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

Solip Park, Fran Supek and Ben Lehner ()
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Solip Park: The Barcelona Institute of Science and Technology
Fran Supek: The Barcelona Institute of Science and Technology
Ben Lehner: The Barcelona Institute of Science and Technology

Nature Communications, 2018, vol. 9, issue 1, 1-13

Abstract: 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.

Date: 2018
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-04900-7

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DOI: 10.1038/s41467-018-04900-7

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