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Combination of Polymorphisms From Genes Related to Estrogen Metabolism and Risk of Prostate Cancers: The Hidden Face of Estrogens

Olivier Cussenot, Abdel Rhamene Azzouzi, Nathalie Nicolaiew, Gaelle Fromont, Philippe Mangin, Luc Cormier, Georges Fournier, Antoine Valeri, Stephane Larre, Frederic Thibault, Jean-Pierre Giordanella, Michel Pouchard, Yan Zheng, Freddie C. Hamdy, Angela Cox, Geraldine Cancel-Tassin

From the Centre de Recherche pour les Pathologies Prostatiques; Assistance Publique-Hôpitaux de Paris, Department of Urology, Tenon Hospital, Groupement Hospitalier Universitaire Est, University Paris VI, Paris; Institut National de la Santé et de la Recherche Médicale, EMI0337; Université Paris 12, Faculté de Médecine, IFR10, Créteil; Centre Hospitalier Universitaire (CHU) d'Angers, Department of Urology, Angers; CHU La Miletrie, Department of Pathology, University of Poitiers, Poitiers; CHU Brabois, Department of Urology, Nancy; Hopital de la Cavale Blanche, Departments of Urology and Breast; and Caisse Nationale d'Assurance Maladie, France Institute for Cancer Studies and Académic Urology Unit, University of Sheffield, Royal Hallamshire Hospital, Sheffield, United Kingdom

Address reprint requests to Olivier Cussenot, MD, PhD, Hôpital Tenon, Service d'Urologie–Batiment Gabriel, 4 rue de la Chine, 75020 Paris, France; e-mail: olivier.cussenot{at}tnn.aphp.fr

Purpose: The association between common functional polymorphisms from the CYP17, CYP19, CYP1B1, and COMT genes involved in the estrogen metabolism and the risk of prostate carcinoma was evaluated.

Patients and Methods: The study investigated 1,983 white French men (1,101 patients with prostate cancer and 882 healthy controls) aged between 40 and 98 years. The different alleles and genotypes were analyzed according to case-control status, aggressiveness pattern of the tumors, age at onset, and family history of cancers.

Results: The VV (high activity) genotype of the V432L polymorphism from CYP1B1 (odds ratio [OR] = 1.36; 95% CI, 1.03 to 1.79; P = .031), and the long allele (> 175 bp) of the TTTA repeat from CYP19 (OR, 1.26; 95% CI, 1.08 to 1.47; P = .003) were significantly associated with the risk of prostate cancer. An additive effect was observed when we combined the two at-risk alleles (OR = 1.63; 95% CI, 1.24 to 2.13; P < .001). The association was stronger for the CYP1B1 VV genotype (OR = 1.55; 95% CI, 1.13 to 2.13; P = .007) among the group of patients with highly aggressive disease. Stratification by age at onset showed that the associations of CYP1B1 and CYP19 variants were largely confined to the younger prostate cancer patients.

Conclusion: This association between polymorphisms from genes related to estrogen metabolism and prostate cancer risk suggest new clinical considerations in the management of prostate cancer: the development of new prevention trials based on genetic profiling and the evaluation of specific inhibitors involving the estrogen pathways.

Supported by Association pour la Recherche sur les Tumeurs de la Prostate and Sheffield Hospitals Charitable Trust. The study sponsors had no role in the design of the study; in the collection, analysis, or interpretation of the data; or in the writing of the report. The corresponding author had full access to all of the data in the study and had final responsibility for the decision to submit the article for publication.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.