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

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

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

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
Number of pages7
JournalNature Communications
Publication statusPublished - 22 Jun 2016


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