Atlas of Genetics and Cytogenetics

in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS

Gene Section Review

SHC1 (SHC (Src homology 2 domain containing) transforming 1) Lucilla Luzi, Enrica Migliaccio, Pier Giuseppe Pelicci IFOM, FIRC Institute for Molecular Oncology Foundation, Via Adamello 16, 20139 Milano, Italy (LL); EIO, European Institute of Oncology, Via Ripamonti 435, 20141 Milano, Italy (EM, PGP)

Published in Atlas Database: February 2009 Online updated version: http://AtlasGeneticsOncology.org/Genes/SHC1ID42287ch1q21.html DOI: 10.4267/2042/44662 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Identity DNA/RNA Other names: FLJ26504; OTTHUMP00000035409 Description OTTHUMP00000035471; SHC; SHCA; p66 SHC1 covers 12,066 bp of DNA on q21.3 arm of HGNC (Hugo): SHC1 chr1 and counts 13 exons and 13 introns. Location: 1q21.3 Transcription Note SHC1 locus produces two distinct transcripts directed SHC1 is the first discovered and the most studied from alternative promoters; altogether they encode for member of the Shc signal transducer protein family. three overlapping protein isoforms of 66, 52, and 46 The other three members of the Shc-family are SHC2 kDa thus called p66Shc, p52Shc and p46Shc. The first (also known as SLI, SHCB or SCK), SHC3 (RAI, transcript (NM_003029) is 3,076 bp long and SHCC or N-SHC) and SHC4 (RALP or SHCD). Unlike specifically encodes for the p52 and p46 forms from SHC1, that is ubiquitously expressed, the other Shc two different in-frame ATGs and derives from the paralogous show restricted expression pattern. In splicing of the first non-coding exon to an internal site general Shc function as phosphotyrosine of the second exon; this process produces the skipping adaptor molecules in various receptor-mediated of the sequence that encodes for the longest p66Shc signaling pathways and each member seems to be isoform. The second transcript (NM_183001 and specialized to contribute in different manner to critical BX647149) is 3,497 bp long, it is transcribed starting cellular functions such as proliferation, survival, from the beginning of the second exon, under the regulation of oxidative stress, tissue morphogenesis, regulation of a different promoter and it encodes for all cell migration and . Moreover in murine three p66, p52 and p46Shc isoforms by means of models, a genetic deficiency of the p66 (Shc) (the alternative ATGs usage. longest isoform of SHC1 gene products) extends life span by 30% and confers resistance to oxidative stress.

Mapping of SHC1 gene on genomic context of the human 1.

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(1) 52 SHC1 (SHC (Src homology 2 domain containing) transforming protein 1) Luzi L, et al.

SHC1 locus organization and alternative splicing isoforms. Dark blue boxes correspond to CDS; light blue portions represent 5' and 3' UTR respectively; red triangles point to the first ATG codon of p66, p52 and p46 isoforms in that order.

