vol 22 6 2018 - institut de l'information scientifique et...

Volume 22 - Number 6

June 2018

Atlas of Genetics and Cytogenetics

in Oncology and Haematology

OPEN ACCESS JOURNAL INIST-CNRS

Scope

The Atlas of Genetics and Cytogenetics in Oncology and Haematology is made for and by: clinicians and researchers in

cytogenetics, molecular biology, oncology, haematology, and pathology. One main scope of the Atlas is to conjugate the scientific information provided by cytogenetics / molecular genetics to the

clinical setting (diagnostics, prognostics and therapeutic design), another is to provide an encyclopedic knowledge in cancer

genetics. The Atlas deals with cancer research and genomics. It is at the crossroads of research, virtual medical university

(university and post-university e-learning), and telemedicine. It contributes to "meta -medicine", this mediation, using

information technology, between the increasing amount of knowledge and the individual, having to use the

information.Towards a personalized medicine of cancer. It presents structured review articles ("cards") on: 1- Genes, 2- Leukemias, 3- Solid tumors, 4- Cancer-prone diseases, and also 5- "Deep insights": more traditional review articles on the above subjects and on surrounding topics. It also present 6- Case reports in hematology and 7- Educational items in the various related topics for students in Medicine and in Sciences. The Atlas of Genetics and Cytogenetics in Oncology and Haematology does not publish research articles. See also: http://documents.irevues.inist.fr/bitstream/handle/2042/56067/Scope.pdf

Editorial correspondance

Jean-Loup Huret, MD, PhD, [email protected]

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

Myeloid Malignancies Section Editor Robert S. Ohgami (Stanford, California)

Bone Tumors Section Editor Judith Bovee (Leiden, Netherlands)

Head and Neck Tumors Section Editor Cécile Badoual (Paris, France)

Urinary Tumors Section Editor Paola Dal Cin (Boston, Massachusetts)

Pediatric Tumors Section Editor Frederic G. Barr (Bethesda, Maryland)

Cancer Prone Diseases Section Editor Gaia Roversi (Milano, Italy)

Cell Cycle Section Editor João Agostinho Machado-Neto (São Paulo, Brazil)

DNA Repair Section Editor Godefridus Peters (Amsterdam, Netherlands)

Hormones and Growth factors Section Editor Gajanan V. Sherbet (Newcastle upon Tyne, UK)

Mitosis Section Editor Patrizia Lavia (Rome, Italy)

WNT pathway Section Editor Alessandro Beghini (Milano, Italy)

B-cell activation Section Editors Anette Gjörloff Wingren and Barnabas Nyesiga (Malmö, Sweden)

Oxidative stress Section Editor Thierry Soussi (Stockholm, Sweden/Paris, France)

Board Members Sreeparna Banerjee Department of Biological Sciences, Middle East Technical University, Ankara, Turkey; [email protected] Alessandro Beghini Department of Health Sciences, University of Milan, Italy; [email protected] Judith Bovée 2300 RC Leiden, The Netherlands; [email protected] Antonio Cuneo Dipartimento di ScienzeMediche, Sezione di Ematologia e Reumatologia Via Aldo Moro 8, 44124 - Ferrara, Italy; [email protected] Paola Dal Cin Department of Pathology, Brigham, Women's Hospital, 75 Francis Street, Boston, MA 02115, USA; [email protected] François Desangles IRBA, Departement Effets Biologiques des Rayonnements, Laboratoire de Dosimetrie Biologique des Irradiations, Dewoitine C212, 91223

Bretigny-sur-Orge, France; [email protected] Enric Domingo Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, Roosevelt Dr. Oxford, OX37BN, UK

[email protected] Ayse Elif Erson-

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

Ad Geurts van

Kessel Department of Human Genetics, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, 6500 HB Nijmegen,

The Netherlands; [email protected] Oskar A. Haas Department of Pediatrics and Adolescent Medicine, St. Anna Children's Hospital, Medical University Vienna, Children's Cancer Research

Institute Vienna, Vienna, Austria. [email protected] Anne Hagemeijer Center for Human Genetics, University Hospital Leuven and KU Leuven, Leuven, Belgium; [email protected] Nyla Heerema Department of Pathology, The Ohio State University, 129 Hamilton Hall, 1645 Neil Ave, Columbus, OH 43210, USA;

[email protected] Sakari Knuutila Hartmann Institute and HUSLab, University of Helsinki, Department of Pathology, Helsinki, Finland; [email protected] Lidia Larizza Lab Centro di Ricerche e TecnologieBiomedicheIRCCS-IstitutoAuxologico Italiano Milano, Italy; l.larizza@auxologico Roderick Mc Leod Department of Human, Animal Cell Lines, Leibniz-Institute DSMZ-German Collection of Microorganisms, Cell Cultures, Braunschweig,

Germany; [email protected] 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;

[email protected] Konstantin Miller Institute of Human Genetics, Hannover Medical School, 30623 Hannover, Germany; [email protected] Felix Mitelman Department of Clinical Genetics, University and Regional Laboratories, Lund University, SE-221 85 Lund, Sweden;

[email protected] Hossain Mossafa Laboratoire CERBA, 95066 Cergy-Pontoise cedex 9, France; [email protected] Stefan Nagel Department of Human, Animal Cell Lines, Leibniz-Institute DSMZ-German Collection of Microorganisms, Cell Cultures, Braunschweig,

Germany; [email protected] 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-

3678, USA; [email protected] Clelia Tiziana

Storlazzi Department of Biology, University of Bari, Bari, Italy; [email protected]

Sabine Strehl CCRI, Children's Cancer Research Institute, St. Anna Kinderkrebsforschunge.V., Vienna, Austria; [email protected] Nancy Uhrhammer Laboratoire Diagnostic Génétique et Moléculaire, Centre Jean Perrin, Clermont-Ferrand, France; [email protected] Dan L. Van Dyke Mayo Clinic Cytogenetics Laboratory, 200 First St SW, Rochester MN 55905, USA; [email protected] Roberta Vanni Universita di Cagliari, Dipartimento di ScienzeBiomediche(DiSB), CittadellaUniversitaria, 09042 Monserrato (CA) - Italy; [email protected]




Volume 22 - Number 6, June 2018

Table of contents

Gene Section

MYC (MYC proto-oncogene, bHLH transcription factor) 227

Anwar N Mohamed

SNW1 (SNW domain containing 1) 233

Cagla Ece Olgun and Mesut Muyan

PCSK1 (proprotein convertase subtilisin/kexin type 1) 236

Béatrice Demoures, Géraldine Siegfried and Abdel-Majid Khatib

Leukemia Section

t(1;5)(p32;q31) without TAL1 rearrangement 242

Adriana Zamecnikova

t(6;11)(q24.1;p15.5) NUP98/CCDC28A 244

Tatiana Gindina

Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN) 246

Aurelia Meloni-Ehrig

del(1p) solely 252

Adriana Zamecnikova

dup(1q) in ALL 255

Anwar N Mohamed

Solid Tumour Section

Kidney: ALK-rearranged renal cell carcinoma 260

Adrian Marino-Enriquez

Gene Section Review

Atlas Genet Cytogenet Oncol Haematol. 2018; 22(6). 227


in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS

MYC (MYC proto-oncogene, bHLH transcription factor) Anwar N Mohamed

Cytogenetics Laboratory, Pathology Department, Detroit Medical Center, Wayne State University School of

Medicine, Detroit, MI USA; [email protected]

Published in Atlas Database: August 2017

Online updated version : http://AtlasGeneticsOncology.org/Genes/MYCID27.html

Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/68908/08-2017-MYCID27.pdf DOI: 10.4267/2042/68908

This article is an update of : Atkin NB. MYC v-myc myelocytomatosis viral oncogene homolog (avian). Atlas Genet Cytogenet Oncol Haematol 2000;4(4) Larizza L, Beghini A. KIT. Atlas Genet Cytogenet Oncol Haematol 1999;3(1)

This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2018 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Abstract Review the structure, function, and role of CMYC

gene in tumorigenesis

Keywords

MYC; CMYC; MYC signature; transcription factor;

Burkitt lymphoma; diffuse large B-cell lymphoma;

follicular lymphoma; mantle cell lymphoma;

multiple myeloma; lung cancer; breast cancer; colon

cancer ; prostate cancer

Identity Other names

CMYC, MYC proto-oncogene, V-MYC avian

myelocytomatosis viral oncogene homolog, Class E

Basic Helix-Loop-Helix Protein 39, Transcription

Factor P64, BHLHe39

Location

8q24.21

MYC (8q24) in normal cells: PAC 944B18 (top) and PAC 968N11 (below) - Courtesy Mariano Rocchi,

Resources for Molecular Cytogenetics.

MYC (MYC proto-oncogene, bHLH transcription factor)

Atlas Genet Cytogenet Oncol Haematol. 2018; 22(6) 228

MYC (MYC proto-oncogene, bHLH

transcription factor) Hybridization with Vysis LSI

MYC break apart and LSY MYC probe (Abbott

Molecular, US) showing the gene on 8q24.21 -

Courtesy Adriana Zamecnikova.

Note

MYC gene encodes a multifunctional, nuclear

phosphoprotein that controls a variety of cellular

functions, including cell cycle, cell growth,

apoptosis, cellular metabolism and biosynthesis,

adhesion, and mitochondrial biogenesis. MYC has

been shown to be an essential global transcription

factor capable of either promoting or repressing the

expression of a massive array of genes, accounting

for >15% of the human genome, commonly referred

to as the "MYC signature" (Knoepfler 2007). MYC

is among the most frequently affected gene in human

cancers, overexpressed in most human cancers and

contributes to the cause of at least 40% of tumors.

Dysregulation of MYC expression results through

various types of genetic alterations leading to a

constitutive activity of MYC in various cancers

(Dang et al, 2006).

DNA/RNA

Description

CMYC is composed of three exons spanning over 4

kb with the second and third exons encoding most

MYC protein. These two exons have at least 70%

sequence homology among species. However, exon1

is untranslated whose sequence is not as well

conserved through evolution. The exon1 has been

postulated to play a role in translational control and

mRNA stability. There are four MYC

transcriptional promoters. In normal cells, promoter

P2 contributes to approximately 75% of total MYC

transcripts while P1 accounts for most the remaining

25% transcripts (Dang CV 2012).

Transcription

MYC mRNA contains an IRES (internal ribosome

entry site) that allows the RNA to be translated into

protein when 5' cap-dependent translation is

inhibited, such as during viral infection.

Protein

Description

439 amino acids and 48 kDa in the p64; 454 amino

acids in the p67 (15 additional amino acids in N-

term; contains from N-term to C-term: a

transactivation domain, an acidic domain, a nuclear

localization signal, a basic domain, an helix-loop-

helix motif, and a leucin zipper; DNA binding

protein.

Expression

Expressed in almost all proliferating cells in

embryonic and adult tissues; in adult tissues,

expression correlates with cell proliferation;

abnormally high expression is found in a wide

variety of human cancers.

Localisation

located predominantly in the nucleus.

The myc protein contains an unstructured N-terminal

transcriptional regulatory domain followed by a

nuclear localization signal and a C-terminal region

with a basic DNA-binding domain tied to a helix-

loop-helix-leucine zipper (bHLHZip) dimerization

motif. The bHLHzip motif of MYC dimerizes with

the MAX, which is a prerequisite for specific

binding to DNA at E-box sequences (5'-

CA(C/T)G(T/C)G-3') (Dang 2012). Upon DNA

binding the MYC/MAX heterodimer recruits co-

factors, which mediate multiple effects of MYC on

gene expression in a context-dependent manner.

This dimerization process is essential for induction

of cell cycle progression, apoptosis, and

transformation suggesting that MYC exerts its

oncogenic effects by transactivation of target genes

via E-boxes (Amati B, Land H, 1994; Grandori C et

al 2000). The coding exons of MYC encode for the

N-terminal region which has a transcriptional

regulatory domain, a region that contains conserved

MYC Boxes I and II, followed by MYC Box III and

IV, and a nuclear targeting sequence. The N-terminal

region will bind with co-activator complexes,

making MYC acts as the transcription or repression

factor (Cowling et al 2006).

In normal cells, MYC is tightly regulated by mitotic

and developmental signals, and in turn, it regulates

the expression of downstream target genes. Both

MYC mRNA and protein have very short half-lives

in normal cells (20-30 minutes each). Without

appropriate positive regulatory signals, MYC protein

levels are low and insufficient to promote cellular

proliferation. In addition, MYC protein is rapidly

degraded by the ubiquitin-linked proteasome

machinery. The short-life and instability of MYC



protein and mRNA together would seem to be an

effective safeguard mechanism of MYC regulation

(Herrick and Ross et al, 1994). However, these

controls are lost in cancer cells, resulting in

aberrantly high levels of MYC protein. In its

physiological role, MYC is broadly expressed during

embryogenesis and in tissue with high proliferative

capacity such as skin epidermis and gut. Its

expression strongly correlates with cell proliferation.

Function

MYC functions as a transcriptional regulator,

capable to induce or repress the expression of a large

number of genes, which are thought to mediate its

biological functions (Adhikary and Eilers 2005).

MYC protein cannot form homodimers, but it binds

to MAX that is an obligate heterodimeric partner for

MYC in mediating its functions. The MYC-MAX

complex is a potent activator of transcription for a

critical set of cellular target genes. Initially, two

additional partners for Max had been identified,

MXI1 and MXD1 (Mad1). Two more Max-

interacting proteins, MXD3 (Mad3) and MXD4

(Mad4), which behave similarly to MXD1 have been

reported. The transcription activation is mediated

exclusively by MYC-MAX complexes, whereas

MAX-MXD1 and MAX-MXI1 complexes mediate

transcription repression through identical binding

sites. Max expression is not highly regulated and its

protein is very stable; in contrast, MXD1 protein

appears to have a short half-life and to be highly

regulated (Amati and Land, 1994). MXI1 protein is

also regulated. MYC-MAX heterodimers activate

transcription through interactions with

transcriptional coactivators ( TRRAP, ACTL6A

(BAF53)) and their associated histone

acetyltransferases and/or ATPase/helicases,

resulting in transition from the G0/1 phase to the S

phase (Nilsson and Cleveland, 2003). Several studies

have established that MAX is essential for MYC-

mediated gene transactivation, transformation, cell

cycle progression and apoptosis. On the other hand,

overexpression of MXI1 and MXD1 can antagonize

MYC activity in cellular transformation assays and

proliferation and can diminish the malignant

phenotype of tumor cells. MXD1 can also inhibit

apoptosis and reverse the differentiation blocking

effect of MYC in leukemia cells. (Dang 2012). These

findings are consistent with the concept that MXD1

and MXI1 suppress MYC function. In addition to

interacting with proteins involved in transcription

regulation, MYC also interacts with enzymes

controlling histone methylation.

