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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

	ABSTRACT

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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.

	INTRODUCTION

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Prostate cancer killed 9,789 French men in 2002.¹ Its specific mortality is directly related to the stage at diagnosis and age at onset.² An association between the risk of prostate cancer and variations in blood levels of androgens and estrogens has been examined and was found to be controversial in many studies.³ However, evidence supports the hypothesis that exposure to endogenous variations in androgens and estrogens across a man's life span contributes to or may be a causal factor in prostate cancer.⁴ Although androgen deprivation and administration of estrogens are a recognized therapy for prostate cancer, it is suspected that early exposure to estrogens initiates carcinogenesis among different tissues, including the prostate gland,⁵ and that decrease of the androgen/estrogen ratio with aging could be responsible in part for prostate carcinogenesis.^6,7 Moreover, recent studies in rodents have demonstrated that estrogens, through their receptors or their catechol metabolites, are potential carcinogens in various tissues, including the prostate, kidneys, liver, uterus, and mammary glands.^5,8,9

From these hypotheses, polymorphisms from genes related to estrogens metabolism pathways have been proposed as candidates for association studies on prostate cancer risk. The CYP17 (17-alpha hydroxylase) enzyme participates in the biosynthesis of testosterone and estrogen. For this enzyme, the main studied polymorphism for prostate cancer risk is a sequence variation located in the 5'-promoter region. This variant corresponds to a TC transition (34 bp upstream from the initiation site of translation; –34TC), which has been associated with increased enzyme activity and consequently circulating levels of estradiol.¹⁰ For the aromatase enzyme (CYP19), which converts testosterone to estradiol, our group¹¹ initially suggested in 2001 the association between prostate cancer risk and the high number of tetranucleotide simple tandem (TTTA) repeat polymorphisms in intron 4. A study on a small subset of the patients in our study (n = 226) and controls (n = 156) for CYP17 and CYP19 was described by Latil et al.¹¹ Since then, the involvement of CYP19 polymorphisms in prostate cancer risk has been controversial in many reports.^12-18 Experimental studies support that local production of catechol estrogens (in particular, the 4-hydroxy form) by CYP1B1 enzyme and that the insufficiency of their inactivation by catechol-O-methyltransferase (COMT) can generate large quantities of reactive oxygen species, which may cause DNA damage leading to carcinogenesis.⁹ From these experimental data, several association studies, but few conducted on white men, have suggested that the high-activity V432L variant from CYP1B1 and the low-activity M158V variant from COMT gene were also associated with an increased risk of prostate cancer.¹⁹

The study reported herein involves for the first time a large and homogeneous population of white French men. It sought to determine whether common polymorphisms, –34TC (CYP17), TTTA repeat (CYP19), V432L (CYP1B1), and M158V (COMT), from genes that encode enzymes involved in the estrogen metabolism, may be associated with a significant elevated risk of aggressive prostate carcinoma.

	PATIENTS AND METHODS

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Study Population
This case-control study is based on the data and DNA samples selected among the Centre de Recherche pour les Pathologies Prostatiques bioresources. Eligible patients (1,101) and controls (882) are white French residents, age 40 to 98 years. All participants provided written informed consent to participate in the study. The Institutional Review Board from Saint-Louis Hospital approved the study protocol.

Patients were recruited in the department of urology from three hospitals located in Nancy, Brest, and Paris. The patients have incident disease with a histologically confirmed adenocarcinoma of the prostate. The aggressiveness of the cancer was defined using an aggressiveness scale based on the clinical patterns of Gleason score, TNM classification, and prostate-specific antigen (PSA) level (Table 1). Controls were selected from men invited to a systematic health screening performed in the same geographic areas as the hospitals where the sample patients were enrolled, as described previously.²⁰ Controls were defined by a blood test for PSA less than 4 ng/mL, no prostatic symptoms, and normal digital rectal examination.

