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

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, analysi...

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Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4917884/
https://www.ncbi.nlm.nih.gov/pubmed/27329137
http://dx.doi.org/10.1038/ncomms11883
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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.
author_facet 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.
author_sort Chubb, Daniel
collection PubMed
description 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.
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spelling pubmed-49178842016-07-07 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. Nat Commun Article 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. Nature Publishing Group 2016-06-22 /pmc/articles/PMC4917884/ /pubmed/27329137 http://dx.doi.org/10.1038/ncomms11883 Text en Copyright © 2016, Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved. http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Article
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
title Rare disruptive mutations and their contribution to the heritable risk of colorectal cancer
title_full Rare disruptive mutations and their contribution to the heritable risk of colorectal cancer
title_fullStr Rare disruptive mutations and their contribution to the heritable risk of colorectal cancer
title_full_unstemmed Rare disruptive mutations and their contribution to the heritable risk of colorectal cancer
title_short Rare disruptive mutations and their contribution to the heritable risk of colorectal cancer
title_sort rare disruptive mutations and their contribution to the heritable risk of colorectal cancer
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4917884/
https://www.ncbi.nlm.nih.gov/pubmed/27329137
http://dx.doi.org/10.1038/ncomms11883
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