Target Genes Thousands of MYC target genes

have been identified by following mRNA levels in

experimentally controlled activation of the MYC

gene (Menssen and Hermeking 2002). In general,

genes targeted by MYC include mediators of

metabolism, biosynthesis, and cell cycle

progression, such that aberrant MYC expression is

associated with uncontrolled cell growth, division,

and metastasis, whereas loss or inhibition of MYC

expression hinders growth, promotes differentiation,

and sensitizes cells to DNA damage (Miller 2012;

Hsieh 2015). Different target genes are regulated

under specific conditions for specific cell types.

Some of the most biologically important targets are

CCND2 (cyclin D2), and cyclin-dependent kinases

(CDKs), resulting in accelerated cell cycling; down-

regulation of PTEN (phosphatase and tensin

homolog deleted on chromosome ten) with

consequent up-regulation of the phosphoinositide 3-

kinase/protein kinase B/mammalian target of

rapamycin (PI3K/AKT/ MTOR) pathway; and

stabilization of the proapoptotic protein and tumor

suppressor TP53, (Hoffman and Liebermann 2008;

Dang 2012) which can bypass the apoptotic BCL2

program. MYC, on the other hand, activates many

ribosomal protein genes including RPL23, which

binds to and retains NPM1 in the nucleolus, thereby

inhibiting PIAS2 (Miz-1) activity (Wanzel, 2008).

MYC itself is modulated by NPM1, which acts as a

positive MYC coactivator (Schneider A 1997;

Grandori C et al., 2005; Li Z, et al 2008).

MYC-targeted gene network also contains non-

protein coding targets; among those are microRNAs

(miRNAs). The miRNAs are 18- 22 nucleotides non-

coding RNAs that negatively regulate gene

expression at the post-transcriptional level via

binding to 3'-UTRs of target mRNAs and mediate

translational repression or mRNA degradation.

Some miRNA function as an oncogene while others

behave as tumor suppressor gene, in a cell-typed

manner. Growing evidences have suggested that

MYC regulates the expression of a number of

miRNAs, resulting in widespread repression of

miRNA and, at the same time, MYC being subjected

to regulation by miRNAs, leading to sustained MYC

activity and the corresponding MYC downstream

pathways (Chang et al, 2008). Thus, these combined

effects of MYC overexpression and downregulation

of miRNAs play a central regulatory role in the MYC

oncogenic pathways. For example, MYC

upregulates expression of miR-17-92 clusters a set of

oncogenic miRNAs, which contains six mature

miRNAs. Recently, miR-19 was identified as the key

oncogenic component of this cluster (Tao et al 2014;

Koh 2016). Overexpression of miR-17-92 is

observed in a large fraction of human cancers,

including carcinomas of the breast, lung, and colon;

medulloblastomas; neuroblastomas and B-cell

lymphoma. The miR17-92 is commonly amplified at

13q31 in several subtypes of aggressive lymphomas.

Its oncogenic function is reflected by down-

regulation of PTEN, TP53 and E2F1, causing the

activation of the PI3K/AKT pathway and inhibiting

cellular apoptosis. The functional interaction

between miR-17`92 and MYC is further emphasized



by the finding that MYC is a potent transcriptional

activator of miR-17-92 (O'Donnell et al. 2005), thus

suggesting that miR-17-92 may contribute to the

oncogenic properties of MYC. Another MYC-

induced miRNA, MIR22, was recently shown to act

as a potent proto-oncogenic miRNA by genome-

wide deregulation of the epigenetic state through

inhibition of methylcytosine dioxygenase TET

proteins. In addition, MIR22 was characterized as a

key regulator of self-renewal in the hematopoietic

system. MYC also represses several miRNAs with

tumor suppressor function such as MIR15A/ MIR16-

1 and miR-34 that regulate apoptosis by targeting

BCL2 and TP53 respectively. Likewise MYC is

negatively regulated by several miRNAs such as

miR-34 and MIR494. The auto functional interaction

between MYC and miRNAs target genes maintains

persistent expression of MYC, thus promoting the

malignant phenotype (Tao et al 2014; Jackstadt

2015).

Furthermore, over expression of MYC can induce

apoptosis. The apoptosis triggered or sensitized by

MYC can be either TP53-dependent or TP53

independent, determined by the cell type and

apoptotic trigger. The mechanisms of MYC-

mediated apoptosis may involve several pathways.

Overexpression of MYC increases DNA replication

and possibly results in DNA damage that, in turn,

triggers a TP53-mediated response leading to

apoptosis, in some cell types (Hoffman and

Libermann, 2008). As well, MYC expression seems

to downregulate antiapoptotic proteins such as BCL2

or BCL2L1 (Bcl-XL) and upregulate pro-apoptotic

elements such as BCL2L11 (BIM).

MYC also plays an important role in mitochondrial

biogenesis. Large scale studies of gene expression in

rat and human systems first suggested that MYC

overexpression can induce nuclear encoded

mitochondrial genes. In addition, MYC has been

shown to bind to the promoters of genes encoding

proteins involved in mitochondrial function. Using

an inducible MYC-dependent human B cell model of

cell proliferation it was shown that mitochondrial

biogenesis is completely dependent on MYC

expression. Moreover, the genes involved with

mitochondrial biogenesis are among the MYC target

genes most highly induced (Gao et al 2009).

Implicated in Top note

MYC Deregulation

The expression of MYC is deregulated in cancer by

several different mechanisms, including

chromosomal translocations, amplifications, point

mutations, epigenetic reprogramming, enhanced

translation and increased protein stability. In most

cases these alterations lead to a constitutive

expression of intact MYC protein, which is normally

only expressed during certain phases of the cell

cycle. In Burkitt lymphoma (BL), the MYC

oncogene is activated through a reciprocal t(8;14) or

its variant which juxtaposes MYC/8q24 to enhancer

of the immunoglobulin (Ig) heavy Chain (IGH)

locus on chromosome 14q32 or the kappa or lambda

light chain locus on chromosome 2 or 22. There are

three main translocation breakpoints in MYC; class

I breakpoints are within the exon 1 and first intron of

MYC; class II breakpoints are located at the 5' end

of the MYC, and usually within a few kilobases of

exon 1; and the class III breakpoints are distant from

MYC itself, and can be more than 100 kb away.

Endemic BL typically shows class II translocation

breakpoints in MYC while the sporadic BL often

exhibits class I breakpoints of MYC. The t(8;14) or

its variant is considered as an initiative event in BL.

The MYC/8q24 translocations may also occur as

secondary events in non-BL lymphomas such as

diffuse large B-cell lymphoma, follicular lymphoma,

mantle cell lymphoma, and multiple myeloma (Cai

et al, 2015; Nguyen L, et al 2017). Secondary MYC

translocation is associated with a complex karyotype

and most often confer aggressive clinical behavior

and poor outcome. Recently, B-cell large cell

lymphoma with MYC and BCL2 or/and BCL6

rearrangements so called double hit or triple hit

lymphoma are recognized by the 2016 revision of

WHO as a subset of a very aggressive lymphoma

(Petrich 2014). >

Amplification of MYC gene has been shown in both

hematopoietic and non-hematopoietic tumors,

including lung, breast, colon, and prostate cancers.

Insertional mutagenesis is seen in retrovirus-induced

tumors, such as avian leucosis virus (ALV)-induced

hematopoietic tumors, in which the proviral

enhancer is integrated upstream of the MYC gene

and leads to its overexpression. MYC

overexpression may also occur because of post-

translational modifications. MYC protein

overexpression as a result of point mutations in N-

terminal domain is also frequent. The most

recurrently mutated residue is Thr-58, found in

lymphoma. Normally, the phosphorylation of Thr-58

can control MYC degradation and mutation causing

increase of MYC protein half-life in lymphoma (Cai

et al 2017). Detection of MYC rearrangement is

important in the diagnosis of BL and as a prognostic

marker in other aggressive B-cell lymphomas. There

are several techniques to detect MYC deregulation

including conventional cytogenetics, fluorescence in

situ hybridization (FISH), and

immunohistochemistry. In clinical laboratory, FISH

is being most frequently used approach (Figure 2) >

MYC as therapeutic target



MYC is documented to be involved broadly in many

cancers, in which its expression is estimated to be

elevated or deregulated in up to 70% of human

cancers. Overexpression of MYC protein is not only

to drive tumor initiation and progression, but is also

essential for tumor maintenance. Furthermore,

growth arrest, apoptosis and differentiation occur

upon reduction in MYC levels. These features make

MYC molecule a highly attractive target for cancer

therapy. However, the lack of deep pocket in the

structure of MYC protein makes the traditionally

small molecule inhibitors are not feasible. For this

reason, other alternative strategies are proposed. One

approach suggests that the disruption of the

MYC/MAX binding site can be a strategy for the

inactivation of MYC function in neoplastic cells.

Such an approach was already applied and different

small molecule inhibitors that can specifically target

MYC were already successfully produced. Other

approach is based on the inhibition of MYC/MAX

dimers binding to E-boxes in the promoters of

different MYC target genes. Other groups have

focused on transcriptional inhibition of the MYC

gene. Preliminary evidence from experiments using

MYC antisense oligonucleotides has been

encouraging, but has not translated into effective

clinical treatments ( Koh 2016).

FISH using MYC/IGH/CEP8 triple color dual fusion

DNA probe set, showing dual fusion pattern,

consistent with t(8;14)(q24;q32) [left] in a case with

Burkitt lymphoma; MYC amplification in acute

myeloid leukemia [right] - Anwar N. Mohamed.

Note

MYC gene encodes a multifunctional, nuclear

phosphoprotein that controls a variety of cellular

functions, including cell cycle, cell growth,

apoptosis, cellular metabolism and biosynthesis,

adhesion, and mitochondrial biogenesis. MYC has

been shown to be an essential global transcription

factor capable of either promoting or repressing the

expression of a massive array of genes, accounting

for >15% of the human genome, commonly referred

to as the "MYC signature" (Knoepfler 2007). MYC

is among the most frequently affected gene in human

cancers, overexpressed in most human cancers and

contributes to the cause of at least 40% of tumors.

Dysregulation of MYC expression results through

various types of genetic alterations leading to a

constitutive activity of MYC in various cancers

(Dang et al, 2006).

Breakpoints

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Cai Q, Medeiros LJ, Xu X, Young KH. MYC-driven aggressive B-cell lymphomas: biology, entity, differential diagnosis and clinical management. Oncotarget. 2015 Nov 17;6(36):38591-616

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Dang CV. MYC on the path to cancer. Cell. 2012 Mar 30;149(1):22-35

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Gao P, Tchernyshyov I, Chang TC, Lee YS, Kita K, Ochi T, Zeller KI, De Marzo AM, Van Eyk JE, Mendell JT, Dang CV. c-Myc suppression of miR-23a/b enhances mitochondrial glutaminase expression and glutamine metabolism. Nature. 2009 Apr 9;458(7239):762-5

Grandori C, Gomez-Roman N, Felton-Edkins ZA, Ngouenet C, Galloway DA, Eisenman RN, White RJ. c-Myc binds to human ribosomal DNA and stimulates transcription of rRNA genes by RNA polymerase I. Nat Cell Biol. 2005 Mar;7(3):311-8

Herrick DJ, Ross J. The half-life of c-myc mRNA in growing and serum-stimulated cells: influence of the coding and 3' untranslated regions and role of ribosome translocation. Mol Cell Biol. 1994 Mar;14(3):2119-28

Hoffman B, Liebermann DA. Apoptotic signaling by c-MYC. Oncogene. 2008 Oct 27;27(50):6462-72

Hsieh AL, Walton ZE, Altman BJ, Stine ZE, Dang CV. MYC and metabolism on the path to cancer. Semin Cell Dev Biol. 2015 Jul;43:11-21



Jackstadt R, Hermeking H. MicroRNAs as regulators and mediators of c-MYC function. Biochim Biophys Acta. 2015 May;1849(5):544-53

Knoepfler PS. Myc goes global: new tricks for an old oncogene. Cancer Res. 2007 Jun 1;67(11):5061-3

Koh CM, Sabò A, Guccione E. Targeting MYC in cancer therapy: RNA processing offers new opportunities. Bioessays. 2016 Mar;38(3):266-75

Li Z, Boone D, Hann SR. Nucleophosmin interacts directly with c-Myc and controls c-Myc-induced hyperproliferation and transformation. Proc Natl Acad Sci U S A. 2008 Dec 2;105(48):18794-9

Menssen A, Hermeking H. Characterization of the c-MYC-regulated transcriptome by SAGE: identification and analysis of c-MYC target genes. Proc Natl Acad Sci U S A. 2002 Apr 30;99(9):6274-9

Miller DM, Thomas SD, Islam A, Muench D, Sedoris K. c-Myc and cancer metabolism. Clin Cancer Res. 2012 Oct 15;18(20):5546-53

Nguyen L, Papenhausen P, Shao H. The Role of c-MYC in B-Cell Lymphomas: Diagnostic and Molecular Aspects. Genes (Basel). 2017 Apr 5;8(4)

Nilsson JA, Cleveland JL. Myc pathways provoking cell suicide and cancer. Oncogene. 2003 Dec 8;22(56):9007-21

O'Donnell KA, Wentzel EA, Zeller KI, Dang CV, Mendell JT. c-Myc-regulated microRNAs modulate E2F1 expression. Nature. 2005 Jun 9;435(7043):839-43

Petrich AM, Nabhan C, Smith SM. MYC-associated and double-hit lymphomas: a review of pathobiology, prognosis, and therapeutic approaches. Cancer. 2014 Dec 15;120(24):3884-95

Schneider A, Peukert K, Eilers M, Hänel F. Association of Myc with the zinc-finger protein Miz-1 defines a novel pathway for gene regulation by Myc. Curr Top Microbiol Immunol. 1997;224:137-46

Tao J, Zhao X, Tao J. c-MYC-miRNA circuitry: a central regulator of aggressive B-cell malignancies. Cell Cycle. 2014;13(2):191-8

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This article should be referenced as such:

Mohamed AN. MYC (MYC proto-oncogene,

bHLH transcription factor). Atlas Genet

Cytogenet Oncol Haematol. 2018; 22(6):227-232.