Pseudogene supporting different pathways in tissue morphogenesis. The p66Shc specific CH2 region does not become Two possible processed pseudogenes of SHC1 are tyrosine phosphorylated, but gets phosphorylation on located on chrX and chr17. serine 36 (S36) upon oxidative stress; Tetradecanoylphorbol-13-acetate (TPA) induces Protein phosphorylation both of Ser 36 and Ser 138 of p66Shc. Description A new functional region, the "redox centre", responsible for cytochrome c binding, has been recently Regardless of their high structural similarity, a growing characterized within the p66Shc CH2-PTB domains. It bunch of experimental evidences suggests that the has been mapped within a portion that presents the p66Shc and p52/p46Shc isoforms are functionally non- highest degree of identity in sequence alignments of redundant. P66, p52 and p46Shc consist of 583, 474 p66Shc vertebrate orthologous and it is essential for the and 428 aa, respectively. All the three SHC1 protein p66Shc function in ROS regulation. This region isoforms share the same basic modular organization: (designated CB, for cytochrome c binding) contains they contain two different phosphotyrosine-binding three glutamic acid (E125, E132, E133) and two domains, namely a PTB domain in the amino-terminal tryptophan (W134 and W148) conserved residues. and a SH2 in the carboxy-terminal, separated by a poorly characteri-zed glycine/proline-rich region rather Expression similar to the collagen protein and therefore called p52/p46Shc are widely expressed in cultured cell and in Collagen Homology domain 1, CH1. In vitro almost all adult mouse tissues with an invariable experiments suggest that the "proline rich motif" found relative amount; p66Shc protein instead shows a more in the CH1 domain might be responsible for the peculiar pattern since it is expressed in the most of cells interaction between p52Shc and the SH3 domain of except in the hematopoietic lineage, where it is absent SRC, LYN, FYN cytoplasmic tyrosine kinases, but the or barely recognizable. During early rat embryonic functional role of this interaction is still unclear and development SHC1 is most significantly expressed in there are no genetic or biochemical evidences that these the endothelium, in mesenchymal cells of the proteins interact in vivo. The longest p66Shc isoform cardiovascular system and in the forebrain's area of contains a supplementary amino-terminal active proliferation of immature neuroblasts. In glycine/proline-rich region, called CH2. The N-term postnatal and adult rat brain, SHC1 mRNAs and PTB and C-term SH2 modularity is an exclusive proteins are not expressed. In the adult olfactory feature of the Shc protein family. Both PTB and SH2 epithelium, in which neuronal cell renewal occurs domains bind to phosphorylated tyrosines within throughout life, SHC1 remained strongly expressed. In specific, short peptide sequences: amino-terminal both human and murine adult tissues, p52Shc and residues immediately adjacent to the pY confer p46Shc (mRNA and proteins) are ubiquitously specificity on PTB domain; conversely carboxy- expressed, while p66Shc is expressed at different levels terminal amino acids draw specificity for the SH2. The in specific tissues, such as lung, spleen, liver, heart, and CH1 region contains three key tyrosines, Y239, Y240 kidney and is absent in the hematopoietic lineage. and Y317 that become phosphorylated upon The level of p66Shc mRNA is highest in human dermal commitment of a number of cell surface ligand- fibroblasts (DFs) from centenarians in respect to DFs activated receptors. Recently, in murine systems, was from old and young people suggesting that the demonstrated that SHC1 may signal through the CH1 expression of p66Shc increases with age and associates pYs motif both in a dependent and independent manner with human longevity.

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(1) 53 SHC1 (SHC (Src homology 2 domain containing) transforming protein 1) Luzi L, et al.

Modular domain organization of the three SHC1 protein isoforms.

