of 238 and 248

amino acids in length (isoform 1 and 2,

respectively). Both isoforms share the first 228

residues, encoded by exons 2-4.

The two proteins differ in their C-termini. The 10

last amino acids of isoform 1 are encoded by exon

5, which is absent in the transcript coding for

isoform 2.

The last 20 amino acids of isoform 2 are encoded

by exon 6 (Figure 1) (Archangelo, et al. 2006). An

additional transcript variant with retained intron 5

(between exons 5 and 6) was described

(Archangelo, et al. 2006; Coulombe-Huntington, et

al. 2009). There are 4 processed pseudogenes of

FAM64A at other chromosomal locations (2q33,

4p15, 4q24 and 6q15).

Protein

Description

The FAM64A calculated molecular weight is about

27 kDa.

PIMREG (PICALM interacting mitotic regulator) Archangelo LF.


Figure 1: Genomic organization, alternative splicing, and protein isoforms of PIMREG (FAM64). Boxes represent exons, with blue parts symbolizing coding region and gray parts the 5' and 3' UTRs. There are 2 splice variants (sizes are indicated in

parentheses). In splice variant 2, exon 5 is spliced out resulting in a longer protein (FAM64A isoform 2) encoded by exons 2, 3, 4 and 6. The FAM64A isoform 1 (shorter form) is encoded by exons 2, 3, 4 and 5 from splice variants 1 and the transcript with

retained intron 5 (see in the text). Both FAM64A isoforms are identical from amino acids 1-228, they differ in their last 10 and 20 C-terminal residues (isoform 1 and 2, respectively). (Figure modified from Archangelo, et al. 2006)

The protein contains two putative destruction box

motifs (RxxL) at amino acids 14-17 and 53-56

(DB1 and DB2, respectively), the second being a

recognition motif for the ubiquitin ligase anaphase-

promoting complex/cyclosome (APC/C) (Zhao, et

al. 2008).

There are three types of posttranslational

modifications identified within FAM64A isoforms,

namely lysine- acetylation (K-ac), lysine-

ubiquitination (K-ub) and phosphorylation (S-p and

T-p). A total of 22 residues were described as

phosphorylated in FAM64A in a variety of large

scale proteomic studies as revealed by the

phosphoproteomic databases PhosphoSitePlus™

(http://www.phosphosite.org) and Phosida

(http://www.phosida.com/) (Figure 2).

Expression

In normal adult tissue FAM64A is predominantly

expressed in thymus, spleen and colon and to a

lesser extent in small intestines, ovary and brain

(Archangelo, et al. 2006; Archangelo, et al. 2008).

Moreover, FAM64A is highly expressed in

leukemia, lymphoma and tumor cell lines. The

protein levels vary throughout the cell cycle. In

synchronized cells FAM64A accumulates in S and

G2 phases of the cell cycle, peaks in the mitosis and

drops drastically as cells exit from mitosis into the

G1 phase (Archangelo, et al. 2008; Zhao, et al.

2008). FAM64A transcripts covariate with that of

cell cycle regulation genes in tumorigenesis (Zhao,

et al. 2008).

Figure 2: Diagram representing the protein structure of PIMREG (FAM64). FAM64A is a phosphoprotein. All residues described to be phosphorylated in large scale proteomic studies are depicted. Source: Phosphoproteomic databases

PhosphoSitePlus™ (http://www.phosphosite.org) and Phosida (http://www.phosida.com/). Destruction box motifs are depicted as orange boxes (DB1 and DB2). Aminoacids comprising the DB motifs and the unique phospho-residue characterized (S131) are

shown. (Figure modified from Archangelo, et al. 2013)



Resting human peripheral blood lymphocytes

(PBLs), which are not selected for growth in

culture, do not express FAM64A protein.

However, when these cells are induced to

proliferate upon mitogen activation they do express

FAM64A. Likewise, glioblastoma cells induced to

proliferate, show a progressive upregulation of

FAM64A. Conversely, FAM64A expression

drastically decreases when highly proliferative

leukemia cells cease to proliferate upon exposure to

differentiation agents (Barbutti, et al. 2016).Thus,

FAM64A expression positively correlates with the

proliferative state of the cells (Archangelo, et al.

2008).

Expression analysis of the murine Fam64a homolog

revealed a strong expression throughout mouse

embryogenesis, in particular at the developing

central nervous system (CNS). The expression

decreases gradually and proportionally as embryos

develop to later stages (Archangelo, et al. 2008). In

the hematopoietic compartment, Fam64A is widely

expressed in different cell subpopulations

(Archangelo, et al. 2008). Moreover, RNA-Seq

analysis of individual hematopoietic stem cells

(HSCs) to resolve heterogeneity within HSC

population, revealed that Fam64a is highly

expressed in the HSC population primed for

proliferation (Wilson, et al. 2015).

Localisation FAM64A is a nuclear protein enriched in the

nucleoli. Expression levels in the nucleoplasm and

nucleolar accumulation are different from cell to

cell and dependent on the cell cycle phase

(Archangelo, et al. 2008) (Figure 3). In mitotic cells

FAM64A-GFP is diffusely distributed throughout

cells without specific association with

chromosomes, kinetochores, spindle, or centrosome

(Zhao, et al. 2008).

Function Based on the fact that levels of FAM64A protein

strongly correlate with cellular proliferation in both

normal and malignant cells, this protein was

described as a marker for proliferation with a

possible role in the control of cell proliferation and

tumorigenesis (Archangelo, et al. 2008). In fact,

silencing of FAM64A protein in the U937 leukemia

cell line resulted in reduced proliferation and

altered cell cycle progression, as attested by

diminished expression of the cell cycle regulators

CCNA1, CCNE1, CCNB1 (cyclin-A, -E and -B1)

in FAM64A depleted cells (Barbutti, et al. 2016).

Furthermore, Zhao and coworkers described

FAM64A as a regulator of chromosome

segregation. FAM64A is a substrate of the APC/C

complex that controls the metaphase to anaphase

transition and its knock-down resulted in

accelerated anaphase onset. Thus FAM64A plays

an important role in determining the kinetics of

mitotic progression (Zhao, et al. 2008). Although

the literature indicates a putative function of

FAM64A in controlling cell cycle progression,

division and tumorigenesis, the impairment of cell

proliferation upon FAM64A depletion was modest

and not sufficient to inhibit tumor growth of

xenotransplanted U937 cells in an in vivo model

(Barbutti, et al. 2016). Similarly, the faster

metaphase-to-anaphase transition observed in

FAM64A depleted cells was not sufficient to

produce any of the mitotic defects often observed in

cancer cells. Rather, mitotic index, spindle

assembly, chromosome congregation/segregation

and cytokinesis proceeded normally in FAM64A

depleted cells (Zhao, et al. 2008).

FAM64A has also been described to function as a

transcriptional repressor in a GAL4-based reporter

gene assay (Archangelo, et al. 2006). Additionally,

FAM64A was able to repress the transactivation

capacity of the leukemic fusion protein

PICALM/MTT10 (CALM/AF10) (Archangelo, et

al. 2013). Evidence further supporting the

transcriptional inhibitory properties of FAM64A

were provided by Zhao and colleagues, who

described the interaction between FAM64A and

components of the nucleosome remodeling and

deacetylase (NuRD) complex, such as MTA2,

HDAC1/HDAC2 and RBBP7 / RBBP4

(RBAp46/48) (Zhao, et al. 2008).

Figure 3: Subcellular localization of endogenous PIMREG (FAM64). Endogenous protein was visualized by immunofluorescence and confocal microscopy in non-synchronized U2OS cells. FAM64A is a nuclear protein enriched in the

nucleolus of some cells. Note the different levels of FAM64A expression from cell to cell. FAM64A protein levels and nucleolar localization are cell cycle dependent. The figure shows cells labeled with Cy3 (FAM64A) and DAPI with channels merged.



The NuRD complex is implicated in transcriptional

regulation and plays a role in modifying chromatin

structures to initiate and maintain gene repression.

Since its discovery a number of FAM64 interacting

proteins have been described (e.g. PICALM

(Archangelo, et al. 2006), UHMK1 (KIS)

(Archangelo, et al. 2013), PRNP (PrPC) (Satoh, et

al. 2009), PTBP3 (ROD1) (Brazao, et al. 2012) and

NuRD complex (Zhao, et al. 2008), shedding light

on the putative function of this protein.

The interaction of FAM64A with the

Phosphatidylinositol Binding Clathrin Assembly

Protein (PICALM) was identified in a yeast two

hybrid screen (Y2H) and confirmed by GST pull-

down and co-immunoprecipitation experiments for

both FAM64A isoforms. The FAM64A interaction

region was mapped to amino acids 221 to 294 of

PICALM. Through this interaction FAM64A was

able to alter the subcellular localization of

PICALM. The fluorescently-tagged protein YFP-

PICALM localized mainly in the cytoplasm and

plasma membrane of transfected NIH3T3 cells.

However, when CFP-FAM64A was co-expressed,

PICALM was observed both at the

cytoplasm/membrane and in the nucleus of some

cells at almost equal levels (Archangelo, et al.

2006). The interaction between FAM64A and the

Kinase Interacting Stathmin (KIS and UHMK1)

was identified in Y2H screen and confirmed by

GST pull-down, co-immunoprecipitation and co-

localization experiments. KIS interacts with amino-

acids 136-187 of FAM64A. Kinase assay showed

that FAM64A is a substrate of KIS at serine 131

(S131). In a GAL4-based reporter gene assay KIS

enhanced the transcriptional repressor activity of

FAM64A, independently of phosphorylation on

S131 but dependent on KIS kinase activity

(Archangelo, et al. 2013). RNA

immunoprecipitation sequencing (RIP-seq)

described the interaction between FAM64A and

ROD1 (PTBP3), an RNA-binding protein involved

in nonsense-mediated decay (NMD) (Brazao, et al.

2012). Protein microarray analysis identified

FAM64A as an interacting partner of the cellular

prion protein (PrPC). The interaction was

confirmed by co-immunoprecipitation of the

overexpressed tagged-proteins (Satoh, et al. 2009).

Homology

The human FAM64A shares homology with the

species described in Table 1.

Mutations

Somatic

Mutations in the FAM64A gene were reported in

the catalogue of somatic mutations in cancer

(COSMIC) database in 53 out of the 28710 samples

tested, of which 6 are nonsense substitutions, 33

missense substitutions and 10 synonymous

substitutions

(http://cancer.sanger.ac.uk/cancergenome/projects/c

osmic)

Homo sapiens

FAM64A Symbol

Identity (%)

Protein

DNA

vs. P.troglodytes FAM64A 96.6 98.6

vs. vs. M. mulatta LOC712701 91.6 95.9

vs. C. lupus FAM64A 73.3 81.2

vs. B. taurus FAM64A 83.2 85.9

vs. M. musculus Fam64a 74.8 77.5

vs. R. norvegicus Fam64a 76.7 79.1

Table 1. Homology between the human FAM64A and other species (Source: http://www.ncbi.nlm.nih.gov/homologene/)

Implicated in

Leukemia

FAM64A is highly expressed in leukemia and

lymphoma cell lines (Archangelo, et al. 2008).

FAM64A interacts with the central domain of

PICALM, a region contained in the PICALM

moiety of the PICALM/MLLT10 (CALM/AF10)

leukemic fusion protein (Archangelo, et al. 2006).

FAM64A expression markedly increased the

nuclear localization of PICALM/MLLT10

(CALM/AF10) and counteracted the ability of this

fusion protein to activate transcription in vitro

(Archangelo, et al. 2006; Archangelo, et al. 2013).

Additionally, the murine Fam64a transcripts were

up-regulated in hematopoietic cells (B220+

lymphoid cells) transformed by PICALM/MLLT10

(CALM/AF10) in comparison to the same

subpopulation from non-leukemic mice

(Archangelo, et al. 2008).

In a recent report, FAM64A silencing in the

PICALM/MLLT10 (CALM/AF10)-positive U937

leukemia cell line resulted in somewhat reduced

proliferation, altered cell cycle progression, lower

migratory ability in vitro, and reduced

clonogenicity of FAM64A-depleted U937 cells.

Nonetheless, FAM64A silencing was not capable of

interfering with the expression of the

PICALM/MLLT10 (CALM/AF10)-leukemia

deregulated genes (HOXA gene cluster, MEIS1 and

BMI1) nor sufficient to hinder tumor growth of

U937 xenografts (Barbutti, et al. 2016).