Gene Section Short Communication




SNW1 (SNW domain containing 1) Cagla Ece Olgun and Mesut Muyan

Middle East Technical University, Department of Biological Sciences, Cankaya 06800, Ankara, Turkey;

[email protected]; [email protected]

Published in Atlas Database: August 2017

Online updated version : http://AtlasGeneticsOncology.org/Genes/SNW1ID42348ch14q24.html

Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/68909/08-2017-SNW1ID42348ch14q24.pdf DOI: 10.4267/2042/68909


Abstract SNW1 is a spliceosomal component and

transcriptional co-regulator that provides a

modulatory coupling of transcription initiation and

splicing. SNW1 appears to be an essential cancer cell

survival factor by co-transcriptionally regulating

mRNA splicing of proteins involved in cell cycle

checkpoints. As a co-regulator, SNW1 is shown to

attune the activity of a number of transcription

factors, including nuclear hormone receptors as well

as CBF1, Smad2/3, and MyoD by modulating a

transition step between the repressing and activating

transcription complex assembly. SNW1 is also

involved in the cell cycle progression through the

involvement in cell cycle checkpoint-dependent

changes in gene expressions during cellular

proliferation and viral infections.

Keywords

SNW1; cancer; transcription regulation


Homolog Of Drosophila BX42 (Bx42), Nuclear

Receptor Coactivator NCoA-62 (NCOA-62), Prp45,

PRPF45, SKI Interacting Protein (SKIP), SKIIP

HGNC (Hugo)

SNW1

Location

14q24.3. Genomic coordinates: 14: 77717599-

77761220

Human SNW1 located on chromosome 14q24.3 is on the reverse strand.

(https://www.ncbi.nlm.nih.gov/gene/22938, 2017)

DNA/RNA

SNW1 (SNW domain containing 1)


Exons are shown in boxes; introns are indicated by lines. The encoding exons are in blue. The start codon ATG

and stop codon TAG are shown.

Description

The human SNW1 gene contains 14 exons.

Transcription

As a result of alternative splicing, SNW1 has two

transcript variants

(https://www.ncbi.nlm.nih.gov/gene/22938, 2017).

The transcript 1, the long isoform, has 2207 nt

mRNA which encodes a 571 amino acid (aa)-long

protein (protein ID: NP_001305773.1). The

transcript 2, which has 2146 nucleotides, differs in

the 3' UTR and displays multiple coding region

differences compared to transcript 1. One of the

coding region differences results in a frame shift,

giving rise to the isoform 2, which has 536 amino-

acids with a distinct carboxyl-terminus (protein ID:

NP_036377.1).

Pseudogene

There is one reported pseudogene located on

chromosome 1


Protein Note

SNW domain containing protein 1 is also known as

nuclear protein SkiP, nuclear receptor coactivator

NcoA-62 or Ski interacting protein (SKIP).

Description

The genes encoding SNW proteins are present

throughout eukaryotic phylla, including lower

eukaryotes, plants, fungi and animals. There is only

one gene per genome, which encodes for a 60-80

kDa protein that predominantly localizes to the

nucleus (Folk at al., 2004). SNW1 is suggested to

contain protein interaction domains as well as a

carboxyl-terminally located dimerization domain

(Folk at al., 2004).

Expression

SNW1 is expressed in the brain, endocrine tissues,

bone marrow and immune system, muscle, lung,

liver, gall bladder, pancreas, gastrointestinal tract,

kidney, urinary bladder, male and female specific

tissues, adipose and soft tissues and skin, in which

the expression levels are high except kidney

(http://www.proteinatlas.org/ENSG00000100603-

SNW1/tissue, 2017).

Localisation

SNW1 localizes in the nucleus (Dahl et al., 1998).

Function

SNW1 acts as a co-regulator for transcriptions

regulated by vitamin D and RARA / RARB / RARG

(retinoic acid receptors) as well as steroid hormone

receptors including NR3C1 (glucocorticoid

receptor), ESR1 / ESR2 (estrogen receptors), and

AR (androgen receptor) (Folk at al., 2004). SNW1

also plays critical roles in the function of v-Ski avian

retroviral oncogene, bone morphogenetic protein

(BMP) during vertebrate embryogenesis (Wu et al,

2011), telomere function (Lackner et al, 2011) and

Notch signaling-mediated transcription (Vasquez-

Del Carpio, 2013). SNW1 is reported to counteract

transcriptional repression induced by RB1

(retinoblastoma protein) as well (Prathapam et al.

2002). In addition to being a transcriptional co-

regulator, SNW1 is an integral component of

spliceosome by interacting with the U5 small nuclear

ribonucleoprotein (snRNP) subcomplex of the

activated spliceosome as a part of the

PRPF19/nineteen complex (NTC) (Neubauer et al,

1998; Makarova et al, 2004). SNW1 inactivation is

reported to cause a rapid loss of sister chromatid

cohesion (Van Der Lelij et al, 2014) mitotic spindle

and cytokinesis defects (Kittler et al, 2004; Kittler et

al, 2005). It is also suggested that the involvement

of SNW1 in the p21-gene specific splicing is critical

for cancer cell survival under stress (Chen et al,

2011).

Homology

Homologs of SNW1 are found in chimpanzee,

Rhesus monkey, dog, cow, mouse, rat, chicken,

zebrafish, fruit fly, mosquito, C.elegans, S.pombe,

M.oryzae, N.crassa, A.thaliana, rice, and frog


Mutations

There are no gene mutations described for SNW1.

Implicated in

Bladder cancer

SNW1 displays a higher expression in bladder tumor

tissue than surrounding normal adjacent tissues.

Higher expression of SNW1 appears to be correlated

with poor prognosis of bladder cancer. It is also

reported that high-grade urothelial carcinoma

samples express higher levels of SNW1 compared

with low-grade urothelial carcinoma samples (Wang

et al., 2014).

SNW1 (SNW domain containing 1)


Breast cancer

Immunohistochemical and western blot analyses of

breast carcinoma samples showed that the SNW1

expression is augmented in breast cancer tissues

compared with adjacent noncancerous tissues.

SNW1 overexpression appears to have a positive

correlation with the histological grade of cancerous

tissues. Moreover, it is suggested that there is an

inverse relationship between the SNW1 expression

and pathologic prognostic parameters including

estrogen (ER) and progesterone receptors status. In

ER positive cell models derived from breast

carcinoma, there is a lower expression of SNW1

when it is compared with the expression levels of

SNW1 in ER negative cell models (Liu et al., 2014).

Hepatocellular carcinoma

Expression analyses of SNW1 with samples of

hepatocellular carcinoma patients and normal liver

samples revealed that SNW1 is overexpressed in

cancerous cells when compared with noncancerous

liver samples. There is a positive correlation between

high SNW1 expression and aggressiveness of

hepatocellular carcinoma (Liu et al., 2013).

Malignant pleural mesothelioma

As in other cancer types, SNW1 is overexpressed in

malignant pleural mesotheliomas (MPM) patients,

which is correlated with poor prognosis.

Overexpression of SNW1 also correlates with a

reduced survival rate in MPM patient cohort (Turkcu

et al., 2016).

References Chen Y, Zhang L, Jones KA. SKIP counteracts p53-mediated apoptosis via selective regulation of p21Cip1 mRNA splicing. Genes Dev. 2011 Apr 1;25(7):701-16

Dahl R, Wani B, Hayman MJ. The Ski oncoprotein interacts with Skip, the human homolog of Drosophila Bx42. Oncogene. 1998 Mar 26;16(12):1579-86

Folk P, Půta F, Skruzný M. Transcriptional coregulator SNW/SKIP: the concealed tie of dissimilar pathways. Cell Mol Life Sci. 2004 Mar;61(6):629-40

Kittler R, Pelletier L, Ma C, Poser I, Fischer S, Hyman AA, Buchholz F. RNA interference rescue by bacterial artificial chromosome transgenesis in mammalian tissue culture cells. Proc Natl Acad Sci U S A. 2005 Feb 15;102(7):2396-401

Lackner DH, Durocher D, Karlseder J. A siRNA-based screen for genes involved in chromosome end protection. PLoS One. 2011;6(6):e21407

Liu G, Huang X, Cui X, Zhang J, Wei L, Ni R, Lu C. High SKIP expression is correlated with poor prognosis and cell proliferation of hepatocellular carcinoma. Med Oncol. 2013;30(3):537

Liu X, Ni Q, Xu J, Sheng C, Wang Q, Chen J, Yang S, Wang H. Expression and prognostic role of SKIP in human breast carcinoma. J Mol Histol. 2014 Apr;45(2):169-80

Makarova OV, Makarov EM, Urlaub H, Will CL, Gentzel M, Wilm M, Lührmann R. A subset of human 35S U5 proteins, including Prp19, function prior to catalytic step 1 of splicing. EMBO J. 2004 Jun 16;23(12):2381-91

Neubauer G, King A, Rappsilber J, Calvio C, Watson M, Ajuh P, Sleeman J, Lamond A, Mann M. Mass spectrometry and EST-database searching allows characterization of the multi-protein spliceosome complex. Nat Genet. 1998 Sep;20(1):46-50

Prathapam T, Kühne C, Banks L. Skip interacts with the retinoblastoma tumor suppressor and inhibits its transcriptional repression activity. Nucleic Acids Res. 2002 Dec 1;30(23):5261-8

Türkcü G, AlabalIk U, Keles AN, Ibiloglu I, Küçüköner M, Sen HS, Büyükbayram H. Comparison of SKIP expression in malignant pleural mesotheliomas with Ki-67 proliferation index and prognostic parameters. Pol J Pathol. 2016 Jun;67(2):108-13

Vasquez-Del Carpio R, Kaplan FM, Weaver KL, VanWye JD, Alves-Guerra MC, Robbins DJ, Capobianco AJ. Assembly of a Notch transcriptional activation complex requires multimerization. Mol Cell Biol. 2011 Apr;31(7):1396-408

Wang L, Zhang M, Wu Y, Cheng C, Huang Y, Shi Z, Huang H. SKIP expression is correlated with clinical prognosis in patients with bladder cancer. Int J Clin Exp Pathol. 2014;7(4):1695-701

Wu MY, Ramel MC, Howell M, Hill CS. SNW1 is a critical regulator of spatial BMP activity, neural plate border formation, and neural crest specification in vertebrate embryos. PLoS Biol. 2011 Feb 15;9(2):e1000593

van der Lelij P, Stocsits RR, Ladurner R, Petzold G, Kreidl E, Koch B, Schmitz J, Neumann B, Ellenberg J, Peters JM. SNW1 enables sister chromatid cohesion by mediating the splicing of sororin and APC2 pre-mRNAs. EMBO J. 2014 Nov 18;33(22):2643-58


Olgun, CE; Muyan, M. SNW1 (SNW domain

containing 1) Atlas Genet Cytogenet Oncol

Haematol. 2018; 22(6) :233-235.

Gene Section Review




PCSK1 (proprotein convertase subtilisin/kexin type 1) Béatrice Demoures, Géraldine Siegfried and Abdel-Majid Khatib

INSERM U1029, Université Bordeaux,Pessac, France

Published in Atlas Database: September 2017

Online updated version : http://AtlasGeneticsOncology.org/Genes/PCSK1ID41671ch5q15.html

Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/68910/09-2017-PCSK1ID41671ch5q15.pdf DOI: 10.4267/2042/68910


Abstract PCSK1 is a serine protease involved in the

proteolytic processing of a variety of protein

precursors mainly neuropeptides and prohormones.

In 1991, PC1/3; also known as PCSK1, PC1, PC3,

and SPC3 was identified at the same time by two

laboratories separately. The human and mouse

PCSK1 genes are localized on chromosomes 5 and

13, respectively. The cleavage of these protein

precursors is required for the mediation of their

functions including the regulation of glucose

homeostasis and food intake. The PCSK1 substrates

that regulate these functions include proinsulin,

proglucagon, proghrelin and proopiomelanocortin

and others. PCSK1 polymorphisms were associated

with risk of obesity and with various endocrine

disorders. PCSK1 is also involved in the regulation

of macrophage activation and cytokine secretion.

The inhibition of PCSK1 activity was proposed to

reverse the macrophage phenotype from an M2-like

to an M1-like phenotype. PCSK1 is highly expressed

in breast cancers and in neuroendocrine tumors

including carcinoid tumors. The expression of this

protease at the RNA and protein levels is also

increased in liver colorectal metastasis, suggesting

PCSK1 activity in tumorigenesis, however the

evidence of PCSK1 roles in these cancers and

probably others remain to be defined.

Keywords

PCSK1, PC1, endocrine disorders, cancer,

chromosome 5.


NEC1, PC1, PC3, SPC3

HGNC (Hugo)

PCSK1

Location

5q15

Location (base pair)

Starts at 95726040 and ends at 95768985 bp from

pter (according to hg19-Feb_2009)

DNA/RNA

Figure 1: Genomic organization of PCSK1.

PCSK1 (proprotein convertase subtilisin/kexin type 1)


Description

The PCSK1 gene is located on chromosome 5q15-

21 in humans, and chromosome 13c in the mouse

(Seidah NG et al. 1991a, Seidah NG et al. 1991b).

