title: Integrative genomic and transcriptomic analysis identified candidate genes implicated in the pathogenesis of hepatosplenic T-cell lymphoma.
abstract: 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.
authors: Center for Human Genetics, KU Leuven, Leuven, Belgium.
authors: Julio
authors: J
authors: Finalet Ferreiro
authors: Center for Human Genetics, KU Leuven, Leuven, Belgium.
authors: Leila
authors: L
authors: Rouhigharabaei
authors: Center for Human Genetics, KU Leuven, Leuven, Belgium.
authors: Helena
authors: H
authors: Urbankova
authors: Center for Human Genetics, KU Leuven, Leuven, Belgium.
authors: Jo-Anne
authors: JA
authors: van der Krogt
authors: Center for Human Genetics, KU Leuven, Leuven, Belgium.
authors: Lucienne
authors: L
authors: Michaux
authors: Molecular Pathology, Cleveland Clinic, Cleveland, Ohio, United States of America.
authors: Shashirekha
authors: S
authors: Shetty
authors: Laboratory of Tumor Pathology and Molecular Diagnostics, University of Szeged, Szeged, Hungary.
authors: Laszlo
authors: L
authors: Krenacs
authors: Translational Cell and Tissue Research KU Leuven, Department of Pathology UZ Leuven, Leuven, Belgium.
authors: Thomas
authors: T
authors: Tousseyn
authors: Department of Pathology, AZ St Jan AV, Brugge, Belgium.
authors: Pascale
authors: P
authors: De Paepe
authors: Department of Pediatrics, UZ Leuven, Leuven, Belgium.
authors: Anne
authors: A
authors: Uyttebroeck
authors: Department of Hematology, UZ Leuven, Leuven, Belgium.
authors: Gregor
authors: G
authors: Verhoef
authors: Department of Clinical Chemistry, Microbiology and Immunology, Ghent University Hospital, Ghent University, Ghent, Belgium.
authors: Tom
authors: T
authors: Taghon
authors: Center for Human Genetics, KU Leuven, Leuven, Belgium.
authors: Peter
authors: P
authors: Vandenberghe
authors: Center for Human Genetics, KU Leuven, Leuven, Belgium; Center for the Biology of Disease, VIB, Leuven, Belgium.
authors: Jan
authors: J
authors: Cools
authors: Center for Human Genetics, KU Leuven, Leuven, Belgium.
authors: Iwona
authors: I
authors: Wlodarska
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D002648:Child; D020740:Chimerin Proteins / Q000235:genetics* / Q000378:metabolism; D002869:Chromosome Aberrations; D002874:Chromosome Mapping; D002897:Chromosomes, Human, Pair 7; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D056426:Genetic Loci; D015894:Genome, Human; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016399:Lymphoma, T-Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008840:Microfilament Proteins / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D013160:Splenic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D059467:Transcriptome; D000099273:Neurabins
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D020740:Chimerin Proteins; D008840:Microfilament Proteins; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D000099273:Neurabins; C513055:ABCB1 protein, human; C079844:beta-chimaerin; C000593185:chimaerin-beta3 protein, human