Breast cancer

FAM64A was identified together with BIRC5 and

CENPA as the three genes specifically upregulated

in triple-negative breast cancer (TNBC), an

aggressive type of cancer with poor outcome and

short survival. In a broader clinical set analysis,

http://www.ncbi.nlm.nih.gov/homologene/



FAM64A upregulation correlated with poor

survival, despite the molecular type of breast cancer

(Zhang, et al. 2014).

Lung cancer

The fusion gene XAF1 (17p13.1) / FAM64A

(17p13.2) was identified in a single lung

adenocarcinoma patient from a large scale RNA

sequencing study. The fusion gene was validated by

Sanger sequencing and showed no co-occurrence

with other canonical driver point mutation in that

sample. The breakpoints were described at position

chr17:6663920, within exon 4 of the donor

transcript (XAF1), and at position chr17:6348396,

within the 5' untranslated region (5'UTR) of the

acceptor gene FAM64A (Seo, et al. 2012).

In the same study FAM64A was also detected

among a number of cancer outlier genes (CoGs),

being highly expressed in 8 cancer tissue samples

(Seo, et al. 2012).

Head and Neck squamous cell carcinoma

Single gene clustering of RNA sequencing in a set

of 177 lung and 279 head and neck squamous cell

carcinomas, reveled a differential alternative

isoform usage pattern of the FAM64A locus, with

lower expression of a 152 bp cluster within the final

exon of the gene. The implication of the differential

isoform usage remains to be determined (Kimes, et

al. 2014).

To be noted

FAM64A is a marker for proliferation (Archangelo,

et al. 2008) with potential use as a prognostic

marker (Zhang, et al. 2014). FAM64A plays a role

in the regulation of chromosome segregation during

cell division (Zhao, et al. 2008) and in the control

of cell cycle progression and clonogenicity of the

U937 leukemia cell line (Barbutti, et al. 2016).

However, FAM64A depletion is not sufficient to

impair either mitosis or hinder cell growth

(Barbutti, et al. 2016; Zhao, et al. 2008). Hence, it

still to be addressed whether the strong correlation

of FAM64A expression with proliferation is

determinant for tumorigenesis or if it is a

consequence.

References Archangelo LF, Greif PA, Maucuer A, Manceau V, Koneru N, Bigarella CL, Niemann F, dos Santos MT, Kobarg J, Bohlander SK, Saad ST. The CATS (FAM64A) protein is a substrate of the Kinase Interacting Stathmin (KIS). Biochim Biophys Acta. 2013 May;1833(5):1269-79

Barbutti I, Xavier-Ferrucio JM, Machado-Neto JA, Ricon L, Traina F, Bohlander SK, Saad ST, Archangelo LF. CATS (FAM64A) abnormal expression reduces clonogenicity of hematopoietic cells. Oncotarget. 2016 Oct 18;7(42):68385-68396

Brazão TF, Demmers J, van IJcken W, Strouboulis J, Fornerod M, Romão L, Grosveld FG. A new function of ROD1 in nonsense-mediated mRNA decay. FEBS Lett. 2012 Apr 24;586(8):1101-10

Coulombe-Huntington J, Lam KC, Dias C, Majewski J. Fine-scale variation and genetic determinants of alternative splicing across individuals. PLoS Genet. 2009 Dec;5(12):e1000766

Kimes PK, Cabanski CR, Wilkerson MD, Zhao N, Johnson AR, Perou CM, Makowski L, Maher CA, Liu Y, Marron JS, Hayes DN. SigFuge: single gene clustering of RNA-seq reveals differential isoform usage among cancer samples. Nucleic Acids Res. 2014 Aug;42(14):e113

Satoh J, Obayashi S, Misawa T, Sumiyoshi K, Oosumi K, Tabunoki H. Protein microarray analysis identifies human cellular prion protein interactors. Neuropathol Appl Neurobiol. 2009 Feb;35(1):16-35

Seo JS, Ju YS, Lee WC, Shin JY, Lee JK, Bleazard T, Lee J, Jung YJ, Kim JO, Shin JY, Yu SB, Kim J, Lee ER, Kang CH, Park IK, Rhee H, Lee SH, Kim JI, Kang JH, Kim YT. The transcriptional landscape and mutational profile of lung adenocarcinoma. Genome Res. 2012 Nov;22(11):2109-19

Wilson NK, Kent DG, Buettner F, Shehata M, et al. Combined Single-Cell Functional and Gene Expression Analysis Resolves Heterogeneity within Stem Cell Populations. Cell Stem Cell. 2015 Jun 4;16(6):712-24

Zhang C, Han Y, Huang H, Min L, Qu L, Shou C. Integrated analysis of expression profiling data identifies three genes in correlation with poor prognosis of triple-negative breast cancer. Int J Oncol. 2014 Jun;44(6):2025-33

Zhao WM, Coppinger JA, Seki A, Cheng XL, Yates JR 3rd, Fang G. RCS1, a substrate of APC/C, controls the metaphase to anaphase transition. Proc Natl Acad Sci U S A. 2008 Sep 9;105(36):13415-20


Archangelo LF. PIMREG (PICALM interacting mitotic regulator). Atlas Genet Cytogenet Oncol Haematol. 2017; 21(10):358-362.

Leukaemia Section Short Communication





t(2;2)(p22;p22) LTBP1/BIRC6 / del(2)(p22p22) LTBP1/BIRC6 Jean-Loup Huret

Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers,

France. [email protected]

Published in Atlas Database: December 2016

Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t0202p22p22ID1714.html

Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/68738/12-2016-t0202p22p22ID1714.pdf DOI: 10.4267/2042/68738


Abstract

Review on t(2;2)(p22;p22) and del(2)(p22p22)

LTBP1/BIRC6 in acute myeloid leukemia, with

data on the genes involved.

Keywords

chromosome 2; t(2;2)(p22;p22); LTBP1; BIRC6;

acute myeloid leukemia

Clinics and pathology Only two cases to date of t(2;2)(p22;p22) or

del(2)(p22p22) LTBP1/BIRC6 in acute myeloid

leukemia have been described (Cancer Genome

Atlas Research Network 2013; Yoshihara et al.

2015). This chromosomes and genes

rearrangements have also been found in a case of

breast carcinoma, and in a case of lung squamous

cell carcinoma.

Disease

Acute myeloid leukemia

Epidemiology

Data were described in only one case: a 75-year old

male patient presented with AML-M2. Overall

survival was 0.1 month (Cancer Genome Atlas

Research Network 2013).

Cytogenetics

The karyotype was normal (cryptic rearrangement).

Genes involved and proteins FLT3 mutation was positive; IDH1 R132, R140,

R172 were negative; activating RAS was negative;

NPMc was negative.

BIRC6 (Baculoviral IAP repeat-containing 6)

Location 2p22.3

Protein

BIRC6 contains two domains: a N-terminal BIR

repeat (needed for interactions with caspases and

IAP-binding motif (IBM) containing proteins) and a

C-terminal UBC domain (which can form a

thiolester linkage with ubiquitin transferred by E1).

Inhibitor of apoptosis: BIRC6 is a peripheral

membrane protein of the trans-Golgi network that

protects cells from apoptosis

BIRC6 and treatment resistance: Silencing of

BIRC6 has been shown to sensitize cancer cells to

various anticancer agents

BIRC6 is essential in embryonic development.

Regulator of cytokinesis: BIRC6 is a major

regulator of abscission, the final stage of

cytokinesis.

Regulator of mitosis: BIRC6 interacts with CCNA2

(cyclin A) and promotes its degradation in early

mitosis

http://documents.irevues.inist.fr/bitstream/DOI%20t0202p22p22ID1714.txt

t(2;2)(p22;p22) LTBP1/BIRC6 / del(2)(p22p22) LTBP1/BIRC6 Huret JL


BIRC6 and autophagy: BIRC6 is required to inhibit

autophagy (Iris Luk and Wang, 2014).

BIRC6 is involved in myelodysplastic syndromes

and acute myeloid leukemias, colorectal cancer,

neuroblastoma, skin melanoma, non-small cell lung

cancer, prostate cancer, ovarian cancer,

hepatocellular carcinoma and breast cancer.

LTBP1 (latent transforming growth factor beta binding protein 1)

Location 2p22.3

DNA/RNA

Eleven splice variants.

Protein

1721 amino acids; belongs to the LTBP/fibrillin

family.

LTBP1 is composed of a signal peptide: (amino

acids 1-23), 18 epidermal growth factor (EGF)-like

repeats and four cysteines rich domains, the TB

(TGFb binding protein-like) domains.

The LTBP1 C-terminus interacts with the

extracellular matrix via fibrillin microfibrils. EGF-

like repeats provide stability to the protein structure

TGFB1 is secreted as a biologically latent complex

composed of LTBP1, a latency associated peptide

(LAP), (LAP is the TGFB1 pro-peptide which

regulates latency, that is cleaved intracellularly

prior to secretion), and the TGFB1 cytokine.

LTBP1 plays roles in facilitating the folding and

secretion of TGFB1 from the cell, and activation.

LTBP1 interacts with FBN1 (fibrillin 1).

This interaction allows LTBP1 to sequester TGFB1

to fibrillin microfibrils; EFEMP2 (EGF containing

fibulin-like extracellular matrix protein 2, or

fibulin4) and ADAMTSL proteins form ternary

complexes with LTBP1 and fibrillin.

LTBP1 is involved in epithelial-mesenchymal

interaction and epithelial differentiation (Mazzieri

et al., 2005; Robertson et al., 2014).

Result of the chromosomal anomaly

Hybrid gene

Description

5' LTBP1 - 3' BIRC6

References Ley TJ, Miller C, Ding L, et al. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med. 2013 May 30;368(22):2059-74

Jentsch, S ; Pohl, C.. BIRC6 (Baculoviral IAP repeat-containing 6); Atlas Genet Cytogenet Oncol Haematol. http://atlasgeneticsoncology.org/Genes/BIRC6ID798ch2p22.html

Mazzieri R, Jurukovski V, Obata H, Sung J, Platt A, Annes E, Karaman-Jurukovska N, Gleizes PE, Rifkin DB.. Expression of truncated latent TGF-beta-binding protein modulates TGF-beta signaling. J Cell Sci. 2005 May 15;118(Pt 10):2177-87.

Robertson IB, Handford PA, Redfield C.. NMR spectroscopic and bioinformatic analyses of the LTBP1 C-terminus reveal a highly dynamic domain organisation. PLoS One. 2014 Jan 29;9(1):e87125. doi: 10.1371/journal.pone.0087125.

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. doi: 10.1038/onc.2014.406. Epub 2014 Dec 15.


Huret JL. t(2;2)(p22;p22) LTBP1/BIRC6. Atlas Genet Cytogenet Oncol Haematol. 2017; 21(10):363-364.






Classification of Hodgkin lymphoma over years Antonino Carbone, Annunziata Gloghini

Department of Pathology Centro di Riferimento Oncologico Aviano (CRO), Istituto Nazionale

Tumori, IRCCS, Aviano, Italy; [email protected] (AC); Department of Diagnostic Pathology and

Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy;

[email protected] (AG)


Online updated version : http://AtlasGeneticsOncology.org/Anomalies/ClassifHodgkinID1767.html

Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/68739/12-2016-ClassifHodgkinID1767.pdf DOI: 10.4267/2042/68739


Abstract Histologic classification of Hodgkin lymphoma

(HL) evolved through different systems, starting

from the modern histologic classifications by

Jackson and Parker in 1944 and Lukes and Butler in

1966, to the 2008 World Health Organization

(WHO) classification. HL has been classified into

classical HL, which accounts for 95% of all HL

cases, and the less common nodular lymphocyte

predominant HL (NLPHL). Classical HL is a

distinct neoplastic entity with typical clinical and

epidemiological characteristics and unique

pathological, genetic, and virological features.

Keywords

Hodgkin lymphoma; Histologic classification; Rye

classification; REAL classification; WHO

classification.