Choice of Genetic Variants and Genotyping Analysis
We selected candidate gene polymorphisms that have been documented for their prevalence in more than 10% of our population (to obtain good statistical power given the size of our population) and have been highlighted as relevant for cancer predisposition in published case-control studies. Genotype assays were carried out using the genotyping facilities at the Centre de Recherche pour les Pathologies Prostatiques (Paris, France) and Institute from Cancer Studies at the University of Sheffield (Sheffield, United Kingdom). Genotyping of the CYP17, CYP1B1, and COMT polymorphisms was performed by the 5'-nuclease polymerase chain reaction (PCR) method, using the TaqMan system (ABI/PE Biosystems, Foster City, CA). PCR amplification was carried out separately for each polymorphism. The final volume for PCR was 5 µL containing 10 ng genomic DNA template, 900 nmol/L each primer, 200 nmol/L 6-carboxy-fluorescein–labeled probe, 200 nmol/L VIC or TET-labeled probe, and 2.5 µL 2x Universal PCR mastermix (PE Biosystems) containing optimized buffer components and Rox reference dye. Primer and probe sequences were as described in Appendix Table A1 (online only). The PCR amplification cycles were 95°C for 10 minutes, followed by 40 cycles of 95°C for 15 seconds, and 60°C for 1 minute. Levels of 6-carboxy-fluorescein and VIC/TET fluorescence were determined and allelic discrimination was carried out using the ABI 7900 Sequence Detector (ABI/PE Biosystems).

For the tetranucleotide repeat from CYP19, primers (5'-TTATGAAAGGTAAGCAGGTACTTAG-3' and 5'-GTCGTGAGCCAAGGTCACT-3') were used. One primer was fluorescently labeled. PCR was carried out in a final volume of 20 µL, containing 50 ng of genomic DNA, 250 µmol/L deoxynucleotide triphosphate, 1 µmol/L each primer, 2.5 U Taq Gold (ABI/PE Biosciences), 2.5 mmol/L MgCl₂, and 5% dimethylsulfoxide, in the following cycling conditions: 11 minutes at 95°C, then 35 cycles of 40 seconds at 94°C, 30 seconds at 55°C, 30 seconds at 72°C; followed by a final extension step of 10 minutes at 72°C. PCR products were loaded on 5% denaturing polyacrylamide gel and detected with an ABI Prism 377 DNA sequencer. Genotypes were determined with Genescan Analysis 3.1 (ABI/PE Biosciences).

Statistical Analysis
All studied genotypes were tested for consistency with the expected genotype frequencies under Hardy-Weinberg equilibrium among the control population. Odds ratios, as measure of relative risk, and 95% CIs were estimated from logistic regression models, with adjustment for age at interview. The number of repeats of CYP19 was dichotomized: the short allele was defined as having seven TTTA repeats (< 175 bp) and the long allele ( 175 bp) was defined as having eight to 13 repeats according to a previous report.²¹ Tests for additive effect of the at-risk alleles were performed. All statistical analyses were performed using SPSS software version 14.0 (SPSS Inc, Chicago, IL).

	RESULTS

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Distribution of the genotypes and alleles from the CYP17, CYP19, CYP1B1, and COMT polymorphisms in controls and prostate cancer patients are shown in Table 2. All genotype frequencies for healthy controls follow the Hardy-Weinberg equilibrium. No association between CYP17 variant and prostate carcinoma risk was observed. The long allele ( 175 bp) from CYP19 (odds ratio [OR] = 1.26; 95% CI, 1.08 to 1.47; P = .003) and V allele from CYP1B1 (OR = 1.17; 95% CI, 1.02 to 1.33; P = .02) were associated with a higher risk of prostate cancer. A higher frequency of GG genotype from COMT was observed in patients (28%) compared with controls (25%) but the difference was not statistically significant (P = .08).

