Prostate carcinoma risk and allelic variants of genes involved in androgenbiosynthesis and metabolism pathways

BACKGROUND. Ethnicity, when it is used to mean shared genetic inheritance w ithin a group, has become one of the most important factors in determining prostate carcinoma risk. Genetic polymorphisms were hypothesized to be the probable explanation for differences in risk among ethnic groups. The autho rs evaluated the association between polymorphisms in genes involved in the androgen biosynthe sis and metabolism pathway and the risk of prostate car cinoma. METHODS. Two hundred twenty-six patients with the pathologic diagnosis of s poradic prostate tumor and 156 healthy matched (age, ethnic group) male con trols from a large epidemiologic cohort were genotyped for previously descr ibed poly morphisms in the androgen receptor (AR), 5 alpha -reductase type II (SRD5A2), p450c17 (CYP17), and aromatase (CYP19) genes. The different po lymorphisms in prostate carcinoma patients also were analyzed according to age of onset, preoperative prostate-specific antigen level, tumor stage, an d tumor grade. RESULTS. The distribution of the tetranucleotide simple tandem repeat polym or, phism (STRP) in intron 4 of CYP19 was significantly different in contro l and cancer patients (P = 0.012). The 171 allele and the 187 allele were a ssociated with prostate carcinoma risk (P = 0.05 and P = 0.045, respectivel y). Conversely, no association was observed between prostate carcinoma risk and the other polymorphisms studied as follow: the CAG repeat in exon I of AR, the (TA)n dinucleotide repeat polymorphism in the 3 ' untranslated reg ion, and the A49T or V89L substitutions in SDR5A2, the single base pair (bp ) (a T to C transition) polymorphism that creates an additional Spl-type (C CACC box) promoter site in CYP17. In prostate carcinoma patients, CAG repea ts of A-R, and TA repeats of SDR5A2 are associated with age of onset (P = 0 .05 and P < 0.001, respectively). CONCLUSIONS. The association between the 171-bp allele of CYP19 and prostat e carcinoma risk suggests that aromatase could be used as a new indicator f or prostate carcinoma prevention in men of White French ethnogeographic ori gin. Conversely, it is possible that an individual carries both a high- and a low-risk marker (e.g., CYP17A2 allele and V89L in SRD5A2) resulting in n o overall difference in risk observed across the population. For these reas ons, the development of a polygenic model, incorporating multiple loci from the individual genes may max imize the chance of identifying individuals w ith high-risk genotypes. (C) 2001 American Cancer Society.