Clinics and pathology Disease

The modern classification scheme of Hodgkin

lymphoma (HL) (Lukes, Craver, et al., 1966) is

based on the concept that the histologic subtypes

represent morphologic patterns of a neoplasm in

which rare Hodgkin and Reed-Sternberg (HRS)

cells, the HL tumor cells, are embedded in a

dominant reactive background. Based on the

morphologic characteristics of the HRS cells

(lacunar cells, multinucleated giant cells,

pseudosarcomatous cells) and the composition of

the reactive infiltrate, four histologic subtypes have

been distinguished: lymphocyte-rich cHL

(LRCHL),nodular sclerosis (NS) cHL, mixed

cellularity (MC) cHL, and lymphocyte depletion

(LD) cHL. (Stein, 2001; Stein et al., 2008;

Swerdlow et al., 2016). The background shows a

cellular composition which is characteristic for each

histotype. In MC cHL, microenvironmental cell

types include T- and B-reactive lymphocytes,

eosinophils, granulocytes, histiocytes/macrophages,

plasma cells, mast cells. In addition, a great number

of fibroblast-like cells and fibrosis are frequently

found in NS cHL.

Lymphocyte predominant (LP) HL, is characterized

by a lymphocyte- rich background with admixed

histiocytes. In 1944 Jackson and Parker called it in

as "paragranuloma" to separate it from Hodgkin

"granuloma". In 1966 Lukes and Butler (Lukes and

Butler JJ, 1966) renamed paragranuloma

"lymphocytic and/or histiocytic predominance HD",

recognizing a nodular and a diffuse pattern and

used the term of lymphocytic and histiocytic (L&H)

RS-cell variant for the diagnostic cell (Lukes,

Butler et al., 1966), now called LP cell. At the Rye

symposium, it was decided to combine the nodular

and diffuse types of the Lukes and Butler

classification into LPHL (Lukes, Craver et al.,

1966) (Table 1).

In the last decades, a considerable body of evidence

has indicated that LPHL exhibits features of a B-

cell lymphoma, with a characteristic antigen profile

and clinical behavior (reviewed in Younes et al.,

2014). This led the authors of the REAL

classification proposal to separate LPHL as a

distinct clinicopathologic entity from the other

subtypes of HL, which were grouped under the

Classification of Hodgkin lymphoma over years Carbone A, Gloghini A


term "classical HL (CHL) ID: 1569> " (Harris et

al.,1994; Mason et al., 1994; Stein, 2001; Stein et

al., 2008) (Table 1). According to its cell of origin,

phenotype and type of progression to large B-cell

lymphoma, NLPHL should probably be considered

as a B-cell lymphoma tout court.

Phenotype/cell stem origin

HL with a nodular growth pattern and a

lymphocyte-rich background encompasses two

entities, i.e. NLPHL and LRCHL with distinct

phenotypical features. NLPHL which may contain a

broad morphologic spectrum of neoplastic cells,

exhibit a characteristic immunophenotype with

expression of B-cell-specific antigens and absent

expression of CD30 and CD15.

LRCHL cases also exhibit, in the majority of cases,

a nodular growth pattern as well as a broad

morphologic spectrum of the neoplastic cells. The

tumor cell phenotype, however, is always

characteristic of CHL with expression of CD30 and

CD15, infrequent expression of B-cell antigens

(Figure 1). Furthermore, it could be shown by

means of immunostains that the vast majority of

LPHL cases contain areas with nodular growth

pattern, whereas purely diffuse cases are extremely

rare. Probably these cases, could be classified as

grey zone lymphomas because they exhibit

intermediate features between NLPHL and

THCRLBCL (Figure 1) (Younes et al., 2014).

Clinics

Patients with LPHL and LRCHL usually differ

from patients with NS cHL or MC cHL, as they

presented with an earlier disease stage and

infrequent mediastinal involvement. As most LPHL

cases show a complete or partial nodular growth

pattern, their differentiation from THCRLBCL is a

rare problem (Table2).

Pathology

The question of the existence of diffuse LPHL

became more complex when other authors

described a diffuse large B-cell lymphoma variant,

the so-called T-cell or histiocyte-rich large B-cell

lymphoma (THCRLBCL), which frequently

simulate the morphology of diffuse LPHL but

exhibited an aggressive disease course (De Wolf-

Peeters et al., 2008; Carbone and Gloghini, 2016a).

The cases identified as diffuse LPHL exhibit

loosely distributed neoplastic cells embedded in a

reactive background without evidence of nodularity

.In these cases, which closely resemble

THCRLBCL by conventional histology, a majority

of the neoplastic cells have the morphologic

features of LP cells. Immunophenotypic analysis

can disclose an LP cell-characteristic phenotype

with expression of CD20, CD79a, and EMA,

whereas in-situ hybridization for EBER-transcripts

does not provide evidence of a latent EBV

infection. Due to the overlapping features between

THRLBCL and LPHL, it is sometimes impossible

to distinguish these two entities; thus, "grey zone"

lymphoma is used to define some of those cases

(De Wolf-Peeters et al., 2008; Younes et al., 2014)

(Figure 1).



Also, nodular lymphocyte predominant Hodgkin

lymphoma (NLPHL) and T-cell/histiocyte rich

large B-cell lymphoma (THRLBCL) are closely

related: both diseases contain neoplastic cells with

similar morphologic and immunophenotypic

features but differ with respect to their architecture

and the nature of the reactive background (table 2).

An additional type of HL with an abundance of

lymphocytes was subsequently recognized. It was

termed "lymphocyte-rich (LR) form of classical

HL" and included in the REAL classification. This

variant of classical HL (CHL), resembles, in terms

of nodular growth and lymphocyte-richness,

nodular LPHL and, in terms of the

immunophenotype of the tumor cells, CHL (Figure

1). Clinically, patients with LPHL and LRCHL

show similar disease characteristics at presentation

but differ in the frequency of multiple relapses and

prognosis after relapse (Gloghini and Carbone,

2016a; Gloghini and Carbone, 2016b).

Other features

In addition to immunophenotyping, in-situ

hybridization for EBER detection can assist in the

differential diagnosis between the two HL entities

as the neoplastic cells in LPHD appear not to be

permissive for an EBV infection (Table 3).

EBV is found in HRS cells preferentially in cases

of MC and LD cHL, and less frequently in NS and

LRCHL. Notably, EBV is found in HRS cells in

nearly all cases of cHL occurring in patients

infected with HIV (Younes et al., 2014; Dolcetti et

al., 2016; Carbone et al., 2016).

The virologic characteristics of cHL vary according

to the immunocompetence status of the host and

cHL subtype (Carbone et al., 2016).

Evolution

NLPHL may evolve to a completely diffuse T-cell-

rich proliferation lacking any follicular dendritic

cells which would be consistent with a THRLBCL

or can be associated with such a proliferation at a

separate site.

NLPHL may evolve to a completely diffuse T-cell-

rich proliferation lacking any follicular dendritic

cells which would be consistent with a THRLBCL

or can be associated with such a proliferation at a

separate site.

Genetics

Note

See the pertinent sections within the CARDS of the

Atlas of Genetics and Cytogenetics in Oncology

and Haematology describing the general features of

NLPHL and cHL (Küppers, 2011; Carbone and

Gloghini, 2016b; Gloghini and Carbone, 2016a).

cHL NLPHL THRLBCL

Phenotype

CD15 + - -

CD20 Usually - + +

CD30 + - - or +

IRF4/MUM1 + + - or +

BCL6 + (30%) + -

EMA - + Usually -

EBV infection

-/+* - -

Background

T cells + - +

B cells / B and T cells + + -

CD57+ rosetting cells - + -

CD40L+ rosetting cells + + -

Histiocytes +/- +/- +

Eosinophils + - -

Plasma cells + - -

DRCs meshworks - /+ + -

Fibrosis + (Common) + (Rare) -

Table 2. Phenotypic and virologic features of neoplastic cells of classic Hodgkin lymphoma (cHL), nodular lymphocyte predominance Hodgkin lymphoma (NLPHL) and T-cell/histiocyte rich large B-cell lymphoma (THRLBCL) *Association with EBV

is less frequent in NS than in MC cHL and LRCHL.



Host Hodgkin lymphoma subtype EBV infection

HL of the general population

Nodular lymphocyte predominance -

cHL, nodular sclerosis Usually -*

cHL, mixed cellularity Usually +*

Rare types

cHL, lymphocyte rich Variably +

cHL, lymphocyte depleted Variably +

Immunodeficiency-associated HL

HIV-associated HL

cHL, lymphocyte depleted +

cHL, mixed cellularity +

Less frequent

cHL, lymphohistiocyoid +

cHL, nodular sclerosis +

Table 3. Morphologic and virologic characteristics of Hodgkin lymphoma. Abbreviations. cHL, classical Hodgkin lymphoma; -, negative; +, positive. *Association with EBV is less frequent in ns (10-40%) than in mc cHL (approximately 75% of cases)

References Anagnostopoulos I, Hansmann ML, Franssila K, et al. European Task Force on Lymphoma project on lymphocyte predominance Hodgkin disease: histologic and immunohistologic analysis of submitted cases reveals 2 types of Hodgkin disease with a nodular growth pattern and abundant lymphocytes. Blood. 2000 Sep 1;96(5):1889-99

Brune V, Tiacci E, Pfeil I, Döring C, Eckerle S, van Noesel CJ, Klapper W, Falini B, von Heydebreck A, Metzler D, Bräuninger A, Hansmann ML, Küppers R. Origin and

pathogenesis of nodular lymphocyte-predominant Hodgkin lymphoma as revealed by global gene expression analysis. J Exp Med. 2008 Sep 29;205(10):2251-68

Carbone A, Gloghini A, Caruso A, De Paoli P, Dolcetti R. The impact of EBV and HIV infection on the microenvironmental niche underlying Hodgkin lymphoma pathogenesis. Int J Cancer. 2017 Mar 15;140(6):1233-1245

De Wolf-Peeters C, Delabie J, Campo E, Jaffe ES, Delsol G.. T cell/histiocyte-rich large B-cell lymphoma. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele H, Vardiman JW (eds.) World Health Organization Classification of Tumours, Pathology and Genetics of



Tumours of Haematopoietic and Lymphoid Tissues, Lyon: IARC Press, 2008: 238-239.

Dolcetti R, Gloghini A, Caruso A, Carbone A. A lymphomagenic role for HIV beyond immune suppression? Blood 2016 Mar 17;127(11):1403-9 doi: 10

Gloghini A, Carbone A. Lymphocyte-rich classical Hodgkin lymphoma (LRCHL) Atlas Genet Cytogenet Oncol Haematol 2016 (b) http://atlasgeneticsoncology.org/Anomalies/LymphRichClassicHodgkinID1567.html

Harris NL, Jaffe ES, Stein H, Banks PM, Chan JK, Cleary ML, Delsol G, De Wolf-Peeters C, Falini B, Gatter KC, et al. A revised European-American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group Blood 1994 Sep 1;84(5):1361-92

Jackson H, Parker F.. Hodgkins disease. I. General considerations. N Engl J Med 1944; 230(1): 1-8

Jackson H.. Classification and prognosis of Hodgkins disease and allied disorders. Surg Gynecol Obstet 1937; 64: 465-467

Küppers R. Hodgkin lymphoma Atlas Genet Cytogenet Oncol Haematol. 2011; 15(6): 527-528. http://atlasgeneticsoncology.org/Anomalies/HodgkinID2068.html

Lukes RJ, Butler JJ, Hicks EB.. Natural history of Hodgkins disease as related to its pathologic picture. Cancer 1966; 19(3): 317-344

Lukes RJ, Craver LF, Hall TC, Rappaport H, Ruben P.. Report of the nomenclature committee. Cancer Res. 1966;

26: 1311.

Mason DY, Banks PM, Chan J, Cleary ML, Delsol G, de Wolf Peeters C, Falini B, Gatter K, Grogan TM, Harris NL, et al. Nodular lymphocyte predominance Hodgkin's disease A distinct clinicopathological entity Am J Surg Pathol

Stein H, Delsol G, Pileri SA,Weiss LM, Poppema S, Jaffe ES.. Classical Hodgkin lymphoma, introduction. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele H, Vardiman JW (eds.) World Health Organization Classification of Tumours, Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues, Lyon: IARC Press, 2008: 326-329

Stein H.. Classical Hodgkin lymphoma, introduction. Jaffe ES, Harris NL, Stein H, Vardiman JW (eds.) World Health Organization Classification of Tumours, Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues, Lyon: IARC Press, 2001: 239

Swerdlow SH, Campo E, Pileri SA, Harris NL, Stein H, Siebert R, Advani R, Ghielmini M, Salles GA, Zelenetz AD, Jaffe ES. The 2016 revision of the World Health Organization classification of lymphoid neoplasms Blood 2016 May 19;127(20):2375-90

Younes A, Carbone A, Johnson P, Dabaja B, Ansell S, Kuruvilla L.. Hodgkin's lymphoma. De Vita VTJ, Lawrrence TS, Rosemberg SA (eds). De Vita, Hellman, and Rosenberg's Cancer: Principles Practice of Oncology: Wolters Kluwer Health/Lippincott Williams & Wilkins; 2014.