	DISCUSSION

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This study sought to determine whether polymorphisms –34TC (CYP17), TTTA repeat (CYP19), V432L (CYP1B1), and V158M (COMT) in genes involved in estrogen metabolism pathways were associated with an elevated risk of prostate cancer or an aggressive disease pattern.

Inherent difficulties in studies involving various ethnicities, heterogeneous reproducibility of phenotype assignment related to anatomic features, and clinical definition in patients and controls may explain the conflicting results obtained from polymorphisms in candidate genes in previously published studies. Knowing these limitations, we performed this study on a large and homogeneous French population. We have shown that genes related to estrogen metabolism through specific polymorphisms can significantly increase the risk of prostate cancer, affect the risk of aggressive tumors, and have an additive effect.

CYP17 and CYP19 are two genes that encode enzymes that can potentially modulate blood levels of androgens or estrogens.²² CYP17 is expressed constitutively in gonads and adrenal glands. Polymorphism in the promoter region of this gene (CYP17A1 –34TC) defines higher activity (A2 allele) and lower activity (A1 allele) for CYP17 and has been linked to variations of circulating testosterone or estradiol levels. In 1996, Feigelson et al²³ suggested that CYP17 polymorphism may be associated with prostate carcinoma risk. However, studies regarding this promoter variant remained conflicting and suggested that it might play a role in susceptibility to prostate cancer essentially for men of African descent (reviewed by Ntais et al,²⁴ Vesovic et al,²⁵ and Forrest et al²⁶). However, a recent report on Finnish men found that the CYP17A1 –34TC polymorphism could be associated with moderate to poorly differentiated organ-confined disease.¹⁸ Our results are not in favor of a significant role for this polymorphism in term of prostate carcinogenesis risk.

Aromatase is expressed constitutively in the testis, adipose tissue, and fibromuscular stroma of the prostate. In 2001, our group¹¹ and then Modugno et al¹² were the first to suggest that the CYP19 tetranucleotide (TTTA) repeat polymorphism located in intron 4 may be associated with prostate cancer risk. The longer TTTA repeat ( 175 bp) variant in the CYP19 gene has been associated with high levels of estrogens in elderly men and high bone density.²⁷ This functional effect of the CYP19 polymorphism was only observed in men with normal body mass index (BMI). Recently, Mononen et al,¹⁸ using single-strand conformation polymorphism analysis, reported that a new single nucleotide polymorphism (T201M) located in CYP19 gene was linked to prostate cancer risk (OR = 2.04; 95% CI, 1.03 to 4.03; P = .04). However, Li et al¹³ failed to find an effect of CYP19 TTTA repeat on prostate cancer risk when they analyzed a sibling set (< 500 sibpairs) from a multiethnic population or when they restricted the analysis to white individuals only. Conversely, this CYP19 polymorphism was associated significantly with familial prostate cancer risk in a Japanese population,¹⁴ and Tsuchiya et al²¹ have suggested recently that this repeat polymorphism may be also a novel predictor in prostate cancer patients with bone metastasis at diagnosis. Our results suggest that a high-activity (long) allele from the TTTA repeat polymorphism is also associated to prostate cancer risk in a large white population, and particularly among patients at an early age at disease onset. If one agrees that high-activity CYP19 variants or high BMI can modify estrogenic status in men, it is possible to relate our results to previous reports on patients with BMI more than 30 who have a higher risk of being diagnosed with prostate cancer and unfavorable pathologic features on radical prostatectomy specimens (a higher BMI increased the odds of high-grade disease),^28,29 and a worse outcome of their disease.³⁰ Additional studies in other ethnic populations will be worthwhile to confirm our results.

