Hepatosplenic T-cell lymphoma (HSTL) is an aggressive lymphoma cytogenetically characterized by isochromosome 7q [i(7)(q10)], of which the molecular consequences remain unknown. We report here results of an integrative genomic and transcriptomic (expression microarray and RNA-sequencing) study of six i(7)(q10)-positive HSTL cases, including HSTL-derived cell line (DERL-2), and three cases with ring 7 [r(7)], the recently identified rare variant aberration. Using high resolution array CGH, we profiled all cases and mapped the common deleted region (CDR) at 7p22.1p14.1 (34.88 Mb; 3506316-38406226 bp) and the common gained region (CGR) at 7q22.11q31.1 (38.77 Mb; 86259620–124892276 bp). Interestingly, CDR spans a smaller region of 13 Mb (86259620–99271246 bp) constantly amplified in cases with r(7). In addition, we found that TCRG (7p14.1) and TCRB (7q32) are involved in formation of r(7), which seems to be a byproduct of illegitimate somatic rearrangement of both loci. Further transcriptomic analysis has not identified any CDR-related candidate tumor suppressor gene. Instead, loss of 7p22.1p14.1 correlated with an enhanced expression of CHN2 (7p14.1) and the encoded β2-chimerin. Gain and amplification of 7q22.11q31.1 are associated with an increased expression of several genes postulated to be implicated in cancer, including RUNDC3B, PPP1R9A and ABCB1, a known multidrug resistance gene. RNA-sequencing did not identify any disease-defining mutation or gene fusion. Thus, chromosome 7 imbalances remain the only driver events detected in this tumor. We hypothesize that the Δ7p22.1p14.1-associated enhanced expression of CHN2/β2-chimerin leads to downmodulation of the NFAT pathway and a proliferative response, while upregulation of the CGR-related genes provides growth advantage for neoplastic δγT-cells and underlies their intrinsic chemoresistance. Finally, our study confirms the previously described gene expression profile of HSTL and identifies a set of 24 genes, including three located on chromosome 7 (CHN2, ABCB1 and PPP1R9A), distinguishing HSTL from other malignancies.
Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, et al.. (2008) WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: IARC.
[3]
Macon WR, Levy NB, Kurtin PJ, Salhany KE, Elkhalifa MY, et al. (2001) Hepatosplenic alphabeta T-cell lymphomas: a report of 14 cases and comparison with hepatosplenic gammadelta T-cell lymphomas. Am J Surg Pathol 25: 285–296. doi: 10.1097/00000478-200103000-00002
[4]
Suarez F, Wlodarska I, Rigal-Huguet F, Mempel M, Martin-Garcia N, et al. (2000) Hepatosplenic alphabeta T-cell lymphoma: an unusual case with clinical, histologic, and cytogenetic features of gammadelta hepatosplenic T-cell lymphoma. Am J Surg Pathol 24: 1027–1032. doi: 10.1097/00000478-200007000-00016
[5]
Travert M, Huang Y, de Leval L, Martin-Garcia N, Delfau-Larue MH, et al. (2012) Molecular features of hepatosplenic T-cell lymphoma unravels potential novel therapeutic targets. Blood 119: 5795–5806. doi: 10.1182/blood-2011-12-396150
[6]
Gaulard P, Jaffe E, Krenacs L, Macon WR (2008) Hepatosplenic T-cell lymphoma. In: Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, et al.., editors. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: IARC. pp. 292–293.
[7]
Wang CC, Tien HF, Lin MT, Su IJ, Wang CH, et al. (1995) Consistent presence of isochromosome 7q in hepatosplenic T gamma/delta lymphoma: a new cytogenetic-clinicopathologic entity. Genes Chromosomes Cancer 12: 161–164. doi: 10.1002/gcc.2870120302
[8]
Alonsozana EL, Stamberg J, Kumar D, Jaffe ES, Medeiros LJ, et al. (1997) Isochromosome 7q: the primary cytogenetic abnormality in hepatosplenic gammadelta T cell lymphoma. Leukemia 11: 1367–1372. doi: 10.1038/sj.leu.2400742
[9]
Jonveaux P, Daniel MT, Martel V, Maarek O, Berger R (1996) Isochromosome 7q and trisomy 8 are consistent primary, non-random chromosomal abnormalities associated with hepatosplenic T gamma/delta lymphoma. Leukemia 10: 1453–1455.
