Integrative genomic and transcriptomic analysis identified candidate genes implicated in the pathogenesis of hepatosplenic T-cell lymphoma

PLoS One. 2014 Jul 24;9(7):e102977. doi: 10.1371/journal.pone.0102977. eCollection 2014.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B / genetics
  • ATP Binding Cassette Transporter, Subfamily B / metabolism
  • Adolescent
  • Adult
  • Child
  • Chimerin Proteins / genetics*
  • Chimerin Proteins / metabolism
  • Chromosome Aberrations*
  • Chromosome Mapping
  • Chromosomes, Human, Pair 7*
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • Genetic Loci
  • Genome, Human
  • Humans
  • Liver Neoplasms / genetics*
  • Liver Neoplasms / metabolism
  • Liver Neoplasms / pathology
  • Lymphoma, T-Cell / genetics*
  • Lymphoma, T-Cell / metabolism
  • Lymphoma, T-Cell / pathology
  • Male
  • Microfilament Proteins / genetics*
  • Microfilament Proteins / metabolism
  • Middle Aged
  • Neoplasm Proteins / genetics*
  • Neoplasm Proteins / metabolism
  • Nerve Tissue Proteins / genetics*
  • Nerve Tissue Proteins / metabolism
  • Splenic Neoplasms / genetics*
  • Splenic Neoplasms / metabolism
  • Splenic Neoplasms / pathology
  • Transcriptome

Substances

  • ABCB1 protein, human
  • ATP Binding Cassette Transporter, Subfamily B
  • Chimerin Proteins
  • Microfilament Proteins
  • Neoplasm Proteins
  • Nerve Tissue Proteins
  • beta-chimaerin
  • chimaerin-beta3 protein, human
  • neurabin

Grant support

This study was supported by the concerted action grant from the K. U. Leuven no. 3M040406 (J-AvdK, TT, PV, JC and IW) (http://www.kuleuven.be/english), and a research grant from “Stichting tegen Kanker” (PV) (http://www.kanker.be/. PV is a senior clinical investigator of the FWO-Vlaanderen (http://www.fwo.be/en/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.