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dc.contributor.authorChubb, D
dc.contributor.authorBroderick, P
dc.contributor.authorDobbins, SE
dc.contributor.authorFrampton, M
dc.contributor.authorKinnersley, B
dc.contributor.authorPenegar, S
dc.contributor.authorPrice, A
dc.contributor.authorMa, YP
dc.contributor.authorSherborne, AL
dc.contributor.authorPalles, C
dc.contributor.authorTimofeeva, MN
dc.contributor.authorBishop, DT
dc.contributor.authorDunlop, MG
dc.contributor.authorTomlinson, I
dc.contributor.authorHoulston, RS
dc.date.accessioned2017-02-01T12:13:14Z
dc.date.issued2016-06-22
dc.identifier.citationNature communications, 2016, 7 pp. 11883 - ?
dc.identifier.issn2041-1723
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/398
dc.identifier.eissn2041-1723
dc.identifier.doi10.1038/ncomms11883
dc.description.abstractColorectal 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.formatElectronic
dc.format.extent11883 - ?
dc.languageeng
dc.language.isoeng
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.subjectHumans
dc.subjectColorectal Neoplasms
dc.subjectGenetic Predisposition to Disease
dc.subjectRisk Factors
dc.subjectCase-Control Studies
dc.subjectPedigree
dc.subjectAge Factors
dc.subjectAge of Onset
dc.subjectPhenotype
dc.subjectGerm-Line Mutation
dc.subjectAlleles
dc.subjectAdult
dc.subjectMiddle Aged
dc.subjectFemale
dc.subjectMale
dc.subjectGenetic Variation
dc.subjectExome
dc.subjectUnited Kingdom
dc.titleRare disruptive mutations and their contribution to the heritable risk of colorectal cancer.
dc.typeJournal Article
dcterms.dateAccepted2016-05-09
rioxxterms.versionofrecord10.1038/ncomms11883
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0
rioxxterms.licenseref.startdate2016-06-22
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfNature communications
pubs.notesNo 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-statusPublished
pubs.volume7
pubs.embargo.termsNo embargo
icr.researchteamCancer Genomicsen_US
dc.contributor.icrauthorChubb, Danielen
dc.contributor.icrauthorHoulston, Richarden
dc.contributor.icrauthorBroderick, Peteren
dc.contributor.icrauthorKinnersley, Benjaminen


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