Localisation regulate c-Myc activation in response to IL-3 stimulation but little is known about mechanism and P52Shc proteins is localized on endoplasmic reticulum target affected. membranes and is redistributed after tyrosine kinase Signaling by cell adhesion molecules. The role of receptor activation; p46Shc loca-lizes to the SHC1 in signaling lastly includes the integrin family mitochondrial matrix via a N-terminal mitochondrial and G-protein coupled receptors. Indeed, in endothelial targeting signal. The p66Shc isoform localizes in cells, beside the roles in mediating Receptor Tyrosine different intracellular compartments including Kinases signaling, Shc was recently demonstrated endoplasmic reticulum and mitochondria. contribu-ting to sense shear stress, which is the Function mechanical force generated by the blood fluid moving P52/p46Shc and the p66Shc proteins carry out very along the vascular endothelium. SHC1 exerts a role in different cellular roles, therefore p52/p46Shc and all mechanisms described to be responsible for the p66Shc functions are individually described. mechano-transduction signa-ling that are TRK P52/p46Shc pathways, cell matrix adhesion through integrins Ras regulation. Upon growth factor stimulation binding and cell-cell adhesion by interaction with p56Shc physically associate with the activated receptor cadherins in adherent junctions. tyrosine kinases via the SH2 domain and become Cytoskeleton Organization. MEFs lacking rapidly and efficiently tyrosine-phosphorylated in three p52/p46Shc exhibit defective cytoskeletal organization major tyrosine residues present in the CH1 domain and reduced ERK activation when plated on fibronectin (Y239/240, Y317). Tyrosine phosphorylation mediates (an extracellular matrix protein), a defect that is interactions with the SH2 domain of the Grb2 adaptor rescued reintroducing p52/p46Shc. protein that is constitutively complexed with Sos, an Animal model. SHC1 knock-out is embryonic lethal, ubiqui-tously expressed Ras guanine nucleotide infact SHC1 mutants die by E11.5 with evidence of a exchange factor. Recruitment of the Grb2/Sos complex gross cardiovas-cular defect. by phosphorylated p52/p46Shc proteins results in the P66Shc membrane relocalization of Sos, an event considered Negative regulation of growth factors signaling. In sufficient to induce Ras activation. contrast to p52Shc, overexpression of p66Shc is Growth factors signaling and survival. P52/p46Shc incapable of trans-forming mouse fibroblasts, does not has been shown to function in signaling of many induce MAPK activation and has a negative effect on receptors that are them-selves tyrosine kinases, such the FOS promoter in an a transactivation assay. those for epidermal growth factor (EGF), Insulin (I), ROS production. P66Shc is involved in the platelet growth factor (PDGF), nerve growth factor intracellular path-way(s) that regulates reactive oxygen (NGF), hepatocyte growth factor/scatter factor species (ROS) metabo-lism and apoptosis. For this (HGF/SF and ErbB2, but it also signals on receptors function, p66Shc uses reducing equivalents of the associated with cytoplasmic tyrosine kinases such as mitochondrial electron-transfer chain through the direct the antigen T and B cell receptors, and those for the oxidation of cyto-chrome c forming hydrogen peroxide Stem cell factor (SCF) otherwise known as KIT ligand that in turn induces mitochondrial permeability pore or Steel factor (SLF), granulo-cyte macrophage colony- opening and apoptosis. stimula-ting factor (GM-CSF), erythro-poietin (EPO) Animal model. P66Shc is a genetic determinant of life and interleukin IL-2, IL-3, IL-5. In particular, in the span in mammals, as its deletion in mice (p66Shc-/-) interleukin receptors signaling, SHC1, binding to the results in retarded aging, decreased inci-dence of aging- Grb2-Gab2 complex, also has an essential role in the associated diseases, such as atherosclerosis, and PI-3K/Akt pathway. It was reported that Shc could prolonged life span. p66Shc-generated ROS is implicated in regulation of insulin

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(1) 54 SHC1 (SHC (Src homology 2 domain containing) transforming protein 1) Luzi L, et al.

Schematic description of different contribution of SHC1 proteins in survival and apoptosis. Upon growth factor (GF) stimulation p52Shc binds to activated receptor (RTKs) becomes phosphorylated and binds to Grb2-Sos complex. The translocation of Grab2/SOS complex from the cytosol to the cellular membrane induces Ras activation that in turn leads to MAP kinase/Erk pathway triggering that finally regulates cell proliferation and/or differentiation. Pro-apoptotic signals, instead, induce p66Shc release from a putative inhibitory complex (Tim -Tom mitochondrial import complex) on mitochondria. Activated p66Shc then reduces cytochrome c and generates hydrogen peroxide (H2O2) that leads to permeability transition pore (PTP) opening, mitochondrial swelling, cytochrome c release, caspase activation and apoptosis. signaling in the fat tissue, suggesting that intracellular same polymorphism in SHC1 was associated with oxidative stress might accelerate aging by favoring fat longevity. deposition and increasing the incidence and penetrance of fat-related disorders. Implicated in Homology Cancers (indirect) P52Shc protein is highly conserved during evolution Note accounting homologues already in worms and insects; P52/p46 proteins are implicated in cell proliferation the longest isoform, p66Shc seems to represent a later and carcinogenesis. The p52Shc and p46Shc isoforms specialization of the protein being arisen later in the of Shc are overexpressed or hyper-phosphorylated in evolution, infact the first organisms where it can be many tumor types where known Tyrosine kinases found are fishes. Receptors are constitutively activated. Recently was demonstrated that SHC1 is a crucial Mutations determinant of the Neu/ErbB-2 -TGFb cooperation Note signaling that promotes breast cancer cell motility and The SHC1 gene's polymorphisms known in the coding invasion. region correspond to Met225Val in the p46 isoform, The involvement of p66Shc in tumorigenesis is still Met300Val in the p52 isoform and to Met410Val in the controversial. Altered levels of p66Shc were reported p66 isoform. This polymorphism has been associated to be found in some tumors but the results seem with a significantly decreased risk for breast cancer, contradictory. In the breast cancer cells and primary strongly in women diagnosed below the age of 50. The tumors p66Shc was described to be both over-

