dc.contributor.author | Nava Rodrigues, D | |
dc.contributor.author | Casiraghi, N | |
dc.contributor.author | Romanel, A | |
dc.contributor.author | Crespo, M | |
dc.contributor.author | Miranda, S | |
dc.contributor.author | Rescigno, P | |
dc.contributor.author | Figueiredo, I | |
dc.contributor.author | Riisnaes, R | |
dc.contributor.author | Carreira, S | |
dc.contributor.author | Sumanasuriya, S | |
dc.contributor.author | Gasperini, P | |
dc.contributor.author | Sharp, A | |
dc.contributor.author | Mateo, J | |
dc.contributor.author | Makay, A | |
dc.contributor.author | McNair, C | |
dc.contributor.author | Schiewer, M | |
dc.contributor.author | Knudsen, K | |
dc.contributor.author | Boysen, G | |
dc.contributor.author | Demichelis, F | |
dc.contributor.author | de Bono, JS | |
dc.date.accessioned | 2018-11-14T09:43:35Z | |
dc.date.issued | 2019-01-15 | |
dc.identifier.citation | Clinical cancer research : an official journal of the American Association for Cancer Research, 2019, 25 (2), pp. 687 - 697 | |
dc.identifier.issn | 1078-0432 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/2930 | |
dc.identifier.eissn | 1557-3265 | |
dc.identifier.doi | 10.1158/1078-0432.ccr-18-2068 | |
dc.description.abstract | PURPOSE: 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. | |
dc.format | Print-Electronic | |
dc.format.extent | 687 - 697 | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | AMER ASSOC CANCER RESEARCH | |
dc.rights.uri | https://www.rioxx.net/licenses/under-embargo-all-rights-reserved | |
dc.subject | Cell Line, Tumor | |
dc.subject | Humans | |
dc.subject | Ubiquitin-Protein Ligases | |
dc.subject | Neoplasm Staging | |
dc.subject | Immunohistochemistry | |
dc.subject | In Situ Hybridization, Fluorescence | |
dc.subject | Genetic Heterogeneity | |
dc.subject | Aged | |
dc.subject | Middle Aged | |
dc.subject | Male | |
dc.subject | Genetic Variation | |
dc.subject | Genome-Wide Association Study | |
dc.subject | Retinoblastoma Binding Proteins | |
dc.subject | DNA Copy Number Variations | |
dc.subject | Neoplasm Grading | |
dc.subject | Prostatic Neoplasms, Castration-Resistant | |
dc.subject | Biomarkers, Tumor | |
dc.subject | Whole Genome Sequencing | |
dc.title | RB1 Heterogeneity in Advanced Metastatic Castration-Resistant Prostate Cancer. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2018-09-18 | |
rioxxterms.versionofrecord | 10.1158/1078-0432.ccr-18-2068 | |
rioxxterms.licenseref.uri | https://www.rioxx.net/licenses/under-embargo-all-rights-reserved | |
rioxxterms.licenseref.startdate | 2019-01 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | Clinical cancer research : an official journal of the American Association for Cancer Research | |
pubs.issue | 2 | |
pubs.notes | Not 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/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/Clinical Studies/Translational Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology/Glioma Team | |
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/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/Clinical Studies/Translational Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology/Glioma Team | |
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-status | Published | |
pubs.volume | 25 | |
pubs.embargo.terms | Not known | |
icr.researchteam | Cancer Biomarkers | |
icr.researchteam | Prostate Cancer Targeted Therapy Group | |
icr.researchteam | Translational Therapeutics | |
icr.researchteam | Glioma Team | |
dc.contributor.icrauthor | Miranda, Susana | |
dc.contributor.icrauthor | Rescigno, Pasquale | |
dc.contributor.icrauthor | Carreira, Suzanne | |
dc.contributor.icrauthor | Sumanasuriya, Semini | |
dc.contributor.icrauthor | Sharp, Adam | |
dc.contributor.icrauthor | De Bono, Johann | |