The CYP1B1 and COMT genes encode enzymes that are involved in the metabolism of estrogens in various tissues and potentially are involved in local production of carcinogenic estrogen metabolites. CYP1B1 and COMT are expressed constitutively in the prostate, breast, and uterus, as well as in several other tissues.³¹ The estrogen 3,4-quinone resulting from CYP1B1 transformation can form unstable adducts with adenine and guanine in DNA, leading to depurination and mutation. Reduction of estrogen quinones back to hydroquinones and catechols induces reactive oxygen species and probably accounts for the oxidative damage to DNA, leading to carcinogenic events. Moreover, catechol estrogen metabolites may also participate in the regulation of pathways of gene expression, signaling, or both through the estrogen receptors. The 4-hydroxycatechol estrogens have high binding affinities to the human estrogen receptor (150% compared with that of estradiol) and induce estrogen-receptor–dependent gene expression. In the prostate, CYP1B1 and COMT are expressed essentially in the peripheral zone,^32,33 the main localization for prostate cancers. COMT acts as a phase II metabolism enzyme leading to increased protective conjugation of reactive catechol estrogens produced by CYP1B1 activity. It is supposed that high activity of CYP1B1 and low activity of COMT determined by genetic polymorphisms can increase locally the levels of catechol estrogens and determine an increased risk of local carcinogenesis. The V432L CYP1B1 and the V158M COMT polymorphisms are the main variants studied for their involvement in carcinogenesis (first for breast cancer risk).^34,35 Studies suggesting association between those CYP1B1 and COMT variants and prostate cancer or their potential involvement in its aggressiveness have been conducted in Japanese populations^15,16,36,37 and on small panels (< 500) of white patients and controls.^19,38-40 In a large population of white French men, we showed that the CYP1B1 V432L variant is associated significantly with the risk of prostate cancer, and notably among the patients with highly aggressive prostate cancer. Interestingly, the association with the risk of prostate cancer was stronger when this variant was combined with the G allele from the COMT M158V polymorphism (Table 3). Additional studies to confirm these results in other study populations will be of benefit.

In conclusion, estrogens have been suspected to be involved in prostate carcinogenesis for more than two decades, but have been overshadowed by androgens. Recent evidence supports this hypothesis in rodent models and in studies on specific allelic variants in estrogen-related genes. Our results indicate that estrogen-related genes could increase significantly the risk of prostate cancer through specific polymorphisms, and may have affected the risk of tumor aggressiveness in a white French population. Notably, an additive effect on the risk of prostate cancer was found when the at-risk alleles from those polymorphisms were combined. The process through which estrogens and androgens contribute to each phase of the carcinogenic or therapeutic mechanisms in prostate cancer is complex at the molecular level. However, there is accumulating evidence suggesting a central role for estrogens in prostate cancer. This may pave the way for the development of new prevention strategies in addition to approaches targeting the androgen pathways in the management of prostate cancer.

	AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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The author(s) indicated no potential conflicts of interest.

	AUTHOR CONTRIBUTIONS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Conception and design: Olivier Cussenot, Geraldine Cancel-Tassin

Provision of study materials or patients: Olivier Cussenot, Gaelle Fromont, Philippe Mangin, Luc Cormier, Georges Fournier, Antoine Valeri, Frederic Thibault, Jean-Pierre Giordenella, Michel Pouchard, Geraldine Cancel-Tassin

Collection and assembly of data: Olivier Cussenot, Abdel Rhamene Azzouzi, Stephane Larre, Frederic Thibault, Yan Zheng, Angela Cox, Geraldine Cancel-Tassin

Data analysis and interpretation: Olivier Cussenot, Abdel Rhamene Azzouzi, Nathalie Nicolaiew, Freddie C. Hamdy, Angela Cox, Geraldine Cancel-Tassin

Manuscript writing: Olivier Cussenot, Nathalie Nicolaiew, Freddie C. Hamdy, Angela Cox, Geraldine Cancel-Tassin

Final approval of manuscript: Olivier Cussenot, Geraldine Cancel-Tassin

	Appendix

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	ACKNOWLEDGMENTS

 
We thank Beatrice Legrand and Cecile Gaffory for excellent technical assistance.

	NOTES

 
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.

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Submitted February 1, 2007; accepted May 21, 2007.

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