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expressed and down-regulated. Indeed the ablation of recruitment of Shc/Grb2 and association with the cytoskeleton p66Shc does not increase spontaneous or induced of hemidesmosomes. EMBO J. 1995 Sep 15;14(18):4470-81 tumor incidence in mice. P66Shc adaptor protein may Pelicci G, Lanfrancone L, Salcini AE, Romano A, Mele S, have a potential implication in the pathophysiology of Grazia Borrello M, Segatto O, Di Fiore PP, Pelicci PG. Constitutive phosphorylation of Shc proteins in human tumors. aging. Oncogene. 1995 Sep 7;11(5):899-907

Zhou MM, Ravichandran KS, Olejniczak EF, Petros AM, Constitutively Constitutively Human tumor cell Meadows RP, Sattler M, Harlan JE, Wade WS, Burakoff SJ, activated activated Fesik SW. Structure and ligand recognition of the lines p52Shc receptor phosphotyrosine binding domain of Shc. Nature. 1995 Dec 7;378(6557):584-92 Vulval carcinoma, Bonfini L, Migliaccio E, Pelicci G, Lanfrancone L, Pelicci PG. Bladder carcinoma, EGFR Not all Shc's roads lead to Ras. Trends Biochem Sci. 1996 Neuroblastoma Jul;21(7):257-61 Hepatocarcinoma Lotti LV, Lanfrancone L, Migliaccio E, Zompetta C, Pelicci G, Salcini AE, Falini B, Pelicci PG, Torrisi MR. Sch proteins are Stomach carcinoma Met localized on endoplasmic reticulum membranes and are Lung carcinoma ErbB2 redistributed after tyrosine kinase receptor activation. Mol Cell Biol. 1996 May;16(5):1946-54 Chronic myeloid Bcr- Leukaemia Pelicci G, Dente L, De Giuseppe A, Verducci-Galletti B, Giuli S, Mele S, Vetriani C, Giorgio M, Pandolfi PP, Cesareni G, Pelicci

Thyroid carcinoma Ret PG. A family of Shc related proteins with conserved PTB, CH1 and SH2 regions. Oncogene. 1996 Aug 1;13(3):633-41

Pancreatic carcinoma PDGFR Wary KK, Mainiero F, Isakoff SJ, Marcantonio EE, Giancotti

