Copy number analysis of regulatory regions reveal recurrent promoter/enhancer somatic copy number alterations across >8,000 TCGA samples

Somatic copy number alterations (SCNAs) are frequent oncogenic events. Previous studies have identified recurrent gene-level SCNAs using DNA microarray and whole exome sequencing data. These studies have also identified focal amplifications of regulatory regions. High-throughput whole genome sequencing enables deeper, comprehensive analysis of these focal SCNAs in non-coding regions, potentially revealing novel drivers of oncogenesis. To this end, we systematically analyzed SCNAs and structural variants in WGS data from >8,000 tumor-normal pairs across 31 cancer types from The Cancer Genome Atlas (TCGA) using GISTIC2.0 to identify focal, recurrent promoter and enhancer SCNAs near known oncogenes and tumor suppressor genes. We leveraged structural variant calls to orthogonally validate our primary focal SCNA findings. We identified a recurrent amplification event specific to the EGFR promoter/enhancer region in a subset of IDH-wildtype glioblastoma samples. This suggests an additional SCNA-driven mechanism for EGFR upregulation, distinct from canonical gene body amplification or point mutations, in a fraction of these aggressive tumors. Our ongoing work aims to broaden the landscape of regulatory SCNAs across cancers and validate their transcriptional impact to provide new biological insights and candidate therapeutic targets.