Sex Differences in Cancer Driver Genes and Biomarkers

Cancer differs significantly between men and women; even after adjusting for known epidemiologic risk factors, the sexes differ in incidence, outcome, and response to therapy. These differences occur in many but not all tumor types, and their origins remain largely unknown. Here, we compare somatic mutation profiles between tumors arising in men and in women. We discovered large differences in mutation density and sex biases in the frequency of mutation of specific genes; these differences may be associated with sex biases in DNA mismatch repair genes or microsatellite instability. Sex-biased genes include well-known drivers of cancer such as beta-catenin and BAP1. Sex influenced biomarkers of patient outcome, where different genes were associated with tumor aggression in each sex. These data call for increased study and consideration of the molecular role of sex in cancer etiology, progression, treatment, and personalized therapy. Significance: This study provides a comprehensive catalog of sex differences in somatic alterations, including in cancer driver genes, which influence prognostic biomarkers that predict patient outcome after definitive local therapy.