Hormonal and genetic regulation of prostate cancer in Caucasian and Malaysian Chinese ethnic groups

Introduction: Prostate Cancer (PC) is the most common cancer in men and the second biggest cause of cancer-related death of men in the Western world. There are significant ethnic differences in the incidence of PC between African Americans, Caucasians and Asians. At the present time, the only method used for PC screening is Prostate Specific Antigen (PSA). Prostate is an androgen regulated gland and it can also affect the concentration of growth hormone by activation of androgen receptor. The aim of this research was to investigate ethnic group-specific relationship between PC incidence, concentration of circulating hormones and polymorphisms in genes that are involved in regulation of androgen metabolism. Specific objectives were: (i) to determine whether circulating concentration of androgens testosterone, dihydrotestosterone (DHT) and a growth hormone insulin-like growth factor-I (IGF-I) differ between Bristol Caucasian (BC) and Malaysian Chinese (MC) men; (ii) to investigate whether variations in concentration of circulating androgens in control and PC cohorts are ethnic group-specific; (iii) to determine whether frequency of DNA polymorphisms in CYP17, SRD5A2 and androgen receptor (AR) genes are ethnic group-specific; (iv) to investigate the relationship between genetic polymorphisms, concentration of circulating androgens and incidence of PC in BC and MC groups. Material and Method: Blood sample were obtained from newly diagnosed PC patients from Caucasian and MC ethnic groups whose diagnosis was confirmed by biopsy. Control group consisted of patients with confirmed Benign Prostatic Hyperplasia with low risk of PC. The studied populations consisted of 50 Caucasian cancer cases, 50 Caucasian controls, 50 MC cancer cases and 49 MC control participants. Analysis of testosterone, DHT and IGF-I concentrations was performed on serum using ELISA kits. DNA polymorphisms were determined using genomic DNA isolated from whole blood (by PCR amplification) and follow-on DNA sequencing. The obtained DNA sequences were aligned with appropriate DNA sequences of the reference genes. The software "Geneious" was used to identify DNA SNPs and amino acid substitutions in translated protein. Statistical analysis was performed using SPSS version 20.0. Results: This study established ethnic group-specific differences in circulating androgens between control and PC groups. In particular, testosterone concentration was significantly lower, and DHT/T was significantly higher in the MC cancer patients when compared to Caucasians. IGF-I concentration was significantly higher in the Caucasian cancer and controls than the MC sub-groups. A1/A2 and A2 + A1/A2 alleles of CYP17 gene were associated with a higher risk of PC in both ethnic groups. LL and L/V genotypes of SRD5A2 were prevalent in MC cancer and control group when compared to Bristol Caucasian PC and controls. These genotypes, when present, were associated with increased risk of PC in Caucasians but not in MC group. No relationship was found between a number of CAG-repeats in AR gene and PC in Caucasian or MC populations. No significant relationship was found between SNPs in CYP17, SRD5A2 and AR genes and circulating concentration of androgens and IGF-I in Caucasian and MC populations. The only exception was a positive association between the SRD5A2 polymorphism in the position 261C→G and IGF-I concentration in Caucasian control group. Conclusions: This study demonstrated positive relationship between the concentration of circulating androgens, namely testosterone, IGF-I growth factor and the severity of the PC in Bristol Caucasians and MC groups. It also established ethnic-group specific polymorphisms in CYP17 and SRD5A2 genes, but not in the AR gene. It was suggested that the CYP17 and SRD5A2 polymorphisms might contribute to the risk of PC development in Caucasians and MC. Further evaluation of the results on a larger cohort and a wider range of ethnic groups are required in order to make definite conclusions about CYP17, SRD5A2 as ethnic-group specific biomarkers for PC.