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Predisposition to prostate cancer and clinical implications in a real-life cohort

European Journal of Human Genetics volume 33, pages 1163–1172 (2025)Cite this article

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Abstract

Genetic predisposition is identified in 5–10% of prostate cancer patients. Although genetic testing is more frequently proposed, international recommendations are lacking. This study evaluates the impact of germline analysis on management of prostate cancer patients. Retrospective descriptive data were collected from prostate cancer patients who attended oncogenetic counselling between 2018 and 2021. Data included clinical and tumoral characteristics, and genomic analysis. Comparative analysis was performed between patients with germline pathogenic variants (PVs) and non-carriers using non-parametric tests. Fourteen out of the 168 patients (8.3%) had a PV, primarily in DNA repair genes (N = 13/14), including BRCA1/2 (N = 5). Twenty-five patients (14.9%) had variants of undetermined significance. Patients with PVs were more likely to have synchronous metastatic extension (79% vs 43%, p = 0.02) and a Gleason score ≥8 (82% vs 53%, p = 0.11). Significant enrichment of ATM PVs compared to a healthy control cohort was observed with an odds ratio of 32.5 [15.8–67.0] (p < 0.05). Three of five patients with BRCA1/2 PVs received DNA repair-targeted treatment. This cohort provides insights into the impact of oncogenetic counselling on prostate cancer patients’ management. It highlights the need to refine referral criteria based on disease stage and Gleason score and to further investigate ATM PVs. The data also underscore the importance of developing a care pathway with clear criteria for germline and/or somatic analysis to improve theranostic outcomes.

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Fig. 1: Distribution of genes with germline pathogenic variants and variants of undetermined significance.
Fig. 2: Characteristics of patients according to their germline pathogenic variant status.
Fig. 3: Germline variants in prostate cancer: frequency in an independent cohort, enrichment compared with healthy controls.
Fig. 4: The therapeutic and prognostic impacts of pathogenic or likely pathogenic germline variants in prostate cancer patients.

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Data availability

The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.

References

  1. Worldwide cancer data | World Cancer Research Fund International [Internet]. WCRF International. [cited 2024 Apr 7]. Available from: https://www.wcrf.org/cancer-trends/worldwide-cancer-data/.

  2. Mucci LA, Hjelmborg JB, Harris JR, Czene K, Havelick DJ, Scheike T, et al. Familial risk and heritability of cancer among twins in nordic countries. JAMA. 2016;315:68–76.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. Pritchard CC, Mateo J, Walsh MF, De Sarkar N, Abida W, Beltran H, et al. Inherited DNA-repair gene mutations in men with metastatic prostate cancer. N. Engl J Med. 2016;375:443–53.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. Nicolosi P, Ledet E, Yang S, Michalski S, Freschi B, O’Leary E, et al. Prevalence of germline variants in prostate cancer and implications for current genetic testing guidelines. JAMA Oncol. 2019;5:523–8.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Carlo MI, Giri VN, Paller CJ, Abida W, Alumkal JJ, Beer TM, et al. Evolving intersection between inherited cancer genetics and therapeutic clinical trials in prostate cancer: a white paper from the germline genetics Working Group of the Prostate Cancer Clinical Trials Consortium. JCO Precis Oncol. 2018;2018:PO.18.00060.

    PubMed  Google Scholar 

  6. Castro E, Romero-Laorden N, Del Pozo A, Lozano R, Medina A, Puente J, et al. PROREPAIR-B: a prospective cohort study of the impact of germline DNA repair mutations on the outcomes of patients with metastatic castration-resistant prostate cancer. J Clin Oncol. 2019;37:490–503.

    Article  PubMed  CAS  Google Scholar 

  7. Mohler JL, Antonarakis ES, Armstrong AJ, D’Amico AV, Davis BJ, Dorff T, et al. Prostate Cancer, Version 2.2019, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Cancer Netw. 2019;17:479–505.

    Article  CAS  Google Scholar 

  8. Fallah J, Xu J, Weinstock C, Brave MH, Bloomquist E, Fiero MH, et al. FDA approval summary: olaparib in combination with abiraterone for treatment of patients with BRCA-mutated metastatic castration-resistant prostate cancer. J Clin Oncol. 2024;42:605–13.

    Article  PubMed  CAS  Google Scholar 

  9. Lynparza | European Medicines Agency. https://www.ema.europa.eu/en/medicines/human/EPAR/lynparza#authorisation-details.

  10. Humphrey PA, Moch H, Cubilla AL, Ulbright TM, Reuter VE. The 2016 WHO classification of tumours of the urinary system and male genital organs—part B: prostate and bladder tumours. Eur Urol. 2016;70:106–19.

