Project description:We report changes in the DNA methylome in a patient with γδ hepatosplenic T-cell lymphoma (HSTCL) who responded to treatment with interferon-α2c. We studied the methylome by 450k methylation array in 5 blood samples taken within a time period of 20 months. During this time period, the WBC counts dropped from 22,300 to 7,200/μl blood, yet the proportion of γδ T cell lymphoma blasts remained around 90%. We observed time-dependent changes in overall DNA methylation and performed an in-depth bioinformatic analysis of the modulated CpG sites associated with disease progression. We identified a CpG site differentially regulating methylation, possibly related to the interferon response during the course of treatment in this particular case. Therefore, the present case report will help to understand the substantial changes in DNA methylation of lymphoma resulting in a survival benefit of this γδ HSTCL patient.
Project description:Integrative Genomic and Transcriptomic Analysis Identified Candidate Genes Implicated in the Pathogenesis of Hepatosplenic T-cell Lymphoma
Project description: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 HSTL cases with i(7)(q10) and three cases with ring 7 [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 overexpression of β2-chimerin and 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 gene fusions, 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