Carbone A, Gloghini A. Classification of Hodgkin lymphoma over years. Atlas Genet Cytogenet Oncol Haematol. 2017; 21(10):365-369.






t(5;14)(q35;q11) RANBP17 (or TLX3)/TRD Hélène Bruyère

Genetics Laboratory, Department of Pathology and Laboratory Medicine, Vancouver General

Hospital and Department of Pathology and Laboratory Medicine, University of British Columbia/

[email protected]


Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t0514q35q11ID1228.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/68740/12-2016-t0514q35q11ID1228.pdf DOI: 10.4267/2042/68740


Abstract

Review on t(5;14)(q35;q11), with data on clinics

and the genes involved.

Keywords

Chromosome 5; chromosome 14; t(5;14)(q35;q11);

RANBP17; TRD; TLX3; Acute lymphoblastic

leukemia; Acute myeloid leukemia.

Clinics and pathology

Disease

Acute lymphoblastic leukemia (ALL)


T- and B-ALL

Epidemiology

5 patients to date, 4 pediatric cases (14 months, 2,

10 and 12 years) (Whitlock JA et al., 1994; Hansen-

Hagge TE et al., 2002), 1 case with no clinical

information (Hansen-Hagge et al., 2002, case 2)

Clinics

One or more features of bulky disease.

Cytogenetics

Sole abnormality in one case of T-ALL and one

case of B-ALL relapse, additional abnormalities in

2 cases [B-ALL with subclones with

dup(1)(q32q21), add(X)(p22), der(11)t(11;?)(?;?)

and T-ALL with cytogenetically unrelated cell line

with del(9)(p22) and trisomy 15 (t-ALL)], 2 cases

not available].

Evolution

The 2 patients with B-ALL were in remission 19

and 22 months after diagnosis. One patient with T-

ALL relapsed at 6 months and the second patient

with T-ALL developed AML 17 months after

diagnosis, with the t(5;14) being present in the

myeloblasts.

Disease

Acute myeloid leukemia, FAB M5 (Welborn JL et

al., 1993)

Note

Secondary abnormality.

Epidemiology

1 case to date, a 45-year-male.

Cytogenetics

The t(5;14)(q35;q11) was found in a follow-up

specimen together with the primary abnormality,

t(6;11)(q27;q23), identified in the sample obtained

at diagnosis.

Genes

The genes involved in the translocation t(5;14)

identified in this AML case have not been

investigated and may be different from those of the

t(5;14) found in the ALL cases.

Treatment

2 inductions with standard dose cytarabine -

daunorubicin - 6-thioguanine.

t(5;14)(q35;q11) RANBP17 (or TLX3)/TRD Bruyère H


Evolution

No response to treatment.

Genes involved and proteins

RANBP17 (RAN binding protein 17)

Location 5q35.1

Note

The 5q breakpoint was initially reported to be

located at 5q34 (Hansen-Hagge et al., 2002), but the

location of the gene potentially disrupted by the

translocation is 5q35.1 in the hg38 assembly

(UCSC Genome Browser, accessed Dec. 9th, 2016).

However, Harsen-Hagge et al., 2002, mention that

the 5q breakpoint is also in the vinicity of the TLX3

gene, which involvement was neither confirmed nor

excluded. This gene has been involved in other

ALL rearrangements and encodes a DNA-binding

nuclear transcription factor (see Atlas

t(5;7)(q35;q21), t(5;14)(q35;q32)).

DNA/RNA

The RANBP17 gene has 28 exons and spans 438 kb

(hg38, UCSC Genome Browser, accessed Dec. 9th,

2016). Several transcripts have been identified, of

2,5, 4,5, 7,5 and 10 kb (Koch et al., 2000).

Protein

The Ran-binding protein 17 is 90-130 kD in size

and contains an importin- β N-terminal domain.

The RAN-binding protein-17 gene is a member of

the importin-beta superfamily of nuclear transport

receptors. Its protein is localized in the nucleus,

with a restricted expression pattern in the testis

(Koch P et al., 2000). It is a regulator of the E2A

protein's action (Lee et al., 2010).

TLX3 (T-cell leukemia, homeobox protein 3)

Location

5q35.1

TRD

Location

14q11.2


Hybrid gene

Description

In one case, exon 24 of RANBP17 was found to be

joined to TCR Dδ2Dδ3Jδ1 and containing the δ

enhancer sequence located between the Jδ1 and Cδ

elements, while in a second case, data suggested an

illegitimate recombination of TCR δ with

sequences from chromosome 14 and 5, the 5q

breakpoint being about 8 kb downstream of the last

RANBP17 exon (and about 1KB upstream from

TLX3) . There was an increased RANBP17

expression in the leukemic cells (Harsen-Hagge et

al., 2002) .

References Dehring DJ, Wismar BL. Intravascular macrophages in pulmonary capillaries of humans. Am Rev Respir Dis. 1989 Apr;139(4):1027-9

Hansen-Hagge TE, Schäfer M, Kiyoi H, Morris SW, Whitlock JA, Koch P, Bohlmann I, Mahotka C, Bartram CR, Janssen JW. Disruption of the RanBP17/Hox11L2 region by recombination with the TCRdelta locus in acute lymphoblastic leukemias with t(5;14)(q34;q11). Leukemia. 2002 Nov;16(11):2205-12

Koch P, Bohlmann I, Schäfer M, Hansen-Hagge TE, Kiyoi H, Wilda M, Hameister H, Bartram CR, Janssen JW. Identification of a novel putative Ran-binding protein and its close homologue. Biochem Biophys Res Commun. 2000 Nov 11;278(1):241-9

Welborn JL, Jenks HM, Hagemeijer A. Unique clinical features and prognostic significance of the translocation (6;11) in acute leukemia. Cancer Genet Cytogenet. 1993 Feb;65(2):125-9

Whitlock JA, Raimondi SC, Harbott J, Morris SW, McCurley TL, Hansen-Hagge TE, Ludwig WD, Weimann G, Bartram CR. t(5;14)(q33-34;q11), a new recurring cytogenetic abnormality in childhood acute leukemia. Leukemia. 1994 Sep;8(9):1539-43


Bruyère H. t(5;14)(q35;q11) RANBP17 (or TLX3)/TRD. Atlas Genet Cytogenet Oncol Haematol. 2017; 21(10):370-371.






t(7;11)(p15;p15) NUP98/HOXA13 Aurelia M. Meloni-Ehrig

CSI Laboratories, Alpharetta, GA. [email protected]


Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t0711p15p15ID1360.html

Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/68741/12-2016-t0711p15p15ID1360.pdf DOI: 10.4267/2042/68741


Abstract

Several t(7;11)(p15;p15) have been reported in

myeloid neoplasms. The most common is the one

leading to a fusion between the NUP98 (11p15) and

the HOXA9 (7p15).

A more rare t(7;11) is the one that leads to a fusion

between the NUP98 and the HOXA13 gene on

7p15. This particular t(7;11) is associated primarily

with acute myeloid leukemia (AML), primarily

FAB M2 and M4. However, it has been reported

also in one case of chronic myelogenous leukemia

(CML) in blast crisis. The NUP98/HOXA13 fusion

protein is thought to promote leukemogenesis

through inhibition of HOXA13-mediated terminal

differentiation and/or aberrant nucleocytoplasmic

transport. . The protein encoded by the

NUP98/HOXA13 fusion gene is similar to the one

encoded by the NUP98/HOXA9 fusion, and the

expression pattern of the HOXA13 gene in

leukemic cell lines is similar to that of the HOXA9

gene, suggesting that the NUP98/HOXA13 fusion

protein may play a role in leukemogenesis through

a mechanism similar to that of the NUP98/HOXA9

fusion protein.

Keywords

chromosome 7; chromosome 11; t(7;11)(p15;p15);

acute myeloid leukemia (AML); chronic

myelogenous leukemia (CML); NUP98; HOXA13

Identity

Precise breakpoints are the following:

t(7;11)(p15.2;p15.4).

Figure 1 46,XX,t(7;11)(p15;p15)

t(7;11)(p15;p15) NUP98/HOXA13 Meloni-Ehrig AM



Note

This rare t(7;11) has been reported in: Acute

myeloid leukemia (AML) Chronic myelogenous

leukemia (CML) in blast crisis

Disease: Acute myeloid leukemia (AML)


The blasts expressed CD7, CD11b, CD13, CD33,

CD34, and HLADR antigens.

Clinics

De novo AML reported in a single patient, a 57

year-old woman (Taketani et al, 2002). The patient

presented with leukocytosis (118,800/ µL) and 81%

myeloid blasts.

Cytogenetics

At diagnosis, the karyotype was

46,XX,t(7;11)(p15;p15) in all 20 metaphase cells

examined from a bone marrow sample. At

remission, all 20 metaphase cells obtained from the

bone marrow were normal, 46,XX. The t(7;11)

seems to be a solitary abnormality in AML. No

additional abnormalities have been reported so far.

Treatment

Patient received induction therapy with idarubicin

and cytarabine (AraC), followed by multiple cycles

of AraC and anthracyclines.

Evolution

A relapse occurred in the central nervous system 6

months after diagnosis and in the bone marrow 8

months after diagnosis, and the patient died of

progressive disease 16 months after onset.

Prognosis

The prognosis in this single case of AML is

unfavorable.

Disease: Chronic myelogenous leukemia (CML) in blast crisis

Epidemiology

This is the only described case so far of a CML in

blast crisis presenting with a t(7;11)(p15;p15) in

addition to the t(9;22)(q34;q11.2) (Di Giacomo et

al., 2014).

Clinics

The patient is a 39 year-old man referred for

leukocytosis, mild anemia, thrombocytopenia, and

splenomegaly. CML in blast crisis was diagnosed

on peripheral blood and bone marrow smears.

Cytogenetics

Chromosome analysis showed the following

karyotype:

46,XY,t(9;22)(q34;q11.2)[6]/46,idem,t(7;11)(p15;p

15)[9].

Treatment

Patient was treated initially with hydroxyurea,

followed by Dasatinib but did not respond. High-

dose ARA-C and subsequent bone marrow

transplantation from a HLA haploidentical brother,

were also unsuccessful.

Prognosis

The prognosis in this single case of CML in blast

crisis is unfavorable.


HOXA13 (homeobox A13)

Location 7p15.2

The HOXA13 gene is part of the HOXA cluster

genes and contains 2 exons, encoding a protein of

338 amino acids with a homeodomain.

NUP98 (nucleoporin 98 kDa)

Location 11p15.4

Protein

920 amino acids; 97 kDa; contains repeated motifs

(GLFG and FG) in N-term and a RNA binding

motif in C-term.


Fusion protein

Description

The NUP98/HOXA13 fusion protein consists of the

N-terminal phenylalanine-glycine repeat motif of

NUP98 and the C-terminal homeodomain of

HOXA13, similar to the NUP98/HOXA9 fusion

protein (Fujino et al., 2002; Romana et al, 2006).

