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dc.contributor.authorBroderick, P
dc.contributor.authorDobbins, SE
dc.contributor.authorChubb, D
dc.contributor.authorKinnersley, B
dc.contributor.authorDunlop, MG
dc.contributor.authorTomlinson, I
dc.contributor.authorHoulston, RS
dc.date.accessioned2016-11-14T17:02:01Z
dc.date.issued2017-01
dc.identifier.citationGastroenterology, 2017, 152 (1), pp. 75 - 77.e4
dc.identifier.issn0016-5085
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/207
dc.identifier.eissn1528-0012
dc.identifier.doi10.1053/j.gastro.2016.09.041
dc.description.abstractHigh-throughput sequencing analysis has accelerated searches for genes associated with risk for colorectal cancer (CRC); germline mutations in NTHL1, RPS20, FANCM, FAN1, TP53, BUB1, BUB3, LRP6, and PTPN12 have been recently proposed to increase CRC risk. We attempted to validate the association between variants in these genes and development of CRC in a systematic review of 11 publications, using sequence data from 863 familial CRC cases and 1604 individuals without CRC (controls). All cases were diagnosed at an age of 55 years or younger and did not carry mutations in an established CRC predisposition gene. We found sufficient evidence for NTHL1 to be considered a CRC predisposition gene-members of 3 unrelated Dutch families were homozygous for inactivating p.Gln90Ter mutations; a Canadian woman with polyposis, CRC, and multiple tumors was reported to be heterozygous for the inactivating NTHL1 p.Gln90Ter/c.709+1G>A mutations; and a man with polyposis was reported to carry p.Gln90Ter/p.Gln287Ter; whereas no inactivating homozygous or compound heterozygous mutations were detected in controls. Variants that disrupted RPS20 were detected in a Finnish family with early-onset CRC (p.Val50SerfsTer23), a 39-year old individual with metachronous CRC (p.Leu61GlufsTer11 mutation), and a 41-year-old individual with CRC (missense p.Val54Leu), but not in controls. We therefore found published evidence to support the association between variants in NTHL1 and RPS20 with CRC, but not of other recently reported CRC susceptibility variants. We urge the research community to adopt rigorous statistical and biological approaches coupled with independent replication before making claims of pathogenicity.
dc.formatPrint-Electronic
dc.format.extent75 - 77.e4
dc.languageeng
dc.language.isoeng
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/4.0
dc.subjectHumans
dc.subjectAdenomatous Polyposis Coli
dc.subjectColorectal Neoplasms
dc.subjectGenetic Predisposition to Disease
dc.subjectDeoxyribonuclease (Pyrimidine Dimer)
dc.subjectRibosomal Proteins
dc.subjectGerm-Line Mutation
dc.titleValidation of Recently Proposed Colorectal Cancer Susceptibility Gene Variants in an Analysis of Families and Patients-a Systematic Review.
dc.typeJournal Article
dcterms.dateAccepted2016-09-27
rioxxterms.versionofrecord10.1053/j.gastro.2016.09.041
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by-nc-nd/4.0
rioxxterms.licenseref.startdate2017-01
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfGastroenterology
pubs.issue1
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.volume152
pubs.embargo.termsNo embargo
icr.researchteamCancer Genomicsen_US
dc.contributor.icrauthorBroderick, Peteren
dc.contributor.icrauthorKinnersley, Benjaminen
dc.contributor.icrauthorHoulston, Richarden


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