Abstract
The impact of somatic structural variants (SVs) on gene expression in cancer is largely unknown. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole-genome sequencing data and RNA sequencing from a common set of 1220 cancer cases, we report hundreds of genes for which the presence within 100 kb of an SV breakpoint associates with altered expression. For the majority of these genes, expression increases rather than decreases with corresponding breakpoint events. Up-regulated cancer-associated genes impacted by this phenomenon include TERT, MDM2, CDK4, ERBB2, CD274, PDCD1LG2, and IGF2. TERT-associated breakpoints involve ~3% of cases, most frequently in liver biliary, melanoma, sarcoma, stomach, and kidney cancers. SVs associated with up-regulation of PD1 and PDL1 genes involve ~1% of non-amplified cases. For many genes, SVs are significantly associated with increased numbers or greater proximity of enhancer regulatory elements near the gene. DNA methylation near the promoter is often increased with nearby SV breakpoint, which may involve inactivation of repressor elements.
Highlights
The impact of somatic structural variants (SVs) on gene expression in cancer is largely unknown
Inspired by recent observations in kidney cancer[3,14], neuroblastoma[8,15], and B-cell malignancies[16], of recurrent genomic rearrangements affecting the chromosomal region proximal to TERT and resulting in its upregulation, we sought to carry out a pan-cancer analysis of all coding genes, for ones appearing affected by somatic rearrangement
In addition to the 0–20 kb region upstream of each gene, we considered SV breakpoints occurring 20–50 kb upstream of a gene, 50–100 kb upstream of a gene, within a gene body, or 0–20 kb downstream of a gene (Fig. 1a). (SV breakpoints located within a given gene were not included in the other upstream or downstream SV sets for that same gene.) For each of the above SV groups, we assessed each gene for correlation between associated SV event and expression
Summary
The impact of somatic structural variants (SVs) on gene expression in cancer is largely unknown. By integrating somatic copy alterations, gene expression data, and information on topologically associating domains (TADs), a recent pan-cancer study uncovered 18 genes with overexpression resulting from rearrangements of cis-regulatory elements (including enhancer hijacking)[9]. With a genome-wide analysis involving a large sample size and much deeper sequencing coverage (~30–60×), information from multiple genes may be leveraged more effectively, in order to identify common features involving the observed disrupted regulation of genes impacted by somatic genomic rearrangement. In this present study, we utilize the PCAWG datasets in order to analyze high coverage whole-genome sequencing data from 1220 individuals. Mechanisms involved with SV-mediated gene deregulation, as observed here, include enhancer hijacking and altered DNA methylation
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