Dunford, AndrewWeinstock, DavidSavova, VirginiaSchumacher, Steven E.Cleary, John P.Yoda, AkinoriSullivan, Timothy J.Hess, Julian M.Gimelbrant, AlexanderBeroukhim, RameenLawrence, MichaelGetz, GadLane, Andrew2017-06-152016Dunford, A., D. M. Weinstock, V. Savova, S. E. Schumacher, J. P. Cleary, A. Yoda, T. J. Sullivan, et al. 2016. “Tumor suppressor genes that escape from X-inactivation contribute to cancer sex bias.” Nature genetics 49 (1): 10-16. doi:10.1038/ng.3726. http://dx.doi.org/10.1038/ng.3726.http://nrs.harvard.edu/urn-3:HUL.InstRepos:33029898There is a striking and unexplained male predominance across many cancer types. A subset of X chromosome (chrX) genes can escape X-inactivation, which would protect females from complete functional loss by a single mutation. To identify putative “Escape from X-Inactivation Tumor Suppressor” (EXITS) genes, we compared somatic alterations from >4100 cancers across 21 tumor types for sex bias. Six of 783 non-pseudoautosomal region (PAR) chrX genes (ATRX, CNKSR2, DDX3X, KDM5C, KDM6A, and MAGEC3) more frequently harbored loss-of-function mutations in males (based on false discovery rate <0.1), compared to zero of 18,055 autosomal and PAR genes (P<0.0001). Male-biased mutations in genes that escape X-inactivation were observed in combined analysis across many cancers and in several individual tumor types, suggesting a generalized phenomenon. We conclude that biallelic expression of EXITS genes in females explains a portion of the reduced cancer incidence compared to males across a variety of tumor types.en-USJournal Article2017-06-1510.1038/ng.3726