dc.contributor.author | Lundberg, A | |
dc.contributor.author | Zhang, M | |
dc.contributor.author | Aggarwal, R | |
dc.contributor.author | Li, H | |
dc.contributor.author | Zhang, L | |
dc.contributor.author | Foye, A | |
dc.contributor.author | Sjöström, M | |
dc.contributor.author | Chou, J | |
dc.contributor.author | Chang, K | |
dc.contributor.author | Moreno-Rodriguez, T | |
dc.contributor.author | Shrestha, R | |
dc.contributor.author | Baskin, A | |
dc.contributor.author | Zhu, X | |
dc.contributor.author | Weinstein, AS | |
dc.contributor.author | Younger, N | |
dc.contributor.author | Alumkal, JJ | |
dc.contributor.author | Beer, TM | |
dc.contributor.author | Chi, KN | |
dc.contributor.author | Evans, CP | |
dc.contributor.author | Gleave, M | |
dc.contributor.author | Lara, PN | |
dc.contributor.author | Reiter, RE | |
dc.contributor.author | Rettig, MB | |
dc.contributor.author | Witte, ON | |
dc.contributor.author | Wyatt, AW | |
dc.contributor.author | Feng, FY | |
dc.contributor.author | Small, EJ | |
dc.contributor.author | Quigley, DA | |
dc.coverage.spatial | United States | |
dc.date.accessioned | 2024-01-12T13:50:13Z | |
dc.date.available | 2024-01-12T13:50:13Z | |
dc.date.issued | 2023-08-15 | |
dc.identifier | 727214 | |
dc.identifier.citation | Cancer Research, 2023, 83 (16), pp. 2763 - 2774 | en_US |
dc.identifier.issn | 0008-5472 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/6099 | |
dc.identifier.eissn | 1538-7445 | |
dc.identifier.eissn | 1538-7445 | |
dc.identifier.doi | 10.1158/0008-5472.CAN-23-0593 | |
dc.identifier.doi | 10.1158/0008-5472.CAN-23-0593 | |
dc.description.abstract | UNLABELLED: Systemic targeted therapy in prostate cancer is primarily focused on ablating androgen signaling. Androgen deprivation therapy and second-generation androgen receptor (AR)-targeted therapy selectively favor the development of treatment-resistant subtypes of metastatic castration-resistant prostate cancer (mCRPC), defined by AR and neuroendocrine (NE) markers. Molecular drivers of double-negative (AR-/NE-) mCRPC are poorly defined. In this study, we comprehensively characterized treatment-emergent mCRPC by integrating matched RNA sequencing, whole-genome sequencing, and whole-genome bisulfite sequencing from 210 tumors. AR-/NE- tumors were clinically and molecularly distinct from other mCRPC subtypes, with the shortest survival, amplification of the chromatin remodeler CHD7, and PTEN loss. Methylation changes in CHD7 candidate enhancers were linked to elevated CHD7 expression in AR-/NE+ tumors. Genome-wide methylation analysis nominated Krüppel-like factor 5 (KLF5) as a driver of the AR-/NE- phenotype, and KLF5 activity was linked to RB1 loss. These observations reveal the aggressiveness of AR-/NE- mCRPC and could facilitate the identification of therapeutic targets in this highly aggressive disease. SIGNIFICANCE: Comprehensive characterization of the five subtypes of metastatic castration-resistant prostate cancer identified transcription factors that drive each subtype and showed that the double-negative subtype has the worst prognosis. | |
dc.format | Print | |
dc.format.extent | 2763 - 2774 | |
dc.language | eng | |
dc.language.iso | eng | en_US |
dc.publisher | AMER ASSOC CANCER RESEARCH | en_US |
dc.relation.ispartof | Cancer Research | |
dc.rights.uri | https://creativecommons.org/licenses/by-nc-nd/4.0/ | en_US |
dc.subject | Humans | |
dc.subject | Male | |
dc.subject | Prostatic Neoplasms, Castration-Resistant | |
dc.subject | Receptors, Androgen | |
dc.subject | Epigenomics | |
dc.subject | Androgen Antagonists | |
dc.subject | Androgens | |
dc.subject | Genomics | |
dc.subject | Neuroendocrine Tumors | |
dc.title | The Genomic and Epigenomic Landscape of Double-Negative Metastatic Prostate Cancer. | en_US |
dc.type | Journal Article | |
dcterms.dateAccepted | 2023-06-02 | |
dc.date.updated | 2024-01-11T12:06:11Z | |
rioxxterms.version | VoR | en_US |
rioxxterms.versionofrecord | 10.1158/0008-5472.CAN-23-0593 | en_US |
rioxxterms.licenseref.startdate | 2023-08-15 | |
rioxxterms.type | Journal Article/Review | en_US |
pubs.author-url | https://www.ncbi.nlm.nih.gov/pubmed/37289025 | |
pubs.issue | 16 | |
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.publication-status | Published | |
pubs.publisher-url | http://dx.doi.org/10.1158/0008-5472.can-23-0593 | |
pubs.volume | 83 | |
icr.researchteam | Cancer Biomarkers | en_US |
dc.contributor.icrauthor | Lundberg, Arian | |
icr.provenance | Deposited by Dr Arian Lundberg on 2024-01-11. Deposit type is initial. No. of files: 1. Files: The Genomic and Epigenomic Landscape of Double-Negative Metastatic Prostate Cancer.pdf | |
icr.provenance | Deposited by Mr Arek Surman (impersonating Dr Arian Lundberg) on 2024-01-12. Deposit type is subsequent. No. of files: 1. Files: The Genomic and Epigenomic Landscape of Double-Negative Metastatic Prostate Cancer.pdf | |