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Peer-reviewedCC BY-NC-ND 4.0Cancer Discovery

The Landscape of Prostate Tumor Methylation

  • Jaron Arbet1,2,3,4,5
  • Takafumi N. Yamaguchi3,6
  • Yu-Jia Shiah7
  • Rupert Hugh-White6
  • Adriana Wiggins1,3
  • Jieun Oh1,2,3
  • Nicole Zeltser1,3
  • Tsumugi Gebo1,2,3
  • Adrien Foucal7
  • Robert Lesurf7
  • Chol-Hee Jung8
  • Rachel M.A. Dang1,3
19 more authors
  • Raag Agrawal1,3,4
  • Julie Livingstone1,2,3
  • Adriana Salcedo3,4
  • Cindy Q. Yao7
  • Shadrielle Melijah G. Espiritu7
  • Kathleen E. Houlahan1,2,3,7,9
  • Fouad Yousif7
  • Lawrence E. Heisler7
  • Anthony T. Papenfuss10,11
  • Michael Fraser7,12
  • Bernard J. Pope8,13,14
  • Amar U. Kishan1,15
  • Alejandro Berlin12,16
  • Melvin L.K. Chua16,17,18
  • Niall M. Corcoran14,19,20
  • Theodorus van der Kwast12
  • Christopher M. Hovens14,21
  • Robert G. Bristow9,12,16,22
  • Paul C. Boutros6
22 affiliations
  1. 1Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, California.
  2. 2Institute for Precision Health, University of California, Los Angeles, Los Angeles, California.
  3. 3Department of Human Genetics, University of California, Los Angeles, Los Angeles, California.
  4. 4Department of Urology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California.
  5. 5Division of Outcomes Research, Department of Population Sciences, Beckman Research Institute of the City of Hope, Duarte, California.
  6. 6Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California.
  7. 7Ontario Institute for Cancer Research, Toronto, Canada.
  8. 8Melbourne Bioinformatics, University of Melbourne, Parkville, Australia.
  9. 9Department of Medical Biophysics, University of Toronto, Toronto, Canada.
  10. 10Walter and Eliza Hall Institute of Medical Research, Parkville, Australia.
  11. 11Department of Medical Biology, University of Melbourne, Parkville, Australia.
  12. 12Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.
  13. 13Australian BioCommons, University of Melbourne, Parkville, Australia.
  14. 14Department of Surgery, University of Melbourne, Parkville, Australia.
  15. 15Department of Radiation Oncology, University of California, Los Angeles, Los Angeles, California.
  16. 16Department of Radiation Oncology, University of Toronto, Toronto, Canada.
  17. 17Divisions of Radiation Oncology and Medical Sciences, National Cancer Centre Singapore, Singapore, Singapore.
  18. 18Duke-NUS Medical School, Singapore, Singapore.
  19. 19Department of Urology, Western Health, Footscray, Australia.
  20. 20Department of Urology, Royal Melbourne Hospital, Parkville, Australia.
  21. 21Victorian Comprehensive Cancer Centre, Parkville, Australia.
  22. 22Division of Cancer Sciences-FBMH, CRUK Manchester Institute and Manchester Cancer Research Centre, University of Manchester, Manchester, United Kingdom.
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Abstract

Prostate cancer is characterized by profound clinical and molecular heterogeneity. Although its genomic heterogeneity is well characterized, its epigenomic heterogeneity remains less understood. We therefore created a compendium of 3,001 multiancestry prostate methylomes spanning normal tissue through localized disease of all grades to polymetastatic disease. A subset of 884 samples had multiomic DNA and/or RNA characterization. We identify four epigenomic subtypes that risk-stratify patients and reflect distinct evolutionary trajectories. We demonstrate extensive regulatory interplay between DNA copy number and methylation, with transcriptional consequences that vary across genes and disease stages. We define epigenetic dysregulation signatures for 15 important clinicomolecular features, creating predictive models for each. For example, we identify specific epigenetic features that predict patient outcome and are synergistic with clinical prognostic features. These results define a complex interplay between tumor genetics and epigenetics that converges to modify gene expression programs and clinical presentation, in part through modulation of epigenetic aging.

