Effects of functional genetic polymorphisms in theCYP19A1gene on prostate cancer risk and survival

Abstract

CYP19 catalyzes the conversion of androgens to estrogens and is a critical enzyme affecting the sex hormone milieu. In this study, we investigated the functions of CYP19A1 polymorphisms and their associations with prostate cancer risk and clinical outcome. This case-control study evaluated the effects of three single nucleotide polymorphisms (SNPs) in CYP19A1 on the risk of prostate cancer in 330 prostate cancer patients and 354 normal controls. The associations between each SNP and sex hormone levels were evaluated in 164 healthy male patients. The functions of the SNPs were determined by reporter gene assays in PC3 and DU145 cell lines. Prostate-specific antigen nadir was evaluated in 142 patients with metastatic prostate cancer treated with androgen deprivation therapy. Cancer-specific survival (CSS) was determined in 166 patients with metastatic prostate cancer, to evaluate the influence of the three SNPs. Each variant allele of the three SNPs significantly decreased the risk of prostate cancer. Haplotype analysis showed that the T-A-G haplotype (corresponding to rs2470152-rs10459592-rs4775936) increased the risk of prostate cancer, while the C-C-A haplotype decreased the risk. The estrone/ androstenedione ratio was significantly higher in men with the C allele of rs2470152, the C allele of rs10459592, and the A allele of rs4775936 in a gene-dosage-dependent manner. Patients with the variant allele at rs4775936 had significantly shorter CSS. These results indicate that CYP19A1 polymorphisms may influence prostate cancer risk and survival by modifying promoter activity, with subsequent effects on the sex hormone milieu.Sex hormones, especially androgens, appear to play an important role in the carcinogenesis and progression of prostate cancer. 1,2 Testosterone propionate was shown to induce prostate cancer in an Nb rat model, 3 and the 5-a reductase inhibitor, finasteride, inhibited carcinogenesis in rat prostate cancer induced by testosterone (TS) propionate and the carcinogen, 3,2 0 -dimethyl-4-aminobiphenyl. 4 In the clinical setting, Huggins et al. first reported that androgen deprivation therapy (ADT) caused tumor regression in patients with metastatic prostate cancer, 1 since when endocrine therapies became a key part of the treatment for patients with advanced prostate cancer. Abraterone, which inhibits CYP17 androgen-synthesis enzyme activity, was recently shown to be a powerful drug, even in patients with castration-resistant prostate cancer previously treated with chemotherapy. 5 The importance of androgens in prostate cancer means that the synthetic pathways for these hormones have been targets for intensive study. Androgens are synthesized by many enzymes, primarily in the testes and the adrenal gland, and to a lesser extent in peripheral organs including the prostate and skin. 2 Among the enzymes involved in sex hormone synthesis, CYP19, also known as aromatase and encoded by CYP19A1, catalyzes the conversions of androstenedione

An NKX3.1 binding site polymorphism in the l-plastin promoter leads to differential gene expression in human prostate cancer

“…Although it is unclear if decreased L‐plastin expression is defined by genetic factors or is the result of other pathways, it is interesting to note that the homozygous genotype of SNP −1,687 (T/T), which reduced the promoter activity of L‐plastin in prostate cancer cells, was related to an improved prognosis for prostate cancer patients. Previous studies on SNP‐related prostate cancer susceptibility and prognosis indicated that CYP19A1 polymorphisms influence prostate cancer risk and survival by modifying promoter activity, with subsequent effects on the sex hormone environments . In the present study, we demonstrated that SNP −1,687 (T/T) occurred more frequently in the healthy individuals than in the prostate cancer patients compared with the (C/C) and (C/T) genotypes.…”

Androgens and androgen receptor signaling in prostate tumorigenesis

“…CYP19A1 encodes an enzyme that catalyzes the conversion of androgens to estrogens. Recent studies have suggested that functional genetic polymorphisms in the CYP19A1 gene may modify serum and/or intratumoral sex hormone levels and therefore influence prostate cancer risk and survival (Latil et al 2001, Suzuki et al 2003, Tsuchiya et al 2006, Kanda et al 2015. The androgen transporter gene SLCO2B1 also has a polymorphism that has been associated with prostate cancer risk and outcome (Yang et al 2011).…”

Functional analysis implicating the SNP rs61552325 in ERBB2 as an effector for androgen-insensitive prostate cancer cell invasion

“…A case-control study researched the relationship between SNPs in cytochrome P450 family 19 subfamily A member 1 (CYP19A1) and metastatic PCa. They found that patients with the minor variant rs4775936 had decreased chances for survival and verified their discovery in two commonly studied metastatic PCa cell lines, DU145 and PC3 [29]. rs2228013 in NKX3.1 could increase the metastasis in younger PCa patients [30].…”