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

Research output: Contribution to journalArticlepeer-review

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Rare disruptive mutations and their contribution to the heritable risk of colorectal cancer. / Chubb, Daniel; Broderick, Peter; Dobbins, Sara E; Frampton, Matthew; Kinnersley, Ben; Penegar, Steven; Price, Amy; Ma, Yussanne P; Sherborne, Amy L; Palles, Claire; Timofeeva, Maria N; Bishop, D Timothy; Dunlop, Malcolm G; Tomlinson, Ian; Houlston, Richard S.

In: Nature Communications, Vol. 7, 11883, 22.06.2016.

Research output: Contribution to journalArticlepeer-review

Harvard

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 2016, 'Rare disruptive mutations and their contribution to the heritable risk of colorectal cancer', Nature Communications, vol. 7, 11883. https://doi.org/10.1038/ncomms11883

APA

Chubb, D., Broderick, P., Dobbins, S. E., Frampton, M., Kinnersley, B., Penegar, S., Price, A., Ma, Y. P., Sherborne, A. L., Palles, C., Timofeeva, M. N., Bishop, D. T., Dunlop, M. G., Tomlinson, I., & Houlston, R. S. (2016). Rare disruptive mutations and their contribution to the heritable risk of colorectal cancer. Nature Communications, 7, [11883]. https://doi.org/10.1038/ncomms11883

Vancouver

Chubb D, Broderick P, Dobbins SE, Frampton M, Kinnersley B, Penegar S et al. Rare disruptive mutations and their contribution to the heritable risk of colorectal cancer. Nature Communications. 2016 Jun 22;7. 11883. https://doi.org/10.1038/ncomms11883

Author

Chubb, Daniel ; Broderick, Peter ; Dobbins, Sara E ; Frampton, Matthew ; Kinnersley, Ben ; Penegar, Steven ; Price, Amy ; Ma, Yussanne P ; Sherborne, Amy L ; Palles, Claire ; Timofeeva, Maria N ; Bishop, D Timothy ; Dunlop, Malcolm G ; Tomlinson, Ian ; Houlston, Richard S. / Rare disruptive mutations and their contribution to the heritable risk of colorectal cancer. In: Nature Communications. 2016 ; Vol. 7.

Bibtex

@article{9d1dde70344746408eb5f18b1a5cec41,
title = "Rare disruptive mutations and their contribution to the heritable risk of colorectal cancer",
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.",
keywords = "Journal Article",
author = "Daniel Chubb and Peter Broderick and Dobbins, {Sara E} and Matthew Frampton and Ben Kinnersley and Steven Penegar and Amy Price and Ma, {Yussanne P} and Sherborne, {Amy L} and Claire Palles and Timofeeva, {Maria N} and Bishop, {D Timothy} and Dunlop, {Malcolm G} and Ian Tomlinson and Houlston, {Richard S}",
year = "2016",
month = jun,
day = "22",
doi = "10.1038/ncomms11883",
language = "English",
volume = "7",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Springer",

}

RIS

TY - JOUR

T1 - Rare disruptive mutations and their contribution to the heritable risk of colorectal cancer

AU - Chubb, Daniel

AU - Broderick, Peter

AU - Dobbins, Sara E

AU - Frampton, Matthew

AU - Kinnersley, Ben

AU - Penegar, Steven

AU - Price, Amy

AU - Ma, Yussanne P

AU - Sherborne, Amy L

AU - Palles, Claire

AU - Timofeeva, Maria N

AU - Bishop, D Timothy

AU - Dunlop, Malcolm G

AU - Tomlinson, Ian

AU - Houlston, Richard S

PY - 2016/6/22

Y1 - 2016/6/22

N2 - 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.

AB - 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.

KW - Journal Article

U2 - 10.1038/ncomms11883

DO - 10.1038/ncomms11883

M3 - Article

C2 - 27329137

VL - 7

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

M1 - 11883

ER -