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dc.contributor.authorNava Rodrigues, Den_US
dc.contributor.authorRescigno, Pen_US
dc.contributor.authorLiu, Den_US
dc.contributor.authorYuan, Wen_US
dc.contributor.authorCarreira, Sen_US
dc.contributor.authorLambros, MBen_US
dc.contributor.authorSeed, Gen_US
dc.contributor.authorMateo, Jen_US
dc.contributor.authorRiisnaes, Ren_US
dc.contributor.authorMullane, Sen_US
dc.contributor.authorMargolis, Cen_US
dc.contributor.authorMiao, Den_US
dc.contributor.authorMiranda, Sen_US
dc.contributor.authorDolling, Den_US
dc.contributor.authorClarke, Men_US
dc.contributor.authorBertan, Cen_US
dc.contributor.authorCrespo, Men_US
dc.contributor.authorBoysen, Gen_US
dc.contributor.authorFerreira, Aen_US
dc.contributor.authorSharp, Aen_US
dc.contributor.authorFigueiredo, Ien_US
dc.contributor.authorKeliher, Den_US
dc.contributor.authorAldubayan, Sen_US
dc.contributor.authorBurke, KPen_US
dc.contributor.authorSumanasuriya, Sen_US
dc.contributor.authorFontes, MSen_US
dc.contributor.authorBianchini, Den_US
dc.contributor.authorZafeiriou, Zen_US
dc.contributor.authorTeixeira Mendes, LSen_US
dc.contributor.authorMouw, Ken_US
dc.contributor.authorSchweizer, MTen_US
dc.contributor.authorPritchard, CCen_US
dc.contributor.authorSalipante, Sen_US
dc.contributor.authorTaplin, M-Een_US
dc.contributor.authorBeltran, Hen_US
dc.contributor.authorRubin, MAen_US
dc.contributor.authorCieslik, Men_US
dc.contributor.authorRobinson, Den_US
dc.contributor.authorHeath, Een_US
dc.contributor.authorSchultz, Nen_US
dc.contributor.authorArmenia, Jen_US
dc.contributor.authorAbida, Wen_US
dc.contributor.authorScher, Hen_US
dc.contributor.authorLord, Cen_US
dc.contributor.authorD'Andrea, Aen_US
dc.contributor.authorSawyers, CLen_US
dc.contributor.authorChinnaiyan, AMen_US
dc.contributor.authorAlimonti, Aen_US
dc.contributor.authorNelson, PSen_US
dc.contributor.authorDrake, CGen_US
dc.contributor.authorVan Allen, EMen_US
dc.contributor.authorde Bono, JSen_US
dc.coverage.spatialUnited Statesen_US
dc.date.accessioned2019-03-04T14:47:34Z
dc.date.issued2018-10-01en_US
dc.identifierhttps://www.ncbi.nlm.nih.gov/pubmed/30179225en_US
dc.identifier121924en_US
dc.identifier.citationJ Clin Invest, 2018, 128 (10), pp. 4441 - 4453en_US
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/3120
dc.identifier.eissn1558-8238en_US
dc.identifier.doi10.1172/JCI121924en_US
dc.description.abstractBACKGROUND: Understanding the integrated immunogenomic landscape of advanced prostate cancer (APC) could impact stratified treatment selection. METHODS: Defective mismatch repair (dMMR) status was determined by either loss of mismatch repair protein expression on IHC or microsatellite instability (MSI) by PCR in 127 APC biopsies from 124 patients (Royal Marsden [RMH] cohort); MSI by targeted panel next-generation sequencing (MSINGS) was then evaluated in the same cohort and in 254 APC samples from the Stand Up To Cancer/Prostate Cancer Foundation (SU2C/PCF). Whole exome sequencing (WES) data from this latter cohort were analyzed for pathogenic MMR gene variants, mutational load, and mutational signatures. Transcriptomic data, available for 168 samples, was also performed. RESULTS: Overall, 8.1% of patients in the RMH cohort had some evidence of dMMR, which associated with decreased overall survival. Higher MSINGS scores associated with dMMR, and these APCs were enriched for higher T cell infiltration and PD-L1 protein expression. Exome MSINGS scores strongly correlated with targeted panel MSINGS scores (r = 0.73, P < 0.0001), and higher MSINGS scores associated with dMMR mutational signatures in APC exomes. dMMR mutational signatures also associated with MMR gene mutations and increased immune cell, immune checkpoint, and T cell-associated transcripts. APC with dMMR mutational signatures overexpressed a variety of immune transcripts, including CD200R1, BTLA, PD-L1, PD-L2, ADORA2A, PIK3CG, and TIGIT. CONCLUSION: These data could impact immune target selection, combination therapeutic strategy selection, and selection of predictive biomarkers for immunotherapy in APC. FUNDING: We acknowledge funding support from Movember, Prostate Cancer UK, The Prostate Cancer Foundation, SU2C, and Cancer Research UK.en_US
dc.format.extent4441 - 4453en_US
dc.languageengen_US
dc.language.isoengen_US
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en_US
dc.subjectCancer immunotherapyen_US
dc.subjectDNA repairen_US
dc.subjectGeneticsen_US
dc.subjectOncologyen_US
dc.subjectProstate canceren_US
dc.titleImmunogenomic analyses associate immunological alterations with mismatch repair defects in prostate cancer.en_US
dc.typeJournal Article
dcterms.dateAccepted2018-07-10en_US
rioxxterms.versionofrecord10.1172/JCI121924en_US
rioxxterms.licenseref.startdate2018-10-01en_US
rioxxterms.typeJournal Article/Reviewen_US
dc.relation.isPartOfJ Clin Investen_US
pubs.issue10en_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/Cancer Therapeutics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Cancer Biomarkers
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Cancer Biomarkers
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Prostate Cancer Targeted Therapy Group
pubs.publication-statusPublisheden_US
pubs.volume128en_US
pubs.embargo.termsNot knownen_US
icr.researchteamCancer Biomarkersen_US
icr.researchteamProstate Cancer Targeted Therapy Groupen_US
dc.contributor.icrauthorCarreira, Suzanneen_US
dc.contributor.icrauthorDe Bono, Johannen_US
dc.contributor.icrauthorMateo Valderrama, Joaquinen_US
dc.contributor.icrauthorMiranda, Susanaen_US


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Except where otherwise noted, this item's license is described as http://creativecommons.org/licenses/by/4.0/