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

被引:42
作者
Park, Solip [1 ]
Supek, Fran [1 ,2 ,3 ]
Lehner, Ben [1 ,4 ,5 ]
机构
[1] Barcelona Inst Sci & Technol, Ctr Genom Regulat CRG, Syst Biol Program, Dr Aiguader 88, Barcelona 08003, Spain
[2] Barcelona Inst Sci & Technol, Inst Recerca Biomed IRB Barcelona, Barcelona 08028, Spain
[3] Rudjer Boskovic Inst, Div Elect, Zagreb 10000, Croatia
[4] UPF, Barcelona 08003, Spain
[5] ICREA, Pg Luis Co 23, Barcelona 08010, Spain
基金
欧洲研究理事会;
关键词
MUTATIONS; VARIANTS; PATTERNS; NSD1; RARE; HAPLOINSUFFICIENCY; HETEROGENEITY; INACTIVATION; HEALTH; DRIVE;
D O I
10.1038/s41467-018-04900-7
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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 similar 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 similar to 14% of ovarian carcinomas, similar to 7% of breast tumors, similar to 4% of uterine corpus endometrial carcinomas, and to a median of 2% of tumors across 17 cancer types.
引用
收藏
页数:13
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