dc.contributor.author | Chubb, D | |
dc.contributor.author | Broderick, P | |
dc.contributor.author | Dobbins, SE | |
dc.contributor.author | Frampton, M | |
dc.contributor.author | Kinnersley, B | |
dc.contributor.author | Penegar, S | |
dc.contributor.author | Price, A | |
dc.contributor.author | Ma, YP | |
dc.contributor.author | Sherborne, AL | |
dc.contributor.author | Palles, C | |
dc.contributor.author | Timofeeva, MN | |
dc.contributor.author | Bishop, DT | |
dc.contributor.author | Dunlop, MG | |
dc.contributor.author | Tomlinson, I | |
dc.contributor.author | Houlston, RS | |
dc.date.accessioned | 2017-02-01T12:13:14Z | |
dc.date.issued | 2016-06-22 | |
dc.identifier.citation | Nature communications, 2016, 7 pp. 11883 - ? | |
dc.identifier.issn | 2041-1723 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/398 | |
dc.identifier.eissn | 2041-1723 | |
dc.identifier.doi | 10.1038/ncomms11883 | |
dc.description.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. | |
dc.format | Electronic | |
dc.format.extent | 11883 - ? | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | NATURE PUBLISHING GROUP | |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0 | |
dc.subject | Humans | |
dc.subject | Colorectal Neoplasms | |
dc.subject | Genetic Predisposition to Disease | |
dc.subject | Risk Factors | |
dc.subject | Case-Control Studies | |
dc.subject | Pedigree | |
dc.subject | Age Factors | |
dc.subject | Age of Onset | |
dc.subject | Phenotype | |
dc.subject | Germ-Line Mutation | |
dc.subject | Alleles | |
dc.subject | Adult | |
dc.subject | Middle Aged | |
dc.subject | Female | |
dc.subject | Male | |
dc.subject | Genetic Variation | |
dc.subject | Exome | |
dc.subject | United Kingdom | |
dc.title | Rare disruptive mutations and their contribution to the heritable risk of colorectal cancer. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2016-05-09 | |
rioxxterms.versionofrecord | 10.1038/ncomms11883 | |
rioxxterms.licenseref.uri | https://creativecommons.org/licenses/by/4.0 | |
rioxxterms.licenseref.startdate | 2016-06-22 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | Nature communications | |
pubs.notes | No embargo | |
pubs.organisational-group | /ICR | |
pubs.organisational-group | /ICR/Primary Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Genetics and Epidemiology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Genetics and Epidemiology/Cancer Genomics | |
pubs.organisational-group | /ICR | |
pubs.organisational-group | /ICR/Primary Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Genetics and Epidemiology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Genetics and Epidemiology/Cancer Genomics | |
pubs.publication-status | Published | |
pubs.volume | 7 | |
pubs.embargo.terms | No embargo | |
icr.researchteam | Cancer Genomics | |
dc.contributor.icrauthor | Chubb, Daniel | |
dc.contributor.icrauthor | Broderick, Peter | |
dc.contributor.icrauthor | Kinnersley, Benjamin | |
dc.contributor.icrauthor | Penegar, Steven | |
dc.contributor.icrauthor | Houlston, Richard | |