Genome-wide characterization of copy number variations in diffuse large B-cell lymphoma with implications in targeted therapy

Abstract

Diffuse large B-cell lymphoma (DLBCL) is the aggressive form of haematological malignancies with relapse/refractory in ~ 40% of cases. It mostly develops due to accumulation of various genetic and epigenetic variations that contribute to its aggressiveness. Though large-scale structural alterations have been reported in DLBCL, their functional role in pathogenesis and as potential targets for therapy is not yet well understood. In this study we performed detection and analysis of copy number variations (CNVs) in 11 human DLBCL cell lines (4 activated B-cell–like [ABC] and 7 germinal-centre B-cell–like [GCB]), that serve as model systems for DLBCL cancer cell biology. Significant heterogeneity observed in CNV profiles of these cell lines and poor prognosis associated with ABC subtype indicates the importance of individualized screening for diagnostic and prognostic targets. Functional analysis of key cancer genes exhibiting copy alterations across the cell lines revealed activation/disruption of ten potentially targetable immuno-oncogenic pathways. Genome guided in silico therapy that putatively target these pathways is elucidated. Based on our analysis, five CNV-genes associated with worst survival prognosis are proposed as potential prognostic markers of DLBCL.

Spatial Heterogeneity in Large Resected Diffuse Large B-Cell Lymphoma Bulks Analysed by Massively Parallel Sequencing of Multiple Synchronous Biopsies

“…Similarly to what has been reported in cell lines and other patients with DLBCL there was a wide variety of CNVs found in our patients with several different chromosomes involved and no clear pattern of gains or losses [26,27]. In all except for two patients, one or more discordant CNVs were seen.…”

“…Moreover, another patient had a loss of chromosome 10 in one of the biopsies, which causes a loss of the tumour suppressor PTEN , a known cause of resistance to T-cell mediated immunotherapy [ 28 ]. Two groups described the association of specific CNVs with GCB and non-GCB subtypes [ 26 , 27 ]. However, the CNVs varied between the two reports and such an association was not found within our cohort.…”

A comprehensive catalog of 3D genome organization in diverse human genomes facilitates understanding of the impact of structural variation on chromatin structure

“…Thus, we sought to investigate if those two SVs and the associated eGenes and sGenes would have any potential contribution to the risk of complex diseases (Table S7). We found two of the genes (ERICH1, TMEM200A) were previously reported to be associated with various cancers (e.g., such as pancreatic cancer and gastric cancer) and tumor progression 15,61,62,63,64 . Among them, ERICH1 was reported to be related to the genomic imprinting regulatory mechanism (which is frequently linked to ASE 20,21 ) and differential allelic expression 17,65 .…”