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Epidemiology

Tumour-based epigenetic signatures as markers of prostate cancer aggressiveness after radical prostatectomy

British Journal of Cancer volume 134, pages 477–485 (2026)Cite this article

Subjects

Abstract

Background

Prostate-specific antigen (PSA) recurrence after radical prostatectomy signifies increased risk of metastasis and death from prostate cancer. Traditional clinical metrics may not accurately capture the underlying biological heterogeneity of the tumour, which might be improved by consideration of epigenetic biomarkers.

Methods

This study included 293 Australian participants with prostate cancer treated with radical prostatectomy (mean age: 64 years, Gleason score ≥7: 91%). Fourteen tumour DNA methylation-based signatures of aggressiveness and cell division were calculated. The association of epigenetic signatures with clinical variables were assessed using linear regression and risk ratios for PSA recurrence were assessed using modified Poisson regression.

Results

Most epigenetic signatures were strongly associated with age, Gleason score, and tumour stage but not with serum PSA levels at diagnosis. Associations were also found with risk of PSA recurrence, with increased risks ranging from 1% to 17% per SD for signatures of clinical variables and 17% to 33% for cell division scores, after adjusting for the main clinicopathological variables. The strongest association was observed for the cell division score RepliTali.

Conclusion

Prostate cancer tissue DNA methylation-based signatures of aggressiveness and cell division were associated with elevated risk of PSA recurrence, independently of age and traditional clinicopathological variables.

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Fig. 1
Fig. 2: Association between methylation values (y-axis) and standardised epigenetic signatures in matched normal and tumour samples (N = 28).
Fig. 3: Associations (regression coefficients, 95% CIs) between epigenetic signatures and participant characteristics at diagnosis (N = 293).
Fig. 4: Associations (RRs, 95% CIs) between DNAm-based signatures (per 1 SD) and PSA recurrence (N = 240, PSA recurrence events, N = 50).

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Data availability

The individual participant data that support the findings of this study are not publicly available due to privacy and ethical restrictions. The data can be requested by contacting the PEDIGREE resource at pedigree@cancervic.org.au.

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Funding

None of the authors has conflicts of interest to disclose. This work was supported by National Health and Medical Research Council grant #623204 and Prostate Cancer Foundation of Australian PIRA-FLECR-1321. Southey is a recipient of a NHMRC L3 Investigator Fellowship, GNT2017325. Dugué is a Victorian Cancer Agency Mid-career Research Fellow, MCRF22025. The funding bodies played no direct role in the study.

Author information

Authors and Affiliations

  1. Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC, Australia

    Yiyue Zhu, Elaheh Zarean, Danmeng L. Li, Robert L. O’Reilly, Roger L. Milne, Graham G. Giles, Melissa C. Southey & Pierre-Antoine Dugué

  2. Centre for Epidemiology and Biostatistics, School of Population and Global Health, The University of Melbourne, Parkville, VIC, Australia

    Yiyue Zhu, Robert J. MacInnis, Roger L. Milne, Graham G. Giles & Pierre-Antoine Dugué

  3. Eastern Health Clinical School, Monash University, Box Hill, VIC, Australia

    Ian D. Davis

  4. Department of Oncology, Eastern Health, Box Hill, VIC, Australia

    Ian D. Davis

  5. Monash Biomedicine Discovery Institute, Department of Physiology, Monash University, Clayton, VIC, Australia

    Renea A. Taylor

  6. Cancer Immunology Program, Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia

    Renea A. Taylor

  7. Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia

    Renea A. Taylor & Arun A. Azad

  8. Department of Urology, Austin Health, Melbourne, VIC, Australia

    Damien M. Bolton & Nathan Papa

  9. Department of Surgery, University of Melbourne, Melbourne, VIC, Australia

    Damien M. Bolton

  10. EJ Whitten Prostate Cancer Research Centre, Epworth Healthcare, Melbourne, VIC, Australia

    Nathan Lawrentschuk

  11. Department of Urology, The Royal Melbourne Hospital, The University of Melbourne, Melbourne, VIC, Australia

    Nathan Lawrentschuk

  12. Cancer Epidemiology Division, Cancer Council Victoria, East Melbourne, VIC, Australia

    Robert J. MacInnis, Roger L. Milne, Graham G. Giles, Melissa C. Southey & Pierre-Antoine Dugué

  13. Department of Clinical Pathology, Melbourne Medical School, The University of Melbourne, Melbourne, VIC, Australia

    Melissa C. Southey

Authors
  1. Yiyue Zhu
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  15. Pierre-Antoine Dugué
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Contributions

Pierre-Antoine Dugué had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Zhu, Giles, Southey, Dugué. Acquisition of data: O’Reilly, Southey. Analysis and interpretation of data: Zhu, Zarean, Li, Davis, Southey, Dugué. Drafting of the manuscript: Zhu, Dugué. Critical revision of the manuscript for important intellectual content: All authors. Statistical analysis: Zhu, Dugué. Obtaining funding: Davis, Taylor, Azad, Bolton, Papa, Lawrenschuk, MacInnis, Milne, Giles, Southey, Dugué. Administrative, technical, or material support: Milne, Giles, Southey. Supervision: Dugué.

Corresponding author

Correspondence to Pierre-Antoine Dugué.

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Zhu, Y., Zarean, E., Li, D.L. et al. Tumour-based epigenetic signatures as markers of prostate cancer aggressiveness after radical prostatectomy. Br J Cancer 134, 477–485 (2026). https://doi.org/10.1038/s41416-025-03257-1

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