Somatic alterations in both oncogenes and tumor suppressors drive cancer development and progression. Synthetic lethal relationships or collateral lethalities have emerged in the context of these driver mutations, revealing new targets for therapeutic development. Most variation in cancer genomes results from germline variants, rather than somatic mutations. The landscape of cancer vulnerabilities that are engendered by germline variants has not been systematically explored.
In this study, we leverage genome-scale CRISPR/Cas9 screens from over 1,000 cancer cell lines to define variant-dependency interactions. Across all associations identified in this analysis, the most striking was the relationship between a germline frameshift variant in a Holliday junction resolvase and dependency on multiple functionally redundant proteins in an alternative Holliday junction resolution pathway. Herein, we further interrogate the nature of this synthetic lethal relationship across cancer lineages.