The promoter of this gene contains cAMP-response

elements (CRE-1 and CRE-2). Transcription factors

such as cAMP-responsive element-binding protein 1

( CREB1) and Activating Transcription Factor 1 (

ATF1) that can transactivate the PCSK1 promoter

(Jansen E et al, 1997, Espinosa VP et al, 2008).

Transcription

The DNA sequence of PCSK1contains 14 exons and

the transcript length of 5068 bps is translated to a 753

residues protein. 4 spliced variants of PCSK1 are

identified (splice variants) that code for 3 protein

isoforms of 753 aa, 706 aa and 157 aa in length,

respectively (M_000439, NM_001177875).

Protein

Figure 2: Diagram representing the protein structure of PCSK1. PCSK1 is a multi-domain serine proteinase

consisting of a signal peptide followed by prosegment, catalytic, middle, and cytoplasmic domain. The P domain

just after the catalytic domain is required for the stabilization of the catalytic domain. The C-terminal domain is

involved in the routing of PC1/3 to the secretory granules.

Description

PCSK1 is the third member of the proprotein

convertase Subtilisin/Kexin-like family that was

cloned from mammalian organisms, after furin and

PC2 (Seidah NG et al. 1991, Smeekens SP et al,

1991, reviewed in Scamuffa N et al, 2006). The

domain structure of PCSK1 precursor consists of

four domains that include a prodomain (or

prosegment), a catalytic domain, a P domain, and a

carboxy-terminal domain (Figure 2). The propeptide

domain is essential for the appropriate protein

folding and exit from the endoplasmic reticulum

(ER) of PCSK1 (Creemers JW1 et al, 1995). The

catalytic domain is highly conserved among various

species. Similar to the other members of the

subtilisin superfamily the amino acids Asp, His, and

Ser form the catalytic triad. The P domain presents a

key role in the regulation of the PCSK1 activity

through calcium and pH modulation (Zhou A1 et al,

1998). The carboxy-terminal domain is mainly

involved in PCSK1 sorting into secretory granules

(Dikeakos JD et al. 2009).

After the production of PCSK1 preproform in the

endoplasmic reticulum and removal of its signal

peptide, the 94kDa precursor of PCSK1 activation

occurs after both N-and C-terminal domains

cleavages. The 94kDa precursor undergoes an initial

autocatalytic processing of its prosegment

(prodomain). After protein scaffold and N-

glycosylation, proPCSK1 exits the ER and sorts to

the trans-Golgi network. In the early compartment,

proPCSK1 is sulfated on its sugar residues. Lately

during progression to the mildly acidic environment,

an autocatalytic cleavage occurs to remove the

prodomain and generates a 87kDa active PCSK1

form (reviewed in Ramos-Molina B et al , 2016 and

Stijnen P et al 2016). The cleavage of proPCSK1 that

generates the 87 kDa PCSK1 is calcium-independent

and occurs at a neutral pH. PCSK1 is sorted after to

immature secretory granules where is activated by a

cleavages at the C-terminal area and generates the 74

and 66kDa active forms. The active forms are than

accumulated in dense-core secretory granules prior

secretion.

Expression

PCSK1 is expressed in the neuroendocrine system

such as brain, adrenal glands and in endocrine cells

of the small intestine (reviewed in Ramos-Molina B

et al , 2016 and Stijnen P et al 2016). Weak

expression of PCSK1 is detected in adipocytes, α-

cells of the pancreatic islets and certain types of

immune cells. In brain, PC1 is mainly expressed in

the hypothalamus (Dong W et al , 1997), but it is also

found in cerebral cortex (Figure 3), hippocampus,

and cerebellum (Billova S1, ET AL , 2007, Schäfer

MK1, et al 1993). PC1/3 is also expressed in the

adrenal medulla, pituitary, thyroid gland (Scopsi L et

al. 1995, Day R ET AL 1992), endocrine pancreas

(β-cells), liver and small intestine; including L and K

cells (Tanaka S ET AL 1996). At low levels, PC1/3

was also detected in adipocytes (Min SYet al, 2016),

in pancreatic islets (Itoh Y1, et al 1996), and in

certain types of immune cells (LaMendolaet al 1997,

Vindrola O et al 1994).



Localisation

In neuroendocrine cells, PCSK1 is mainly localized

to the secretion granules and traffics within the

regulated secretory pathway (Hornby PJ et al 1993,

Malide D et al 1995). In macrophages PC1/3 is

retained at the TGN as a pool that traffics to LAMP-

related vesicles. PC1 vesicules are mostly detected

during macrophages activation (Gagnon H et al,

2013)

Example of PCSK1 expression in the cerebral cortex and liver. Shown are overviews of stained tissues

(circle) with high magnification of representative region (square). Adapted from Protein Atlas database.

Function

PCSK1 cleaves protein precursors at the consensus

motif (K/R)-Xn-(K/R)↓, with n=0, 2, 4 or 6, and

X=any amino acids except Cys, to release mature

proteins. PCSK1 favors cleavage after K/R motif,

but is also able to cleave after other dibasic residues.

PCSK1 often collaborates with PCSK2 to cleave

substrates, such as neuropeptides and peptide

hormones and its activity can be inhibited by the

endogenous inhibitor proSAAS. PC1/3 gene

disruption results in various developmental

abnormalities' (reviewed in Ramos-Molina B et al ,

2016 and Stijnen P et al 2016) and PC1/3 null mice

exhibit growth retardation (reviewed in Scamuffa N

et al, 2006). The adult mutant mice are 60% of the

normal size and show similarities with mice having

mutant growth hormone releasing hormone (GHRH)

receptor (GHRHR). Further analysis indicated that

insulin-like growth factor-1 (IGF1) and GHRH

levels were significantly decreased in

these mice; that may explain the observed growth

retardation. PCSK1 null mice process normally

pituitary POMC to ACTH and have normal levels of

blood corticosterone. Like PCSK2 null mice, PCSK1

null mice also develop hyperproinsulinemia. These

mice maintain normal glucose (Glc) tolerance in

response to injection of glucose, suggesting that their

hyperproinsulinemia does not impair their glucose

homeostasis. Previously, Jackson et al. (reviewed in

Scamuffa N et al, 2006) reported a human case of



PC1/3 deficiency. The latter is due to PCSK1 gene

mutation that prevents activation and secretion of

proPC1/3 from the endoplasmic reticulum. The

patient showed neonatal obesity. Subsequent studies

revealed the presence of various endocrine defects,

including the presence of very high circulating levels

of proinsulin and multiple forms of partially

processed POMC [ACTH precursors intermediate],

low-serum estradiol, follicle-stimulating hormone,

and LH. In 2003, another PCSK1 deficiency female

subject was reported. In addition to the shared

phenotypes with the previous subject, this female

infant presented severe diarrhea, which started on the

third postnatal day. Metabolic studies revealed a

defect in the absorption of monosaccharides and fat,

revealing the role of PC1/3 in the small intestinal

absorptive function. Although the phenotypes of the

PCSK1 null mice differ from those observed in these

patients (PCSK1 null mice are not obese), the

findings confirmed the importance of PCSK1 as a

key neuroendocrine convertase (reviewed in Ramos-

Molina B et al , 2016 and Stijnen P et al 2016).

Homology

An important paralog of this gene is PCSK2.

Analysis of PCSK1 structure revealed that PCSK1

catalytic domain present a low percentage of

homology with those of the other PCs (only 39%

between PCSK1 and FURIN). The PCSK1

prodomain is formed by 83 residues and is highly

conserved between orthologs (∼80% of sequence

identity), although is not well conserved among

paralogs of the convertase family (∼30-40%). The

catalytic domain of PC1/3 is formed by 343 residues

and is the most conserved region among proproteine

convertases family members, with 50-60% sequence

similarity. The P domain is a well-conserved region

in PCs of approximately 150 residues and the Arg526-

Arg-Gly-Asp529 (RRGD motif) is crucial for proper

proPC1/3 processing and sorting to the secretory

granules (reviewed in Ramos-Molina B et al , 2016

and Stijnen P et al 2016). The C-terminus of PCSK1

with 159 aa is involved in the sorting processes to

the dense core secretory granules, as well as in

PCSK1 activity and stability ((reviewed in Ramos-

Molina B et al , 2016 and Stijnen P et al 2016).

Mutations

Germinal

Various mutations were reported for human PCSK1

gene and were associated with various syndromes

including obesity, malabsorptive diarrhea,

hypogonadotropic hypogonadism, altered thyroid

and adrenal function, and impaired regulation of

plasma glucose levels (reviewed in Ramos-Molina B

et al , 2016 and Stijnen P et al 2016).

Implicated in

Breast cancer

PC1 is highly elevated in human breast carcinomas

(Cheng et al.1997). Stable expression of PC1 in

human breast cancer cells MCF-7 altered their

growth rate and response to estrogen and anti-

estrogen treatments (Cheng et al. 2001). The use of

transgenic mouse model revealed that PCSK1

expression promote normal and neoplastic

mammary development and growth (Blanchard A et

al 2009).

Colon cancer and colon cancer metastasis

PC1 expression and protein cleavage profiles are

altered in colon cancer and liver colorectal

metastasis, compared to unaffected and normal liver.

Active PCSK1 protein is overexpressed in these

tumors and was found to correlate with the mRNA

profiles (Tzimas G, et al 2005)

Neuroendocrine tumors

High expression of PCSK1 is reported for neural

and/or endocrine phenotype (Takumi I et al 1998, Jin

L et al, 1999, Kajiwara H et al. 1999). However the

role and prognostic value of PCSK1 in endocrine-

related cancers is still unclear.

Endocrine disorders

PCSK1 deficiency is a very rare genetic disorder,

few patient cases have been reported. In human, the

lack of PCSK1 was reported to be associated with

several cases of hypogonadotropic and/or

hypogonadism (O'Rahilly et al, 1995). Several

patients showed low serum estradiol, FSH, and LH

(Jackson R et al 1997, Martèn MG et al 2013,

Bandsma RH, et al 2013, Wilschanski ET AL 2014,

Solorzano-Vargas RS et al 2013).

References Bandsma RH, Sokollik C, Chami R, Cutz E, Brubaker PL, Hamilton JK, Perlman K, Zlotkin S, Sigalet DL, Sherman PM, Martin MG, Avitzur Y. From diarrhea to obesity in prohormone convertase 1/3 deficiency: age-dependent clinical, pathologic, and enteroendocrine characteristics. J Clin Gastroenterol. 2013 Nov-Dec;47(10):834-43

Billova S, Galanopoulou AS, Seidah NG, Qiu X, Kumar U. Immunohistochemical expression and colocalization of somatostatin, carboxypeptidase-E and prohormone convertases 1 and 2 in rat brain. Neuroscience. 2007 Jun 29;147(2):403-18

Blanchard A, Iwasiow B, Yarmill A, Fresnosa A, Silha J, Myal Y, Murphy LC, Chrétien M, Seidah N, Shiu RP. Targeted production of proprotein convertase PC1 enhances mammary development and tumorigenesis in transgenic mice. Can J Physiol Pharmacol. 2009 Oct;87(10):831-8

Cheng M, Watson PH, Paterson JA, Seidah N, Chrétien M, Shiu RP. Pro-protein convertase gene expression in human breast cancer. Int J Cancer. 1997 Jun 11;71(6):966-71

Cheng M, Xu N, Iwasiow B, Seidah N, Chrétien M, Shiu RP. Elevated expression of proprotein convertases alters breast



cancer cell growth in response to estrogen and tamoxifen. J Mol Endocrinol. 2001 Apr;26(2):95-105

Creemers JW, Vey M, Schäfer W, Ayoubi TA, Roebroek AJ, Klenk HD, Garten W, Van de Ven WJ. Endoproteolytic cleavage of its propeptide is a prerequisite for efficient transport of furin out of the endoplasmic reticulum. J Biol Chem. 1995 Feb 10;270(6):2695-702

Day R, Schafer MK, Watson SJ, Chrétien M, Seidah NG. Distribution and regulation of the prohormone convertases PC1 and PC2 in the rat pituitary. Mol Endocrinol. 1992 Mar;6(3):485-97

Dikeakos JD, Di Lello P, Lacombe MJ, Ghirlando R, Legault P, Reudelhuber TL, Omichinski JG. Functional and structural characterization of a dense core secretory granule sorting domain from the PC1/3 protease. Proc Natl Acad Sci U S A. 2009 May 5;106(18):7408-13

Dong W, Seidel B, Marcinkiewicz M, Chrétien M, Seidah NG, Day R. Cellular localization of the prohormone convertases in the hypothalamic paraventricular and supraoptic nuclei: selective regulation of PC1 in corticotrophin-releasing hormone parvocellular neurons mediated by glucocorticoids. J Neurosci. 1997 Jan 15;17(2):563-75

Duhamel M, Rodet F, Delhem N, Vanden Abeele F, Kobeissy F, Nataf S, Pays L, Desjardins R, Gagnon H, Wisztorski M, Fournier I, Day R, Salzet M. Molecular Consequences of Proprotein Convertase 1/3 (PC1/3) Inhibition in Macrophages for Application to Cancer Immunotherapy: A Proteomic Study. Mol Cell Proteomics. 2015 Nov;14(11):2857-77

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Gagnon H, Refaie S, Gagnon S, Desjardins R, Salzet M, Day R. Proprotein convertase 1/3 (PC1/3) in the rat alveolar macrophage cell line NR8383: localization, trafficking and effects on cytokine secretion. PLoS One. 2013;8(4):e61557

Hornby PJ, Rosenthal SD, Mathis JP, Vindrola O, Lindberg I. Immunocytochemical localization of the neuropeptide-synthesizing enzyme PC1 in AtT-20 cells. Neuroendocrinology. 1993 Nov;58(5):555-63

Itoh Y, Tanaka S, Takekoshi S, Itoh J, Osamura RY. Prohormone convertases (PC1/3 and PC2) in rat and human pancreas and islet cell tumors: subcellular immunohistochemical analysis. Pathol Int. 1996 Oct;46(10):726-37

