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dc.contributor.authorNava Rodrigues, Den_US
dc.contributor.authorCasiraghi, Nen_US
dc.contributor.authorRomanel, Aen_US
dc.contributor.authorCrespo, Men_US
dc.contributor.authorMiranda, Sen_US
dc.contributor.authorRescigno, Pen_US
dc.contributor.authorFigueiredo, Ien_US
dc.contributor.authorRiisnaes, Ren_US
dc.contributor.authorCarreira, Sen_US
dc.contributor.authorSumanasuriya, Sen_US
dc.contributor.authorGasperini, Pen_US
dc.contributor.authorSharp, Aen_US
dc.contributor.authorMateo, Jen_US
dc.contributor.authorMakay, Aen_US
dc.contributor.authorMcNair, Cen_US
dc.contributor.authorSchiewer, Men_US
dc.contributor.authorKnudsen, Ken_US
dc.contributor.authorBoysen, Gen_US
dc.contributor.authorDemichelis, Fen_US
dc.contributor.authorde Bono, JSen_US
dc.coverage.spatialUnited Statesen_US
dc.date.accessioned2018-11-14T09:43:35Z
dc.date.issued2019-01-15en_US
dc.identifierhttps://www.ncbi.nlm.nih.gov/pubmed/30257982en_US
dc.identifier1078-0432.CCR-18-2068en_US
dc.identifier.citationClin Cancer Res, 2019, 25 (2), pp. 687 - 697en_US
dc.identifier.issn1078-0432en_US
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/2930
dc.identifier.doi10.1158/1078-0432.CCR-18-2068en_US
dc.description.abstractPURPOSE: Metastatic castration-resistant prostate cancer (mCRPC) is a lethal but clinically heterogeneous disease, with patients having variable benefit from endocrine and cytotoxic treatments. Intrapatient genomic heterogeneity could be a contributing factor to this clinical heterogeneity. Here, we used whole-genome sequencing (WGS) to investigate genomic heterogeneity in 21 previously treated CRPC metastases from 10 patients to investigate intrapatient molecular heterogeneity (IPMH).Experimental Design: WGS was performed on topographically separate metastases from patients with advanced metastatic prostate cancer. IPMH of the RB1 gene was identified and further evaluated by FISH and IHC assays. RESULTS: WGS identified limited IPMH for putative driver events. However, heterogeneous genomic aberrations of RB1 were detected. We confirmed the presence of these RB1 somatic copy-number aberrations, initially identified by WGS, with FISH, and identified novel structural variants involving RB1 in 6 samples from 3 of these 10 patients (30%; 3/10). WGS uncovered a novel deleterious RB1 structural lesion constituted of an intragenic tandem duplication involving multiple exons and associating with protein loss. Using RB1 IHC in a large series of mCRPC biopsies, we identified heterogeneous expression in approximately 28% of mCRPCs. CONCLUSIONS: mCRPCs have a high prevalence of RB1 genomic aberrations, with structural variants, including rearrangements, being common. Intrapatient genomic and expression heterogeneity favors RB1 aberrations as late, subclonal events that increase in prevalence due to treatment-selective pressures.en_US
dc.format.extent687 - 697en_US
dc.languageengen_US
dc.language.isoengen_US
dc.rights.urihttp://www.rioxx.net/licenses/under-embargo-all-rights-reserveden_US
dc.titleRB1 Heterogeneity in Advanced Metastatic Castration-Resistant Prostate Cancer.en_US
dc.typeJournal Article
dcterms.dateAccepted2018-09-18en_US
rioxxterms.versionofrecord10.1158/1078-0432.CCR-18-2068en_US
rioxxterms.licenseref.startdate2019-01-15en_US
rioxxterms.typeJournal Article/Reviewen_US
dc.relation.isPartOfClin Cancer Resen_US
pubs.issue2en_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/Cancer Therapeutics/Glioma Team
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/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Glioma Team
pubs.publication-statusPublisheden_US
pubs.volume25en_US
pubs.embargo.termsNot knownen_US
icr.researchteamCancer Biomarkersen_US
icr.researchteamProstate Cancer Targeted Therapy Groupen_US
icr.researchteamGlioma Teamen_US
dc.contributor.icrauthorCarreira, Suzanneen_US
dc.contributor.icrauthorMackay, Alanen_US
dc.contributor.icrauthorDe Bono, Johannen_US


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