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

Julio Finalet Ferreiro, Leila Rouhigharabaei, Helena Urbankova, Jo Anne Van Der Krogt, Lucienne Michaux, Shashirekha Shetty, L. Krenács, Thomas Tousseyn, Pascale De Paepe, Anne Uyttebroeck, Gregor Verhoef, Tom Taghon, Peter Vandenberghe, Jan Cools, Iwona Wlodarska

Research output: Contribution to journalArticle

22 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)e102977
JournalPLoS One
Volume9
Issue number7
DOIs
Publication statusPublished - 2014

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T-cells
T-Cell Lymphoma
Genetic Association Studies
lymphoma
transcriptomics
pathogenesis
T-lymphocytes
Genes
genomics
RNA Sequence Analysis
Chromosomes, Human, Pair 7
genes
Chromosomes
Tumors
Isochromosomes
MDR Genes
sequence analysis
Neoplasms
RNA
Gene Fusion

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Ferreiro, J. F., Rouhigharabaei, L., Urbankova, H., Van Der Krogt, J. A., Michaux, L., Shetty, S., ... Wlodarska, I. (2014). Integrative genomic and transcriptomic analysis identified candidate genes implicated in the pathogenesis of hepatosplenic T-cell lymphoma. PLoS One, 9(7), e102977. https://doi.org/10.1371/journal.pone.0102977

Integrative genomic and transcriptomic analysis identified candidate genes implicated in the pathogenesis of hepatosplenic T-cell lymphoma. / Ferreiro, Julio Finalet; Rouhigharabaei, Leila; Urbankova, Helena; Van Der Krogt, Jo Anne; Michaux, Lucienne; Shetty, Shashirekha; Krenács, L.; Tousseyn, Thomas; De Paepe, Pascale; Uyttebroeck, Anne; Verhoef, Gregor; Taghon, Tom; Vandenberghe, Peter; Cools, Jan; Wlodarska, Iwona.

In: PLoS One, Vol. 9, No. 7, 2014, p. e102977.

Research output: Contribution to journalArticle

Ferreiro, JF, Rouhigharabaei, L, Urbankova, H, Van Der Krogt, JA, Michaux, L, Shetty, S, Krenács, L, Tousseyn, T, De Paepe, P, Uyttebroeck, A, Verhoef, G, Taghon, T, Vandenberghe, P, Cools, J & Wlodarska, I 2014, 'Integrative genomic and transcriptomic analysis identified candidate genes implicated in the pathogenesis of hepatosplenic T-cell lymphoma', PLoS One, vol. 9, no. 7, pp. e102977. https://doi.org/10.1371/journal.pone.0102977
Ferreiro, Julio Finalet ; Rouhigharabaei, Leila ; Urbankova, Helena ; Van Der Krogt, Jo Anne ; Michaux, Lucienne ; Shetty, Shashirekha ; Krenács, L. ; Tousseyn, Thomas ; De Paepe, Pascale ; Uyttebroeck, Anne ; Verhoef, Gregor ; Taghon, Tom ; Vandenberghe, Peter ; Cools, Jan ; Wlodarska, Iwona. / Integrative genomic and transcriptomic analysis identified candidate genes implicated in the pathogenesis of hepatosplenic T-cell lymphoma. In: PLoS One. 2014 ; Vol. 9, No. 7. pp. e102977.
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AU - Ferreiro, Julio Finalet

AU - Rouhigharabaei, Leila

AU - Urbankova, Helena

AU - Van Der Krogt, Jo Anne

AU - Michaux, Lucienne

AU - Shetty, Shashirekha

AU - Krenács, L.

AU - Tousseyn, Thomas

AU - De Paepe, Pascale

AU - Uyttebroeck, Anne

AU - Verhoef, Gregor

AU - Taghon, Tom

AU - Vandenberghe, Peter

AU - Cools, Jan

AU - Wlodarska, Iwona

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N2 - 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.

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