References Di Giacomo D, Pierini V, Barba G, Ceccarelli V, Vecchini A, Mecucci C. Blast crisis Ph+ chronic myeloid leukemia with NUP98/HOXA13 up-regulating MSI2. Mol Cytogenet. 2014;7:42

Fujino T, Suzuki A, Ito Y, Ohyashiki K, Hatano Y, Miura I, Nakamura T. Single-translocation and double-chimeric transcripts: detection of NUP98-HOXA9 in myeloid leukemias with HOXA11 or HOXA13 breaks of the chromosomal translocation t(7;11)(p15;p15). Blood. 2002 Feb 15;99(4):1428-33

t(7;11)(p15;p15) NUP98/HOXA13 Meloni-Ehrig AM


Brann BS 4th, Wofsy C, Wicks J, Brayer J. Quantification of neonatal cerebral ventricular volume by real-time ultrasonography. Derivation and in vitro confirmation of a mathematical model. J Ultrasound Med. 1990 Jan;9(1):1-8

Taketani T, Taki T, Ono R, Kobayashi Y, Ida K, Hayashi Y. The chromosome translocation t(7;11)(p15;p15) in acute myeloid leukemia results in fusion of the NUP98 gene with

a HOXA cluster gene, HOXA13, but not HOXA9. Genes Chromosomes Cancer. 2002 Aug;34(4):437-43


Meloni-Ehrig AM. t(7;11)(p15;p15) NUP98/HOXA13. Atlas Genet Cytogenet Oncol Haematol. 2017; 21(10):372-374.






dic(5;17)(q11-14;p11-13) Adriana Zamecnikova, Soad al Bahar

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


Online updated version : http://AtlasGeneticsOncology.org/Anomalies/dic0517q11p11ID1164.html

Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/68742/12-2016-dic0517q11p11ID1164.pdf DOI: 10.4267/2042/68742


Abstract

Complete or partial monosomies of the long arm of

chromosome 5 and/or 17p are common findings in

myeloid malignancies, particularly in therapy-

related myeloid disorders.

They usually result from interstitial or terminal

deletions and less frequently from unbalanced

rearrangements such as dicentric chromosomes.

One of the recurring unbalanced translocation in

myeloid malignancies is the unbalanced dicentric

translocation dic(5;17)(q11-14;p11-13) that results

in complete or partial monosomy for the long arm

of chromosome 5 and the short arm of chromosome

17.

Keywords

dicentric; chromosome 5; chromosome 17; chronic

myelogenous leukemia; acute myeloid leukemia;

myelodysplastic syndrome; therapy-related

leukemmia.

Identity

Note

Included are 5q11-14 and 17p11-13 breakpoints

(breakpoints described at or near the centromeres),

the related unbalanced der(5)t(5;17) and

der(17)t(5;17) are not included.

Figure 1 dic(5;17)(q11.2~13;p11.2~13) G- banding: - Courtesy Ronnie Ghuman and Charles D. Bangs.

dic(5;17)(q11-14;p11-13) Zamecnikova A, al Bahar S



Disease

Chronic myeloproliferative neoplasms and acute

myeloid leukemia (AML)

16 patients had a primary myelodysplastic

syndrome (MDS) (Knapp et al., 1985; Herry et al.,

2007; Lange et al., 2010) or de novo AML (Huret et

al., 1991; Kwong et al., 1994; Arkesteijn et al.,

1996; Tosi et al 1996; Wang et al., 1997; Mrozek

et al., 2002; Zatkova et al., 2006; Herry et al., 2007;

Hangai et al., 2013) and 2 patients had chronic

myelogenous leukemia in advanced phase

(Hagemeijer et al., 1981; Wang et al., 1997). 23

patients developed therapy-related MDS (Hatzis et

al., 1995; Wang et al 1997; Andersen et al., 2005;

Andersen et al., Andersen et al., 2008) or AML

(Kerim et al., 1991; Heyn et al., 1994; Wang et al.,

1997; Nakamori et al., 2003; Andersen et al., 2005;

McNerney et al., 2014) after cytotoxic treatment

and/or radiotherapy (Table 1).

Sex/Age Diagnosis Karyotype

1 M/26 CML 44-45,XY,dic(5;17)(q11;p11),t(9;22),r(18)

blast crisis

2 M/57 RAEB 45,XY,dic(5;17)(q11;p11),-7,+8/46,idem,add(18)(q23),+mar

3 M/69 AML-M2 45,XY,r(3),dic(5;17)(q14;p13),del(7)(q11),add(9)(p2?),add(9)(q34),-12,-13,i(21)(q10),+mar/90,

idemx2

4 M/71 AML-M1 47,XY,+8/44,XY,-5,-17,-18,+mar/44,XY,dic(5;17)(q11;p11),-18/46,XY,dic(5;17),-18,+mar

idiopathic myelofibrosis, chemotherapy

5 M/1 AML

45,XY,hsr(2)(q22),dic(5;17)(q11;p11),der(7)del(7)(q11)hsr(7)(q11),der(12)t(12;19)(p11;q12),-19,

+mar

embryonal rhabdomyosarcoma, chemotherapy, radiotherapy

6 M/77 AML-M1 47,XY,+14/45,XY,dic(5;17)(q11;p11),dmin/95-96,XXY,-Y,-5,+9,+11,+12,+13,+13, +14,+14,+ 17

7 F/59 RAEB 45,XX,dic(5;17)(q11;p11)

acute promyelocytic leukemia, relapse, chemotherapy

8 M/45 AML-M1 46,XY,t(1;15)(p21;q23),t(3;5)(q23;q12),ins(4;12)(q28;p?),dic(5;17)(q11;p11),der(7)t(7;18)(q11;q12)

t(14;18)(q12;q23),+8,-14,del(18)(q12q23),add(19)(q23), +21

9 F/63 AML 46,XX,dic(5;17)(q11;p11),-7,der(10)t(10;19)(p11;q11),-19,+2mar

10 M/75 AML 46,XY,-3,dic(5;17)(q11;p11),del(7)(q22q?),+8,+11,-15,+mar

11 M/66 AML-M6 43,XY,der(5)t(5;12)(q13;q14),dic(5;17)(q13;p11),-7,dup(9)(q21q12),-12,-15, add(16)(q13),

add(17)(p11),-18, +add(21)(p11),+mar/44,idem,+13

12 F/64 MDS

45,XX,-7/45,XX,dic(5;17)(q11;p11)/44,XX,dic(5;17),der(7)t(7;13)(q11;q14), add(13)(q14),-17/

44,XX,-3, dic(5;17),der(7)t(3;7)(p14;q32)/44,XX,-3,der(5)t (5;7)(q11;p1?5),dic(5;17),

der(7)t(7;16)(p1?5;p13)t(3;7), der(16;17)t(16;17)(p13;p11)ins(16;5)(p13;q11q11),add(21)(q22)

adenocarcinoma, chemotherapy, radiotherapy

13 F/50 AML

45,XX,dic(5;17)(q13;p11),inv(5)(p13q11)/46,idem,+8/44,idem,-11,add(16)(p13)

,der(19)t(11;19)(q11q25;p13) add(11)(q11)

multiple myeloma, chemotherapy

14 F/64 AML

45,XX,add(1)(q42),add(4)(q2?5),dic(5;17)(q11;p11),der(6)t(6;12)(q21;q21),-12,+mar/46,idem,+8/

46,idem,+11, der(11;11)t(11;11)(p15;q25)ins(11;?)(p15;?)/46,idem,+11,der(11;11),+13,-mar,+mar

adenocarcinoma, chemotherapy

15 F/73 AML 43,XX,dic(3;22)(p21;p11),dic(5;17)(q11;p11),-7,+8,add(12)(p13),add(14)(p11), -16/44,idem,+mar

adenocarcinoma, radiotherapy

16 F/48 MDS

46,XX,t(8;17)(p11;q22) or t(8;17)(p21;q23)/46,XX,del(7)(q22q34)/46,XX,t(2;18)(p21;p11)/

46,XX,t(2;12)(q11;q21-22),t(11;17)(q13;q25)/45,XX,del(1) (p34p36),dic(5;17)(q13;p11),+8,-18

follicular lymphoma, chemotherapy, radiotherapy

17 M/55 MDS 44,XY,dic(5;17)(q13;p11),dic(19;20)(p13;q11)/45,idem,+mar

Hodgkin disease, chemotherapy

18 F/81 MDS 47,XX,del(3)(p21p24),dic(5;17)(q13;p11),+8,+22/48,idem,+X

adenocarcinoma, radiotherapy

19 M/58 MDS

45,XY,dic(5;17)(q11;p11),r(7)(p2?2q1?1)/45,idem,dic(5;17),i(9)(p10),del(13)(q12q14)/43,XY,

dic(5;17),-7, dic(9;18)(q13;p11)/44,XY,dic(5;17),-7/46,XY,del(11)(q14q23)

chronic lymphocytic leukemia, chemotherapy



20 M/73 AML

43,XY,-3,dic(5;17)(q11;p11),-7,+12,t(12;?12)(p13;q13-14),-18,+19,-22/42, idem,-12,del(22)(q11)/

43,idem,-12,del(22),+del(22)/44,idem,-12,del(22),+del(22),+mar/42,idem,t(9;15)(p2?2;q2?1),-12,

del(22)

21 M/57 AML-M7 47,XY,dic(5;17)(q11;p11),-7,-13,add(19)(p13),+4mar

22 M/59 CML

45,XY,dic(5;17)(q11;p11),del(9)(q34) or

del(9)(q34q34),t(9;22)(q34;q11)/45,idem,+22/45,XY,t(9;22),

der(18) t(17;18)(q11;p11)

23 M/25 AML 44,XY,del(3)(p13),dic(5;17)(q11;p11),-7

Hodgkin disease, chemotherapy, radiotherapy

24 M/8 AML

45,XY,dic(5;17)(q11;p11),del(7)(q22q35)/46,idem,+21/44,idem,der(11;21)t(11;21)(p15;p13)

ins(11;?)(p15;?) add(11)(q22)

rhabdomyosarcoma, chemotherapy, radiotherapy

25 M/48 AML-M2

45-46,XY,der(5)t(5;17)(q11;q11),r(11;11)(p15q25;q?),-17,+mar/47,idem,+der(5)t(5;17)(q11;q11)/

44,XY,der(4) t(4;11)(q3?5;q13)ins(4;11)(q3?5;?)t(11;11)(q25;?),der(5)t(5;17),-11,-17/42,XY,

dic(5;17)(q11;p11-12),-7,der(11)del(11)(q13q23)dup(11)(q24q22)t(11;12)(q2?2;q22),-

12,der(16)del(16)(q22q24)?dup(16)(q24q24)t(7;16(q11;q24),-18 ?

26 M/54 AML-M6

44,XY,dic(5;17)(q13;p11),-7,add(15)(q24)/44,idem,-dic(5;17),+mar

43,XY,dic(5;17),-7,add(12)(p11),add(15)(q24),-16

56,XY,+Y,+1,+2,add(3)(p13),add(4)(p11),+6,+14,+15,add(15)x2,add(19)(p13), +20,+4mar/113-

116,

idemx2,+8,+8,+5mar


27 M/62 AML-M1

43-47,X,-Y,dic(5;17)(q11;p11),der(5;17)t(5;17)t(13;17)(q?14;q?),-

7,der(9)t(9;12)(q34;q?13),+der(10)del(10)(p?)del(10)(q?),-12,der(13;21)(q10;q10),i(13)(q10),

der(18)t(14;18)(q?;p?)t(14;21)(q?24;q?11),der(18)t(9;18)(?;p11)t(9;14)t(9;21)

Wegeners granulomatosis, chemotherapy

28 M/69 MDS

46,X,t(Y;16)(q12;q?),del(3)(p24p?),del(5)(q31q31),dic(5;17)(q11;p11),dup(19)(q?),+del(21)(q21)/

48,idem,+18, +19,-dup(19),+22


29 F/53 MDS

43,XX,dic(5;17)(q11;p11),dic(6;19)(p2?4;?),-21/43,XX,dic(5;17),-7,ider(21)(q10)del(21)(q22),-22,

der(22)t(9;22)(q?;p11)


30 F/86 AML

44,XX,dic(5;17)(q11;p11),-7,der(10)t(10;11)(q25;q22)/43,idem,del(3)(p21),dic(4;7)(q11;q11),+7,

der(8)t(4;8) (q21;p21),-12,der(12)t(12;21)(p13;q22),der(21)t(12;21)(q?;q21)/43,idem,del(3),

dic(4;7),+7,der(8)t(4;8),dup(11)(q23q23),-12,der(12)t(12;21),der(21)t(12;21)


31 M/73 AML 44,XY,dic(5;17)(q11;p11),der(6)del(6)(p?)del(6)(q?),dup(6)(q?),-7,dup(8)(p?),ins(9;5)(q34;q31q31)


32 M/39 AML-M1

45,XY,dic(5;17)(q11;p11),+11,-19,der(20)t(19;20)t(19;20)/43,idem,-11,-16/43-

46,idem,dic(3;15)(p11;p11),

-4, der(19)t(4;19)(?;q?),der(20)t(19;20)t(4;19)


