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Nature Research, Nature Communications, 1(7), 2016

DOI: 10.1038/ncomms11883

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

Journal article published in 2016 by Daniel Chubb, Peter Broderick ORCID, Sara E. Dobbins, Matthew Frampton, Ben Kinnersley ORCID, Steven Penegar, Amy Price, Yussanne P. Ma, Amy L. Sherborne, Claire Palles ORCID, Maria N. Timofeeva ORCID, D. Timothy Bishop ORCID, Malcolm G. Dunlop, Ian Tomlinson, Richard S. Houlston ORCID
This paper is made freely available by the publisher.
This paper is made freely available by the publisher.

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Abstract

AbstractColorectal 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.