[10]
Wlodarska I, Martin-Garcia N, Achten R, De Wolf-Peeters C, Pauwels P, et al. (2002) Fluorescence in situ hybridization study of chromosome 7 aberrations in hepatosplenic T-cell lymphoma: isochromosome 7q as a common abnormality accumulating in forms with features of cytologic progression. Genes Chromosomes Cancer 33: 243–251. doi: 10.1002/gcc.10021
[11]
Shetty S, Mansoor A, Roland B (2006) Ring chromosome 7 with amplification of 7q sequences in a pediatric case of hepatosplenic T-cell lymphoma. Cancer Genet Cytogenet 167: 161–163. doi: 10.1016/j.cancergencyto.2005.12.003
[12]
Patkar N, Nair S, Alex AA, Parihar M, Manipadam MT, et al. (2012) Clinicopathological features of hepatosplenic T cell lymphoma: a single centre experience from India. Leuk Lymphoma 53: 609–615. doi: 10.3109/10428194.2011.622421
[13]
Tamaska J, Adam E, Kozma A, Gopcsa L, Andrikovics H, et al. (2006) Hepatosplenic gammadelta T-cell lymphoma with ring chromosome 7, an isochromosome 7q equivalent clonal chromosomal aberration. Virchows Arch 449: 479–483. doi: 10.1007/s00428-006-0267-5
[14]
Mandava S, Sonar R, Ahmad F, Yadav AK, Chheda P, et al. (2011) Cytogenetic and molecular characterization of a hepatosplenic T-cell lymphoma: report of a novel chromosomal aberration. Cancer Genet 204: 103–107. doi: 10.1016/j.cancergencyto.2010.08.021
[15]
Rossbach HC, Chamizo W, Dumont DP, Barbosa JL, Sutcliffe MJ (2002) Hepatosplenic gamma/delta T-cell lymphoma with isochromosome 7q, translocation t(7;21), and tetrasomy 8 in a 9-year-old girl. J Pediatr Hematol Oncol 24: 154–157. doi: 10.1097/00043426-200202000-00020
[16]
Lewi PJ (1976) Spectral mapping, a technique for classifying biological activity profiles of chemical compounds. Arzneimittelforschung 26: 1295–1300.
[17]
Hu J, Ge H, Newman M, Liu K (2012) OSA: a fast and accurate alignment tool for RNA-Seq. Bioinformatics 28: 1933–1934. doi: 10.1093/bioinformatics/bts294
[18]
Anders S, Huber W (2010) Differential expression analysis for sequence count data. Genome Biol 11: R106 gb-2010-11-10-r106 [pii];10.1186/gb-2010-11-10-r106 [doi]. doi: 10.1186/gb-2010-11-10-r106
[19]
Kalender AZ, Gianfelici V, Hulselmans G, De KK, Devasia AG, et al. (2013) Comprehensive analysis of transcriptome variation uncovers known and novel driver events in T-cell acute lymphoblastic leukemia. PLoS Genet 9: e1003997 10.1371/journal.pgen.1003997 [doi];PGENETICS-D-13-01641 [pii]. doi: 10.1371/journal.pgen.1003997
[20]
McPherson A, Hormozdiari F, Zayed A, Giuliany R, Ha G, et al. (2011) deFuse: an algorithm for gene fusion discovery in tumor RNA-Seq data. PLoS Comput Biol 7: e1001138 10.1371/journal.pcbi.1001138 [doi];10-PLCB-RA-2589R4 [pii]. doi: 10.1371/journal.pcbi.1001138
[21]
Ge H, Liu K, Juan T, Fang F, Newman M, et al. (2011) FusionMap: detecting fusion genes from next-generation sequencing data at base-pair resolution. Bioinformatics 27: 1922–1928. doi: 10.1093/bioinformatics/btr310
[22]
Di Noto R, Pane F, Camera A, Luciano L, Barone M, et al. (2001) Characterization of two novel cell lines, DERL-2 (CD56+/CD3+/Tcry5+) and DERL-7 (CD56+/CD3-/TCRgammadelta-), derived from a single patient with CD56+ non-Hodgkin's lymphoma. Leukemia 15: 1641–1649. doi: 10.1038/sj.leu.2402239
[23]
Ivanov I, Lo KC, Hawthorn L, Cowell JK, Ionov Y (2007) Identifying candidate colon cancer tumor suppressor genes using inhibition of nonsense-mediated mRNA decay in colon cancer cells. Oncogene 26: 2873–2884. doi: 10.1038/sj.onc.1210098
[24]