33 M/76 MDS

45,XY,dic(5;17)(q11;p11),+6,der(6)t(6;11)(p23;q14-

21)x2,del(7)(q22),dic(15;16)(p11;q11)/45,idem,

+del(7)(q31),-del(7)(q22),+dup(7)(q31q31)/45,idem, +15,-dic(15;16),+del(16)(q12),-18

Hodgkin disease, chemotherapy

34 M/72 AML-M1 47-49,XY,der(2;7)dic(2;7)(p23;q11)t(2;12)(q33;q11),dic(5;17)(q11;p12),+8,+r(11)x3,

der(12)t(2;12)(p23;q11),+13

35 F/32 MDS 45,XX,dic(5;17)(q11;p11),-7,+r/45,idem,add(14)(p11)

36 F/79 MDS 46,XX,dic(5;7)(q11;p11),idic(5)(q11),r(5),?dic(7;8)(q31;p22),?dic(12;17)(p12;q22)

37 M/69 AML-M2 46,XY,dic(5;17)(q11;p11),-7,+add(11)(q25),+13,del(13)(q31)x2,-16,-17,-18, +3mar

38 M/69 MDS

46,X,t(Y;16)(q12;q?),del(3)(p24p?),del(5)(q13q31),dic(5;17)(q11;p11),dup(19)(q?),+del(21)(q21)/

48,idem,+18,+19,-dup(19),+22


39 M/73 RAEB 44-45,XY,dic(5;17)(q11;p11),+8,-13,-21,+1-2mar/45-47,idem,+13,t(15;18)(q10;q10),+i(21)(q10)

40 M/79 AML-M6 44,XY,add(2)(q21),dic(5;17)(q13;p11),-7,+8,add(12)(p11),-15,-16,+mar



41 M/39 AML

45,XY,-3,r(5)(p14q11),-7,+der(19)t(3;19)(q2?5;q13)/44,XY,-3,dic(5;17)(q12;p11),-7,+mar/ 44,XY,

t(3;15) (p2?3;q15),dic(5;12)(q12;p11),-7,add(10)(p13)

squamous cell carcinoma, chemotherapy, radiotherapy

Table 1. Reported patients with dic(5;17)(q11-14;p11-13). Abbreviations: CML, chronic myeloid leukemia; RAEB, Refractory anemia with excess of blasts; AML-M2, Acute myeloblastic

leukemia with maturation (FAB type M2); AML-M1, Acute myeloblastic leukemia without maturation (FAB type M1); AML, Acute myeloid leukemia, NOS; AML-M6, Acute erythroleukemia (FAB type M6); MDS, Myelodysplastic syndrome; AML-M7, Acute

megakaryoblastic leukemia (FAB type M7). 1. Hagemeijer et al., 1981; 2. Knapp et al., 1985; 3. Huret et al., 1991; 4. Kerim et al., 1991; 5. Heyn et al., 1994; 6. Kwong et al., 1994; 7. Hatzis et al., 1995; 8. Arkesteijn et al., 1996; 9-10. Tosi et al., 1996; 11-

24. Wang et al., 1997; 25.Mrozek et al., 2002; 26. Nakamori et al., 2003; 27.Andersen et al., 2005; 28-33.Andersen et al.,2005; 34. Zatkova et al., 2006; 35-37. Herry et al., 2007; 38. Andersen et al., 2008; 39.Lange et al., 2010; 40. Hangai et al.,

2013; 41. McNerney et al., 2014.


Phenotype / cell stem origin de novo and therapy

related myeloid malignancies.

Epidemiology

29 male and 12 female patients (sex ratio 2.4) aged

1 to 86 years (median age 63 years).

There were 2 pediatric cases (aged 1 and 8 years),

both of them developed AML after therapy for

rhabdomyosarcoma.

Prognosis

Patients with 5q and/or 17p deletions and complex

karyotypes represent an unfavorable cytogenetic

prognostic category, particularly when the disorder

is related to previous cytotoxic therapy.

Cytogenetics

Cytogenetics morphological

Presents as 1 normal chromosome 5 and 17 and a

dic(5;17) chromosome that contains the short arm

of chromosome 5, the long arm of chromosome 17

and centromeres of both chromosomes; breakpoints

at or near the centromeres may be difficult to

ascertain, the most common described breakpoints

were q11 on chromosome 5 and p11 on 17p,

reported in 31 out of 41 patients.

Combining karyotyping with fluorescence in situ

hybridization of centromere-specific probes for

chromosomes 5 and 17 allows precise breakpoint

definition and confirm the presence of both

centromeres.

Additional anomalies

Sole anomaly in 1 MDS patient previously treated

for acute promyelocytic leukemia and found in

association with increased karyotype complexity in

most of the cases.

The most commonly observed anomaly was

monosomy 7, observed in 19, while 7q deletion was

found in 5 patients. Monosomy 5/5q- was found in

4 and +8 in 10 patients.


Fusion protein

Oncogenesis

Deletion of 5q and 17p through formation of an

unbalanced dicentric rearrangement is a non-

random event in myeloid malignancies, particularly

in therapy-related disorders. dic(5;17)(q11-14;p11-

13) result in partial monosomy for 5q and 17p

leading to altered gene dosages, affecting tumor

suppressor genes. The key mechanism might be the

combined loss of tumor suppressor genes in 5q and

17p containing the TP53 gene. It is likely that TP53

loss that is frequently accompanied by inactivating

mutations in the remaining TP53 allele (Wang et

al., 1997) represent one of the instigators of the

genome instability that is manifested by complex

karyotypes. Highly complex rearrangements

containing unbalanced translocations, ring

chromosomes, insertions, marker chromosomes,

homogeneously staining regions, dicentric

chromosomes and cytogenetically unrelated clones

were overrepresented in patients with therapy-

related myeloid malignancies, indicative of the role

of mutagenic effect of previous therapy. The

probable sequence of genetic events is unclear;

however dic(5;17) usually presents with additional

common anomalies such as monosomy 7/7q or 5/5q

and trisomy 8, therefore the formation of dic(5;17)

likely represent a therapy-induced abnormality that

occurred during the multistep process of

leukemogenesis

References Andersen MK, Christiansen DH, Pedersen-Bjergaard J. Centromeric breakage and highly rearranged chromosome derivatives associated with mutations of TP53 are common in therapy-related MDS and AML after therapy with alkylating agents: an M-FISH study. Genes Chromosomes Cancer. 2005 Apr;42(4):358-71



Andersen MT, Andersen MK, Christiansen DH, Pedersen-Bjergaard J. NPM1 mutations in therapy-related acute myeloid leukemia with uncharacteristic features Leukemia 2008 May;22(5):951-5

Arkesteijn GJ, Erpelinck SL, Martens AC, Hagemeijer A, Hagenbeek A. The use of FISH with chromosome-specific repetitive DNA probes for the follow-up of leukemia patients Correlations and discrepancies with bone marrow cytology Cancer Genet Cytogenet

Hagemeijer A, Sizoo W, Smit EM, Abels J. Translocation (5p; 17q) in blast crisis of chronic myeloid leukemia Cytogenet Cell Genet 1981;30(4):205-10

Hangai S, Nakamura F, Kamikubo Y, Honda A, Arai S, Nakagawa M, Ichikawa M, Kurokawa M. Erythroleukemia showing early erythroid and cytogenetic responses to azacitidine therapy Ann Hematol 2013 May;92(5):707-9

Hatzis T, Standen GR, Howell RT, Savill C, Wagstaff M, Scott GL. Acute promyelocytic leukaemia (M3): relapse with acute myeloblastic leukaemia (M2) and dic(5;17) (q11;p11) Am J Hematol 1995 Jan;48(1):40-4

Herry A, Douet-Guilbert N, Morel F, Le Bris MJ, Morice P, Abgrall JF, Berthou C, De Braekeleer M. Evaluation of chromosome 5 aberrations in complex karyotypes of patients with myeloid disorders reveals their contribution to dicentric and tricentric chromosomes, resulting in the loss of critical 5q regions Cancer Genet Cytogenet 2007 Jun;175(2):125-31

Heyn R, Khan F, Ensign LG, Donaldson SS, Ruymann F, Smith MA, Vietti T, Maurer HM. Acute myeloid leukemia in patients treated for rhabdomyosarcoma with cyclophosphamide and low-dose etoposide on Intergroup Rhabdomyosarcoma Study III: an interim report Med Pediatr Oncol 1994;23(2):99-106

Huret JL, Schoenwald M, Gabarre J, Vaugier GL, Tanzer J. Two additional cases of isochromosome 21q or translocation 21q21q in hematological malignancies Acta Haematol 1991;86(2):111-4

Kerim S, Rege-Cambrin G, Scaravaglio P, Godio L, Saglio G, Aglietta M. Trisomy 8 and an unbalanced t(5;17)(q11;p11) characterize two karyotypically independent clones in a case of idiopathic myelofibrosis evolving to acute nonlymphoid leukemia Cancer Genet Cytogenet 1991 Mar;52(1):63-9

Knapp RH, Dewald GW, Pierre RV. Cytogenetic studies in

174 consecutive patients with preleukemic or myelodysplastic syndromes Mayo Clin Proc 1985 Aug;60(8):507-16

Kwong YL, Lam CK, Chan AY, Lie AK, Chan LC. Cytogenetic triclonality in acute myeloid leukemia: a morphologic, immunologic and in situ hybridization study Cancer Genet Cytogenet 1994 Feb;72(2):86-91

Lange K, Holm L, Vang Nielsen K, Hahn A, Hofmann W, Kreipe H, Schlegelberger B, Göhring G. Telomere shortening and chromosomal instability in myelodysplastic syndromes Genes Chromosomes Cancer 2010 Mar;49(3):260-9

McNerney ME, Brown CD, Peterson AL, Banerjee M, Larson RA, Anastasi J, Le Beau MM, White KP. The spectrum of somatic mutations in high-risk acute myeloid leukaemia with -7/del(7q) Br J Haematol 2014 Aug;166(4):550-6

Mrózek K, Heinonen K, Theil KS, Bloomfield CD. Spectral karyotyping in patients with acute myeloid leukemia and a complex karyotype shows hidden aberrations, including recurrent overrepresentation of 21q, 11q, and 22q Genes Chromosomes Cancer 2002 Jun;34(2):137-53

Nakamori Y, Miyazaki M, Tominaga T, Taguchi A, Shinohara K. Therapy-related erythroleukemia caused by the administration of UFT and mitomycin C in a patient with colon cancer Int J Clin Oncol 2003 Feb;8(1):56-9

Tosi S, Harbott J, Haas OA, Douglas A, Hughes DM, Ross FM, Biondi A, Scherer SW, Kearney L. Classification of deletions and identification of cryptic translocations involving 7q by fluorescence in situ hybridization (FISH) Leukemia 1996 Apr;10(4):644-9

Wang P, Spielberger RT, Thangavelu M, Zhao N, Davis EM, Iannantuoni K, Larson RA, Le Beau MM. dic(5;17): a recurring abnormality in malignant myeloid disorders associated with mutations of TP53 Genes Chromosomes Cancer 1997 Nov;20(3):282-91

Zatkova A, Schoch C, Speleman F, Poppe B, Mannhalter C, Fonatsch C, Wimmer K. GAB2 is a novel target of 11q amplification in AML/MDS Genes Chromosomes Cancer 2006 Sep;45(9):798-807


Zamecnikova A, al Bahar S. dic(5;17)(q11-14;p11-13). Atlas Genet Cytogenet Oncol Haematol. 2017; 21(10):375-379.

Solid Tumour Section Short Communication





Kidney: Renal cell carcinoma with t(X;1)(p11;q21) PRCC/TFE3 Pedram Argani

Department of Pathology, The Johns Hopkins Hospital, Baltimore MD (PA) [email protected]

Published in Atlas Database: August 2016

Online updated version : http://AtlasGeneticsOncology.org/Tumors/tX1ID5009.html

Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/68743/08-2016-tX1ID5009.pdf DOI: 10.4267/2042/68743

This article is an update of : Desangles F. Kidney: t(X;1)(p11.2;q21.2) in renal cell carcinoma. Atlas Genet Cytogenet Oncol Haematol 1998;2(3)


Abstract Review on Renal cell carcinoma with

t(X;1)(p11;q21) PRCC/TFE3, with data on clinics,

and the genes involve

Keywords

Renal cell carcinoma; chromosome X; chromosome

1; PRCC; TFE3; MiT family

Classification

Xp11 translocation renal cell carcinoma (RCCs)

harbor gene fusions involving TFE3 transcription

factor. The The t(6;11) RCCs harbor a specific

MALAT1 (Alpha) - TFEB gene fusion. TFEB and

TFE3 belong to the same MiT subfamily of

transcription factors.

