Whole genome and RNA sequencing of 1,220 cancers reveals hundreds of genes deregulated by rearrangement of cis-regulatory elements

Using a dataset of somatic Structural Variants (SVs) in cancers from 2658 patients—1220 with corresponding gene expression data—we identified hundreds of genes for which the nearby presence (within 100kb) of an SV breakpoint was associated with altered expression. For the vast majority of these genes, expression was increased rather than decreased with corresponding SV event. Well-known up-regulated cancer-associated genes impacted by this phenomenon included TERT , MDM2 , CDK4 , ERBB2 , CD274 , PDCD1LG2 , and IGF2 . SVs upstream of TERT involved ~3% of cancer cases and were most frequent in liver-biliary, melanoma, sarcoma, stomach, and kidney cancers. SVs associated with up-regulation of PD1 and PDL1 genes involved ~1% of non-amplified cases. For many genes, SVs were significantly associated with either increased numbers or greater proximity of enhancer regulatory elements near the gene. DNA methylation near the gene promoter was often increased with nearby SV breakpoint, which may involve inactivation of repressor elements. Abbreviations PCAWG the Pan-Cancer Analysis of Whole Genomes project SV Structural Variant