Defining the landscape of cancer vulnerabilities that are engendered by germline genetic variation

Abstract

ID 55303 Poster Board 246A range of somatic alterations in both oncogenes and tumor suppressor genes promote cancer development. Synthetic lethal relationships or collateral lethalities have emerged in the context of these genetic driver mutations, revealing new targets for therapeutic development. Most variation within cancer genomes results from germline, as opposed to somatic, mutations, but the genetic dependencies engendered by these variants have not been systematically explored. We sought to define the landscape of these interactions by leveraging the genome-scale CRISPR/Cas9 screens that were performed as part of The Cancer Dependency Map (DepMap).In this study we systematically analyzed the associations between individual germline variants in 612 cancer cell lines and >16,000 genetic dependencies. Across all genes profiled in this analysis, we identified 121 genes whose dependency profiles are associated with the presence of specific germline variants. The top association in this analysis was between two functionally redundant Holliday junction resolvases. In this study we seek to define the nature of this synthetic lethal relationship, with a focus on how this variant impacts protein activity.