Because of similarities at the clinical, morphologic,

immunohistochemical, and genetic levels, the Xp11

translocation RCCs and t(6;11) RCCs are currently

grouped together under the category of MiT family

translocation renal cell carcinoma.)


Disease

Renal cell carcinoma.

Phenotype / cell stem origin

t(X;1) (p11;q21) PRCC/TFE3 is found in Xp11

translocation renal cell carcinoma.

Figure 1 t(X;1)(p11;q21) (G banding) - Courtesy Francois Desangles.

http://documents.irevues.inist.fr/bitstream/DOI%20tX1ID5009.txt

Kidney: Renal cell carcinoma with t(X;1)(p11;q21) PRCC/TFE3

Argani P


Epidemiology

Approximately 40 reported cases, median age 20

yrs (range 2-69); sex ratio: 17M/20F. A subset of

cases has been associated with prior exposure to

cytotoxic chemotherapy.

Pathology

PRCC frequently have papillary architecture with

clear cytoplasm and abundant psammoma bodies.

Other cases are nested and mimic clear cell RCC.

Treatment

Radical nephrectomy.

Prognosis

Similar to that of others papillary renal cell

carcinoma.

Cytogenetics

Probes

TFE3 and PRCC/TFE3

Additional anomalies

+17.


TFE3 (transcription factor E3)

Location Xp11.23

Protein

Transcription factor; binds to the immunoglobulin

enhancer.

PRCC (papillary renal cell carcinoma)

Location 1q23.1

Protein

491aa; widely expressed; proline rich.


Hybrid Gene

Description

5' TFE3 - 3' PRCC and 5' PRCC - 3' TFE3

Detection

positional cloning; screening in a tumor cDNA

library and hybridization with TFE3

Fusion Protein

Description

PRCC/TFE3 fusion protein includes the

transcription activating, helix-loop-helix and

leucine-zipper domains of TFE3; the TFE3/PRCC

fusion protein (513 amino acids) is also expressed.

References Amin MB, Corless CL, Renshaw AA, Tickoo SK, Kubus J, Schultz DS. Papillary (chromophil) renal cell carcinoma: histomorphologic characteristics and evaluation of conventional pathologic prognostic parameters in 62 cases. Am J Surg Pathol. 1997 Jun;21(6):621-35

Argani P, Antonescu CR, Couturier J, Fournet JC, Sciot R, Debiec-Rychter M, Hutchinson B, Reuter VE, Boccon-Gibod L, Timmons C, Hafez N, Ladanyi M. PRCC-TFE3 renal carcinomas: morphologic, immunohistochemical, ultrastructural, and molecular analysis of an entity associated with the t(X;1)(p11.2;q21). Am J Surg Pathol. 2002 Dec;26(12):1553-66

Argani P, Laé M, Ballard ET, Amin M, Manivel C, Hutchinson B, Reuter VE, Ladanyi M. Translocation carcinomas of the kidney after chemotherapy in childhood. J Clin Oncol. 2006 Apr 1;24(10):1529-34

Auffray C, Rougeon F. Purification of mouse immunoglobulin heavy-chain messenger RNAs from total myeloma tumor RNA. Eur J Biochem. 1980 Jun;107(2):303-14

Dijkhuizen T, van den Berg E, Wilbrink M, Weterman M, Geurts van Kessel A, Störkel S, Folkers RP, Braam A, de Jong B. Distinct Xp11.2 breakpoints in two renal cell carcinomas exhibiting X;autosome translocations. Genes Chromosomes Cancer. 1995 Sep;14(1):43-50

Ellis CL, Eble JN, Subhawong AP, Martignoni G, Zhong M, Ladanyi M, Epstein JI, Netto GJ, Argani P. Clinical heterogeneity of Xp11 translocation renal cell carcinoma: impact of fusion subtype, age, and stage. Mod Pathol. 2014 Jun;27(6):875-86

Meloni AM, Dobbs RM, Pontes JE, Sandberg AA. Translocation (X;1) in papillary renal cell carcinoma. A new cytogenetic subtype. Cancer Genet Cytogenet. 1993 Jan;65(1):1-6

Tomlinson GE, Nisen PD, Timmons CF, Schneider NR. Cytogenetics of a renal cell carcinoma in a 17-month-old child. Evidence for Xp11.2 as a recurring breakpoint. Cancer Genet Cytogenet. 1991 Nov;57(1):11-7

Weterman MA, Wilbrink M, Geurts van Kessel A. Fusion of the transcription factor TFE3 gene to a novel gene, PRCC, in t(X;1)(p11;q21)-positive papillary renal cell carcinomas. Proc Natl Acad Sci U S A. 1996 Dec 24;93(26):15294-8

de Jong B, Molenaar IM, Leeuw JA, Idenberg VJ, Oosterhuis JW. Cytogenetics of a renal adenocarcinoma in a 2-year-old child. Cancer Genet Cytogenet. 1986 Mar 15;21(2):165-9

van den Berg E, Dijkhuizen T, Oosterhuis JW, Geurts van Kessel A, de Jong B, Störkel S. Cytogenetic classification of renal cell cancer. Cancer Genet Cytogenet. 1997 May;95(1):103-7


Argani P. Kidney: Renal cell carcinoma with t(X;1)(p11;q21) PRCC/TFE3. Atlas Genet Cytogenet Oncol Haematol. 2017; 21(10):380-381.

Solid Tumour Section Short Communication





Kidney: Renal cell carcinoma with t(X;17)(p11;q23) CLTC/TFE3 Pedram Argani, Marc Ladanyi

Department of Pathology, The Johns Hopkins Hospital, Baltimore MD (PA) [email protected].

Published in Atlas Database: August 2016

Online updated version : http://AtlasGeneticsOncology.org/Tumors/RenalCellt0X17ID5035.html

Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/68744/08-2016-RenalCellt0X17ID5035.pdf DOI: 10.4267/2042/68744

This article is an update of : Argani P, Ladanyi M. Kidney: t(X;17)(p11.2;q23) in renal cell carcinoma. Atlas Genet Cytogenet Oncol Haematol 2005;9(3)


Abstract Review on Renal cell carcinoma with

t(X;17)(p11;q23) CLTC/TFE3, with data on clinics,

and the genes involved.

Keywords

Renal cell carcinoma; chromosome X; chromosome

17; CLTC; TFE3; MiT family

Identity

Other names

Renal cell carcinoma with CLTC-TFE3 gene fusion

Classification This renal cell carcinoma, of which there is only a

single reported case, belongs to the family of Xp11

translocation renal carcinomas. Xp11 translocation

renal cell carcinoma (RCCs) harbor gene fusions

involving TFE3 transcription factor.

The t(6;11) RCCs harbor a specific MALAT1

(Alpha) - TFEB gene fusion.

TFEB and TFE3 belong to the same MiT subfamily

of transcription factors.

Because of similarities at the clinical, morphologic,

immunohistochemical, and genetic levels, the Xp11

translocation RCCs and t(6;11) RCCs are currently

grouped together under the category of MiT family

translocation renal cell carcinoma.


Etiology

Unclear.

Epidemiology

Single case report in a 14 year old male.

Pathology

The tumor was bounded by a calcified fibrous

pseudocapsule. The tumor had predominantly a

solid, compact nested pattern, as islands of tumor

cells were demarcated by fibrovascular septa. More

dyscohesive areas yielded a papillary architecture.

Focal calcifications, some in the form of

psammoma bodies, were frequent, often associated

with hyaline nodules. Tumor cells were polygonal

with well-demarcated, predominantly clear,

voluminous cytoplasm. However, there were

scattered areas in which the cells were smaller and

others where they demonstrated densely

eosinophilic cytoplasm; the latter areas had a nested

growth pattern and foci of central necrosis,

somewhat reminiscent of hepatocellular carcinoma.

Mitoses were sparse.

Immunohistochemical (IHC) analysis showed

strong and diffuse nuclear labeling with a

polyclonal antibody to the TFE3 C-terminal

portion, as seen in other tumors associated with

TFE3 gene fusions.

Kidney: Renal cell carcinoma with t(X;17)(p11;q23) CLTC/TFE3

Argani P, Ladanyi M


Since native TFE3 protein is not detectable in non-

neoplastic cells by the same assay, this finding is

consistent with constitutive expression of a nuclear

fusion protein containing the TFE3 C-terminal

portion, such as the predicted CLTC-TFE3 protein.

Like most conventional (clear cell) and papillary

RCCs, the tumor contained tumor cells were

strongly and diffusely immunoreactive for CD10,

showing strong cytoplasmic staining with

membranous accentuation. However, unlike most

typical adult RCCs, IHC with all cytokeratin

antibodies (Cam5.2, AE1/3, Cytokeratin 7) and the

"RCC" monoclonal antibody yielded negative

reactions, though tumor cells did label in one

isolated area for Epithelial Membrane Antigen

(EMA).

Underexpression of common epithelial proteins is a

typical feature of Xp11.2-translocation carcinomas.

Surprisingly, the tumor was focally immunoreactive

for the melanocytic proteins Melan-A and HMB45

but IHC assays for MiTF and S100 protein were

negative. While unusual, the immunoreactivity for

melanocytic markers can be seen in Xp11

translocation carcinomas.

Kidney: Renal cell carcinoma with t(X;17)(p11;q23) CLTC/TFE3

Argani P, Ladanyi M


Treatment

Nephrectomy.

Prognosis

Unclear.


Note

The t(X;17)(p11.2;q23) results in a CLTC/TFE3

gene fusion.

TFE3 (transcription factor E3)

Location Xp11.23

DNA / RNA

The TFE3 gene includes a 5¹ untranslated region, 8

exons, and a 3¹ untranslated region.

Protein

TFE3 is a transcription factor with a basic helix-

loop-helix DNA binding domain and a leucine

zipper dimerization domain. TFE3 contains a

nuclear localization signal, encoded at the junction

of exons 5 and 6, which is retained within all

known TFE3 fusion proteins. TFE3 protein is 575

amino acids, and is ubiquitously expressed.

TFE3, TFEB, TFEC and Mitf comprise the

members of the microphthalmia transcription factor

subfamily, which have homologous DNA binding

domains and can bind to a common DNA sequence.

These four transcription factors may homo- or

heterodimerize to bind DNA, and they may have

functional overlap.

CLTC (clathrin heavy polypeptide)

Location 17q23.1

Note

Clathrin is the major protein constituent of the coat

that surrounds organelles (cytoplasmic vesicles) to

mediate selective protein transport. Clathrin coats

are involved in receptor-mediated endocytosis and

intracellular trafficking and recycling of receptors,

which accounts for its characteristic punctate

cytoplasmic and perinuclear cellular distribution.

Structurally, clathrin is a triskelion (three-legged)

shaped protein complex that is composed of a

trimer of heavy chains (CLTC) each bound to a

single light chain. CLTC is a 1675 amino acid

residue protein encoded by a gene consisting of 32

exons. Its known domains include a N-terminal

globular domain (residues 1-494) that interacts with

adaptor proteins (AP-1, AP-2, b-arrestin), a light

chain-binding region (residues 1074-1552), and a

trimerization domain (residues 1550-1600) near the

C-terminus.


Fusion Protein

Description

In the CLTC-TFE3 fusion, the fusion point on

CLTC is at amino acid 932 (corresponding to the

end of exon 17), thereby excluding the CLTC

trimerization domain from the predicted fusion

protein. As in other TFE3 gene fusions, the nuclear

localization and DNA binding domains of TFE3 are

retained in CLTC-TFE3. Based on these features

and existing data on other TFE3 fusion proteins,

CLTC-TFE3 may act as an aberrant transcription

factor, with the CLTC promoter driving constitutive

expression.

