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Intraindividual epigenetic heterogeneity underlying phenotypic subtypes of advanced prostate cancer
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Intraindividual epigenetic heterogeneity underlying phenotypic subtypes of advanced prostate cancer
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Journal Article
Intraindividual epigenetic heterogeneity underlying phenotypic subtypes of advanced prostate cancer
2025
Overview
Castration-resistant prostate cancer is a heterogeneous disease with variable phenotypes commonly observed in later stages of the disease. These include cases that retain expression of luminal markers and those that lose hormone dependence and acquire neuroendocrine features. While there are distinct transcriptomic and epigenomic differences between castration-resistant adenocarcinoma and neuroendocrine prostate cancer, the extent of overlap and degree of diversity across tumor metastases in individual patients has not been fully characterized. Here we perform combined DNA methylation, RNA-sequencing, H3K27ac, and H3K27me3 profiling across metastatic lesions from patients with CRPC/NEPC. Integrative analyses identify DNA methylation-driven gene links based on location (H3K27ac, H3K27me3, promoters, gene bodies) pointing to mechanisms underlying dysregulation of genes involved in tumor lineage (ASCL1, AR
)
and therapeutic targets (PSMA, DLL3, STEAP1, B7-H3). Overall, these data highlight how integration of DNA methylation with RNA-sequencing and histone marks can inform intraindividual epigenetic heterogeneity and identify putative mechanisms driving transcriptional reprogramming in castration-resistant prostate cancer.
The epigenetic mechanisms underlying phenotypic diversity across different metastatic sites in castration-resistant prostate cancer (CRPC) remain to be characterised. Here, multi-omic profiling across metastatic lesions identifies regulatory networks driving tumour lineage programs and potential therapeutic targets.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 45/23
/ 45/91
/ Biopsy
/ DNA
/ Gene Expression Regulation, Neoplastic
/ Genomes
/ Histones
/ Humanities and Social Sciences
/ Humans
/ Lesions
/ Male
/ Patients
/ Prostatic Neoplasms - genetics
/ Prostatic Neoplasms - pathology
/ Prostatic Neoplasms, Castration-Resistant - genetics
/ Prostatic Neoplasms, Castration-Resistant - pathology
/ RNA
/ Science
/ Tumors
