Integrative Genomic and Transcriptomic Analysis Identified Candidate Genes Implicated in the Pathogenesis of Hepatosplenic T-Cell LymphomaReportar como inadecuado




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Hepatosplenic T-cell lymphoma HSTL is an aggressive lymphoma cytogenetically characterized by isochromosome 7q i7q10, 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 i7q10-positive HSTL cases, including HSTL-derived cell line DERL-2, and three cases with ring 7 r7, 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 r7. In addition, we found that TCRG 7p14.1 and TCRB 7q32 are involved in formation of r7, 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.



Autor: Julio Finalet Ferreiro, Leila Rouhigharabaei, Helena Urbankova, Jo-Anne van der Krogt, Lucienne Michaux, Shashirekha Shetty, Lasz

Fuente: http://plos.srce.hr/



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