Abstract 1978: Copy number analysis of regulatory regions reveal recurrent promoter/enhancer somatic copy number alterations across >8,000 TCGA samples.

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Abstract 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. Citation Format: Haruna Tomono, Chunyang Bao, Antonia Kowalewski, David Lehotzky, Ron Solan, Matthew Leventhal, Luis Antonio Corchete Sanchez, David I. Heiman, Samantha Van Seters, Saveliy Belkin, Sam Wiseman, Brian P. Danysh, Chip Stewart, Vasuki Narasimha Swamy, Gengchao Wang, Xavi Loinaz, Zachary Everton, Gang-Hee Lee, Won-Chul Lee, Hansol Park, Ryul Kim, Young Seok Ju, Esther Rheinbay, Gad Getz, Andrew D. Cherniack, Matthew L. Meyerson, Rameen Beroukhim. Copy number analysis of regulatory regions reveal recurrent promoter/enhancer somatic copy number alterations across >8,000 TCGA samples [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1978.

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