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

Research output: Contribution to journalArticlepeer-review


  • Daniel Chubb
  • Peter Broderick
  • Sara E Dobbins
  • Matthew Frampton
  • Ben Kinnersley
  • Steven Penegar
  • Amy Price
  • Yussanne P Ma
  • Amy L Sherborne
  • Maria N Timofeeva
  • D Timothy Bishop
  • Malcolm G Dunlop
  • Ian Tomlinson
  • Richard S Houlston

Colleges, School and Institutes

External organisations

  • Division of Genetics and Epidemiology, The Institute of Cancer Research, London SM2 5NG, UK.
  • Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, University of Oxford
  • Centre for Population Health Sciences, University of Edinburgh, Edinburgh, EH8 9AG, UK.
  • University of Leeds
  • Division 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.


Original languageEnglish
Article number11883
JournalNature Communications
Publication statusPublished - 22 Jun 2016


  • Journal Article