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dc.contributor.authorNava Rodrigues, D
dc.contributor.authorRescigno, P
dc.contributor.authorLiu, D
dc.contributor.authorYuan, W
dc.contributor.authorCarreira, S
dc.contributor.authorLambros, MB
dc.contributor.authorSeed, G
dc.contributor.authorMateo, J
dc.contributor.authorRiisnaes, R
dc.contributor.authorMullane, S
dc.contributor.authorMargolis, C
dc.contributor.authorMiao, D
dc.contributor.authorMiranda, S
dc.contributor.authorDolling, D
dc.contributor.authorClarke, M
dc.contributor.authorBertan, C
dc.contributor.authorCrespo, M
dc.contributor.authorBoysen, G
dc.contributor.authorFerreira, A
dc.contributor.authorSharp, A
dc.contributor.authorFigueiredo, I
dc.contributor.authorKeliher, D
dc.contributor.authorAldubayan, S
dc.contributor.authorBurke, KP
dc.contributor.authorSumanasuriya, S
dc.contributor.authorFontes, MS
dc.contributor.authorBianchini, D
dc.contributor.authorZafeiriou, Z
dc.contributor.authorTeixeira Mendes, LS
dc.contributor.authorMouw, K
dc.contributor.authorSchweizer, MT
dc.contributor.authorPritchard, CC
dc.contributor.authorSalipante, S
dc.contributor.authorTaplin, M-E
dc.contributor.authorBeltran, H
dc.contributor.authorRubin, MA
dc.contributor.authorCieslik, M
dc.contributor.authorRobinson, D
dc.contributor.authorHeath, E
dc.contributor.authorSchultz, N
dc.contributor.authorArmenia, J
dc.contributor.authorAbida, W
dc.contributor.authorScher, H
dc.contributor.authorLord, C
dc.contributor.authorD'Andrea, A
dc.contributor.authorSawyers, CL
dc.contributor.authorChinnaiyan, AM
dc.contributor.authorAlimonti, A
dc.contributor.authorNelson, PS
dc.contributor.authorDrake, CG
dc.contributor.authorVan Allen, EM
dc.contributor.authorde Bono, JS
dc.date.accessioned2019-03-04T14:47:34Z
dc.date.issued2018-10-01
dc.identifier.citationThe Journal of clinical investigation, 2018, 128 (10), pp. 4441 - 4453
dc.identifier.issn0021-9738
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/3120
dc.identifier.eissn1558-8238
dc.identifier.doi10.1172/jci121924
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.
dc.formatPrint-Electronic
dc.format.extent4441 - 4453
dc.languageeng
dc.language.isoeng
dc.publisherAMER SOC CLINICAL INVESTIGATION INC
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.subjectHumans
dc.subjectProstatic Neoplasms
dc.subjectNeoplasm Proteins
dc.subjectImmunotherapy
dc.subjectMutation
dc.subjectAdult
dc.subjectAged
dc.subjectMiddle Aged
dc.subjectMale
dc.subjectMicrosatellite Instability
dc.subjectDNA Mismatch Repair
dc.subjectHigh-Throughput Nucleotide Sequencing
dc.subjectB7-H1 Antigen
dc.titleImmunogenomic analyses associate immunological alterations with mismatch repair defects in prostate cancer.
dc.typeJournal Article
dcterms.dateAccepted2018-07-10
rioxxterms.versionofrecord10.1172/jci121924
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0
rioxxterms.licenseref.startdate2018-10
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfThe Journal of clinical investigation
pubs.issue10
pubs.notesNot known
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.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Translational Therapeutics
pubs.organisational-group/ICR/Students
pubs.organisational-group/ICR/Students/PhD and MPhil
pubs.organisational-group/ICR/Students/PhD and MPhil/16/17 Starting Cohort
pubs.organisational-group/ICR/Students/PhD and MPhil/18/19 Starting Cohort
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.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Translational Therapeutics
pubs.organisational-group/ICR/Students
pubs.organisational-group/ICR/Students/PhD and MPhil
pubs.organisational-group/ICR/Students/PhD and MPhil/16/17 Starting Cohort
pubs.organisational-group/ICR/Students/PhD and MPhil/18/19 Starting Cohort
pubs.publication-statusPublished
pubs.volume128
pubs.embargo.termsNot known
icr.researchteamCancer Biomarkers
icr.researchteamProstate Cancer Targeted Therapy Group
icr.researchteamTranslational Therapeutics
dc.contributor.icrauthorRescigno, Pasquale
dc.contributor.icrauthorCarreira, Suzanne
dc.contributor.icrauthorSeed, George
dc.contributor.icrauthorMiranda, Susana
dc.contributor.icrauthorClarke, Matthew
dc.contributor.icrauthorSharp, Adam
dc.contributor.icrauthorSumanasuriya, Semini
dc.contributor.icrauthorLord, Christopher
dc.contributor.icrauthorDe Bono, Johann


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