The interaction of CYP3A5 polymorphisms along the androgen metabolism pathway in prostate cancer

Abstract

Prostate cancer is a leading solid tumor among men in the Western world. Androgens play an important role in the carcinogenesis and treatment of prostate cancer. CYP3A5 is a cytochrome P450 superfamily member which also has activity in testosterone metabolism. In this study, we looked for two-gene interactions associated with clinical characteristics of prostate cancer in the Finnish population. We used multifactor-dimensionality reduction for the identification of the two-gene interactions in androgen metabolism pathway genes together with clinical characteristics of prostate cancer among 754 genotyped prostate cancer patients. The CYP3A5*3/*3 and SRD5A2 A49T GG genotype interaction was associated with the clinical tumor stage T2-T4 (T-stage, TNM classification) with odds ratio (OR) 2.14, 95% confidence interval (CI) 1.35-3.40. Patients with CYP3A5*3/*3 and KLK3 I179T CC/ TC genotypes had increased OR 2.30, 95% CI 1.16-4.58 for metastatic disease. Further, two-gene interaction CYP3A5*3/*3 and KLK3 2252A > G AA was associated with Gleason scores 7 with OR 1.52, 95% CI 1.11-2.09. Prostate cancer patients with CYP3A5*3/*3 and KLK 2252A > G GG/AG genotypes had decreased OR of 0.70 with 95% CI 0.50-0.98 for high prostatespecific antigen levels at diagnosis. For prostate cancer patients aged below 65 years, the OR for interaction of CYP3A5*1/*3 or *1/*1 and AKR1C3 Q5H CC genotypes was 1.84 with 95% CI 1.03-3.28. For prostate cancer, the best two-gene interaction included genotypes SRD5A2 V89L GG and AKR1C3 Q5H CC with OR 1.30, 95% CI 1.01-1.66. It remains to be clarified whether these polymorphism associations identified here are also present in other populations. ' 2008 Wiley-Liss, Inc.Key words: polymorphism; androgen metabolism; multifactordimensionality reduction; prostate cancer Androgens are essential for both development and normal and malignant growth of the prostate. Prostate cancer is the most common cancer among men in the Western world. 1 In Finland, the current age-adjusted incidence rate is 115.4/100,000 inhabitants, and still rising (Finnish Cancer Registry 2006, www.cancerregistry. fi). In Finland, the association of single nucleotide polymorphisms (SNPs) of androgen synthesizing and metabolizing genes with prostate cancer risk has recently been shown. 2 Further, carriers of 5 high-risk alleles in the AR, CYP17 and SRD5A2 genes have been shown to be at increased risk of developing prostate cancer in the Swedish population. 3 Cytochrome P450 (CYP) enzymes form a large superfamily of heme-containing monooxygenases. 4 CYP3A subfamily enzymes are the most abundantly expressed CYP enzymes in the liver. They are responsible for the metabolism of over 50% of all clinically used drugs, and also metabolize several toxins and endogenous compounds. 5 CYP3A5 catalyzes the 6b-hydroxylation of testosterone, producing a metabolite that is less biologically active and more readily eliminated, thus inhibiting testosterone metabolism to more biologically active androgen forms. 6,7 Expression of CYP3A5 is androgen regu...

Frequency of common CYP3A5 gene variants in healthy Polish newborn infants

“…Highly similar frequencies were observed for German, Finnish, Swedish and Greek populations [2,7,11,14,17,22]. Interestingly, the allelic frequencies described in our work are not significantly different from the ones published for the Baltic Sea area.…”

“…These CYP3A5 genotypes have been associated with the lower mean clearances of benzodiazepines and etopo- USA/(Afro-Americans) Healthy adults, (34) 0.721 0.279 [9] Finnish/(Caucasians) Healthy adults, (754) 0.070 0.930 [22] USA/(Afro-Americans) Healthy adults, (25) 0.540 0.460 [11] side, which might increase the probability of drugrelated adverse reactions, such as peripheral neuropathy [16]. Additionally, a strong association between the CYP3A5*1 genotype and tacrolimus dose requirement was observed.…”

Genetic variations in androgen metabolism genes and associations with prostate cancer in South African men

“…6 We demonstrated that the rs776746 A allele was associated with developing PCa in South African white men, whereas in Finnish men the allele was not associated with development of PCa but was associated with bone metastases (disease progression). 5 The (10) 17 (6) 1.83 (0.92 -3.74) 0.0869 0.1312* *Corrected p-value for the effect of population stratification in coloured men obtained by multiplying age-adjusted value by an inflation factor λ = 3.06 (Fernandez et al, 2008 11 ).…”

“…4 In Finnish men, the rs776746 A allele was significantly associated with PCa bone metastases. 5 The CYP3A4 enzyme is involved in the oxidation of testosterone to 2β-, 6β-or 15β-hydroxytestosterone. For the SNP rs2740574 (-392A>G; the A allele = CYP3A4*1A and G allele = CYP3A4*1B) in the 5´ regulatory region of the gene, the G allele was initially shown to be associated with PCa in white and black American men, 6 which was replicated in subsequent investigations.…”

Genetic polymorphisms in estrogen metabolism and breast cancer risk in case–control studies in Japanese, Japanese Brazilians and non-Japanese Brazilians

“…For this reason, CYP3A5*1 is considered a protective genotype of prostate cancer, and an association between CYP3A5*3 and prostate cancer risk has been demonstrated. 42 Therefore, a second possibility is that a portion of endogenous estradiol derived from testosterone might be modulated by the CYP3A5*1 genotype to result in a lower breast cancer risk among CYP3A5*1 carriers in JB and NJB. Further studies are required to confirm whether the CYP3A5*3 mutation is associated with an increased or decreased risk of breast cancer.…”