Jackson RS, Creemers JW, Ohagi S, Raffin-Sanson ML, Sanders L, Montague CT, Hutton JC, O'Rahilly S. Obesity and impaired prohormone processing associated with mutations in the human prohormone convertase 1 gene. Nat Genet. 1997 Jul;16(3):303-6

Jansen E, Ayoubi TA, Meulemans SM, Van de Ven WJ. Cell type-specific protein-DNA interactions at the cAMP response elements of the prohormone convertase 1 promoter. Evidence for additional transactivators distinct from CREB/ATF family members. J Biol Chem. 1997 Jan 24;272(4):2500-8

Jin L, Kulig E, Qian X, Scheithauer BW, Young WF Jr, Davis DH, Seidah NG, Chretien M, Lloyd RV. Distribution and regulation of proconvertases PC1 and PC2 in human pituitary adenomas. Pituitary. 1999 May;1(3-4):187-95

Kajiwara H, Itoh Y, Itoh J, Yasuda M, Osamura RY. Immunohistochemical expressions of prohormone convertase (PC)1/3 and PC2 in carcinoids of various organs. Tokai J Exp Clin Med. 1999 Apr;24(1):13-20

LaMendola J, Martin SK, Steiner DF. Expression of PC3, carboxypeptidase E and enkephalin in human monocyte-derived macrophages as a tool for genetic studies. FEBS Lett. 1997 Mar 3;404(1):19-22

Malide D, Seidah NG, Chrétien M, Bendayan M. Electron microscopic immunocytochemical evidence for the involvement of the convertases PC1 and PC2 in the processing of proinsulin in pancreatic beta-cells. J Histochem Cytochem. 1995 Jan;43(1):11-9

Martín MG, Lindberg I, Solorzano-Vargas RS, Wang J, Avitzur Y, Bandsma R, Sokollik C, Lawrence S, Pickett LA, Chen Z, Egritas O, Dalgic B, Albornoz V, de Ridder L, Hulst J, Gok F, Aydoğan A, Al-Hussaini A, Gok DE, Yourshaw M, Wu SV, Cortina G, Stanford S, Georgia S. Congenital proprotein convertase 1/3 deficiency causes malabsorptive diarrhea and other endocrinopathies in a pediatric cohort. Gastroenterology. 2013 Jul;145(1):138-148

Min SY, Kady J, Nam M, Rojas-Rodriguez R, Berkenwald A, Kim JH, Noh HL, Kim JK, Cooper MP, Fitzgibbons T, Brehm MA, Corvera S. Human 'brite/beige' adipocytes develop from capillary networks, and their implantation improves metabolic homeostasis in mice. Nat Med. 2016 Mar;22(3):312-8

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Scopsi L, Gullo M, Rilke F, Martin S, Steiner DF. Proprotein convertases (PC1/PC3 and PC2) in normal and neoplastic human tissues: their use as markers of neuroendocrine differentiation J Clin Endocrinol Metab 1995 Jan;80(1):294-301

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Demoures B, Siegfried G, Khatib AM. PCSK1

(proprotein convertase subtilisin/kexin type 1).

Atlas Genet Cytogenet Oncol Haematol. 2018;

22(6):236-241.

Leukaemia Section Short Communication




t(1;5)(p32;q31) without TAL1 rearrangement Adriana Zamecnikova

Kuwait Cancer Control Center, Department of Hematology, Laboratory of Cancer Genetics, Kuwait;

[email protected]

Published in Atlas Database: April 2017

Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t0105p32q31ID1787.html

Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/68911/04-2017-t0105p32q31ID1787.pdf DOI: 10.4267/2042/68911


Abstract

1p32 translocations and submicroscopic interstitial

deletions resulting in TAL1 deregulation are known

aberrations in T lymphoblastic leukemia/lymphoma.

The t(1;5)(p32;q31) is a rare translocation of 1p32

described only in 1 patient with aberrantly expressed

TAL1 mRNA and protein (François et al., 1998) and

in 2 other patients without involvement of the TAL1

gene.

KEYWORDS

chromosome 1; chromosome 5; 1p deletion; tumor

supressor genes; TAL1; t(1;5)(p32;q31).

Clinics and pathology

Disease

Acute lymphocytic leukaemia (ALL) and acute

promyelocytic leukemia (APL)

Epidemiology

Only 2 ALL cases reported: a 49-years old male with

T-cell ALL (Cho et al., 2009) and a 10-years old

male diagnosed with B-ALL (Kaleem et al., 2000).

In addition, a t(1;5)(p32;q31) was detected as an

additional anomaly in a 29-years old female patient

diagnosed with acute promyelocyte leukemia

(Zamecnikova, unpublished case).

Prognosis

Yet poorly known; the pediatric case with B-

precursor phenotype achieved complete remission

after induction chemotherapy and remains in

complete continuous remission for 24 months

(Kaleem et al., 2000). Induction chemotherapy failed

to induce remission in the adult patient with T-ALL

and 5 months later the patient died due to renal

failure and metabolic acidosis (Cho et al., 2009). In

the APL case, induction was started with ATRA

based therapy resulting in complete remission and

she remains in complete remission for 14+ months.

Cytogenetics

t(1;5)(p32;q31) without TAL1 rearrangement

Atlas Genet Cytogenet Oncol Haematol. 2018; 22(6)

243

Figure 1. Partial karyotypes with t(1;5)(p32;q31).

Cytogenetics morphological

May be overlooked in suboptimal preparations.

Figure 2. (A) Fluorescence in situ hybridization with LSI CSF1R (SpectrumOrange)/D5S23, D5S721

(SpectrumGreen) showing the presence of 5q sequences on der(1) chromosome. (B) Hybridization with Vysis

LSI 1p36 (SpectrumOrange) / LSI 1q25 (SpectrumGreen) probes showing translocation of 1p sequences to

der(5) chromosome.

Probes

LSI CSF1R (SpectrumOrange/D5S23, D5S721

SpectrumGreen, and Vysis LSI 1p36

(SpectrumOrange) / LSI 1q25 (SpectrumGreen)

probes.

Additional anomalies

Secondary anomaly in addition to t(8;14)(q11.2;q32)

in a pediatic B-ALL patient (Kaleem et al., 2000),

associated with del(6q) in a sideline in the T-ALL

case (Cho et al., 2009) and found in association

witht(15;17)(q24;q21) in the APL case.

Result of the chromosomal anomaly

Fusion protein

Oncogenesis

Because of its rarity, the role of t(1;5)(p32;q31) in

disease pathogenesis as well as its clinical

significance is unclear. Unlike in the T-ALL case

described by François et al., 1998, neither TAL1

translocation nor its aberrant expression was

detected FISH and by immunohistochemical

staining in the other T-ALL patient (Cho et al.,

2009). Therefore it is likely that some other genes

located at 1p32 such as BLYM, EPS15, CDKN2C,

and JUN may be involved in leukemogenesis (Cho

et al., 2009). In the remaining 2 cases,

t(1;5)(p32;q31) was found in addition to

t(8;14)(q11.2;q32) and to t(15;17)(q24;q21) likely

representing a secondary event in these cases.

References Cho HS, Kim MK, Bae YK. A novel translocation t(1;5)(p32;q31) that was not associated with the TAL1 rearrangement in a case of T lymphoblastic leukemia/lymphoma. Korean J Lab Med. 2009 Jun;29(3):199-203

François S, Delabesse E, Baranger L, Dautel M, Foussard C, Boasson M, Blanchet O, Bernard O, Macintyre EA, Ifrah N. Deregulated expression of the TAL1 gene by t(1;5)(p32;31) in patient with T-cell acute lymphoblastic leukemia. Genes Chromosomes Cancer. 1998 Sep;23(1):36-43

Kaleem Z, Shuster JJ, Carroll AJ, Borowitz MJ, Pullen DJ, Camitta BM, Zutter MM, Watson MS. Acute lymphoblastic leukemia with an unusual t(8;14)(q11.2;q32): a Pediatric Oncology Group Study. Leukemia. 2000 Feb;14(2):238-40


Zamecnikova A. t(1;5)(p32;q31) without TAL1

rearrangement. Atlas Genet Cytogenet Oncol

Haematol. 2018; 22(6):242-243.





t(6;11)(q24.1;p15.5) NUP98/CCDC28A Tatiana Gindina

Gorbacheva Memorial Institute of Oncology, Hematology and Transplantation at Pavlov First Saint-Petersburg

State Medical University, Saint-Petersburg, Russian Federation / e-mail: [email protected]

Published in Atlas Database: April 2017

Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t0611q24p15ID1395.html

Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/68912/04-2017-t0611q24p15ID1395.pdf DOI: 10.4267/2042/68912


Abstract Review on t(6;11)(q24.1;p15.5), with data on the

genes involved

KEYWORDS

Chromosome 6; chromosome 11; Acute

megakaryoblastic leukemia; T lymphoblastic

leukaemia/lymphoma


Disease

Acute megakaryoblastic leukemia (M7 AML) and T

lymphoblastic leukemia

Epidemiology

Only two cases to date: a 5-year-old female patient

(Tosi et al, 2005) and a 26-year-old male patient

(Romana et al, 2006).

Cytogenetics

Cytogenetics molecular

FISH technique with the NUP98 probe and BAC

RP11-900M13 probe has been used to confirm the

translocation in the reported case (Romana et al,

2006).

Additional anomalies

The T-ALL adult patient showed an additional

abnormality of 12p13 (Romana et al, 2006).

Genes involved and proteins

CCDC28A (coiled-coil domain containing 28A)

Location

6q24.1

Protein

CCDC28A encodes a coiled-coil domain containing

protein. The native CCDC28A protein has no

recognizable similarity to other proteins or

functional domains, and no function has so far been

assigned to the coiled-coil domain, leaving the

biological function of CCDC28A undetermined.

NUP98 (nucleoporin 98 kDa)

Location

11p15.4

Note

also known as C6orf80 and MGC131913

Protein

NUP98 belongs to the nucleoporin gene family and

encodes a 186 kDa precursor protein that undergoes

autoproteolytic cleavage to produce a 98 kDa

nucleoporin and 96 kDa nucleoporin. The 98 kDa

nucleoporin contains a Gly-Leu-Phe-Gly repeat

domain and participates in many cellular processes

including nuclear import/export, mitotic

progression, and regulation of gene expression. The

t(6;11)(q24.1;p15.5) NUP98/CCDC28A


96 kDa nucleoporin is a component of the nuclear

pore complex.


Hybrid gene

NUP98/CCDC28A

Description

Nucleotide sequence analyses revealed an in-frame

fusion between the 13th exon of NUP98 and the

second exon of CCDC28A. A reciprocal

CCDC28A/NUP98 fusion transcript was detected

but is likely devoid of biological activity due to the

lack of a predicted fusion protein (Petit et al, 2012).

Fusion protein

NUP98/CCDC28A

Schematic representation of the wild-type NUP98 and CCDC28 products and of the chimeric fusion protein

NUP98-CCDC28.

Oncogenesis

In mouse models it has been demonstrated that the

enforced NUP98/CCDC28A expression promoted

the proliferative and self-renewal capacities of

hematopoietic progenitors and rapidly caused fatal

myeloproliferative neoplasms and defects in the

differentiaton of the erythro-megakaryocytic

lineage. Although the leukemogenic mechanism

remains unknown, NUP98/CCDC28A retains the

NUP98 GLFG-repeats able to associate with core

binding protein and/or EP300 and has a nuclear

localization suggesting possible transactivation

activity. The transformation mediated by

NUP98/CCDC28A was not associated with

deregulation of the HOXA-Meis1 pathway, a feature

shared by a diverse set of NUP98 fusions. Additional

investigation will be needed to elucidate the role of

NUP98/CCDC28A in lymphoid transformation

(Petit et al, 2012).

References Petit A, Ragu C, Soler G, Ottolenghi C, Schluth C, Radford-Weiss I, Schneider-Maunoury S, Callebaut I,

Dastugue N, Drabkin HA, Bernard OA, Romana S, Penard-Lacronique V. Functional analysis of the NUP98-CCDC28A fusion protein. Haematologica. 2012 Mar;97(3):379-87

Romana SP, Radford-Weiss I, Ben Abdelali R, Schluth C, Petit A, Dastugue N, Talmant P, Bilhou-Nabera C, Mugneret F, Lafage-Pochitaloff M, Mozziconacci MJ, Andrieu J, Lai JL, Terre C, Rack K, Cornillet-Lefebvre P, Luquet I, Nadal N, Nguyen-Khac F, Perot C, Van den Akker J, Fert-Ferrer S, Cabrol C, Charrin C, Tigaud I, Poirel H, Vekemans M, Bernard OA, Berger R. NUP98 rearrangements in hematopoietic malignancies: a study of the Groupe Francophone de Cytogénétique Hématologique. Leukemia. 2006 Apr;20(4):696-706

Tosi S, Ballabio E, Teigler-Schlegel A, Boultwood J, Bruch J, Harbott J. Characterization of 6q abnormalities in childhood acute myeloid leukemia and identification of a novel t(6;11)(q24.1;p15.5) resulting in a NUP98-C6orf80 fusion in a case of acute megakaryoblastic leukemia. Genes Chromosomes Cancer. 2005 Nov;44(3):225-32


Gindina T. t(6;11)(q24.1;p15.5)

NUP98/CCDC28A. Atlas Genet Cytogenet Oncol

Haematol. 2018; 22(6):244-245.

Leukaemia Section Review




Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN) Aurelia Meloni-Ehrig

CSI Laboratories, Alpharetta, GA, USA; [email protected]

Published in Atlas Database:May 2017

Online updated version : http://AtlasGeneticsOncology.org/Anomalies/BPDCNID2146.html

Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/68913/05-2017-BPDCNID2146.pdf DOI: 10.4267/2042/68913


Abstract Review on Blastic Plasmacytoid Dendritic Cell

Neoplasm (BPDCN), with data on clinics, and the

genes involved.