Akazawa T, Yasui K, Gen Y, Yamada N, Tomie A, et al. (2013) Aberrant expression of the gene in biliary tract cancer cells. Oncol Lett 5: 1849–1853. doi: 10.3892/ol.2013.1278
[25]
Kitagawa M, Takebe A, Ono Y, Imai T, Nakao K, et al. (2012) Phf14, a novel regulator of mesenchyme growth via platelet-derived growth factor (PDGF) receptor-alpha1. J Biol Chem 287: 27983–27996. doi: 10.1074/jbc.m112.350074
[26]
Viola JP, Carvalho LD, Fonseca BP, Teixeira LK (2005) NFAT transcription factors: from cell cycle to tumor development. Braz J Med Biol Res 38: 335–344. doi: 10.1590/s0100-879x2005000300003
[27]
Muller MR, Rao A (2010) NFAT, immunity and cancer: a transcription factor comes of age. Nat Rev Immunol 10: 645–656. doi: 10.1038/nri2818
[28]
Mancini M, Toker A (2009) NFAT proteins: emerging roles in cancer progression. Nat Rev Cancer 9: 810–820. doi: 10.1038/nrc2735
[29]
Macian F (2005) NFAT proteins: key regulators of T-cell development and function. Nat Rev Immunol 5: 472–484. doi: 10.1038/nri1632
[30]
Willingham AT, Orth AP, Batalov S, Peters EC, Wen BG, et al. (2005) A strategy for probing the function of noncoding RNAs finds a repressor of NFAT. Science 309: 1570–1573. doi: 10.1126/science.1115901
[31]
Sharma S, Findlay GM, Bandukwala HS, Oberdoerffer S, Baust B, et al. (2011) Dephosphorylation of the nuclear factor of activated T cells (NFAT) transcription factor is regulated by an RNA-protein scaffold complex. Proc Natl Acad Sci U S A 108: 11381–11386. doi: 10.1073/pnas.1019711108
[32]
Jabri B, Barreiro LB (2011) Don't move: LRRK2 arrests NFAT in the cytoplasm. Nat Immunol 12: 1029–1030. doi: 10.1038/ni.2139
[33]
Liu Z, Lee J, Krummey S, Lu W, Cai H, et al. (2011) The kinase LRRK2 is a regulator of the transcription factor NFAT that modulates the severity of inflammatory bowel disease. Nat Immunol 12: 1063–1070. doi: 10.1038/ni.2113
[34]
Racioppi L, Means AR (2008) Calcium/calmodulin-dependent kinase IV in immune and inflammatory responses: novel routes for an ancient traveller. Trends Immunol 29: 600–607. doi: 10.1016/j.it.2008.08.005
[35]
Hanissian SH, Frangakis M, Bland MM, Jawahar S, Chatila TA (1993) Expression of a Ca2+/calmodulin-dependent protein kinase, CaM kinase-Gr, in human T lymphocytes. Regulation of kinase activity by T cell receptor signaling. J Biol Chem 268: 20055–20063.
[36]
Sims TN, Dustin ML (2002) The immunological synapse: integrins take the stage. Immunol Rev 186: 100–117. doi: 10.1034/j.1600-065x.2002.18610.x
[37]
Caloca MJ, Delgado P, Alarcon B, Bustelo XR (2008) Role of chimaerins, a group of Rac-specific GTPase activating proteins, in T-cell receptor signaling. Cell Signal 20: 758–770. doi: 10.1016/j.cellsig.2007.12.015
[38]
Taylor AM (2001) Chromosome instability syndromes. Best Pract Res Clin Haematol 14: 631–644. doi: 10.1053/beha.2001.0158
Van Vlierberghe P, Palomero T, Khiabanian H, Van der Meulen J, Castillo M, et al. (2010) PHF6 mutations in T-cell acute lymphoblastic leukemia. Nat Genet 42: 338–342. doi: 10.1038/ng.542
[41]
Siliceo M, Garcia-Bernal D, Carrasco S, Diaz-Flores E, Coluccio LF, et al. (2006) Beta2-chimaerin provides a diacylglycerol-dependent mechanism for regulation of adhesion and chemotaxis of T cells. J Cell Sci 119: 141–152. doi: 10.1242/jcs.02722
[42]
Siliceo M, Merida I (2009) T cell receptor-dependent tyrosine phosphorylation of beta2-chimaerin modulates its Rac-GAP function in T cells. J Biol Chem 284: 11354–11363. doi: 10.1074/jbc.m806098200
[43]
Deb G, Singh AK, Gupta S (2014) EZH2: Not EZHY (Easy) to Deal. Mol Cancer Res e-pub ahead of print. 1541–7786.MCR-13–0546 [pii];10.1158/1541-7786.MCR-13-0546 [doi].
