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Nat Genet DOI:10.1038/ng.3726

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

Publication TypeJournal Article
Year of Publication2017
AuthorsDunford, A, Weinstock, DM, Savova, V, Schumacher, SE, Cleary, JP, Yoda, A, Sullivan, TJ, Hess, JM, Gimelbrant, AA, Beroukhim, R, Lawrence, MS, Getz, G, Lane, AA
JournalNat Genet
Volume49
Issue1
Pages10-16
Date Published2017 Jan
ISSN1546-1718
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.

DOI10.1038/ng.3726
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/27869828?dopt=Abstract

Alternate JournalNat. Genet.
PubMed ID27869828
PubMed Central IDPMC5206905
Grant ListK08 CA181340 / CA / NCI NIH HHS / United States