Sex Differences in Cancer Functional Genomics: Gene Dependency and Drug Sensitivity

Abstract

Patient sex influences a wide range of cancer phenotypes, including prevalence, response to therapy and survival endpoints. Molecular sex differences across the central dogma have been identified that may drive these phenotypic differences. Despite a growing catalog of specific genomic, transcriptomic and proteomic sex differences in a range of cancer types, their functional consequences remain unclear. To assess how patient sex impacts cancer cell function, we evaluated 1,209 cell lines subjected to CRISPR knockout, RNAi knockdown or drug exposures. Despite limited statistical power, we identified pan- and per-cancer sex differences in gene essentiality in six sex-linked and fourteen autosomal genes, and in drug sensitivity for two compounds. These data expand our understanding of the propagation of sex-differing molecular features to functional outcomes, and their role in influencing patient phenotypes. They highlight the importance of considering sex-specific effects in mechanistic and functional studies.