The Genomic and Epigenomic Landscape of Double-Negative Metastatic Prostate Cancer.
Journal
Cancer research
ISSN: 1538-7445
Titre abrégé: Cancer Res
Pays: United States
ID NLM: 2984705R
Informations de publication
Date de publication:
15 08 2023
15 08 2023
Historique:
received:
21
02
2023
revised:
20
04
2023
accepted:
02
06
2023
medline:
16
8
2023
pubmed:
8
6
2023
entrez:
8
6
2023
Statut:
ppublish
Résumé
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. 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.
Identifiants
pubmed: 37289025
pii: 727214
doi: 10.1158/0008-5472.CAN-23-0593
pmc: PMC10425725
doi:
Substances chimiques
Receptors, Androgen
0
Androgen Antagonists
0
Androgens
0
Types de publication
Journal Article
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
2763-2774Subventions
Organisme : NCI NIH HHS
ID : P50 CA186786
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA227025
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA230516
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA251245
Pays : United States
Informations de copyright
©2023 The Authors; Published by the American Association for Cancer Research.
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