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.
Highlights
The genetic causes of cancer include both somatic mutations and inherited germline variants
We have shown that this classic insight still provides a powerful hypothesis for the discovery of cancer predisposition genes (CPGs) and, in particular, that it can be used to discover CPGs from cancer exomes without the use of control samples
Three of the genes identified by ALFRED (BRCA1, BRCA2, and ATM) are known CPGs reported in two large-scale literature surveys of CPGs identified through family studies[2,10]
Summary
The genetic causes of cancer include both somatic mutations and inherited germline variants. 1234567890():,; Inherited risk for cancer was first proposed by Broca because of the history of breast cancer in 15 members of his wife’s family[1] It was Alfred Knudson’s ‘two-hit’ hypothesis that initiated the identification of cancer predisposition genes (CPGs) in which deleterious germline variants have been associated with increased risks of cancer[2]. Through a statistical analysis of retinoblastoma cases, Knudson proposed that ‘two hits’ to the DNA were necessary to cause cancer and that in children with the inherited form of the disease the first hit is inherited variation in one allele of the gene with the ‘second hit’ being a somatically acquired inactivation of the second allele[3] This model was confirmed by the identification of biallelic inactivation of the RB1 gene in retinoblastoma and most known high-penetrance inherited cancer predisposition variants are loss-of-function mutations in recessively acting tumor suppressor (TS) genes[2,4]. We present a method to achieve this and its application to the analysis of ~10,000 tumor exomes
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