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Intraindividual epigenetic heterogeneity underlying phenotypic subtypes of advanced prostate cancer

Author

Listed:
  • 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
    University of Melbourne
    St. Vincent’s Institute of Medical Research
    Monash University)

  • 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
    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
    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)

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.

Suggested Citation

  • 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 , 2025. "Intraindividual epigenetic heterogeneity underlying phenotypic subtypes of advanced prostate cancer," Nature Communications, Nature, vol. 16(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-60654-z
    DOI: 10.1038/s41467-025-60654-z
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