title: Tumor-suppressor genes that escape from X-inactivation contribute to cancer sex bias.
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.
authors.affiliation: Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Dunford
authors.affiliation: Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.|Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Weinstock
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Virginia
authors.initials: V
authors.lastname: Savova
authors.affiliation: Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.|Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Steven E
authors.initials: SE
authors.lastname: Schumacher
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: John P
authors.initials: JP
authors.lastname: Cleary
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Akinori
authors.initials: A
authors.lastname: Yoda
authors.affiliation: Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Sullivan
authors.affiliation: Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
authors.forename: Julian M
authors.initials: JM
authors.lastname: Hess
authors.affiliation: Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.|Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Alexander A
authors.identifier: 0000-0001-6986-0285
authors.initials: AA
authors.lastname: Gimelbrant
authors.affiliation: Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.|Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.|Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Rameen
authors.initials: R
authors.lastname: Beroukhim
authors.affiliation: Department of Pathology and Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Lawrence
authors.affiliation: Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.|Department of Pathology and Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Gad
authors.initials: G
authors.lastname: Getz
authors.affiliation: Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.|Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Lane
mesh_terms: D041321:Chromosomes, Human, X / Q000235:genetics*; D005260:Female; D016147:Genes, Tumor Suppressor; D050172:Genes, X-Linked / Q000235:genetics*; D006801:Humans; D008297:Male; D009154:Mutation / Q000235:genetics*; D009369:Neoplasms / Q000235:genetics*; D063507:Sexism / Q000706:statistics & numerical data*; D049951:X Chromosome Inactivation / Q000235:genetics*