Abstract 3344: Widespread BRCA1/2-independent homologous recombination defects are caused by alterations in RNA binding proteins

Abstract Summary: Defects in homologous recombination DNA repair (HRD) both predispose to cancer development and produce therapeutic vulnerabilities, making it critical to define the spectrum of genetic events that cause HRD. However, we found that mutations in BRCA1/2 and other canonical HR genes only identified 10-20% of tumors that display genomic evidence of HRD. Using a networks-based approach, we discovered that over half of putative genes causing HRD originated outside of canonical DNA damage response genes, with a particular enrichment for RNA binding protein (RBP)-encoding genes. These putative drivers of HRD were experimentally validated, cross-validated in an independent cohort, and enriched in cancer-associated GWAS loci. Mechanistic studies indicate that some RBPs are recruited to sites of DNA damage to facilitate repair, whereas others control the expression of canonical HR genes. Overall, this study greatly expands the repertoire of known drivers of HRD, with implications for basic biology, genetic screening, and therapy stratification. Citation Format: Babita Kaundal, Daniel J. McGrail, Yang Li, Roger S. Smith, Bin Feng, Hui Dai, Limei Hu, Briana Dennehey, Sharad Awasthi, Marc L. Mendillo, Anil K. Sood, Gordon B. Mills, Shiaw-Yih Lin, S. Stephen Yi, Nidhi Sahni. Widespread BRCA1/2-independent homologous recombination defects are caused by alterations in RNA binding proteins [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3344.