References Argani P, Ladanyi M. Distinctive neoplasms characterised by specific chromosomal translocations comprise a significant proportion of paediatric renal cell carcinomas. Pathology. 2003 Dec;35(6):492-8

Argani P, Lui MY, Couturier J, Bouvier R, Fournet JC, Ladanyi M. A novel CLTC-TFE3 gene fusion in pediatric renal adenocarcinoma with t(X;17)(p11.2;q23). Oncogene. 2003 Aug 14;22(34):5374-8


Argani P, Ladanyi M. Kidney: Renal cell carcinoma with t(X;17)(p11;q23) CLTC/TFE3. Atlas Genet Cytogenet Oncol Haematol. 2017; 21(10):382-384.

Case Report Section





Amplification of the MET/7q31 gene in a patient with myelodysplastic syndrome Brandon S. Twardy, Deborah Schloff, Anwar N. Mohamed

Cytogenetics Laboratory, Pathology Department, Wayne State University School of Medicine and

Detroit Medical Center, Detroit MI, USA

Published in Atlas Database: June 2016

Online updated version : http://AtlasGeneticsOncology.org/Reports/METampTwardyID100086.html

Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/68745/06-2016-METampTwardyID100086.pdf DOI: 10.4267/2042/68745


Abstract Case report on t(14;20)(q11.2;q13.3) involving the

T-cell receptor α/δ gene in a pediatric acute

lymphoblastic leukemia B-cell type.

Clinics

Age and sex: 52 years old male patient.

Previous history: no preleukemia , no previous

malignancy , no inborn condition of note

Organomegaly: no hepatomegaly, no

splenomegaly (t), no enlarged lymph nodes, no

central nervous system involvement

Note: A non-contributory past medical history.

Patient had no previous leukemia or malignancy,

and had not received chemotherapy or radiation in

the past.

Blood WBC: 1.7X 109/l

HB: 11.3g/dl

Platelets: 50X 109/l

Blasts: Peripheral blood smear showed

pancytopenia with 1% circulating myeloblasts.%

Bone marrow: Bone marrow biopsy was

hypercellular (90%) with dysmegakaryopoiesis,

dysgranulopiesis, markedly increased

erythrogenesis with dysplastic features, and 10%

myeloblasts with no Auer rods. No metastatic

tumor or granuloma

Cyto-Pathology Classification

Phenotype

Findings were consistent with myelodysplastic

syndrome, best classified as refractory anemia with

excess blasts (RAEB-2)

Immunophenotype

Flow cytometric analysis of the bone marrow

aspirate detected 5% myeloblasts with dim

expression of CD45. Blasts were positive for CD13,

CD33, CD34, CD117, CD38, and HLA-DR.

Erythroid precursors constituted 55% of the gated

cells and were positive for CD36 and glycophorin

A.

Diagnosis Myelodysplastic syndrome, RAEB-2

Survival

Date of diagnosis 01-2015

Treatment

In January 2015, the patient received high dose

Ara-C chemotherapy followed by multiple doses of

Vidaza. In December 2015, he underwent

allogeneic peripheral blood stem cell transplant

from a matched-unrelated female donor.

Complete remission: no

Treatment related death: yes

Status Dead 80 days after transplant

Survival 15 months

Amplification of the MET/7q31 gene in a patient with myelodysplastic syndrome

Twardy BS, et al.


Karyotype Sample Bone marrow aspirate

Culture time 24 hours unstimulated culture; 48

hours with 10% conditioned media

Banding G- banding

Results

Two unrelated clones were identified:

clone 1 44-47,Y,inv(X)(p21p22.1), del(7)(p11.2),

add(7)(q21),+der(?)r(7)amp(q31), del(9)(p22),-13,

add(16)(p12), add(19)(p13.2)[cp16]

clone 2 46,XY,del(5)(q13q33),add(20)(q11.2)[3]

Other molecular cytogenetics results

Fluorescence in situ hybridization (FISH) was

performed on the pellet from the harvested bone

marrow specimen using the MDS panel DNA

probes that included D5S23:D5S721/5p15.2,

EGR1/5q31, D7Z1/CEP-7, D7S486/7q31,

D8Z2/CEP-8, and D20S108/20q12. Results of

FISH revealed an amplification the D7S486 /7q31

region in approximately 60% of cells (>6 copies per

nucleus), and deletions of EGR1/5q and 20q12 in

10% of cells. In addition, we investigated the status

of MET as a candidate oncogene for the amplified

7q31 region.

Accordingly, the LSI MET SpectrumRed probe

along with CEP-7 SpectrumGreen as a control were

hybridized on the same specimen.

The LSI MET probe is approximately 456 kb and

contains the entire MET gene on chromosome

7q31.2. The hybridization revealed amplification of

the MET gene with only 2 signals/copies for the

control CEP-7 (Figure 2). All FISH probes were

purchased from Abbott Molecular, Downers Grove

IL, USA.

Figure 1: G-banded karyotype at time of diagnosis showing multiple abnormalities including a ring chromosome, and other unbalanced aberrations

Figure 2: FISH with LSI MET SepectrumRed probe showing multiple red signals for MET while two green signals for centromere 7, On metaphase cells the red signals hybridized to the ring chromosome.


Twardy BS, et al.


Comments Gene amplification in leukemia is relatively rare,

mostly reported for the MLL and CMYC

oncogenes. However, MET amplification has not

been reported in leukemia. Here, we report the first

case of MDS with MET amplification in the form

of a ring chromosome. The patient was a 52-year-

old male who initially presented with shortness of

breath and fatigue during the latter part of

December 2014. A CBC was performed at this time

and revealed marked leukopenia, anemia, and

thrombocytopenia. Upon arrival to our facility,

assessment of bone marrow biopsy and aspirate

revealed dysplastic changes consistent with the

diagnosis of myelodysplastic syndrome (MDS),

classified as RAEB-2. Chromosomal analysis at

that time revealed at least two unrelated clones; the

dominant clone presented with multiple unbalanced

chromosomal rearrangements, and extreme

karyotypic heterogeneity. However, the most

notable chromosomal aberrations were additional

genetic material on chromosomes 7q, 16p and 19p,

a large ring that appeared to be derived from

chromosome 7, and an inversion of Xp. Clone 2,

was a minor clone and showed 5q and 20q

deletions, the classic abnormalities for MDS. FISH

demonstrated deletions of EGR1/5q31 and 20q12 in

8-12% of cells, but unexpectedly amplification of

the 7q31 region was noticed in 60% of cells. The

FISH probe, D7S486/7q31, spans a region of

306kb, which contains several tumor suppressor

genes such as MDFIC, TES, CAV1. The closest

candidate oncogene to D7S486 region at 7q31 is the

MET gene. Therefore, MET/7q31.2 probe was

hybridized to the same specimen that confirmed an

amplification of MET oncogene. In metaphase

cells, the amplified signals are located on the ring

chromosome which lacks a centromere 7 signal

(Figure 2).

The MET gene encodes a tyrosine kinase receptor

for the hepatocyte growth factor (HGF). Whereas

the physiological expression of MET is essential for

wound healing and embryonic development,

aberrant overexpression of MET results in up-

regulation of cell proliferation, motility, migration,

invasion, and survival. MET MET activating

mutations and gene amplification have been

identified in a variety of solid tumors including,

gastric, pharynx, colon, lung, and breast cancer.

Further studies have shown that inhibition of MET

signaling pathways has led to inhibition of growth,

migration and invasion. For these reasons MET has

become a valuable target for cancer therapy and

several drugs targeting MET and its ligand HGF are

being evaluated in clinical trials in various cancers.

The MET gene is also overexpressed in

hematological malignancies. The most recent

studies on multiple myeloma showed that the

HGF/MET pathway is constitutively active in

plasma cells of myeloma patients and it confers

multidrug resistance. These findings were also true

for acute myeloid leukemia (AML).

Studies of samples taken from AML patients and

cell lines revealed that MET is activated in

leukemic cells as a result of aberrant autocrine

signaling by HGF, and inhibition of this autocrine

activation loop would inhibit the growth and

survival of these cells.

Other genes of significance within the region of

chromosome 7q31 include MDFIC, TFEC, TES,

CAV-1, CAV-2, and ST7.

These genes have been implicated in various

malignancies but their role has not yet been fully

elucidated. TES, CAV-1, CAV-2, and ST7 are

considered candidate tumor suppressors implicated

in numerous malignancies.

MDFIC, also known as HIC, is frequently deleted

in myeloid malignancies. TFEC is a member of the

microphthalmia family of transcription factors

whose dysregulation may have a role in renal cell

carcinoma, melanoma, and sarcoma.

Despite aggressive therapy, our patient never

achieved remission, and he died from disease

progression shortly after transplant.

The complex karyotype as well as MET

amplification certainly contributes to the dismal

sequence of the disease. Therapeutic agents

targeting the MET pathway may help improve

patient survival.

References Cigognini D, Corneo G, Fermo E, Zanella A, Tripputi P. HIC gene, a candidate suppressor gene within a minimal region of loss at 7q31.1 in myeloid neoplasms. Leuk Res. 2007 Apr;31(4):477-82

Tripputi P, Bianchi P, Fermo E, Bignotto M, Zanella A. Chromosome 7q31.1 deletion in myeloid neoplasms. Hum Pathol. 2014 Feb;45(2):368-71

Pons E, Uphoff CC, Drexler HG. Expression of hepatocyte growth factor and its receptor c-met in human leukemia-lymphoma cell lines. Leuk Res. 1998 Sep;22(9):797-804

Kentsis A, Reed C, Rice KL, Sanda T, Rodig SJ, Tholouli E, Christie A, Valk PJ, Delwel R, Ngo V, Kutok JL, Dahlberg SE, Moreau LA, Byers RJ, Christensen JG, Vande Woude G, Licht JD, Kung AL, Staudt LM, Look AT. Autocrine activation of the MET receptor tyrosine kinase in acute myeloid leukemia. Nat Med. 2012 Jul;18(7):1118-22

Ferrucci A, Moschetta M, Frassanito MA, Berardi S, Catacchio I, Ria R, Racanelli V, Caivano A, Solimando AG, Vergara D, Maffia M, Latorre D, Rizzello A, Zito A, Ditonno P, Maiorano E, Ribatti D, Vacca A. A HGF/cMET autocrine loop is operative in multiple myeloma bone marrow endothelial cells and may represent a novel therapeutic target. Clin Cancer Res. 2014 Nov 15;20(22):5796-807

Moschetta M, Basile A, Ferrucci A, Frassanito MA, Rao L, Ria R, Solimando AG, Giuliani N, Boccarelli A, Fumarola F, Coluccia M, Rossini B, Ruggieri S, Nico B, Maiorano E, Ribatti D, Roccaro AM, Vacca A. Novel targeting of phospho-cMET overcomes drug resistance and induces


Twardy BS, et al.


antitumor activity in multiple myeloma. Clin Cancer Res. 2013 Aug 15;19(16):4371-82

Phillip CJ, Zaman S, Shentu S, Balakrishnan K, Zhang J, Baladandayuthapani V, Taverna P, Redkar S, Wang M, Stellrecht CM, Gandhi V. Targeting MET kinase with the small-molecule inhibitor amuvatinib induces cytotoxicity in primary myeloma cells and cell lines. J Hematol Oncol. 2013 Dec 10;6:92

Beau-Faller M, Ruppert AM, Voegeli AC, Neuville A, Meyer N, Guerin E, Legrain M, Mennecier B, Wihlm JM, Massard G, Quoix E, Oudet P, Gaub MP. MET gene copy number in non-small cell lung cancer: molecular analysis in a targeted tyrosine kinase inhibitor naïve cohort. J Thorac Oncol. 2008 Apr;3(4):331-9

Ho-Yen CM, Jones JL, Kermorgant S. The clinical and functional significance of c-Met in breast cancer: a review. Breast Cancer Res. 2015 Apr 8;17:52

Kawakami H, Okamoto I, Okamoto W, Tanizaki J, Nakagawa K, Nishio K. Targeting MET Amplification as a New Oncogenic Driver. Cancers (Basel). 2014 Jul 22;6(3):1540-52


Twardy BS, Schloff D, Mohamed AN. Amplification of the MET/7q31 gene in a patient with myelodysplastic syndrome.. Atlas Genet Cytogenet Oncol Haematol. 2017; 21(10):385-388.



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