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

Park, Solip; Supek, Fran; Lehner, Ben (2018) Systematic discovery of germline cancer predisposition genes through the identification of somatic second hits. Nature Communications, 9 (1). p. 2601. ISSN 2041-1723

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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.

Item Type:	Article
Uncontrolled Keywords:	genomics ; mutation ; cancer
Subjects:	NATURAL SCIENCES > Biology
Divisions:	Division of Electronics
Depositing User:	Sofija Konjević
Date Deposited:	01 Aug 2018 12:02
URI:	http://fulir.irb.hr/id/eprint/4116
DOI:	10.1038/s41467-018-04900-7

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