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Molecular Diagnostics

A DNA copy number alteration classifier as a prognostic tool for prostate cancer patients

British Journal of Cancer volume 128, pages 2165–2174 (2023)Cite this article

Subjects

Abstract

Background

Distinguishing between true indolent and potentially life-threatening prostate cancer is challenging in tumours displaying clinicopathologic features associated with low or intermediate risk of relapse. Several somatic DNA copy number alterations (CNAs) have been identified as potential prognostic biomarkers, but the standard cytogenetic method to assess them has a limited multiplexing capability.

Methods

Multiplex ligation-dependent probe amplification (MLPA) targeting 14 genes was optimised to survey 448 tumours of patients with low or intermediate risk (Grade Group 1–3, Gleason score ≤7) who underwent radical prostatectomy. A 6-gene CNA classifier was developed using random survival forest and Cox proportional hazard modelling to predict biochemical recurrence.

Results

The classifier score was significantly associated with biochemical recurrence after adjusting for standard clinicopathologic variables and the known prognostic index CAPRA-S score with a hazard ratio of 2.17 and 1.80, respectively (n = 406, P < 0.01). The prognostic value of this classifier was externally validated in published CNA data from three radical prostatectomy cohorts and one radiation therapy pre-treatment biopsy cohort.

Conclusion

The 6-gene CNA classifier generated by a single MLPA assay compatible with the small quantities of DNA extracted from formalin-fixed paraffin-embedded (FFPE) tissue specimens has the potential to improve the clinical management of patients with low or intermediate risk disease.

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Fig. 1: Copy number alteration (CNA) profiles of the MLPA cohort and generation of a 6-gene CNA model to predict biochemical recurrence (BCR).
Fig. 2: Prognostic value of the 6-gene CNA model in published radical prostatectomy datasets.
Fig. 3: Six-gene CNA model improved prognostication of pre-treatment clinicopathologic variables in MLPA, published radical prostatectomy, and pre-radiation biopsy datasets.

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Data availability

Data are available from the corresponding author upon reasonable request.

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Acknowledgements

Authors thank all the patients who consented to provide prostate tissues for research.

Funding

This study was funded by the Movember Foundation through Prostate Cancer Canada (grant #T2014.01) and carried out as a part of personalised risk stratification for patients with early prostate cancer (PRONTO). WE received a studentship and doctoral training award from the Research Institute of McGill University Health Centre and Fonds de la Recherche du Québec–Santé (FRQS), respectively.

Author information

Author notes

  1. Walead Ebrahimizadeh

    Present address: Current affiliation: IMV Inc., Dartmouth, Canada

Authors and Affiliations

  1. Department of Surgery, Division of Urology, McGill University and the Research Institute of the McGill University Health Centre (RI MUHC), Montreal, QC, Canada

    Walead Ebrahimizadeh, Karl-Philippe Guérard, Shaghayegh Rouzbeh, Eleonora Scarlata, Lucie Hamel, Armen G. Aprikian, Simone Chevalier & Jacques Lapointe

  2. Department of Pathology, McGill University and the Research Institute of the McGill University Health Centre (RI MUHC), Montreal, QC, Canada

    Fadi Brimo

  3. Department of Pathology & Molecular Medicine, Queen’s University, Kingston, ON, Canada

    Palak G. Patel, Tamara Jamaspishvili & David M. Berman

  4. Department of Pathology & Laboratory Medicine, SUNY Upstate Medical University, Syracuse, NY, USA

    Tamara Jamaspishvili

  5. Ontario Institute for Cancer Research, Toronto, ON, Canada

    Anna Y. Lee & John M. S. Bartlett

  6. Laboratory Medicine & Pathobiology, University of Toronto, Toronto, ON, Canada

    John M. S. Bartlett

  7. Cancer Research UK Edinburgh Centre, Institute of Genetics and Cancer, The University of Edinburgh, Edinburgh, UK

    John M. S. Bartlett

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  1. Walead Ebrahimizadeh
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Contributions

Conception and design: WE, KPG and JL. Development of methodology: WE, KPG and JL. Acquisition of the data: WE, KPG, SR, ES, FB, PGP, TJ, LH, AGA, AYL, DMB, JMSB, SC and JL. Analysis and interpretation of the data: WE, KPG, AYL and JL. Writing, review, and/or revision of the manuscript: WE, KPG, SR, ES, FB, PGP, TJ, LH, AGA, AYL, DMB, JMSB, SC and JL. Administrative, technical, or material support: ES, LH, TJ and AGA. Study supervision: JL.

Corresponding author

Correspondence to Jacques Lapointe.

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The authors declare no competing interests.

Ethics approval and consent to participate

The study was approved by the Research Ethics Board of McGill University Health Centre (Quebec, Canada, BDM-10-115) and by the Queen’s University Research Ethics Board (Ontario, Canada, PATH-144-14). Informed consent was obtained from participants and the study was performed in accordance with the Declaration of Helsinki.

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Ebrahimizadeh, W., Guérard, KP., Rouzbeh, S. et al. A DNA copy number alteration classifier as a prognostic tool for prostate cancer patients. Br J Cancer 128, 2165–2174 (2023). https://doi.org/10.1038/s41416-023-02236-8

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