Intraindividual epigenetic heterogeneity underlying phenotypic subtypes of advanced prostate cancer

Kei Mizuno, Sheng-Yu Ku, Varadha Balaji Venkadakrishnan, Martin K. Bakht, Michael Sigouros, Joanna Chan, Anna Trigos, Jordan H. Driskill, Jyothi Manohar, Abigail King, Adam G. Presser, Min Jin Kim, Alok K. Tewari, Henry W. Long, David Quigley, Toni K. Choueiri, Steven Balk, Sarah Hill, Juan Miguel Mosquera, David Einstein, Shahneen Sandhu, Mary-Ellen Taplin and Himisha Beltran ()
Additional contact information
Kei Mizuno: Harvard Medical School
Sheng-Yu Ku: Harvard Medical School
Varadha Balaji Venkadakrishnan: Harvard Medical School
Martin K. Bakht: Harvard Medical School
Michael Sigouros: Weill Cornell Medicine
Joanna Chan: Peter MacCallum Cancer Centre
Anna Trigos: Peter MacCallum Cancer Centre
Jordan H. Driskill: Weill Cornell Medicine
Jyothi Manohar: Weill Cornell Medicine
Abigail King: Weill Cornell Medicine
Adam G. Presser: Harvard Medical School
Min Jin Kim: Harvard Medical School
Alok K. Tewari: Harvard Medical School
Henry W. Long: Harvard Medical School
David Quigley: University of California San Francisco
Toni K. Choueiri: Harvard Medical School
Steven Balk: Beth Israel Deaconess Medical Center, Harvard Medical School
Sarah Hill: Harvard Medical School
Juan Miguel Mosquera: Weill Cornell Medicine
David Einstein: Beth Israel Deaconess Medical Center, Harvard Medical School
Shahneen Sandhu: University of Melbourne
Mary-Ellen Taplin: Harvard Medical School
Himisha Beltran: Harvard Medical School

Nature Communications, 2025, vol. 16, issue 1, 1-13

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-60654-z

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