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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 ?2-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/?2-chimerin leads to downmodulation of the NFAT pathway and a proliferative response, while upregulation of the CGR-related genes provides growth advantage for neoplastic ??T-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.

SUBMITTER: Finalet Ferreiro J

PROVIDER: S-EPMC4109958 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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

Finalet Ferreiro Julio J Rouhigharabaei Leila L Urbankova Helena H van der Krogt Jo-Anne JA Michaux Lucienne L Shetty Shashirekha S Krenacs Laszlo L Tousseyn Thomas T De Paepe Pascale P Uyttebroeck Anne A Verhoef Gregor G Taghon Tom T Vandenberghe Peter P Cools Jan J Wlodarska Iwona I

PloS one 20140724 7

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 pro ...[more]

PMID: 25057852

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Project description:Hepatosplenic T-cell lymphoma (HSTL) is an aggressive lymphoma cytogenetically characterized by isochromosome 7q M-BM- [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 HSTL cases with i(7)(q10) and three cases with ring 7 M-BM- [r(7)], a rare variant aberration. Using high resolution array CGH, we prove that HSTL is characterized by the common loss of a 34.88 Mb region at 7p22.1p14.1 (3506316-38406226 bp) and duplication/amplification of a 38.77 Mb region at 7q22.11q31.1 (86259620-124892276 bp). Our data indicate that i(7)(q10)/r(7)-associated loss of 7p22.1p14.1 is a critical event in the development of HSTL, while gain of 7q sequences drives progression of the disease and underlies its intrinsic chemoresistance. Loss of 7p22.1p14.1 does not target a postulated tumor suppressor gene but unexpectedly enhances the expression of CHN2 from the remaining 7p allele, resulting in dysregulation of a pathway involving RAC1 and NFATC2 with a cell proliferation response. Gain of 7q leads to increased expression of critical genes, including RUNDC3B, PPP1R9A and ABCB1, a known multidrug resistance gene. RNA-sequencing did not identify any additional recurrent mutations or fusion, suggesting that i(7)(q10) is the only driver event in this tumor. 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 The fastq files of all samples were mapped to the reference human genome (assembly GRCh37.68). The mapping was performed allowing detection of insertions and deletions (indels). The mapped reads were used to calculate read counts and FPKM (Fragment Per Kilobase of exon model per Million of mapped read) per gene. The DESeq algorithm was applied to identify differentially expressed genes. The mapped reads were used to predict mutations and gene fusions.

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

Publications

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

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