FG. The adaptor protein Shc couples a class of integrins to the References control of cell cycle progression. Cell. 1996 Nov 15;87(4):733- 43 Pelicci G, Lanfrancone L, Grignani F, McGlade J, Cavallo F, Forni G, Nicoletti I, Grignani F, Pawson T, Pelicci PG. A novel Migliaccio E, Mele S, Salcini AE, Pelicci G, Lai KM, Superti- transforming protein (SHC) with an SH2 domain is implicated Furga G, Pawson T, Di Fiore PP, Lanfrancone L, Pelicci PG. in mitogenic signal transduction. Cell. 1992 Jul 10;70(1):93-104 Opposite effects of the p52shc/p46shc and p66shc splicing isoforms on the EGF receptor-MAP kinase-fos signalling Rozakis-Adcock M, McGlade J, Mbamalu G, Pelicci G, Daly R, pathway. EMBO J. 1997 Feb 17;16(4):706-16 Li W, Batzer A, Thomas S, Brugge J, Pelicci PG. Association of the Shc and Grb2/Sem5 SH2-containing proteins is Okada S, Kao AW, Ceresa BP, Blaikie P, Margolis B, Pessin implicated in activation of the Ras pathway by tyrosine kinases. JE. The 66-kDa Shc isoform is a negative regulator of the Nature. 1992 Dec 17;360(6405):689-92 epidermal growth factor-stimulated mitogen-activated protein kinase pathway. J Biol Chem. 1997 Oct 31;272(44):28042-9 Egan SE, Giddings BW, Brooks MW, Buday L, Sizeland AM, Weinberg RA. Association of Sos Ras exchange protein with Wary KK, Mariotti A, Zurzolo C, Giancotti FG. A requirement Grb2 is implicated in tyrosine kinase signal transduction and for caveolin-1 and associated kinase Fyn in integrin signaling transformation. Nature. 1993 May 6;363(6424):45-51 and anchorage-dependent cell growth. Cell. 1998 Sep 4;94(5):625-34 Ravichandran KS, Lee KK, Songyang Z, Cantley LC, Burn P, Burakoff SJ. Interaction of Shc with the zeta chain of the T cell Chen KD, Li YS, Kim M, Li S, Yuan S, Chien S, Shyy JY. receptor upon T cell activation. Science. 1993 Nov Mechanotransduction in response to shear stress. Roles of 5;262(5135):902-5 receptor tyrosine kinases, integrins, and Shc. J Biol Chem. 1999 Jun 25;274(26):18393-400 Sato N, Sakamaki K, Terada N, Arai K, Miyajima A. Signal transduction by the high-affinity GM-CSF receptor: two distinct Migliaccio E, Giorgio M, Mele S, Pelicci G, Reboldi P, Pandolfi cytoplasmic regions of the common beta subunit responsible PP, Lanfrancone L, Pelicci PG. The p66shc adaptor protein for different signaling. EMBO J. 1993 Nov;12(11):4181-9 controls oxidative stress response and life span in mammals. Nature. 1999 Nov 18;402(6759):309-13 Segatto O, Pelicci G, Giuli S, Digiesi G, Di Fiore PP, McGlade J, Pawson T, Pelicci PG. Shc products are substrates of erbB- Lai KM, Pawson T. The ShcA phosphotyrosine docking protein 2 kinase. Oncogene. 1993 Aug;8(8):2105-12 sensitizes cardiovascular signaling in the mouse embryo. Genes Dev. 2000 May 1;14(9):1132-45 Skolnik EY, Batzer A, Li N, Lee CH, Lowenstein E, Mohammadi M, Margolis B, Schlessinger J. The function of Luzi L, Confalonieri S, Di Fiore PP, Pelicci PG. Evolution of GRB2 in linking the insulin receptor to Ras signaling pathways. Shc functions from nematode to human. Curr Opin Genet Dev. Science. 1993 Jun 25;260(5116):1953-5 2000 Dec;10(6):668-74 Weng Z, Thomas SM, Rickles RJ, Taylor JA, Brauer AW, Conti L, Sipione S, Magrassi L, Bonfanti L, Rigamonti D, Seidel-Dugan C, Michael WM, Dreyfuss G, Brugge JS. Pettirossi V, Peschanski M, Haddad B, Pelicci P, Milanesi G, Identification of Src, Fyn, and Lyn SH3-binding proteins: Pelicci G, Cattaneo E. Shc signaling in differentiating neural implications for a function of SH3 domains. Mol Cell Biol. 1994 progenitor cells. Nat Neurosci. 2001 Jun;4(6):579-86 Jul;14(7):4509-21 Faisal A, el-Shemerly M, Hess D, Nagamine Y. Mainiero F, Pepe A, Wary KK, Spinardi L, Mohammadi M, Serine/threonine phosphorylation of ShcA. Regulation of Schlessinger J, Giancotti FG. Signal transduction by the alpha protein-tyrosine phosphatase-pest binding and involvement in 6 beta 4 integrin: distinct beta 4 subunit sites mediate insulin signaling. J Biol Chem. 2002 Aug 16;277(33):30144-52

