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dc.contributor.authorLeongamornlert, DAen_US
dc.contributor.authorSaunders, EJen_US
dc.contributor.authorWakerell, Sen_US
dc.contributor.authorWhitmore, Ien_US
dc.contributor.authorDadaev, Ten_US
dc.contributor.authorCieza-Borrella, Cen_US
dc.contributor.authorBenafif, Sen_US
dc.contributor.authorBrook, MNen_US
dc.contributor.authorDonovan, JLen_US
dc.contributor.authorHamdy, FCen_US
dc.contributor.authorNeal, DEen_US
dc.contributor.authorMuir, Ken_US
dc.contributor.authorGovindasami, Ken_US
dc.contributor.authorConti, DVen_US
dc.contributor.authorKote-Jarai, Zen_US
dc.contributor.authorEeles, RAen_US
dc.coverage.spatialSwitzerlanden_US
dc.date.accessioned2019-03-08T11:41:25Z
dc.date.issued2019-02-15en_US
dc.identifierhttps://www.ncbi.nlm.nih.gov/pubmed/30777372en_US
dc.identifierS0302-2838(19)30096-Xen_US
dc.identifier.citationEur Urol, 2019en_US
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/3144
dc.identifier.eissn1873-7560en_US
dc.identifier.doi10.1016/j.eururo.2019.01.050en_US
dc.description.abstractBACKGROUND: Rare germline mutations in DNA repair genes are associated with prostate cancer (PCa) predisposition and prognosis. OBJECTIVE: To quantify the frequency of germline DNA repair gene mutations in UK PCa cases and controls, in order to more comprehensively evaluate the contribution of individual genes to overall PCa risk and likelihood of aggressive disease. DESIGN, SETTING, AND PARTICIPANTS: We sequenced 167 DNA repair and eight PCa candidate genes in a UK-based cohort of 1281 young-onset PCa cases (diagnosed at ≤60yr) and 1160 selected controls. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Gene-level SKAT-O and gene-set adaptive combination of p values (ADA) analyses were performed separately for cases versus controls, and aggressive (Gleason score ≥8, n=201) versus nonaggressive (Gleason score ≤7, n=1048) cases. RESULTS AND LIMITATIONS: We identified 233 unique protein truncating variants (PTVs) with minor allele frequency <0.5% in controls in 97 genes. The total proportion of PTV carriers was higher in cases than in controls (15% vs 12%, odds ratio [OR]=1.29, 95% confidence interval [CI] 1.01-1.64, p=0.036). Gene-level analyses selected NBN (pSKAT-O=2.4×10-4) for overall risk and XPC (pSKAT-O=1.6×10-4) for aggressive disease, both at candidate-level significance (p<3.1×10-4 and p<3.4×10-4, respectively). Gene-set analysis identified a subset of 20 genes associated with increased PCa risk (OR=3.2, 95% CI 2.1-4.8, pADA=4.1×10-3) and four genes that increased risk of aggressive disease (OR=11.2, 95% CI 4.6-27.7, pADA=5.6×10-3), three of which overlap the predisposition gene set. CONCLUSIONS: The union of the gene-level and gene-set-level analyses identified 23 unique DNA repair genes associated with PCa predisposition or risk of aggressive disease. These findings will help facilitate the development of a PCa-specific sequencing panel with both predictive and prognostic potential. PATIENT SUMMARY: This large sequencing study assessed the rate of inherited DNA repair gene mutations between prostate cancer patients and disease-free men. A panel of 23 genes was identified, which may improve risk prediction or treatment pathways in future clinical practice.en_US
dc.languageengen_US
dc.language.isoengen_US
dc.rights.urihttp://www.rioxx.net/licenses/under-embargo-all-rights-reserveden_US
dc.subjectAggressive phenotypeen_US
dc.subjectDNA repair genesen_US
dc.subjectGene panel testingen_US
dc.subjectGenetic predispositionen_US
dc.subjectProstate canceren_US
dc.titleGermline DNA Repair Gene Mutations in Young-onset Prostate Cancer Cases in the UK: Evidence for a More Extensive Genetic Panel.en_US
dc.typeJournal Article
dcterms.dateAccepted2019-01-31en_US
rioxxterms.versionofrecord10.1016/j.eururo.2019.01.050en_US
rioxxterms.licenseref.startdate2019-02-15en_US
rioxxterms.typeJournal Article/Reviewen_US
dc.relation.isPartOfEur Urolen_US
pubs.notesNot knownen_US
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/Oncogenetics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging/Oncogenetics
pubs.publication-statusPublished onlineen_US
pubs.embargo.termsNot knownen_US
icr.researchteamOncogeneticsen_US
dc.contributor.icrauthorBrook, Marken_US
dc.contributor.icrauthorSaunders, Edwarden_US
dc.contributor.icrauthorKote-Jarai, Zsofiaen_US
dc.contributor.icrauthorEeles, Rosalinden_US


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