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

Patient sex influences a wide range of cancer phenotypes, including prevalence, response to therapy and survival endpoints. Molecular sex differences have been identified at all levels of the central dogma. It is hypothesized that these molecular differences may drive the observed clinical sex differences. Yet despite a growing catalog of molecular sex differences in a range of cancer types, their specific functional consequences remain unclear. To directly 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 fill a gap in our understanding of the link between sex-differential molecular effects and patient phenotypes. They call for much more careful and systematic consideration of sex-specific effects in mechanistic and functional studies.