Significance:: We define the largest prostate cancer methylome resource to date, revealing four epigenomic subtypes that stratify cancers by their genetics, evolution, and clinical phenotypes. These data demonstrate that genome–epigenome interactions are stage-dependent, positioning DNA methylation as a central, clinically informative driver of prostate cancer heterogeneity.

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Cite

BibTeXRIS
BibTeX
@article{arbet2026landscape,
  title = {{The Landscape of Prostate Tumor Methylation}},
  author = {Jaron Arbet and Takafumi N. Yamaguchi and Yu-Jia Shiah and Rupert Hugh-White and Adriana Wiggins and Jieun Oh and Nicole Zeltser and Tsumugi Gebo and Adrien Foucal and Robert Lesurf and Chol-Hee Jung and Rachel M.A. Dang and Raag Agrawal and Julie Livingstone and Adriana Salcedo and Cindy Q. Yao and Shadrielle Melijah G. Espiritu and Kathleen E. Houlahan and Fouad Yousif and Lawrence E. Heisler and Anthony T. Papenfuss and Michael Fraser and Bernard J. Pope and Amar U. Kishan and Alejandro Berlin and Melvin L.K. Chua and Niall M. Corcoran and Theodorus van der Kwast and Christopher M. Hovens and Robert G. Bristow and Paul C. Boutros},
  journal = {Cancer Discovery},
  year = {2026},
  month = jun,
  doi = {10.1158/2159-8290.cd-25-0761},
  url = {https://doi.org/10.1158/2159-8290.cd-25-0761},
  note = {CC BY-NC-ND 4.0},
}
RIS
TY  - JOUR
TI  - The Landscape of Prostate Tumor Methylation
AU  - Jaron Arbet
AU  - Takafumi N. Yamaguchi
AU  - Yu-Jia Shiah
AU  - Rupert Hugh-White
AU  - Adriana Wiggins
AU  - Jieun Oh
AU  - Nicole Zeltser
AU  - Tsumugi Gebo
AU  - Adrien Foucal
AU  - Robert Lesurf
AU  - Chol-Hee Jung
AU  - Rachel M.A. Dang
AU  - Raag Agrawal
AU  - Julie Livingstone
AU  - Adriana Salcedo
AU  - Cindy Q. Yao
AU  - Shadrielle Melijah G. Espiritu
AU  - Kathleen E. Houlahan
AU  - Fouad Yousif
AU  - Lawrence E. Heisler
AU  - Anthony T. Papenfuss
AU  - Michael Fraser
AU  - Bernard J. Pope
AU  - Amar U. Kishan
AU  - Alejandro Berlin
AU  - Melvin L.K. Chua
AU  - Niall M. Corcoran
AU  - Theodorus van der Kwast
AU  - Christopher M. Hovens
AU  - Robert G. Bristow
AU  - Paul C. Boutros
PY  - 2026
DA  - 2026/06/17
JO  - Cancer Discovery
DO  - 10.1158/2159-8290.cd-25-0761
UR  - https://doi.org/10.1158/2159-8290.cd-25-0761
AB  - Prostate cancer is characterized by profound clinical and molecular heterogeneity. Although its genomic heterogeneity is well characterized, its epigenomic heterogeneity remains less understood. We therefore created a compendium of 3,001 multiancestry prostate methylomes spanning normal tissue through localized disease of all grades to polymetastatic disease. A subset of 884 samples had multiomic DNA and/or RNA characterization. We identify four epigenomic subtypes that risk-stratify patients and reflect distinct evolutionary trajectories. We demonstrate extensive regulatory interplay between DNA copy number and methylation, with transcriptional consequences that vary across genes and disease stages. We define epigenetic dysregulation signatures for 15 important clinicomolecular features, creating predictive models for each. For example, we identify specific epigenetic features that predict patient outcome and are synergistic with clinical prognostic features. These results define a complex interplay between tumor genetics and epigenetics that converges to modify gene expression programs and clinical presentation, in part through modulation of epigenetic aging.  Significance:: We define the largest prostate cancer methylome resource to date, revealing four epigenomic subtypes that stratify cancers by their genetics, evolution, and clinical phenotypes. These data demonstrate that genome–epigenome interactions are stage-dependent, positioning DNA methylation as a central, clinically informative driver of prostate cancer heterogeneity.
SN  - 2159-8274
SN  - 2159-8290
ER  -