Rare disruptive mutations and their contribution to the heritable risk of colorectal cancer
Research output: Contribution to journal › Article › peer-review
Colleges, School and Institutes
- 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.
|Publication status||Published - 22 Jun 2016|
- Journal Article