KEYWORDS

Blastic Plasmacytoid Dendritic Cell Neoplas;

Del(5q),; del(12p); del(13q); TET2; ZRSR2; TP53;

ASXL1, CDKN1B; RB1; CDKN2A; CDKN2B;

IKZF1; KMT2A


Disease

Phenotype/cell stem origin

Blastic plasmacytoid dendritic cell neoplasm

(BPDCN) is a rare and aggressive hematologic

neoplasm. Despite its rarity, there is extensive

historic and scientific literature. Since 1994, when

this neoplasm was first described (Adachi et al.,

1994), BPDCN has been known with various names,

including agranular CD4+ natural killer (NK)

leukemia, CD4+/CD56+ hematodermic neoplasm,

and blastic NK lymphoma (Facchetti et al., 2009;

Pilichowska et al., 2007; Petrella et al., 2005; Assaf

et al., 2007). In 2008, the WHO has placed this

neoplasm in the category of acute myeloid leukemia

(AML) and related precursor neoplasms (Facchetti et

al., 2008; Swerdlow et al., 2008) following the

realization that BPDCN results from the clonal

proliferation of immature plasmacytoid dendritic

cells (PDC) (Facchetti et al., 2008). In normal

situations, the PDC are an essential part of the innate

adaptive immunoresponse (Jegalian et al., 2009;

Reizis et al., 2011). These cells respond to viral and

bacterial infection by producing alpha-interferon. As

such, they are also known also as alpha-interferon

producing cells or plasmacytoid monocytes.

Expansion of the normal PDCs can occur in

autoimmune disorders, as well as Hodgkin

lymphoma, and various carcinomas. Flow cytometry

and immunohistochemistry studies have revealed

that the neoplastic PDC of virtually all patients are

typically found in the CD45dim blast gate region and

are phenotypically defined by the co-expression of

CD4, CD56, and CD123, absence of CD34, and lack

of specific myeloid-, T-, B-, or NK-lineage markers

(Pagano et al., 2013). Very rarely CD56 might not be

expressed. In those cases, the expression of CD4,

CD123, and TCL1 would be sufficient to suspect

BPDCN (Herling et al., 2003). Approximately 50%

of the cases might also express CD43, CD45RA, and

CD68. Other markers observed less frequently

include CD7, HLA-DR, TCL1, CD33,

BDCA2/CD303, BDCA4/CD304, CLA, and MxA

(Petrella et al., 2004; Pilichowska et al., 2007).

Epidemiology

BPDCN is quite rare; less than 100 cases have been

reported so far. The disease does not have a

geographic predilection as it has been observed in

Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN)


various countries around the world (Tsagarakis et al.,

2010; Qayoom et al., 2015; Assaf et al., 2007). The

exact incidence might be difficult to determine due

to the various definitions of BPDCN as a leukemia

or a skin lymphoma prior to the 2008 WHO inclusion

of this neoplasm into the AML and related

precursors neoplasms (Facchetti et al., 2008). Recent

reports in the incidence, indicate that this neoplasm

accounts for 0.4% of all hematologic neoplasms,

0.7% of the primary cutaneous lymphomas, and less

than 1% of all acute leukemias (Facchetti et al.,

2008; Riaz et al., 2014; Rossi et al., 2006; Pagano et

al., 2013). BPDCN has been described in all age

groups, but is most common in adults; the majority

of patients are older adults and the median age at

diagnosis is 65 years. Some patients are younger

than 40 years old, and even children with this

neoplasm have been reported. The male to female

ratio is 3:1.

Clinics

The first symptom in most patients with BPDCN is

the presence of multiple cutaneous lesions, often

detected incidentally by dermatologists (Gera et al.,

2014). As such, histologic diagnosis is required to

distinguish BPDCN from other primary skin lesions

or other leukemias and lymphomas characterized by

cutaneous involvement (Gera et al., 2014). At the

same time, or soon after, involvement of bone

marrow and/or peripheral blood occurs. This

involvement is thought to occur in approximately

90% of the cases. Lymph nodes might also be

involved (approximately 50% of the cases). Overt

leukemia is a common feature of BPDC during

progression or relapse, often with a myelomonocytic

phenotype, and is nearly always present in the

terminal stage of the disease. However, a minority of

patients (5-10% of cases) do not have cutaneous

lesions, but present with a very aggressive

(fulminant) leukemia (Wang et al., 2012; Rauh et al.,

2012; Qayoom et al., 2015). In addition to the

typically sites of involvement, other unusual sites

might be also affected. Paluri et al. (2015) reported a

patient diagnosed with a BPDCN confined to the

sinonasal region and central nervous system (CNS).

Although CNS is not typically considered a common

site of involvement for BPDCN, a recent study has

reported a frequent CNS involvement in their group

of patients suggesting that the CNS might be a safe

reservoir of blast cells in patients with leukemic

presentation, due to the fact that drugs are unable to

cross the blood-brain barrier (Martin-Martin et al.,

2016). Regardless of the presentation, the overall

prognosis for patients with BPDCN is unfavorable,

with a median overall survival of approximately one

year (Facchetti et al., 2008; Julia et al., 2013). In

children, BPDCN is characterized by less frequent

cutaneous involvement and a significant response to

intensive acute lymphoblastic leukemia (ALL)-type

chemotherapy, allowing patients to reach complete

remission. The overall prognosis and long-term

survival in pediatric patients is better than in adults.

Some reports made the suggestion that childhood

BPDCN might represent a different neoplasm than

the one seen in adults (Jegalian et al., 2010; Rossi et

al., 2006).

Immunohistologic studies on lymph node sections show reactivity for CD56 and CD43 and lack reactivity for

CD45 and TdT (original magnification ×375). Image available at Blastic plasmacytoid dendritic cell neoplasm.

PathologyOutlines.com website.

http://www.pathologyoutlines.com/topic/lymphomanonBblasticplasmacytoid.html. Accessed April 30th, 2017



Cytology

Examination of BPDCN patients with skin

presentation reveals that the neoplasm involves the

entire dermis and may extend to the subcutis, but not

the epidermis (Gera et al., 2014. When the bone

marrow is affected, there is a variable degree of

involvement with variable dysplasia. The lymph

nodes show a diffuse interfollicular and medullary

involvement. Microscopic examination of the skin

biopsy typically shows a diffuse monotonous

infiltrate of intermediate-sized blast cells with round

to oval nuclei and nucleoli, and scant agranular

cytoplasm that resemble myeloid blasts, but with NK

cell lineage differentiation (Ferreira et al., 2016; Ru

et al., 2014). Intracytoplasmic microvacuoles are

present in the majority of cases (Ferreira et al.,

2016). The mitotic activity is variable.

(A) Lymph node biopsy. Monomorphous infiltrate of medium-sized cells with scant cytoplasm, round nuclear

contours, finely granular chromatin, and numerous mitotic figures (hematoxylin-eosin, original magnification

×375); (B) Bone marrow core biopsy specimen. Hypercellular marrow with trilineage hematopoiesis and an

interstitial infiltrate of immature blast-like cells (hematoxylin-eosin, original magnification ×375). (C) Peripheral

blood smear after bone marrow transplantation. Immature blasts with high nuclear-to-cytoplasmic ratio,

agranular cytoplasm, and round nuclear contours (Wright-Giemsa, original magnification ×500). Image available

at Blastic plasmacytoid dendritic cell neoplasm. PathologyOutlines.com website.

http://www.pathologyoutlines.com/topic/lymphomanonBblasticplasmacytoid.html. Accessed April 30th, 2017

Prognosis

BPDCNA is an aggressive neoplasm with a median

survival of approximately 12 months and typically

poor response to chemotherapy (Facchetti et al.,

2008; Julia et al., 2013). Patients with the leukemic

form of the neoplasm have a shorter survival

(approximately 8 months) (Riaz et al., 2014). Since

skin presentation occurs in the majority of patients,

the first therapeutic approach is targeted to treat the

skin lesions. There is no specific induction therapy

designed specifically to treat this neoplasm. Patients

have been treated with existing therapies typically

used for non-Hodgkin lymphoma, AML, and ALL

(Falcone et al., 2016). Various AML and ALL

therapeutic protocols have been used. The AML

protocol consists of variable combinations of

cytarabine, etoposide, idarubicin, anthracycline,

fludarabine, and filgrastim, whereas the ALL

protocol includes variable combinations of

cyclophosphamide, vincristine, doxorubicin,

dexamethasone, methotrexate, cytarabine,

prednisone, asparaginase, and CHOP with and

without etoposide (Pagano et al., 2013).

Approximately 90% of patients seem to respond

initially to these therapies, but the disease later recurs

in the majority of patients (Bayerl et al., 2002).

However, Voelkl et al. (2011) reported an elderly

patient with BPDCN with AML presentation and

skin lesions who achieved a 26 month long remission

after treatment with dose intensive multiagent

chemotherapy. Long lasting remissions might occur

in pediatric patients with good response to acute

leukemia chemotherapy and allogeneic stem cell

transplantation (Paluri et al., 2015; Male et al.,

2010). Several studies have demonstrated that

allogeneic stem cell transplantation following a

reduced intensity conditioning (avoidance of high-

dose therapy) offers the best chance for long lasting

remission, particularly when performed during the

first complete remission, and suggests that this form

of therapy should be pursued aggressively for all

BPDCN patients (Dietrich et al. 2011; Roos-Weil et

al., 2013; Aoki et al., 2015). There are also clinical

trials presently being conducted that are showing

promising results. One of these trials consists in the

administration of a single cycle of therapy of SL-

401. This is a recombinant human interleukin 3a

protein conjugated with truncated diphtheria a-toxin

DT388-IL3, a potent inhibitor of protein synthesis

(Stemline Therapeutics) (Frankel et al., 2014;

Fitzgerald et al., 2014). The other clinical trial

consists of a targeted therapy against CD56+ tumors.



The drug in in this case is lorvotuzumab mertansine,

which has been used to targets other hematologic

neoplasms that express CD56 (Whiteman et al.,

2014).

Cytogenetics

G-banded karyotype of a patient with BPDCN:

44,XY,del(5)(q15q33),del(6)(q13q23),add(9)(p13),add(12)(p11.2),-13,-15, add(17)(p12). Hypodiploidy with

deletions of 5q, 6q, 9p, 12p, and 17p is a common finding. Typically these karyotypes also show loss of

chromosome 13 and 15, as seen in this case

.


An interesting fact about BPDCN is that the

chromosome abnormalities are more similar to those

that have been observed in high-grade

myelodysplasia (MDS) and AML with MDS-related

changes than those that have been described in

lymphoma. Karyotypes are usually are complex like

those that have also been described in therapy related

MDS/AML, and are often hypodiploid. Recurrent

deletions, some leading to loss of specific gene, have

been identified by both conventional cytogenetics

and array comparative genomic hybridization

(aCGH) (Leroux et al., 2002; Oiso et al., 2012;

Lucioni et al., 2011; Dijkman et al., 2007). The most

common deletions are those involving 5q (72% of

cases), 12p13.1-p13.2/ CDKN1B (64%), 13q13.1-

14.2/ RB1 (64%), 6q (50%), 15q (43%), 9p21.3/

CDKN2A/ CDKN2B (28%), and 7p12.2/ IKZF1.

Among these, the biallelic loss of 9p21.3 suggests a

more aggressive course. In addition, three cases of

MLL rearrangement, two with t(11;19)(q23;p13.3)

KMT2A/ MLLT1 and one with a 3-way

t(4;9;11)(q12;p22;q23) have been reported in 3

patients aged 8, 42, and 50 years old, respectively

(Leung et al., 2006; Toya et al., 2012; Yang et al.

2015). The involvement of MLL and the other

recurrent chromosome abnormalities observed in

BPDCN might pose a challenge for differentiating

PBDCN from MDS, AML, or ALL since some of the

abnormalities seen in PBDCN are common to these

neoplasms. Therefore, authors urge careful

evaluation of suspected cases of BPDCN and

encourage the use of plasmacytoid dendritic cell

markers to ensure that the blasts have no expression

of myeloid or monocytic markers (particularly cases

with MLL rearrangements), as well as perform

extensive immunohistochemical and genetic

analyses before definitively considering the

diagnosis of BPDCN (Lee et al., 2016). In contrast,

it is relatively easier to genetically differentiate

BPDCN from NK neoplasms, since BPDCN does

not have rearrangements of heavy chain, light chain,

or T-cell receptor genes.

Genes involved and proteins In addition to the loss of tumor suppressor genes due

to the various chromosome deletions mentioned in

the cytogenetic section (i.e., CDKN1B, RB1,

CDKN2A/CDKN2B, and IKZF1), several mutations



involving oncogenes have been described. The most

common are TET2 at 4q24 (57%), ZRSR2 at Xp22.2

(57%), TP53 at 17p13.2 (14%), and ASXL1 at

20q11.2 (Jardin et al., 2011; Alayed et al., 2013).

Exome sequencing has also revealed mutations of

other less common genes such as IKZF3 at 17q12,

HOXB9at 17q21.3, UBE2G2 at 21q22.3 and ZEB2

at 2q22.3 (Menezes et al., 2014). Furthermore, some

patients were found to have a FLT3-ITD mutation

(Pagano et al. 2013).

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Meloni-Ehrig A. Blastic Plasmacytoid Dendritic

Cell Neoplasm (BPDCN). Atlas Genet Cytogenet

Oncol Haematol. 2018; 22(6):246-251.





del(1p) solely Adriana Zamecnikova

Kuwait Cancer Control Center, Department of Hematology, Laboratory of Cancer Genetics, Kuwait;

[email protected]

Published in Atlas Database: May 2017

Online updated version : http://AtlasGeneticsOncology.org/Anomalies/del1pID1501.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/68914/05-2017-del1pID1501.pdf DOI: 10.4267/2042/68914


Abstract Deletions of the short arm of chromosome 1 are

observed in a broad range of hematological

malignances including myeloid disorders, acute

lymphoblastic leukemia (ALL), multiple myeloma

(MM) and lymphomas. They generally occur as part

of complex karyotypes and in advanced disease

stages. Their association with complex karyotypes

likely reflect an inherent chromosomal instability

correlated with a poor prognosis. The occurrence of

1p deletions as a sole anomaly is infrequent and their

clinical significance is less well characterized.

