Abstract 7274: Structural variant signature discovery across >8,000 TCGA whole genomes using QuantHDP

Abstract Many cancers have inherent defects in DNA damage response (DDR) which influence their sensitivity to tumor-targeting therapies. Examples include increased activity of immunotherapies in cancers with mismatch-repair deficiency and sensitivity to PARP inhibitors and platinum-based therapies in the context of homologous recombination (HR) deficiency. However, we are currently unable to reliably determine which DDR defects are present in a given cancer sample, which severely limits our ability to exploit these therapeutic vulnerabilities. Structural variants (SVs), or genomic rearrangements formed as a product of aberrant double strand break repair, hold promise as biomarkers of DDR state. Indeed, SVs affect a larger proportion of the cancer genome than any other form of genetic alteration and have features that reflect their mechanism of formation. Here, we develop QuantHDP, a novel computational method for detecting SV signatures which leverages complex modeling of genetic features to distinguish between cancers with different DDR alterations and potentially identify clinically relevant biomarkers. QuantHDP models SV features with probability distributions that reflect our knowledge of the biological mechanisms that generate them, accounts for expected differences in signature content by cancer type, and automatically infers the number of signatures present in a given dataset. In addition to recapitulating multiple previously established associations with defects in DDR - including signatures of BRCA1, BRCA2, and CDK12 alterations — we also uncover novel signatures that warrant further investigation. Citation Format: Gregory Raskind, Youyun Zheng, Anthony Zhao, Julia Sun, Simona Dalin, Siyun Lee, Chunyang Bao, Antonia Kowalewski, Ron Solan, Sam Wiseman, Samantha Van Seters, Saveliy Belkin, David I. Heiman, Chip Stewart, David Lehotzky, Vasuki Narasimha Swamy, Brian P. Danysh, Luis Antonio Corchete Sanchez, Andrew D. Cherniack, Haruna Tomono, Gengchao Wang, Xavi Loinaz, Zachary Everton, Gang-Hee Lee, Won-Chul Lee, Hansol Park, Ryul Kim, Young Seok Ju, Gad Getz, Esther Rheinbay, Rameen Beroukhim. Structural variant signature discovery across >8,000 TCGA whole genomes using QuantHDP [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 7274.