rare disruptive mutations and their contribution to the heritable risk of colorectal cancer
2016 jun 22;7:11883. doi: 10.1038/ncomms11883.
1, 1, 1, 1, 1, 1, 1, 1, 1, 2, 3, 4, 3, 2, 1,5.
1division of genetics and epidemiology, the institute of cancer research, london sm2 5ng, uk.
2molecular and population genetics laboratory, wellcome trust centre for human genetics, university of oxford, oxford ox3 7bn, uk.
3centre for population health sciences, university of edinburgh, edinburgh eh8 9ag, uk.
4section of epidemiology and biostatistics, leeds institute of cancer and pathology, university of leeds, st james's university hospital, leeds ls9 7tf, uk.
5division of pathology, the institute of cancer research, london sm2 5ng, uk.
colorectal cancer (crc) displays a complex pattern of inheritance. it is postulated that much of the missing heritability of crc is enshrined in high-impact rare alleles, which are mechanistically and clinically important. in this study, we assay the impact of rare germline mutations on crc, analysing high-coverage exome sequencing data on 1,006 early-onset familial crc cases and 1,609 healthy controls, with additional sequencing and array data on up to 5,552 cases and 6,792 controls. we identify highly penetrant rare mutations in 16% of familial crc. although the majority of these reside in known genes, we identify pot1, pole2 and mre11 as candidate crc genes. we did not identify any coding low-frequency alleles (1-5%) with moderate effect. our study clarifies the genetic architecture of crc and probably discounts the existence of further major high-penetrance susceptibility genes, which individually account for >1% of the familial risk. our results inform future study design and provide a resource for contextualizing the impact of new crc genes.