[44]
Miyazaki K, Yamaguchi M, Imai H, Kobayashi T, Tamaru S, et al. (2009) Gene expression profiling of peripheral T-cell lymphoma including gammadelta T-cell lymphoma. Blood 113: 1071–1074. doi: 10.1182/blood-2008-07-166363
[45]
Gottesman MM, Pastan I, Ambudkar SV (1996) P-glycoprotein and multidrug resistance. Curr Opin Genet Dev 6: 610–617. doi: 10.1016/s0959-437x(96)80091-8
[46]
Szakacs G, Paterson JK, Ludwig JA, Booth-Genthe C, Gottesman MM (2006) Targeting multidrug resistance in cancer. Nat Rev Drug Discov 5: 219–234. doi: 10.1038/nrd1984
[47]
Holohan C, Van SS, Longley DB, Johnston PG (2013) Cancer drug resistance: an evolving paradigm. Nat Rev Cancer 13: 714–726. doi: 10.1038/nrc3599
[48]
Huff LM, Lee JS, Robey RW, Fojo T (2006) Characterization of gene rearrangements leading to activation of MDR-1. J Biol Chem 281: 36501–36509. doi: 10.1074/jbc.m602998200
[49]
Knutsen T, Mickley LA, Ried T, Green ED, du MS, et al. (1998) Cytogenetic and molecular characterization of random chromosomal rearrangements activating the drug resistance gene, MDR1/P-glycoprotein, in drug-selected cell lines and patients with drug refractory ALL. Genes Chromosomes Cancer 23: 44–54. doi: 10.1002/(sici)1098-2264(199809)23:1<44::aid-gcc7>3.0.co;2-6
[50]
Wang YC, Juric D, Francisco B, Yu RX, Duran GE, et al. (2006) Regional activation of chromosomal arm 7q with and without gene amplification in taxane-selected human ovarian cancer cell lines. Genes Chromosomes Cancer 45: 365–374. doi: 10.1002/gcc.20300
[51]
Wang J, Tai LS, Tzang CH, Fong WF, Guan XY, et al. (2008) 1p31, 7q21 and 18q21 chromosomal aberrations and candidate genes in acquired vinblastine resistance of human cervical carcinoma KB cells. Oncol Rep 19: 1155–1164. doi: 10.3892/or.19.5.1155
[52]
Balaguer TM, Gomez-Martinez A, Garcia-Morales P, Lacueva J, Calpena R, et al. (2012) Dual regulation of P-glycoprotein expression by trichostatin A in cancer cell lines. BMC Mol Biol 13: 25 1471-2199-13-25 [pii];10.1186/1471-2199-13-25 [doi]. doi: 10.1186/1471-2199-13-25
[53]
Wang S, Zhang Z, Ying K, Chen JZ, Meng XF, et al. (2003) Cloning, expression, and genomic structure of a novel human Rap2 interacting gene (RPIP9). Biochem Genet 41: 13–25.
[54]
Raguz S, De Bella MT, Slade MJ, Higgins CF, Coombes RC, et al. (2005) Expression of RPIP9 (Rap2 interacting protein 9) is activated in breast carcinoma and correlates with a poor prognosis. Int J Cancer 117: 934–941. doi: 10.1002/ijc.21252
[55]
Nakabayashi K, Makino S, Minagawa S, Smith AC, Bamforth JS, et al. (2004) Genomic imprinting of PPP1R9A encoding neurabin I in skeletal muscle and extra-embryonic tissues. J Med Genet 41: 601–608. doi: 10.1136/jmg.2003.014142
[56]
McCluskey A, Ackland SP, Gardiner E, Walkom CC, Sakoff JA (2001) The inhibition of protein phosphatases 1 and 2A: a new target for rational anti-cancer drug design? Anticancer Drug Des 16: 291–303.
