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rare disruptive mutations and their contribution to the heritable risk of colorectal cancer

2016-09-05

 
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.

abstract

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.