Rare disruptive mutations and their contribution to the heritable risk of colorectal cancer.
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Authors
Chubb, D
Broderick, P
Dobbins, SE
Frampton, M
Kinnersley, B
Penegar, S
Price, A
Ma, YP
Sherborne, AL
Palles, C
Timofeeva, MN
Bishop, DT
Dunlop, MG
Tomlinson, I
Houlston, RS
Broderick, P
Dobbins, SE
Frampton, M
Kinnersley, B
Penegar, S
Price, A
Ma, YP
Sherborne, AL
Palles, C
Timofeeva, MN
Bishop, DT
Dunlop, MG
Tomlinson, I
Houlston, RS
Document Type
Journal Article
Date
2016-06-22
Date Accepted
2016-05-09
Abstract
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.
Citation
Nature communications, 2016, 7 pp. 11883 - ?
Source Title
Publisher
NATURE PUBLISHING GROUP
ISSN
2041-1723
eISSN
2041-1723
Collections
Research Team
Cancer Genomics