Tumor-suppressor genes that escape from X-inactivation contribute to cancer sex bias

A Dunford, DM Weinstock, V Savova, SE Schumacher… - Nature …, 2017 - nature.com
Nature genetics, 2017nature.com
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 …
Abstract
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.
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