Role of an androgen receptor gene polymorphism in development of hormone refractory prostate cancer in Indian population.

BACKGROUND: Androgen receptors play critical roles in the development of primary as well as advanced hormone-refractory prostate cancers. Since the growth of prostate cancer is androgen-sensitive, metastatic disease has been treated by hormonal therapy in the form of androgen ablation. Prostate cancer cells rely on androgen receptor (AR) for proliferation and survival. AIM: To evaluate the prognostic significance of androgen receptor polymorphism in patients under hormonal therapy in any form. METHODS: Complete follow up data were available for 87 patients out of 130 patients enrolled for study. DNA was extracted from blood samples using salting out method and then subjected to PCR Genscan for CAG and GGN genotyping. The mean follow up was 10.12+/-8.83 months. RESULTS: Out of 87 patients, 64 experienced clinical as well as biochemical recurrence. The overall hormone refractory rates were 73.4% after one year. We observed a significant shorter median CAG repeats in HRPC patients (20 vs 22). The hazard ratio for HRPCs with the < or =20 CAG repeat genotype was 0.602 (0.33-1.08, p=0.09). Kaplan-Meier analysis showed that HRPC rates were not significantly associated with CAG repeat (p=0.06) but a trend was observed with short CAG repeats. No significant association was observed with AR-GGN repeats. CONCLUSIONS: A trend for association of AR-CAG repeats with HRPC patients in north Indian population was observed, suggesting this to be a prognostic factor for determining the therapeutic regimen.

Evaluating polymorphic status of glutathione-S-transferase genes in blood and tissue samples of prostate cancer patients.

Prostate cancer is the most common urologic malignancy, involving multiple factors. There is evidence that suggests that detoxification enzymes and growth factors may play a role in its development . The glutathione S-transferase (GST) enzymes detoxify several carcinogens and genetic polymorphisms in GSTM1, T1, and P1 (Ile105Val) have been reported to be associated with prostate cancer, mainly from blood samples. As expression studies suggest differential expression of different genes in tissues, we hypothesize that polymorphic status may be differently expressed for GSTM1, GSTT1 and GSTP1 gene in blood and tissues of prostate cancer patients and BPH controls, impacting on the development of prostate cancer. To study this, we extracted DNA from blood and tissue samples of patients undergoing biopsy procedures or transurethral resection of prostate tissue. Genotyping for GSTM1 and T1 was conducted by multiplex PCR and for GSTP1 by the PCR-RFLP method. Our results suggested no significant differences in frequency distribution of M1, T1 and P1 between blood and tissue samples of patients and controls, but in a few patients differences in polymorphic status were observed. However, they were not significant. Furthermore, we observed a significant risk of prostate cancer with null allele of GSTT1 and GSTM1 and Val allele of GSTP1, supporting our previous findings. A study with large sample size using radical prostectomy tissue now needs to be performed to attain a specific conclusion.

Vitamin-D receptor (VDR) gene (Fok-I, Taq-I and Apa-I) polymorphisms in healthy individuals from north Indian population.

The vitamin-D endocrine system is involved in a wide variety of biological processes including bone metabolism, modulation of immune responses, and regulation of cell proliferation and differentiation. Variation in this endocrine system have, thus, been linked to several common diseases, including osteoarthritis (OA), diabetes, cancer, cardiovascular ailments, urolithiasis and tuberculosis. Activity of Vit-D is mediated by the vitamin D receptor (VDR), a ligand dependent receptor. VDR gene polymorphisms thus represent strong positional candidates for different diseases like prostate cancer, urolithiasis, inflammatory bowl disease and osteoporosis. Genetic studies provide excellent opportunities to link molecular insights with epidemiological data and can reveal modest and subtle but true biological effects. The abundance of polymorphisms in the human genome as well as high frequencies in human populations have made them targets to explain variation in risk of common diseases. The present study was carried out to determine the distribution of VDR gene (Fok-I, Taq-I and Apa-I) polymorphisms using a PCR-based restriction analysis in unrelated normal healthy individuals from a north Indian population. We obtained allelic frequencies of (68.5% vs 31.5%), (66% vs 34%) and (58% vs 42%) for (F vs f), (T vs t) and (A vs a) alleles, with 44%, 49% and 7%, respectively, for genotypes FF, Ff and ff , 49%, 40% and 11% for TT, Tt and tt and 36%, 44% and 20% for AA, Aa and aa. Our results suggest that the frequency and distribution of the polymorphisms in India are substantially different from in other populations and ethnic groups. Thus the data signify an impact of ethnicity and provide a basis for future epidemiological and clinical studies.

Allelic variation of GSTT1, GSTM1 and GSTP1 genes in North Indian population.

Glutathione S-transferase (GST) enzymes are involved in detoxification of many potentially carcinogenic compounds. Homozygous deletions or null genotypes of GSTT1 and GSTM1 genes and an A to G substitution at nucleotide 313 in GSTP1 have been reported in different populations. Intra-ethnic as well as interethnic differences are known to exist in the frequencies of the above GST genes. The present study was therefore undertaken to determine the prevalence of GSTM1 and GSTT1null alleles, as well as the GSTP1 gene polymorphism, in 370 healthy individuals in a North Indian population. Genotyping of M1 and T1 was performed using a multiplex polymerase chain reaction and the GSTP1 polymorphism was determined by the polymerase chain reaction/restriction fragment length polymorphism (PCR-RFLP) method. The frequencies of GSTM1 and GSTT1 null alleles in normal healthy individuals were observed to be 33.0% and 18.4% respectively. In 7.0% of individuals' concomitant lack of M1 and T1 genes were observed. For GSTP1, wild (Ile/Ile), heterozygous (Ile/Val) and mutant (Val/Val) genotypes were observed for 44.3%, 50.3% and 5.4% of individuals respectively. The prevalence of the M1 null allele is significantly lower than those documented for English, Turkish, Chinese, Caucasians, Japanese and white (Brazilian and American) populations. However, a significantly higher frequency for T1 null was reported in Chinese and Japanese population. Furthermore, Japanese and African American populations have exhibited significantly higher frequencies of wild and mutant P1 genotypes, respectively, than the Indian population. Thus, our results signify an impact of ethnicity and provide a basis for future epidemiological and clinical studies.