[57]
Ip WK, Lai PB, Wong NL, Sy SM, Beheshti B, et al. (2007) Identification of PEG10 as a progression related biomarker for hepatocellular carcinoma. Cancer Lett 250: 284–291. doi: 10.1016/j.canlet.2006.10.012
[58]
Tsou AP, Chuang YC, Su JY, Yang CW, Liao YL, et al. (2003) Overexpression of a novel imprinted gene, PEG10, in human hepatocellular carcinoma and in regenerating mouse livers. J Biomed Sci 10: 625–635. doi: 10.1007/bf02256313
[59]
Tsuji K, Yasui K, Gen Y, Endo M, Dohi O, et al. (2010) PEG10 is a probable target for the amplification at 7q21 detected in hepatocellular carcinoma. Cancer Genet Cytogenet 198: 118–125. doi: 10.1016/j.cancergencyto.2010.01.004
[60]
Kainz B, Shehata M, Bilban M, Kienle D, Heintel D, et al. (2007) Overexpression of the paternally expressed gene 10 (PEG10) from the imprinted locus on chromosome 7q21 in high-risk B-cell chronic lymphocytic leukemia. Int J Cancer 121: 1984–1993. doi: 10.1002/ijc.22929
[61]
Iqbal J, Weisenburger DD, Chowdhury A, Tsai MY, Srivastava G, et al. (2011) Natural killer cell lymphoma shares strikingly similar molecular features with a group of non-hepatosplenic gammadelta T-cell lymphoma and is highly sensitive to a novel aurora kinase A inhibitor in vitro. Leukemia 25: 348–358. doi: 10.1038/leu.2010.255
[62]
Zheng J, Fang F, Zeng X, Medler TR, Fiorillo AA, et al. (2011) Negative cross talk between NFAT1 and Stat5 signaling in breast cancer. Mol Endocrinol 25: 2054–2064. doi: 10.1210/me.2011-1141
[63]
Robbs BK, Lucena PI, Viola JP (2013) The transcription factor NFAT1 induces apoptosis through cooperation with Ras/Raf/MEK/ERK pathway and upregulation of TNF-alpha expression. Biochim Biophys Acta 1833: 2016–2028. doi: 10.1016/j.bbamcr.2013.04.003
[64]
Daniel C, Gerlach K, Vath M, Neurath MF, Weigmann B (2013) Nuclear factor of activated T cells-A transcription factor family as critical regulator in lung and colon cancer. Int J Cancer. 10.1002/ijc.28329 [doi].
[65]
Mognol GP, de Araujo-Souza PS, Robbs BK, Teixeira LK, Viola JP (2012) Transcriptional regulation of the c-Myc promoter by NFAT1 involves negative and positive NFAT-responsive elements. Cell Cycle 11: 1014–1028. doi: 10.4161/cc.11.5.19518
Robbs BK, Cruz AL, Werneck MB, Mognol GP, Viola JP (2008) Dual roles for NFAT transcription factor genes as oncogenes and tumor suppressors. Mol Cell Biol 28: 7168–7181. doi: 10.1128/mcb.00256-08
[68]
Hodge MR, Ranger AM, Charles dlB, Hoey T, Grusby MJ, Glimcher LH (1996) Hyperproliferation and dysregulation of IL-4 expression in NF-ATp-deficient mice. Immunity 4: 397–405. doi: 10.1016/s1074-7613(00)80253-8
[69]
Caetano MS, Vieira-de-Abreu A, Teixeira LK, Werneck MB, Barcinski MA, et al. (2002) NFATC2 transcription factor regulates cell cycle progression during lymphocyte activation: evidence of its involvement in the control of cyclin gene expression. FASEB J 16: 1940–1942. doi: 10.1096/fj.02-0282fje
[70]
Schuh K, Kneitz B, Heyer J, Bommhardt U, Jankevics E, et al. (1998) Retarded thymic involution and massive germinal center formation in NF-ATp-deficient mice. Eur J Immunol 28: 2456–2466. doi: 10.1002/(sici)1521-4141(199808)28:08<2456::aid-immu2456>3.0.co;2-9
