Polymorphisms in base-excision & nucleotide-excision repair genes & prostate cancer risk in north Indian population.

Background & objectives: Genetic variation in the DNA repair genes might be associated with altered DNA repair capacities (DRC). Reduced DRC due to inherited polymorphisms may increase the susceptibility to cancers. Base excision and nucleotide excision are the two major repair pathways. We investigated the association between two base excision repair (BER) genes (APE1 exon 5, OGG1 exon 7) and two nucleotide excision repair (NER) genes (XPC PAT, XPC exon 15) with risk of prostate cancer (PCa). Methods: The study was designed with 192 histopathologically confirmed PCa patients and 224 age matched healthy controls of similar ethnicity. Genotypes were determined by amplification refractory mutation specific (ARMS) and PCR-restriction fragment length polymorphism (RFLP) methods. Results: Overall, a significant association in NER gene, XPC PAT Ins/Ins (I/I) genotype with PCa risk was observed (Adjusted OR- 2.55, 95%CI-1.22-5.33, P=0.012). XPC exon 15 variant CC genotypes presented statistically significant risk of PCa (Adjusted OR- 2.15, 95% CI-1.09-4.23, P=0.026). However, no association was observed for polymorphism with BER genes. Diplotype analysis of XPC PAT and exon 15 revealed that the frequency of the D-C and I-A diplotype was statistically significant in PCa. The variant genotypes of NER genes were also associated with high Gleason grade. Interpretation & conclusions: The results indicated that there was a significant modifying effect on the association between genotype XPC PAT and exon 15 polymorphism and PCa risk which was further confirmed by diplotype analysis of XPC PAT and exon 15 in north Indian population.

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.