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dc.contributor.authorMijuskovic, Men_US
dc.contributor.authorSaunders, EJen_US
dc.contributor.authorLeongamornlert, DAen_US
dc.contributor.authorWakerell, Sen_US
dc.contributor.authorWhitmore, Ien_US
dc.contributor.authorDadaev, Ten_US
dc.contributor.authorCieza-Borrella, Cen_US
dc.contributor.authorGovindasami, Ken_US
dc.contributor.authorBrook, MNen_US
dc.contributor.authorHaiman, CAen_US
dc.contributor.authorConti, DVen_US
dc.contributor.authorEeles, RAen_US
dc.contributor.authorKote-Jarai, Zen_US
dc.date.accessioned2018-07-18T13:29:02Z
dc.date.issued2018-07en_US
dc.identifier.citationBritish journal of cancer, 2018, 119 (1), pp. 96 - 104en_US
dc.identifier.issn0007-0920en_US
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/2090
dc.identifier.eissn1532-1827en_US
dc.identifier.doi10.1038/s41416-018-0141-7en_US
dc.description.abstract<h4>Background</h4>Prostate cancer (PrCa) demonstrates a heterogeneous clinical presentation ranging from largely indolent to lethal. We sought to identify a signature of rare inherited variants that distinguishes between these two extreme phenotypes.<h4>Methods</h4>We sequenced germline whole exomes from 139 aggressive (metastatic, age of diagnosis < 60) and 141 non-aggressive (low clinical grade, age of diagnosis ≥60) PrCa cases. We conducted rare variant association analyses at gene and gene set levels using SKAT and Bayesian risk index techniques. GO term enrichment analysis was performed for genes with the highest differential burden of rare disruptive variants.<h4>Results</h4>Protein truncating variants (PTVs) in specific DNA repair genes were significantly overrepresented among patients with the aggressive phenotype, with BRCA2, ATM and NBN the most frequently mutated genes. Differential burden of rare variants was identified between metastatic and non-aggressive cases for several genes implicated in angiogenesis, conferring both deleterious and protective effects.<h4>Conclusions</h4>Inherited PTVs in several DNA repair genes distinguish aggressive from non-aggressive PrCa cases. Furthermore, inherited variants in genes with roles in angiogenesis may be potential predictors for risk of metastases. If validated in a larger dataset, these findings have potential for future clinical application.en_US
dc.formatPrint-Electronicen_US
dc.format.extent96 - 104en_US
dc.languageengen_US
dc.language.isoengen_US
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en_US
dc.subjectHumansen_US
dc.subjectProstatic Neoplasmsen_US
dc.subjectNeoplasm Metastasisen_US
dc.subjectGenetic Predisposition to Diseaseen_US
dc.subjectNeovascularization, Pathologicen_US
dc.subjectCell Cycle Proteinsen_US
dc.subjectBRCA2 Proteinen_US
dc.subjectNuclear Proteinsen_US
dc.subjectDNA Repairen_US
dc.subjectPolymorphism, Single Nucleotideen_US
dc.subjectAgeden_US
dc.subjectMiddle Ageden_US
dc.subjectMaleen_US
dc.subjectGenetic Association Studiesen_US
dc.subjectAtaxia Telangiectasia Mutated Proteinsen_US
dc.subjectWhole Exome Sequencingen_US
dc.titleRare germline variants in DNA repair genes and the angiogenesis pathway predispose prostate cancer patients to develop metastatic disease.en_US
dc.typeJournal Article
dcterms.dateAccepted2018-05-17en_US
rioxxterms.versionofrecord10.1038/s41416-018-0141-7en_US
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0en_US
rioxxterms.licenseref.startdate2018-07en_US
rioxxterms.typeJournal Article/Reviewen_US
dc.relation.isPartOfBritish journal of canceren_US
pubs.issue1en_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.organisational-group/ICR/Students
pubs.organisational-group/ICR/Students/PhD and MPhil
pubs.organisational-group/ICR/Students/PhD and MPhil/18/19 Starting Cohort
pubs.publication-statusPublisheden_US
pubs.volume119en_US
pubs.embargo.termsNot knownen_US
icr.researchteamOncogeneticsen_US
dc.contributor.icrauthorEeles, Rosalinden_US
dc.contributor.icrauthorSaunders, Edwarden_US
dc.contributor.icrauthorBrook, Marken_US
dc.contributor.icrauthorKote-Jarai, Zsofiaen_US


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