KEYWORDS

Chromosome deletions; tumor suppressor genes;

gene downregulation; nonrandom 1p deletions.

del(1p) solely


Partial karyotypes showing deletions of the short arm of chromosome 1 (A). Fluorescence in situ hybridization

with LSI 1p36 (red)/1q25 (green) probes (Vysis/Abott Molecular, US) showing deletion of terminal 1p36

sequences from chromosome 1 (absence of the red signal).


Disease

Myeloid malignancies, acute lymphoblastic

leukemia (ALL) and multiple myeloma (MM)

Epidemiology

Myeloid malignancies mainly (10 patients): 5

patients with myelodysplastic syndromes (MDS) (3

males, 2 females aged 64 to 71 years) (Parlier et al.,

1994; Westbrook et al., 2000; Lubbert et al., 2001;

Mallo et al., 2008; Wang et al., 2010; ) and 5 acute

myeloid leukemia (AML) cases (2 males and 3

females aged 16 to 46 years) (Raimondi et al., 1999;

Lemez et al., 2000; Coupland et al., 2002; Casas et

al., 2004; Gmidène et al., 2012). In addition, there

was 1 ALL patient (Zuelzer et al., 1976), a 7-years

old T-ALL patient (Kaneko et al., 1989), 1 infant

patient with biphenotypic leukemia (Al-Seraihy et

al., 2009) and 7 multiple myeloma cases (3 males

and 4 females aged 41 to 72 years) (Ankathil et al.,

1995; Calasanz et al., 1997; Pantau et al., 2005).

Cytogenetics


Various breakpoints; found in a form of interstitial

or terminal deletion, the most commonly breakpoint

described is p11p22 found in 4 out of 7 MM cases;

found in a sideline in 1 AML (Raimondi et al., 1999)

and in 1 MM case (Pantou et al., 2005).


Fusion protein

Oncogenesis

Deletions of the short arm of chromosome 1

represent nonrandom structural aberrations in

hematological malignancies, suggesting the

existence of tumor suppressor genes encoded in this

region. Loss of genetic information from the deleted

region may contribute to disease pathogenesis via

dosage reduction of genes leading to their aberrant

expression. Most 1p deletions involve large regions

containing a certain fraction of genes, therefore

multiple tumor suppressive genes might cooperate in

an additive or synergistic way leading to their

simultaneous downregulation

References Al-Seraihy AS, Owaidah TM, Ayas M, El-Solh H, Al-Mahr M, Al-Ahmari A, Belgaumi AF. Clinical characteristics and outcome of children with biphenotypic acute leukemia. Haematologica. 2009 Dec;94(12):1682-90

Ankathil R, Madhavan J, Gangadharan VP, Pillai GR, Nair MK. Nonrandom karyotype abnormalities in 36 multiple myeloma patients. Cancer Genet Cytogenet. 1995 Aug;83(1):71-4

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del(1p) solely


correlations. Genes Chromosomes Cancer. 1997 Feb;18(2):84-93

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Mallo M, Arenillas L, Espinet B, Salido M, Hernández JM, Lumbreras E, del Rey M, Arranz E, Ramiro S, Font P, González O, Renedo M, Cervera J, Such E, Sanz GF, Luño E, Sanzo C, González M, Calasanz MJ, Mayans J, García-Ballesteros C, Amigo V, Collado R, Oliver I, Carbonell F, Bureo E, Insunza A, Yañez L, Muruzabal MJ, Gómez-Beltrán E, Andreu R, León P, Gómez V, Sanz A, Casasola

N, Moreno E, Alegre A, Martín ML, Pedro C, Serrano S, Florensa L, Solé F. Fluorescence in situ hybridization improves the detection of 5q31 deletion in myelodysplastic syndromes without cytogenetic evidence of 5q-. Haematologica. 2008 Jul;93(7):1001-8

Pantou D, Rizou H, Tsarouha H, Pouli A, Papanastasiou K, Stamatellou M, Trangas T, Pandis N, Bardi G. Cytogenetic manifestations of multiple myeloma heterogeneity. Genes Chromosomes Cancer. 2005 Jan;42(1):44-57

Parlier V, van Melle G, Beris P, Schmidt PM, Tobler A, Haller E, Bellomo MJ. Hematologic, clinical, and cytogenetic analysis in 109 patients with primary myelodysplastic syndrome. Prognostic significance of morphology and chromosome findings. Cancer Genet Cytogenet. 1994 Dec;78(2):219-31

Raimondi SC, Chang MN, Ravindranath Y, Behm FG, Gresik MV, Steuber CP, Weinstein HJ, Carroll AJ. Chromosomal abnormalities in 478 children with acute myeloid leukemia: clinical characteristics and treatment outcome in a cooperative pediatric oncology group study-POG 8821. Blood. 1999 Dec 1;94(11):3707-16

Wang H, Wang XQ, Xu XP, Lin GW. Cytogenetic evolution correlates with poor prognosis in myelodysplastic syndrome. Cancer Genet Cytogenet. 2010 Jan 15;196(2):159-66

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Zuelzer WW, Inoue S, Thompson RI, Ottenbreit MJ. Long-term cytogenetic studies in acute leukemia of children; the nature of relapse. Am J Hematol. 1976;1(2):143-90


Zamecnikova A. del(1p) solely. Atlas Genet


Leukaemia Section Review




dup(1q) in ALL Anwar N. Mohamed

Cytogenetics Laboratory, Pathology Department, Detroit Medical Center, Wayne State University School of

Medicine, Detroit, MI USA; [email protected]

Published in Atlas Database: May 2017

Online updated version : http://AtlasGeneticsOncology.org/Anomalies/dup1qALLID1049.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/68915/05-2017-dup1qALLID1049.pdf DOI: 10.4267/2042/68915


Abstract Review on duplication of 1q in acute lymphoblastic

leukemia, with data on clinics, and the genes

involved.

KEYWORDS

Chromosome 1; Acute lymphoblastic leukemia;

DAP3; B4GALT3; UCK2; RGS16; TMEM183A

Identity

dup(1q) in ALL


Top: G-banded hyperdiploid karyotype with duplication 1q from an ALL case. Bottom: G-banded

hyperdiploid karyotype fom ALL patient showing an unbalanced der(1;6)(q10;p10) resulting in gain/trisomy 1q.

dup(1q) in ALL Fluorescence in situ hybridization with Vysis LSI 1p36/LSI 1q25 dual-color probe (Abbott

molecular, US) showing 2 normal copies of 1q25 on normal (A) and 3 copies of green signal on metaphase with

dup(1q) in ALL


1q duplication (B) and on metaphase with inverted 1q duplication (C). Partial karyotypes and metaphase with C-

band showing the inverted duplication of 1q (D) Courtesy Adriana Zamecnikova.


Disease

Acute Lymphoblastic Leukemia (ALL)

Cytogenetics

Duplication or gain of 1q may result from a partial

interstitial duplication of 1q or more often from an

unbalanced translocation (Figure 1, 2). Although

dup(1q) is rarely seen as a sole abnormality, it is

mostly found in association with well-known

primary cytogenetic abnormalities. In high

hyperdiploid ALL, duplication of 1q is the most

frequent structural aberration found in

approximately 15% cases (Figure 1). Gain of 1q is

also associated with t(1;19) translocation; 75% of

those cases have an unbalanced translocation leading

to gain/trisomy 1q. Additionally, partial trisomy of

1q is found in almost 25% of Burkitt

lymphoma/leukemia (BL) cases in particular the

endemic type. Therefore, duplication/gain of 1q in

ALL is an apparently a secondary event.

The size of the duplicated region of 1q is variable but

mostly reported form 1q21 -> qter. Using array

CGH, Davidsson et al studied ten cases with

duplicated 1q; six cases of B-cell precursor pediatric

high hyperdiploid ALL and four cases of BL. The

proximal breakpoints in all cases were near the

centromere, mostly clustering within a 1.4 Mb

segment at 1q12-21.1. There was no evidence

hypomethylation of sat II DNA in ALLs with or

without 1q gains indicating that aberrant methylation

was not involved in the formation of dup(1q), as

previously suggested for other neoplasms with 1q

rearrangements. However, the 1q distal breakpoints

were heterogeneous, being more distal in the ALLs

than in the BLs. Thus, the minimally gained segment

was larger in the ALLs (57.4 Mb) than in the BLs

(35 Mb), corresponding to dup(1)(q22q32.3) and

dup(1)(q12q25.2), respectively.

Prognosis

The presence of dup(1q) has no effect on the

outcome of ALL patients with high hyperdiploidy

(Paulsson et al, 2013). It is unclear yet whether the

presence of balanced or unbalanced

t(1;19)(q23;p13.3) in ALLs has an effect on the

prognosis.

Genes involved and proteins Note

The molecular characterization of dup(1q) in ALL is

not well-defined and very limited data is available.

However, the unbalanced nature of dup(1q) suggests

that gene dosage effect is likely contribute to the

neoplastic process. Nevertheless, gene expression

profile revealed that five genes, DAP3, B4GALT3,

UCK2, RGS16 and TMEM183A were significantly

up-regulated in high hyperdiploid ALL carrying

dup(1q) compared to those without dup(1q). DAP3

and UCK2 genes were among the highly expressed

in BL with gain of 1q (Davidsson et al 2007).

DAP3 (death associated protein 3)

Location

1q22

Note

Alternative symbol MRPS29 (mitochondrial

ribosomal protein S29).

Protein

DAP3 gene is transcribed into a 1.7-kb mRNA and

translates into a 46 kDa protein located in the lower

area of the small mitoribosomal subunit. This protein

contains a P-loop motif that binds GTP and a highly

conserved 17-residue targeting sequence responsible

for its localization to the mitochondria. Many of the

phosphorylation sites on this protein are highly

conserved and clustered around GTP-binding motifs.

DAP3 forms an important portion of the a 28S

subunit protein of the mitochondrial ribosome and

plays key roles in translation, cellular respiration,

and apoptosis. The protein is normally reserved

inactive as phosphoprotein. When activated, it co-

localizes with FADD and participates in the

formation of the death inducing signaling complex

(DISC). Recent studies suggests that DAP3 is

strongly associated with the Fas receptor related

DISC. It is presumed that DAP3 may have tumor

suppressant role predicated by its function as a pro-

apoptotic molecule. Counterintuitively, DAP3 has a

pro-survival role in mitochondrial function. The

current literature places DAP3 at the link of several

highly significant and occasionally antagonistic

pathways (Kissil JL et al 1995, 1998).

There is limited literature with regards to DAP3 role

in cancer. Studies have demonstrated low DAP3

expression in various tumors such as B-cell

lymphoma, lung cancer, head and neck cancer ,

breast cancer, gastric cancer, and colorectal

carcinoma, possibly due to hypermethylation of the

gene's promoter (Wazir U et al, 2015). In breast

cancer it has been demonstrated that this gene may

have a tumor suppressor function through promoting

apoptosis and could act as a useful prognostic

indicator in breast cancer (Wazir U et al, 2012).

Moreover, DAP3 expression has been positively

correlated with improved cancer prognosis,

indicating that the protein combats cancer

progression through its proapoptotic function. As a

result, DAP3 could serve as a potential biomarker to

dup(1q) in ALL


monitor the effectiveness of therapeutic treatments

(Wazir et al, 2015). However, Mariani et al. found

an upregulated expression of DAP3 in glioblastoma

multiforme and in glioma cell lines with induced

migratory phenotype. These observations can be

explained by the fact that P-loop mutant DAP3 is less

effective in inducing apoptosis, and the COOH-

terminal deleted protein (230 amino acids) acts in a

dominant negative fashion, protecting cells from

induced apoptosis (Mariani et al, 2001).

Furthermore, such findings could reflect a different

balance between the mitochondrial maintenance and

the pro-apoptotic functions of the DAP3 levels in

glioma.

B4GALT3 (beta-1,4-galactosyltransferase 3)

Location

1q23.3

Protein

B4GALT3 gene encodes an enzyme belongs to the

family of B4GALTs, which catalyzes the

biosynthesis of poly-N-acetyllactosamines.

B4GALTs transfer galactose from uridine

diphosphate galactose to N-acetylglucosamine

(GlcNAc)-terminated oligosaccharides to form N-

acetyllactosamine. The B4GALT family consists of

seven members with different tissue distributions,

acceptor preferences and enzyme activities. Among

its related pathways are transport to the Golgi and

subsequent modification and metabolism. In

colorectal carcinoma (CRC), the expression of

B4GALT3 is negatively correlated with poorly

differentiated histology, advanced stages and

metastasis. It has shown that B4GALT3 may

function as a metastasis suppressor in CRC through

modulating β1 integrin glycosylation and activation

(Chen et al 2014).

UCK2 (uridine-cytidine kinase 2)

Location

1q24.1

DNA/RNA

UCK2 gene contains 7 exons and spans over 19 kb

Protein

It encodes a 261 amino-acid protein with a predicted

molecular mass of 29 kDa. It is an enzyme, catalyzes

the phosphorylation of uridine and cytidine to

uridine monophosphate (UMP) and cytidine

monophosphate (CMP), respectively. UCK2 has

only been detected in human placental tissue and

overexpressed in various tumor cells, including

neuroblastoma. Recent studies suggest that UCK2

could be used as a selective target for chemotherapy

delivery in neuroblastoma cells expressing this

specific isoform of UCK while sparing normal

tissues (van Kuilenburg and Meinsma 2016).

