Journal Article

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

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

2016

Overview

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. The genetic factors that predispose individuals to familial colorectal cancer are poorly understood. In this study, the authors use whole exome sequencing of 1,006 patients and 1,609 healthy controls and show it is unlikely that further major high-penetrance susceptibility genes exist.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 631/208/68 / 631/208/737 / 631/67/1504/1885 / 692/700/1750 / Adult / Age Factors / Age of Onset / Alleles / Cancer research / Case-Control Studies / Colorectal cancer / Colorectal carcinoma / Colorectal Neoplasms - genetics / Epidemiology / Exome / Female / Genes / Genetic Predisposition to Disease / Genetic Variation / Genetics / Germ-Line Mutation / Humanities and Social Sciences / Humans / Male / Medical research / Middle Aged / multidisciplinary / Mutation / Pedigree / Phenotype / Risk Factors / Science / Science (multidisciplinary) / United Kingdom