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Pelicci G, Troglio F, Bodini A, Melillo RM, Pettirossi V, Coda L, Trinei M, Berniakovich I, Pelicci PG, Giorgio M. Mitochondrial De Giuseppe A, Santoro M, Pelicci PG. The neuron-specific DNA copy number is regulated by cellular proliferation: a role Rai (ShcC) adaptor protein inhibits apoptosis by coupling Ret for Ras and p66(Shc). Biochim Biophys Acta. 2006 May- to the phosphatidylinositol 3-kinase/Akt signaling pathway. Mol Jun;1757(5-6):624-30 Cell Biol. 2002 Oct;22(20):7351-63 Fagiani E, Giardina G, Luzi L, Cesaroni M, Quarto M, Capra M, Ventura A, Luzi L, Pacini S, Baldari CT, Pelicci PG. The Germano G, Bono M, Capillo M, Pelicci P, Lanfrancone L. p66Shc longevity gene is silenced through epigenetic RaLP, a new member of the Src homology and collagen family, modifications of an alternative promoter. J Biol Chem. 2002 regulates cell migration and tumor growth of metastatic Jun 21;277(25):22370-6 melanomas. Cancer Res. 2007 Apr 1;67(7):3064-73 Mooijaart SP, van Heemst D, Schreuder J, van Gerwen S, Hardy WR, Li L, Wang Z, Sedy J, Fawcett J, Frank E, Kucera Beekman M, Brandt BW, Eline Slagboom P, Westendorp RG. J, Pawson T. Combinatorial ShcA docking interactions support Variation in the SHC1 gene and longevity in humans. Exp diversity in tissue morphogenesis. Science. 2007 Jul Gerontol. 2004 Feb;39(2):263-8 13;317(5835):251-6 Orsini F, Migliaccio E, Moroni M, Contursi C, Raker VA, Piccini Jones N, Hardy WR, Friese MB, Jorgensen C, Smith MJ, D, Martin-Padura I, Pelliccia G, Trinei M, Bono M, Puri C, Woody NM, Burden SJ, Pawson T. Analysis of a Shc family Tacchetti C, Ferrini M, Mannucci R, Nicoletti I, Lanfrancone L, adaptor protein, ShcD/Shc4, that associates with muscle- Giorgio M, Pelicci PG. The life span determinant p66Shc specific kinase. Mol Cell Biol. 2007 Jul;27(13):4759-73 localizes to mitochondria where it associates with mitochondrial heat shock protein 70 and regulates trans- Berniakovich I, Trinei M, Stendardo M, Migliaccio E, Minucci S, membrane potential. J Biol Chem. 2004 Jun 11;279(24):25689- Bernardi P, Pelicci PG, Giorgio M. p66Shc-generated oxidative 95 signal promotes fat accumulation. J Biol Chem. 2008 Dec 5;283(49):34283-93 Wagner K, Hemminki K, Grzybowska E, Klaes R, Butkiewicz D, Pamula J, Pekala W, Zientek H, Mielzynska D, Siwinska E, Liu Y, Sweet DT, Irani-Tehrani M, Maeda N, Tzima E. Shc Försti A. The insulin-like growth factor-1 pathway mediator coordinates signals from intercellular junctions and integrins to genes: SHC1 Met300Val shows a protective effect in breast regulate flow-induced inflammation. J Cell Biol. 2008 Jul cancer. Carcinogenesis. 2004 Dec;25(12):2473-8 14;182(1):185-96 Yukimasa S, Masaki T, Yoshida S, Uchida N, Watanabe S, Northey JJ, Chmielecki J, Ngan E, Russo C, Annis MG, Muller Usuki H, Yoshiji H, Maeta T, Ebara K, Nakatsu T, Kurokohchi WJ, Siegel PM. Signaling through ShcA is required for K, Kuriyama S. Enhanced expression of p46 Shc in the transforming growth factor beta- and Neu/ErbB-2-induced nucleus and p52 Shc in the cytoplasm of human gastric breast cancer cell motility and invasion. Mol Cell Biol. 2008 cancer. Int J Oncol. 2005 Apr;26(4):905-11 May;28(10):3162-76 Migliaccio E, Giorgio M, Pelicci PG. Apoptosis and aging: role Sweet DT, Tzima E. Spatial signaling networks converge at the of p66Shc redox protein. Antioxid Redox Signal. 2006 Mar- adaptor protein Shc. Cell Cycle. 2009 Jan 15;8(2):231-5 Apr;8(3-4):600-8 This article should be referenced as such: Orsini F, Moroni M, Contursi C, Yano M, Pelicci P, Giorgio M, Migliaccio E. Regulatory effects of the mitochondrial energetic Luzi L, Migliaccio E, Pelicci PG. SHC1 (SHC (Src homology 2 status on mitochondrial p66Shc. Biol Chem. 2006 Oct- domain containing) transforming protein 1). Atlas Genet Nov;387(10-11):1405-10 Cytogenet Oncol Haematol. 2010; 14(1):52-57.

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