Abstract C131: Influences of ancestry-associated non-pathogenic germline variants as cancer vulnerabilities

Abstract

The advent of precision oncology has transformed cancer care. Yet only approximately 25% of patients are eligible for targeted therapies, as current approaches exploit tumors harboring well-characterized somatic driver alterations. This limitation has restricted the broader clinical impact of precision medicine and contributed to persistent disparities in outcomes across diverse patient populations. To address this gap, we present a framework that identifies therapeutic vulnerabilities arising from ancestry-dependent germline genetic variation and frequent tumor loss of heterozygosity (LOH). While canonical strategies focus on driver mutations, LOH affects 1/6th of the cancer genome, creating cancer-specific contexts where essential functions depend on a single remaining allele. By analyzing genome-scale loss-of-function CRISPR screens from The Cancer Dependency Map, we systematically identified for the first time, non-pathogenic germline variants that confer synthetic lethal interactions. Our approach revealed 209 genes whose dependency profiles associate with specific germline variants in an ancestry dependent manner. Here, we establish proof-of-concept that these germline-driven dependencies are experimentally tractable and represent actionable therapeutic targets. We prioritize an identified novel cancer dependency between a germline variant in the Holliday junction resolvase GEN1, and the endonuclease MUS81. Approximately 17% of the U.S. population are carriers of this GEN1 germline variant and GEN1 undergoes LOH in 20% of breast and ovarian cancers. Therefore, we hypothesize that tumor-specific loss of the wild-type GEN1 allele renders cancer cells selectively dependent on MUS81 for survival. To model this genotype, we generated isogenic cell lines using prime editing and allele-specific CRISPR to create cells harboring homozygous GEN1 variant alleles following LOH. Genetic suppression of MUS81 selectively impaired the growth and survival of GEN1 variant cells while sparing GEN1 wild-type controls, demonstrating a genotype-specific synthetic lethal interaction. Breast and ovarian cancers frequently undergo GEN1 LOH and are associated with persistent disparities in survival, with patients of African and American ancestry experiencing disproportionately higher mortality rates. By identifying therapeutic vulnerabilities created by inherited genetic variation and somatic LOH, this work expands the precision oncology paradigm beyond canonical somatic drivers and establishes a framework for discovering ancestry-informed cancer dependencies. These findings support the development of genotype-directed therapeutic strategies that could benefit larger and more diverse patient populations while helping address persistent disparities in cancer outcomes. Nicole Peiris, Sean Misek, Angela Chen, Julie Parikh, Aaron Fultineer, Neha Nanda, Jesse Boehm, Francisco Sánchez-Rivera, Rameen Beroukhim. Influences of ancestry-associated non-pathogenic germline variants as cancer vulnerabilities [abstract]. In: Proceedings of the 19th AACR Conference on the Science of Cancer Health Disparities; 2026 Oct 18-21; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2026;35(10 Suppl):Abstract nr C131.