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dc.contributor.authorKerns, SLen_US
dc.contributor.authorFachal, Len_US
dc.contributor.authorDorling, Len_US
dc.contributor.authorBarnett, GCen_US
dc.contributor.authorBaran, Aen_US
dc.contributor.authorPeterson, DRen_US
dc.contributor.authorHollenberg, Men_US
dc.contributor.authorHao, Ken_US
dc.contributor.authorNarzo, ADen_US
dc.contributor.authorAhsen, MEen_US
dc.contributor.authorPandey, Gen_US
dc.contributor.authorBentzen, SMen_US
dc.contributor.authorJanelsins, Men_US
dc.contributor.authorElliott, RMen_US
dc.contributor.authorPharoah, PDPen_US
dc.contributor.authorBurnet, NGen_US
dc.contributor.authorDearnaley, DPen_US
dc.contributor.authorGulliford, SLen_US
dc.contributor.authorHall, Een_US
dc.contributor.authorSydes, MRen_US
dc.contributor.authorAguado-Barrera, MEen_US
dc.contributor.authorGómez-Caamaño, Aen_US
dc.contributor.authorCarballo, AMen_US
dc.contributor.authorPeleteiro, Pen_US
dc.contributor.authorLobato-Busto, Ren_US
dc.contributor.authorStock, Ren_US
dc.contributor.authorStone, NNen_US
dc.contributor.authorOstrer, Hen_US
dc.contributor.authorUsmani, Nen_US
dc.contributor.authorSinghal, Sen_US
dc.contributor.authorTsuji, Hen_US
dc.contributor.authorImai, Ten_US
dc.contributor.authorSaito, Sen_US
dc.contributor.authorEeles, Ren_US
dc.contributor.authorDeRuyck, Ken_US
dc.contributor.authorParliament, Men_US
dc.contributor.authorDunning, AMen_US
dc.contributor.authorVega, Aen_US
dc.contributor.authorRosenstein, BSen_US
dc.contributor.authorWest, CMLen_US
dc.coverage.spatialUnited Statesen_US
dc.date.accessioned2019-06-24T08:52:06Z
dc.date.issued2019-05-16en_US
dc.identifierhttps://www.ncbi.nlm.nih.gov/pubmed/31095341en_US
dc.identifier5490201en_US
dc.identifier.citationJ Natl Cancer Inst, 2019en_US
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/3268
dc.identifier.eissn1460-2105en_US
dc.identifier.doi10.1093/jnci/djz075en_US
dc.description.abstractBACKGROUND: 10-20% of patients develop long-term toxicity following radiotherapy for prostate cancer. Identification of common genetic variants associated with susceptibility to radiotoxicity might improve risk prediction and inform functional mechanistic studies. METHODS: We conducted an individual patient data meta-analysis of six genome-wide association studies (n = 3,871) in men with European ancestry who underwent radiotherapy for prostate cancer. Radiotoxicities (increased urinary frequency, decreased urinary stream, hematuria, rectal bleeding) were graded prospectively. Grouped relative risk models tested associations with ∼6 million genotyped/imputed variants (time to first ≥grade 2 toxicity event). Variants with two-sided Pmeta<5x10-8 were considered statistically significant. Bayesian false discovery probability provided an additional measure of confidence. Statistically significant variants were evaluated in three Japanese cohorts (n = 962). All statistical tests were two-sided. RESULTS: Meta-analysis of the European ancestry cohorts identified three genomic signals: single nucleotide polymorphism (SNP) rs17055178 with rectal bleeding (Pmeta=6.2x10-10), rs10969913 with decreased urinary stream (Pmeta=2.9x10-10) and rs11122573 with hematuria (Pmeta=1.8x10-8). Fine scale mapping of these three regions identified another independent signal (rs147121532) associated with hematuria (Pconditional=4.7x10-6). Credible causal variants at these four signals lie in gene-regulatory regions, some modulating expression of nearby genes. Previously identified variants showed consistent associations (rs17599026 with increased urinary frequency, rs7720298 with decreased urinary stream, rs1801516 with overall toxicity) in new cohorts. rs10969913 and rs17599026 had similar effects in the photon-treated Japanese cohorts. CONCLUSIONS: This study increases understanding of the architecture of common genetic variants affecting radiotoxicity, points to novel radio-pathogenic mechanisms, and develops risk models for testing in clinical studies. Further multi-national radiogenomics studies in larger cohorts are worthwhile.en_US
dc.languageengen_US
dc.language.isoengen_US
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en_US
dc.titleRadiogenomics Consortium Genome-Wide Association Study Meta-analysis of Late Toxicity after Prostate Cancer Radiotherapy.en_US
dc.typeJournal Article
dcterms.dateAccepted2019-04-26en_US
rioxxterms.versionofrecord10.1093/jnci/djz075en_US
rioxxterms.licenseref.startdate2019-05-16en_US
rioxxterms.typeJournal Article/Reviewen_US
dc.relation.isPartOfJ Natl Cancer Insten_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/Clinical Studies
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/ICR-CTSU Urology and Head and Neck Trials Team
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/Clinical Academic Radiotherapy (Dearnaley)
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging/Oncogenetics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging/Radiotherapy Physics Modelling
pubs.publication-statusPublished onlineen_US
pubs.embargo.termsNot knownen_US
icr.researchteamICR-CTSU Urology and Head and Neck Trials Teamen_US
icr.researchteamClinical Academic Radiotherapy (Dearnaley)en_US
icr.researchteamOncogeneticsen_US
icr.researchteamRadiotherapy Physics Modellingen_US
dc.contributor.icrauthorDearnaley, Daviden_US
dc.contributor.icrauthorEeles, Rosalinden_US
dc.contributor.icrauthorGulliford, Sarahen_US
dc.contributor.icrauthorHall, Emmaen_US


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