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

Nat Commun. 2016 Jun 22;7:11883. doi: 10.1038/ncomms11883.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Age Factors
  • Age of Onset
  • Alleles
  • Case-Control Studies
  • Colorectal Neoplasms / genetics*
  • Exome
  • Female
  • Genetic Predisposition to Disease*
  • Genetic Variation
  • Germ-Line Mutation*
  • Humans
  • Male
  • Middle Aged
  • Pedigree
  • Phenotype
  • Risk Factors
  • United Kingdom