CYP19A1 Genetic Variation in Relation to Prostate Cancer Risk and Circulating Sex Hormone Concentrations in Men from the Breast and Prostate Cancer Cohort Consortium

Cancer Epidemiology Unit, Nuffield Department of Clinical Medicine, University of Oxford, Richard Doll Building, Oxford, United Kingdom.
Cancer Epidemiology Biomarkers & Prevention (Impact Factor: 4.13). 10/2009; 18(10):2734-44. DOI: 10.1158/1055-9965.EPI-09-0496
Source: PubMed


Sex hormones, particularly the androgens, are important for the growth of the prostate gland and have been implicated in prostate cancer carcinogenesis, yet the determinants of endogenous steroid hormone levels remain poorly understood. Twin studies suggest a heritable component for circulating concentrations of sex hormones, although epidemiologic evidence linking steroid hormone gene variants to prostate cancer is limited. Here we report on findings from a comprehensive study of genetic variation at the CYP19A1 locus in relation to prostate cancer risk and to circulating steroid hormone concentrations in men by the Breast and Prostate Cancer Cohort Consortium (BPC3), a large collaborative prospective study. The BPC3 systematically characterized variation in CYP19A1 by targeted resequencing and dense genotyping; selected haplotype-tagging single nucleotide polymorphisms (htSNP) that efficiently predict common variants in U.S. and European whites, Latinos, Japanese Americans, and Native Hawaiians; and genotyped these htSNPs in 8,166 prostate cancer cases and 9,079 study-, age-, and ethnicity-matched controls. CYP19A1 htSNPs, two common missense variants and common haplotypes were not significantly associated with risk of prostate cancer. However, several htSNPs in linkage disequilibrium blocks 3 and 4 were significantly associated with a 5% to 10% difference in estradiol concentrations in men [association per copy of the two-SNP haplotype rs749292-rs727479 (A-A) versus noncarriers; P = 1 x 10(-5)], and with inverse, although less marked changes, in free testosterone concentrations. These results suggest that although germline variation in CYP19A1 characterized by the htSNPs produces measurable differences in sex hormone concentrations in men, they do not substantially influence risk of prostate cancer.

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    • "[107] [111] [118]. Studies among Caucasian and Indian men showed a tendency for this polymorphism to increase risk [117] [118], but large case studies failed to confirm the results in Caucasian men [107] [111] [113]. "
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    ABSTRACT: Prostate cancer (PCa) is the most commonly diagnosed male malignancy and the second biggest cause of cancer death in men of the Western world. Higher incidences of PCa occur in men from North America, Oceania and Western countries, whereas men from Asia and North Africa have a much lower PCa incidence rate. Investigations into this population disparity of PCa incidence, in order to identify potential preventive factors or targets for the therapeutic intervention of PCa, have found differences in both environmental and genetic variations between these populations. Environmental variations include both diet and lifestyle, which vary widely between populations. Evidence that diet comes into play has been shown by men who immigrate from Eastern to Western countries. PCa incidence in these men is higher than men in their native countries. However the number of immigrants developing PCa still doesn't match native black/white men, therefore genetic factors also contribute to PCa risk, which are supported by familial studies. There are a number of genetic polymorphisms that are differentially presented between Western and Eastern men, which are potentially associated with PCa incidence. Androgen and its receptor (AR) play a major role in PCa development and progression. In this study, we focus on genes involved in androgen biosynthesis and metabolism, as well as those associated with AR pathway, whose polymorphisms affect androgen level and biological or physiological functions of androgen. While many of the genetic polymorphisms in this androgen/AR system showed different frequencies between populations, contradictory evidences exist for most of these genes investigated individually as to the true contribution to PCa risk. More accurate measurements of androgen activity within the prostate are required and further studies need to include more African and Asian subjects. As many of these genetic polymorphisms may contribute to different steps in the same biological/physiological function of androgen and AR pathway, an integrated analysis considering the combined effect of all the genetic polymorphisms may be necessary to assess their contribution to PCa initiation and progression.
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    • "In humans, however, there is no evidence of an association between circulating estrogens levels and risk of prostate cancer,[8992] with the possible exception of African–American men, in whom the serum estrogen level and the ratio of estradiol-to-testosterone has been positively associated with risk in a large NHANES III-based study.[93] There has also been no evidence of an association of risk with single nucleotide polymorphisms (SNPs) in the aromatase (CYP19A1) gene that are associated with altered serum levels of total and free estradiol and even free (but not total) testosterone.[94] On the other hand, evidence of an association between risk and TTTA repeat length polymorphisms in the estrogen receptor has been found,[95] but is not biologically plausible.[96] "
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