There is a striking and unexplained male predominance across many cancer types. 
A subset of X-chromosome 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 examined somatic 
alterations from >4,100 cancers across 21 tumor types for sex bias. Six of 783 
non-pseudoautosomal region (PAR) X-chromosome genes (ATRX, CNKSR2, DDX3X, KDM5C, 
KDM6A, and MAGEC3) harbored loss-of-function mutations more frequently in males 
(based on a false discovery rate < 0.1), in comparison to zero of 18,055 
autosomal and PAR genes (Fisher's exact 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 in females as compared to 
males across a variety of tumor types.