[71]
Xanthoudakis S, Viola JP, Shaw KT, Luo C, Wallace JD, et al. (1996) An enhanced immune response in mice lacking the transcription factor NFAT1. Science 272: 892–895. doi: 10.1126/science.272.5263.892
[72]
Ranger AM, Oukka M, Rengarajan J, Glimcher LH (1998) Inhibitory function of two NFAT family members in lymphoid homeostasis and Th2 development. Immunity 9: 627–635. doi: 10.1016/s1074-7613(00)80660-3
[73]
Ranger AM, Gerstenfeld LC, Wang J, Kon T, Bae H, et al. (2000) The nuclear factor of activated T cells (NFAT) transcription factor NFATp (NFATc2) is a repressor of chondrogenesis. J Exp Med 191: 9–22. doi: 10.1084/jem.191.1.9
[74]
Kondo E, Harashima A, Takabatake T, Takahashi H, Matsuo Y, et al. (2003) NF-ATc2 induces apoptosis in Burkitt's lymphoma cells through signaling via the B cell antigen receptor. Eur J Immunol 33: 1–11. doi: 10.1002/immu.200390000
[75]
Baksh S, Widlund HR, Frazer-Abel AA, Du J, Fosmire S, et al. (2002) NFATc2-mediated repression of cyclin-dependent kinase 4 expression. Mol Cell 10: 1071–1081. doi: 10.1016/s1097-2765(02)00701-3
[76]
Carvalho LD, Teixeira LK, Carrossini N, Caldeira AT, Ansel KM, et al. (2007) The NFAT1 transcription factor is a repressor of cyclin A2 gene expression. Cell Cycle 6: 1789–1795. doi: 10.4161/cc.6.14.4473
[77]
Caetano MS, Vieira-de-Abreu A, Teixeira LK, Werneck MB, Barcinski MA, et al. (2002) NFATC2 transcription factor regulates cell cycle progression during lymphocyte activation: evidence of its involvement in the control of cyclin gene expression. FASEB J 16: 1940–1942. doi: 10.1096/fj.02-0282fje
[78]
Vieira L, Vaz A, Matos P, Ambrosio AP, Nogueira M, et al. (2012) Three-way translocation (X;20;16)(p11;q13;q23) in essential thrombocythemia implicates NFATC2 in dysregulation of CSF2 expression and megakaryocyte proliferation. Genes Chromosomes Cancer 51: 1093–1108. doi: 10.1002/gcc.21994
[79]
Turner H, Gomez M, McKenzie E, Kirchem A, Lennard A, et al. (1998) Rac-1 regulates nuclear factor of activated T cells (NFAT) C1 nuclear translocation in response to Fcepsilon receptor type 1 stimulation of mast cells. J Exp Med 188: 527–537. doi: 10.1084/jem.188.3.527
[80]
Ritter AT, Angus KL, Griffiths GM (2013) The role of the cytoskeleton at the immunological synapse. Immunol Rev 256: 107–117.
[81]
Li J, Maruyama T, Zhang P, Konkel JE, Hoffman V, et al. (2010) Mutation of inhibitory helix-loop-helix protein Id3 causes gammadelta T-cell lymphoma in mice. Blood 116: 5615–5621. doi: 10.1182/blood-2010-03-274506
[82]
Jacquemet G, Morgan MR, Byron A, Humphries JD, Choi CK, et al. (2013) Rac1 is deactivated at integrin activation sites through an IQGAP1-filamin-A-RacGAP1 pathway. J Cell Sci 126: 4121–4135. doi: 10.1242/jcs.121988
[83]
Fukata M, Kuroda S, Nakagawa M, Kawajiri A, Itoh N, et al. (1999) Cdc42 and Rac1 regulate the interaction of IQGAP1 with beta-catenin. J Biol Chem 274: 26044–26050. doi: 10.1074/jbc.274.37.26044
[84]
Shaffer LG, MwGowan-Jordan J, Schmid M (2013) ISCN An International System for Human Cytogenetic Nomenclature (2013). Basel: S. Karger.