RGS16 (regulator of G protein signaling 16)

Location

1q25.3

Protein

This gene encodes protein belongs to the 'regulator

of G protein signaling' family. It inhibits signal

transduction by increasing the GTPase activity of G

protein alpha subunits. Also it may play a role in

regulating the kinetics of signaling in the

phototransduction cascade. The RGS family,

comprising 22 homologues of proteins, plays a role

in cellular proliferation, differentiation, membrane

trafficking, and embryonic development through the

involvement of the mitogen-activated protein kinase

signalling pathway. The activity and specificity of

Rgs16 protein are regulated through

phosphorylation, in which several oncogenes are

involved, by modulating the phosphorylation on a

tyrosine residue in the RGS box. Previous studies

showed that RGS16 is overexpressed in high

hyperdiploid ALL and several other cancers such as

CRC. Patients with RGS16 high-expression had a

poorer overall survival rate than patients with low-

expression suggesting that RGS16 is useful as a

predictive marker for patient prognosis of CRC

(Miyoshi et al 2009).

TMEM183A (transmembrane protein 183A)

Location

1q32.1

Note

Also known C1orf37 DNA/RNA The TMEM183A is the parental gene of

TMEM138B, which is a young gene derived through

retroposition after the divergence of human and

chimpanzee. There are only 6 nucleotide changes in

the coding region between TMEM183A and

TMEM183B genes (Yu et al 2006).

References Chen CH, Wang SH, Liu CH, Wu YL, Wang WJ, Huang J, Hung JS, Lai IR, Liang JT, Huang MC. β-1,4-Galactosyltransferase III suppresses β1 integrin-mediated invasive phenotypes and negatively correlates with metastasis in colorectal cancer. Carcinogenesis. 2014 Jun;35(6):1258-66

Davidsson J, Andersson A, Paulsson K, Heidenblad M, Isaksson M, Borg A, Heldrup J, Behrendtz M, Panagopoulos I, Fioretos T, Johansson B. Tiling resolution array comparative genomic hybridization, expression and methylation analyses of dup(1q) in Burkitt lymphomas and pediatric high hyperdiploid acute lymphoblastic leukemias reveal clustered near-centromeric breakpoints and overexpression of genes in 1q22-32.3. Hum Mol Genet. 2007 Sep 15;16(18):2215-25

Kissil JL, Deiss LP, Bayewitch M, Raveh T, Khaspekov G, Kimchi A. Isolation of DAP3, a novel mediator of interferon-gamma-induced cell death. J Biol Chem. 1995 Nov 17;270(46):27932-6

dup(1q) in ALL


Kissil JL, Kimchi A. Death-associated proteins: from gene identification to the analysis of their apoptotic and tumour suppressive functions. Mol Med Today. 1998 Jun;4(6):268-74

Mariani L, Beaudry C, McDonough WS, Hoelzinger DB, Kaczmarek E, Ponce F, Coons SW, Giese A, Seiler RW, Berens ME. Death-associated protein 3 (Dap-3) is overexpressed in invasive glioblastoma cells in vivo and in glioma cell lines with induced motility phenotype in vitro. Clin Cancer Res. 2001 Aug;7(8):2480-9

Miyoshi N, Ishii H, Sekimoto M, Doki Y, Mori M. RGS16 is a marker for prognosis in colorectal cancer. Ann Surg Oncol. 2009 Dec;16(12):3507-14

Paulsson K, Forestier E, Andersen MK, Autio K, Barbany G, Borgström G, Cavelier L, Golovleva I, Heim S, Heinonen K, Hovland R, Johannsson JH, Kjeldsen E, Nordgren A, Palmqvist L, Johansson B. High modal number and triple trisomies are highly correlated favorable factors in childhood B-cell precursor high hyperdiploid acute lymphoblastic leukemia treated according to the NOPHO ALL 1992/2000 protocols. Haematologica. 2013 Sep;98(9):1424-32

Wazir U, Jiang WG, Sharma AK, Mokbel K. The mRNA expression of DAP3 in human breast cancer: correlation with clinicopathological parameters. Anticancer Res. 2012 Feb;32(2):671-4

Wazir U, Orakzai MM, Khanzada ZS, Jiang WG, Sharma AK, Kasem A, Mokbel K. The role of death-associated protein 3 in apoptosis, anoikis and human cancer. Cancer Cell Int. 2015;15:39

Yu H, Jiang H, Zhou Q, Yang J, Cun Y, Su B, Xiao C, Wang W. Origination and evolution of a human-specific transmembrane protein gene, c1orf37-dup. Hum Mol Genet. 2006 Jun 1;15(11):1870-5

van Kuilenburg AB, Meinsma R. The pivotal role of uridine-cytidine kinases in pyrimidine metabolism and activation of cytotoxic nucleoside analogues in neuroblastoma. Biochim Biophys Acta. 2016 Sep;1862(9):1504-12


Mohamed AN. dup(1q) in ALL. Atlas Genet


Solid Tumour Section Short Communication




Kidney: ALK-rearranged renal cell carcinoma Adrian Marino-Enriquez

Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA USA;

[email protected]

Published in Atlas Database: February 2017

Online updated version : http://AtlasGeneticsOncology.org/Tumors/ALKrenalCellCarcID6279.html

Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/68916/02-2017-ALKrenalCellCarcID6279.pdf DOI: 10.4267/2042/68916


Abstract Review on ALK-rearranged renal cell carcinoma,

summarizing clinical and genetic data

Keywords

Renal cell carcinoma; ALK; HOOK1; TPM3;

STRN; EML4; VCL

Identity Phylum

Urinary system:Kidney: Renal cell tumors: :ALK-

rearranged renal cell carcinoma

Classification ALK-rearranged renal cell carcinoma is a distinct

type of renal cell carcinoma included in the so-called

emerging/provisional RCC. The 2013 International

Society of Urological Pathology (ISUP) Vancouver

Classification of (adult) renal neoplasia identified a

category of emerging or provisional new entities.

Although these entities appeared to be distinct, these

are rare tumors not fully characterized and additional

reports will be needed to refine their diagnostic

criteria and established clinical outcome.


Disease

ALK-rearranged renal cell carcinoma is a distinct

emerging type of RCC that commonly affects

children and young adults. The disease is defined as

a RCC harboring ALK gene rearrangements,

resulting in oncogenic fusions with a variety of

partner genes.

Epidemiology

ALK-rearranged renal cell carcinoma is an

uncommon type of RCC. Initially described in

children, in which it may be over-represented,

further investigations demonstrated that a small

proportion of adult RCC belong to this ALK-

rearranged category. Of 18 well-documented cases

reported to date, 8 have been described in children

(6-16 yo), and 10 in adults (33-61 yo). An

association with sickle cell trait was observed in the

first cases described, but this association seems

inconsistent and may be limited to cases with a

specific VCL/ALK gene fusion.

Clinics

These form masses in the kidney. The majority of

cases described so far have been confined to the

kidney with a median size of 4.5 cm. Nodal

extension at presentation has been observed; distant

metastases are rare and have been observed more

commonly in adult patients. The clinical course of

ALK-rearranged RCC is frequently indolent,

although rare cases, more frequently in adult

patients, pursue a more aggressive clinical course.

Pathology

Grossly, ALK-rearranged RCC are brown to tan

solid masses that may be well circumscribed or

Kidney: ALK-rearranged renal cell carcinoma


infiltrative, usually located centrally with extension

into the renal pelvis. Histologically, the tumors most

commonly feature a solid architecture, with

occasional trabecular and tubular features, and are

composed of sheets of epithelioid cells with

abundant palely eosinophilic cytoplasm and frequent

intracytoplasmic lumina. Cell nuclei show high-

grade features, with vesicular chromatin and

prominent nucleoli -usually ISUP grade 3, but

occasionally ISUP grade 4. Rhabdoid morphology or

intracytoplasmic inclusions may be focally present.

There is a prominent capillary network. Less

frequently, ALK-rearranged RCC may show a

predominantly papillary architecture, mucin

deposition and focal psammomatous calcification. It

is unclear if some of this features correlate with

specific fusion partners. Immunohistochemically,

the tumor cells consistently express ALK, CK7,

EMA, and TFE3 (which should not be interpreted as

evidence of TFE3 rearrangement, absent in this

tumor type); nuclear INI1 expression is retained.

Treatment

Treatment: surgical excision. Treatment with ALK

inhibitors has provided clinical benefit in cases with

advanced disease.

Cytogenetics

Cytogenetics Morphological

ALK Gene Fusions in renal cell carcinoma (RCC)

Neoplasm Fusion Age Range (years) (n)

ALK-rearranged RCC t(2;10)(p23;q22) VCL/ALK 6-16 (3)

ALK-rearranged RCC t(1;2)(q25;p23) TPM3/ALK 12-49 (7)

ALK-rearranged RCC inv(2)(p22p23) STRN/ALK 33,38 (2)

ALK-rearranged RCC inv(2)(p21p23) EML4/ALK 52,53 (2)

ALK-rearranged RCC t(1;2)(p32;p23) HOOK1/ALK 16 (1)

ALK-rearranged RCC ALK/unknown 44-61 (3)


Fusion Protein

Description

ALK-rearranged RCC are characterized by fusion of

the ALK tyrosine kinase gene with one of several

gene partners including VCL, TPM3, STRN, EML4,

and HOOK1 (Table 1). The originally described

translocation in ALK-rearranged RCC was

t(2;10)(p23;q22) which fuses the 5' end of VCL to

the 3' end of ALK. So far, VCL/ALK fusions have

been described only in ALK-rearranged RCC -

interestingly, in 3 tumors affecting pediatric patients

with sickle cell trait. Similarly, HOOK1/ALK fusion

has been identified only in RCC. The TPM3/ALK,

STRN/ALK and EML4/ALK gene fusions,

however, are similar to those found in other tumor

types such as inflammatory myofibroblastic

sarcoma, thyroid carcinoma and lung

adenocarcinoma. All of these ALK gene fusions

result in oncogenic proteins that include the kinase

domain of ALK, fused to structural protein motifs

that enable direct or indirect oligomerization. The

ALK fusion partners also contribute active

promoters that lead to strong expression of ALK,

which can be detected by immunohistochemistry.

References Cajaiba MM, Jennings LJ, George D, Perlman EJ. Expanding the spectrum of ALK-rearranged renal cell carcinomas in children: Identification of a novel HOOK1-ALK fusion transcript. Genes Chromosomes Cancer. 2016 Oct;55(10):814-7

Chen YB, Xu J, Skanderup AJ, Dong Y, Brannon AR, Wang L, Won HH, Wang PI, Nanjangud GJ, Jungbluth AA, Li W, Ojeda V, Hakimi AA, Voss MH, Schultz N, Motzer RJ, Russo P, Cheng EH, Giancotti FG, Lee W, Berger MF, Tickoo SK, Reuter VE, Hsieh JJ. Molecular analysis of aggressive renal cell carcinoma with unclassified histology reveals distinct subsets. Nat Commun. 2016 Oct 7;7:13131

Debelenko LV, Raimondi SC, Daw N, Shivakumar BR, Huang D, Nelson M, Bridge JA. Renal cell carcinoma with novel VCL-ALK fusion: new representative of ALK-associated tumor spectrum. Mod Pathol. 2011 Mar;24(3):430-42

Jeanneau M, Gregoire V, Desplechain C, Escande F, Tica DP, Aubert S, Leroy X. ALK rearrangements-associated

Kidney: ALK-rearranged renal cell carcinoma


renal cell carcinoma (RCC) with unique pathological features in an adult. Pathol Res Pract. 2016 Nov;212(11):1064-1066

Kusano H, Togashi Y, Akiba J, Moriya F, Baba K, Matsuzaki N, Yuba Y, Shiraishi Y, Kanamaru H, Kuroda N, Sakata S, Takeuchi K, Yano H. Two Cases of Renal Cell Carcinoma Harboring a Novel STRN-ALK Fusion Gene. Am J Surg Pathol. 2016 Jun;40(6):761-9

Lee C, Park JW, Suh JH, Nam KH, Moon KC. ALK-Positive Renal Cell Carcinoma in a Large Series of Consecutively Resected Korean Renal Cell Carcinoma Patients. Korean J Pathol. 2013 Oct;47(5):452-7

Mariño-Enríquez A, Ou WB, Weldon CB, Fletcher JA, Pérez-Atayde AR. ALK rearrangement in sickle cell trait-associated renal medullary carcinoma. Genes Chromosomes Cancer. 2011 Mar;50(3):146-53

Moch, H., Humphrey, P.A., Ulbright, T.M., Reuter, V.E. eds (4th edition);. World Health Organization Classification of Tumours of the Urinary Systems and Male Genital Organs IARC Press, Lyon 2016; 16-17.

Smith NE, Deyrup AT, Mariño-Enriquez A, Fletcher JA, Bridge JA, Illei PB, Netto GJ, Argani P.. VCL-ALK renal cell carcinoma in children with sickle-cell trait: the eighth sickle-cell nephropathy? Am J Surg Pathol. 2014 Jun;38(6):858-63.

Srigley JR, Delahunt B, Eble JN, Egevad L, Epstein JI, Grignon D, Hes O, Moch H, Montironi R, Tickoo SK, Zhou M, Argani P; ISUP Renal Tumor Panel.. The International Society of Urological Pathology (ISUP) Vancouver Classification of Renal Neoplasia.

Sukov WR, Hodge JC, Lohse CM, Akre MK, Leibovich BC, Thompson RH, Cheville JC.. ALK alterations in adult renal cell carcinoma: frequency, clinicopathologic features and outcome in a large series of consecutively treated patients. Mod Pathol. 2012 Nov;25(11):1516-25.

Thorner PS, Shago M, Marrano P, Shaikh F, Somers GR.. TFE3-positive renal cell carcinomas are not always Xp11 translocation carcinomas: Report of a case with a TPM3-ALK translocation. Pathol Res Pract. 2016 Oct;212(10):937-942.

Yu W, Wang Y, Jiang Y, Zhang W, Li Y.. Genetic analysis and clinicopathological features of ALK-rearranged renal cell carcinoma in a large series of resected Chinese renal cell carcinoma patients and literature review. Histopathology. 2017 Feb 15. doi: 10.1111/his.13185.


Marino-Enriquez A. Kidney: ALK-rearranged

renal cell carcinoma. Atlas Genet Cytogenet

Oncol Haematol. 2018; 22(6):260-262.





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