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Nat Commun. 2018 Jul 4;9(1):2601. doi: 10.1038/s41467-018-04900-7.

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

Park S1, Supek F1,2,3,2, Lehner B4,5,6.

Author information

1
Systems Biology Program, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr Aiguader 88, 08003, Barcelona, Spain.
2
Institut de Recerca Biomedica (IRB Barcelona), The Barcelona Institute of Science and Technology, 08028, Barcelona, Spain.
3
Division of Electronics, Rudjer Boskovic Institute, 10000, Zagreb, Croatia.
4
Systems Biology Program, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr Aiguader 88, 08003, Barcelona, Spain. ben.lehner@crg.eu.
5
Universitat Pompeu Fabra (UPF), 08003, Barcelona, Spain. ben.lehner@crg.eu.
6
Institució Catalana de Recerca i Estudis Avançats (ICREA), Pg. Luis Companys 23, 08010, Barcelona, Spain. ben.lehner@crg.eu.

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.

PMID:
29973584
PMCID:
PMC6031629
DOI:
10.1038/s41467-018-04900-7
[Indexed for MEDLINE]
Free PMC Article

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