%0 Journal Article
%T Integrative Genomic and Transcriptomic Analysis Identified Candidate Genes Implicated in the Pathogenesis of Hepatosplenic T-Cell Lymphoma
%A Julio Finalet Ferreiro
%A Leila Rouhigharabaei
%A Helena Urbankova
%A Jo-Anne van der Krogt
%A Lucienne Michaux
%A Shashirekha Shetty
%A Laszlo Krenacs
%A Thomas Tousseyn
%A Pascale De Paepe
%A Anne Uyttebroeck
%A Gregor Verhoef
%A Tom Taghon
%A Peter Vandenberghe
%A Jan Cools
%A Iwona Wlodarska
%J PLOS ONE
%D 2014
%I Public Library of Science (PLoS)
%R 10.1371/journal.pone.0102977
%X 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¨C124892276 bp). Interestingly, CDR spans a smaller region of 13 Mb (86259620¨C99271246 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 ¦Â2-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 ¦¤7p22.1p14.1-associated enhanced expression of CHN2/¦Â2-chimerin leads to downmodulation of the NFAT pathway and a proliferative response, while upregulation of the CGR-related genes provides growth advantage for neoplastic ¦Ä¦ÃT-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.
%U http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0102977