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, Oxford OX3 7BN, UK.
Nat Commun. 2016 Jun 22;7:11883. doi: 10.1038/ncomms11883.
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.
结直肠癌（CRC）表现出复杂的遗传模式。据推测，CRC 大部分缺失的遗传率包含在高影响的罕见等位基因中，这些等位基因在机制和临床上都很重要。在这项研究中，我们检测了罕见种系突变对 CRC 的影响，分析了 1006 例早发性家族性 CRC 病例和 1609 例健康对照者的高覆盖率外显子组测序数据，对多达 5552 例病例和 6792 例对照者进行了额外的测序和阵列数据检测。我们在 16%的家族性 CRC 中发现了高外显率的罕见突变。尽管这些突变大部分位于已知基因中，但我们鉴定了 POT1、POLE2 和 MRE11 为候选 CRC 基因。我们没有发现任何具有中度效应的编码低频等位基因（1-5%）。我们的研究阐明了 CRC 的遗传结构，可能排除了进一步存在高外显率易感性基因的可能性，这些基因单独占家族风险的>1%。我们的研究结果为未来的研究设计提供了信息，并为新的 CRC 基因的影响提供了一个背景。
