Systematic discovery of germline cancer predisposition genes through the identification of somatic second hits

Park, Solip; Supek, Fran; Lehner, Ben, 1978-

doi:http://dx.doi.org/10.1038/s41467-018-04900-7

Systematic discovery of germline cancer predisposition genes through the identification of somatic second hits

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Park S, Supek F, Lehner B. Systematic discovery of germline cancer predisposition genes through the identification of somatic second hits. Nat Commun. 2018;9(1):2601. DOI: 10.1038/s41467-018-04900-7

Abstract

The genetic causes of cancer include both somatic mutations and inherited germline variants. Large-scale tumor sequencing has revolutionized the identification of somatic driver alterations but has had limited impact on the identification of cancer predisposition genes (CPGs). Here we present a statistical method, ALFRED, that tests Knudson's two-hit hypothesis to systematically identify CPGs from cancer genome data. Applied to ~10,000 tumor exomes the approach identifies known and putative CPGs - including the chromatin modifier NSD1 - that contribute to cancer through a combination of rare germline variants and somatic loss-of-heterozygosity (LOH). Rare germline variants in these genes contribute substantially to cancer risk, including to ~14% of ovarian carcinomas, ~7% of breast tumors, ~4% of uterine corpus endometrial carcinomas, and to a median of 2% of tumors across 17 cancer types.