94: Intraindividual epigenetic heterogeneity in advanced prostate cancer

Mizuno K et al., Nature Communications - Multi-omic profiling (DNA methylation, RNA-seq, H3K27ac and H3K27me3) of 98 metastatic CRPC samples from 35 patients reveals patient-specific epigenetic signatures and methylation-driven regulation of lineage genes and therapeutic targets. Integrative analyses identify >21,000 region–gene links and highlight intraindividual heterogeneity including double-negative tumors with BMP4 signaling or immune-high profiles. Key terms: DNA methylation, castration-resistant prostate cancer, neuroendocrine prostate cancer, H3K27ac/H3K27me3, epigenetic heterogeneity. Study Highlights:The study profiled 98 metastatic tumor samples from 35 patients using RRBS/ERRBS, RNA-seq and H3K27ac/H3K27me3 ChIP-seq or CUT&Tag and found DNA methylation patterns were generally conserved within patients across metastases. Integrative analyses produced 21,721 significant methylation region–gene links implicating epigenetic regulation of lineage genes (e.g., ASCL1, AR) and therapeutic targets (PSMA, DLL3, STEAP1, B7-H3). Five patients showed intraindividual molecular subtype heterogeneity, and double-negative CRPC samples segregated into BMP4-activated or immune-enriched subsets. Functional inhibition of BMP4 signaling reduced viability in a DN model cell line (DU145), supporting pathway relevance. Conclusion:Integration of DNA methylation with transcriptomic and histone mark data reveals patient-specific epigenetic landscapes that drive phenotypic diversity in advanced prostate cancer and identify methylation-linked mechanisms regulating lineage programs and therapeutic target expression, with potential implications for biomarker development and targeted therapy selection. Music:Enjoy the music based on this article at the end of the episode. Article title:Intraindividual epigenetic heterogeneity underlying phenotypic subtypes of advanced prostate cancer First author:Mizuno K Journal:Nature Communications DOI:10.1038/s41467-025-60654-z Reference:Mizuno K., Ku S-Y., Venkadakrishnan VB., et al. Intraindividual epigenetic heterogeneity underlying phenotypic subtypes of advanced prostate cancer. Nature Communications (2025). DOI: https://doi.org/10.1038/s41467-025-60654-z License:This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/ Support:Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 Official website https://basebybase.com On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics. Episode link: https://basebybase.com/episodes/ep94-intraindividual-epigenetic-heterogeneity-advanced-prostate-cancer QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-08-02. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Audited portions describing study design and cohorts, multi-omics methods, DNA methylation–gene expression links, intraindividual heterogeneity and subtypes, BMP4/immune pathways, and BMP4 inhibition functional data.- transcript topics: Study cohort and rapid autopsy samples; Multi-omics profiling (RRBS/ERRBS, RNA-seq, H3K27ac, H3K27me3, CUT&Tag/ChIP-seq); DNA methylation–gene expression links and epigenetic regulation; Intraindividual heterogeneity and molecular subtypes (AR+/NE-, AR-/NE-, double-negative); BMP4 signaling and immune-high double-negative CRPC; Functional validation of BMP4 pathway inhibition in DU145 (LDN-193189) QC Summary:- factual score: 10/10- metadata score: 10/10- sup...