    Article  PubMed  Google Scholar 

  11. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405–24.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Kobayashi Y, Yang S, Nykamp K, Garcia J, Lincoln SE, Topper SE. Pathogenic variant burden in the ExAC database: an empirical approach to evaluating population data for clinical variant interpretation. Genome Med. 2017;9:13.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Karczewski KJ, Francioli LC, Tiao G, Cummings BB, Alföldi J, Wang Q, et al. The mutational constraint spectrum quantified from variation in 141,456 humans. Nature. 2020;581:434–43.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Castro E, Goh C, Olmos D, Saunders E, Leongamornlert D, Tymrakiewicz M, et al. Germline BRCA mutations are associated with higher risk of nodal involvement, distant metastasis, and poor survival outcomes in prostate cancer. J Clin Oncol. 2013 ;31:1748–57.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Bancroft EK, Page EC, Castro E, Lilja H, Vickers A, Sjoberg D, et al. Targeted prostate cancer screening in BRCA1 and BRCA2 mutation carriers: results from the initial screening round of the IMPACT Study. Eur Urol. 2014;66:489–99.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Nyberg T, Frost D, Barrowdale D, Evans DG, Bancroft E, Adlard J, et al. Prostate cancer risks for male BRCA1 and BRCA2 mutation carriers: a prospective cohort study. Eur Urol. 2020;77:24–35.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Darst BF, Saunders E, Dadaev T, Sheng X, Wan P, Pooler L, et al. Germline sequencing analysis to inform clinical gene panel testing for aggressive prostate cancer. JAMA Oncol. 2023;9:1514–24.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Nguyen-Dumont T, MacInnis RJ, Steen JA, Theys D, Tsimiklis H, Hammet F, et al. Rare germline genetic variants and risk of aggressive prostate cancer. Int J Cancer. 2020;147:2142–9.

    Article  PubMed  CAS  Google Scholar 

  19. Karlsson Q, Brook MN, Dadaev T, Wakerell S, Saunders EJ, Muir K, et al. Rare Germline Variants in ATM Predispose to Prostate Cancer: A PRACTICAL Consortium Study. Eur Urol Oncol. 2021;4:570–9.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Choi M, Kipps T, Kurzrock R. ATM Mutations in Cancer: Therapeutic Implications. Mol Cancer Therapeutics. 2016;15:1781–91.

    Article  CAS  Google Scholar 

  21. Hall R, Bancroft E, Pashayan N, Kote-Jarai Z, Eeles RA. Genetics of prostate cancer: a review of latest evidence. 2024 Oct [cited 2025 Mar 5]; Available from: https://jmg.bmj.com/content/61/10/915.long.

  22. Brandão A, Paulo P, Teixeira MR. Hereditary predisposition to prostate cancer: from genetics to clinical implications. Int J Mol Sci. 2020;21:5036.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Dombernowsky SL, Weischer M, Allin KH, Bojesen SE, Tybjaerg-Hansen A, Nordestgaard BG. Risk of cancer by ATM missense mutations in the general population. J Clin Oncol. 2008;26:3057–62.

    Article  PubMed  CAS  Google Scholar 

  24. Helgason H, Rafnar T, Olafsdottir HS, Jonasson JG, Sigurdsson A, Stacey SN, et al. Loss-of-function variants in ATM confer risk of gastric cancer. Nat Genet. 2015;47:906–10.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Medical Oncology, Hôpital Cochin, Paris Cancer Institute CARPEM, Université Paris Cité, APHP.Centre, Paris, France

    Julie Chartier, Arunya Srikaran, Olivier Huillard, Manuela Tiako & Camille Tlemsani

  2. Department of Genomic Medicine of Tumors and Cancers, Fédération de Génétique et Médecine Génomique, Cochin Hospital, Université Paris Cité, APHP.Centre, Paris, France

    Albain Chansavang, Nadim Hamzaoui & Eric Pasmant

  3. Institut Cochin, INSERM U1016, CNRS UMR8104, Université Paris Cité, CARPEM, Paris, France

    Albain Chansavang, Anne Jouinot, Nadim Hamzaoui, Eric Pasmant & Camille Tlemsani

  4. Institut du Cancer Paris Carpem, AP-HP, Genomic medicine of tumors and cancers department, Fédération de Génétique et Médecine Génomique, Université Paris Cité, APHP.Centre, Paris, France

    Diane Molière & Pierre Laurent-Puig

  5. Department of Medical Oncology, Hôpital Européen Georges Pompidou, Paris Cancer Institute CARPEM, Université Paris Cité, APHP.Centre, Paris, France

    Constance Thibault

  6. Department of Pathology, Hôpital Cochin, Paris Cancer Institute CARPEM, Université Paris Cité, APHP.Centre, Paris, France

    Mathilde Sibony

  7. Centre de Recherche des Cordeliers, INSERM, CNRS SNC 5096, Université Paris Cité, Paris, France

    Pierre Laurent-Puig

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Contributions

JC: Formal analysis, Investigation, Visualization, Writing—Original Draft, Writing—Review and Editing. AC: Formal analysis, Investigation, Visualization, Writing—Original Draft, Writing—Review and Editing. AJ: Formal Analysis, Investigation, Visualization, Methodology, Writing—Review and Editing. NH: Formal Analysis, Investigation, Writing—Review and Editing. AS: Formal Analysis, Investigation, Writing—Review and Editing. DM: Formal Analysis, Investigation, Writing—Review and Editing. OH: Investigation, Writing—Review and Editing. CT: Investigation, Writing—Review and Editing. MT: Investigation, Writing—Review and Editing. MS: Investigation, Writing—Review and Editing. PLP: Investigation, Writing—Review & Editing. EP: Conceptualization, Methodology, Resources, Supervision, Validation, Writing—Review & Editing. CT: Conceptualization, Formal Analysis, Funding Acquisition, Methodology, Investigation, Validation, Visualization, Writing—Review & Editing.

Corresponding author

Correspondence to Camille Tlemsani.

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The authors declare no competing interests.

Ethical approval

The study was registered under the French General Data Protection Act (MR-004 French reference methodology). All patients had signed an informed consent form authorizing germline analysis and the use of data from their medical records for research. A specific information note about this study was also sent to them.

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Chartier, J., Chansavang, A., Jouinot, A. et al. Predisposition to prostate cancer and clinical implications in a real-life cohort. Eur J Hum Genet 33, 1163–1172 (2025). https://doi.org/10.1038/s41431-025-01859-0

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