Polymorphism of GSTM1 and GSTT1 genes in prostate cancer: A study from North India

BACKGROUND: Glutathione-S-transferases (GSTs) are active in the detoxification of wide variety of endogenous or exogenous carcinogens. The genetic polymorphisms of GSTM1 and GSTT1 genes have been studied earlier to evaluate the relative risk of various cancers. AIM, SETTING AND DESIGN: In the present study, we examined the association of the GSTM1 and GSTT1 gene polymorphisms with sporadic prostate cancer patients in north Indian population. MATERIAL AND METHODS: This case control study was undertaken over a period of 24 months and included 103 prostate cancer patients and 117 controls; both patients and controls originated from northern part of India. The GSTT1 and GSTM1 genotypes were identified by multiplex PCR in peripheral blood DNA samples. STATISTICAL ANALYSIS: Difference in genotype prevalence and association between case and control group were assessed by the Chi square and Fisher Exact tests. RESULTS: Frequencies of null genotypes in GSTT1 and GSTM1, was 11% (13/117) and 30% (35/117) respectively in control individuals. The frequencies of GSTT1 and GSTM1 null genotypes in prostate cancer patients were 34% (35/103) and 53% (55/103) respectively. CONCLUSION: Our study demonstrates that the null genotypes of GSTT1 and GSTM1 are substantially at higher risk for prostate carcinoma as compared to the normal healthy controls. The GSTT1 and GSTM1 null genotypes did not show significant association with tobacco usage in prostate cancer patients. However, the null genotypes were significantly stratified in 50-60 year-old patients when incidence of prostate cancer is high

Association of pro/anti-inflammatory cytokine gene variants in renal transplant patients with allograft outcome and cyclosporine immunosuppressant levels

T-helper (Th) type 1/Th2 cytokines are key mediators in induction/effecter phases of all immune and inflammatory responses playing role in acute/chronic renal allograft rejection. Association studies lead to identification of patient risk profiles enabling individualization of level of immunosuppressions. We investigated the association of allograft rejection with interleukin-2 (IL-2), IL-4, IL-6, tumor necrosis factor-α (TNF-α) −308, transforming growth factor-β (TGF-β) (C-del, codon 10 and 25) gene variants in 184 renal transplant recipients and 180 controls. These cytokine genotypes were also evaluated with cyclosporine levels (C2) at one month in 135 stable recipients. High producing genotypes B1B1 of IL-4 and AA of TNF-α α308 showed significant association with rejection of allograft. The dose-adjusted C2 levels were significantly lower in patients with the high producing genotype T/T of IL-2 and heterozygous G/C of TGF-β codon 25 (P = 0.012 and 0.010, respectively). Haplotype frequencies were comparable in subjects for TGF-β codon-10 and 25. Combined inter-gene interaction showed high risk for rejection in recipients with high producing genotype B1B1 of IL-4 and AA of TNF-α and high TNF-α (AA) with low TGF-β (CC or Pro/Pro). In conclusion, association of IL-4 VNTR and TNF-α −308 suggested the involvement of these cytokines contributing to pathogenesis of allograft rejection. Recipients with TT genotype of IL-2 and GC of TGF-β codon 25 having low C2 levels may require higher cyclosporine dosage. Combined analysis of gene-gene interaction demonstrated synergistic effect of cytokines increasing risk for rejection. Thus, this information may help in pre-assessment of allograft outcome and to optimize cyclosporine therapy in post-transplant patients

Free to total serum prostate specific antigen ratio in symptomatic men does not help in differentiating benign from malignant disease of the prostate

Introduction: Free to total prostate specific antigen ratio (f/t PSA) has been used to help improving specificity of PSA in the range of 4-10 ng/ml based on the data on population based screening. There is no data on test characteristics of f/t PSA in men presenting with clinical symptoms of benign prostatic hyperplasia (BPH). This study is aimed to determine the usefulness of f/t PSA in symptomatic men. Methodology: From January 2006 to June 2012, men of 50-75 years with lower urinary tract symptoms (LUTS), normal rectal examination and PSA between 4-20 ng/ml had free and total PSA assessment. Men with clinical evidence of prostatitis, retention, history of 5α blocker reductase inhibitors and those who had surgery or biopsy on the prostate in last 3 months were excluded. Receiver operating characteristic curves were derived for f/t PSA and total PSA. The effect of age, prostate volume and Gleason score on the f/t PSA was also analyzed. All statistical analyses were performed on SPSS 16 (Chicago, USA). Results: Out of 170 men with the mean age of 67.4 ΁ 6.6 years, 43 (25.3%) had cancer on biopsy. Area under the curve for predicting the presence or absence of prostate cancer in all the men with f/t ratio was 0.63 (confidence interval [CI]: 0.54-0.71). The median value of f/t PSA for men with cancer was 5.5% (1-25%) and 9.2% (1-63%) for those with no cancer. Cut-offs derived at 95% specificity at PSA between 4-10 ng/ml and 4-20 ng/ml were 0.5% and 1% respectively. The specificity of f/t PSA ratio at cut-off levels 7%, 10% and 15% was 73%, 60%, 45% for PSA range of 4-10 ng/ml and 63%, 47% and 35% for PSA range of 4-20 ng/ml PSA. Age, prostate volume and Gleason grade did not show any effect on f/t PSA. Conclusion: In men with LUTS the specificity of various f/t PSA ratio cut-offs; described for population based screening, is too low to be used as an aid to defer the decision of biopsy in PSA ranges of 4-20 ng/ml

CD44 gene polymorphisms in breast cancer risk and prognosis: a study in North Indian population.

BACKGROUND: Cell surface biomarker CD44 plays an important role in breast cancer cell growth, differentiation, invasion, angiogenesis and tumour metastasis. Therefore, we aimed to investigate the role of CD44 gene polymorphisms in breast cancer risk and prognosis in North Indian population. MATERIALS & METHODS: A total of 258 breast cancer patients and 241 healthy controls were included in the case-control study for risk prediction. According to RECIST, 114 patients who received neo-adjuvant chemotherapy were recruited for the evaluation of breast cancer prognosis. We examined the association of tagging SNP (rs353639) of Hapmap Gujrati Indians in Houston (GIH population) in CD44 gene along with a significant reported SNP (rs13347) in Chinese population by genotyping using Taqman allelic discrimination assays. Statistical analysis was done using SPSS software, version 17. In-silico analysis for prediction of functional effects was done using F-SNP and FAST-SNP. RESULTS: No significant association of both the genetic variants of the CD44 gene polymorphisms was found with breast cancer risk. On performing univariate analysis with clinicopathological characteristics and treatment response, we found significant association of genotype (CT+TT) of rs13347 polymorphism with earlier age of onset (P = 0.029, OR = 0.037). However, significance was lost in multivariate analysis. For rs353639 polymorphism, significant association was seen with clinical tumour size, both at the genotypic (AC+CC) (P = 0.039, OR = 3.02) as well as the allelic (C) (P = 0.042, OR = 2.87) levels. On performing multivariate analysis, increased significance of variant genotype (P = 0.017, OR = 4.29) and allele (P = 0.025, OR = 3.34) of rs353639 was found with clinical tumour size. In-silico analysis using F-SNP, showed altered transcriptional regulation for rs353639 polymorphism. CONCLUSIONS: These findings suggest that CD44 rs353639 genetic variants may have significant effect in breast cancer prognosis. However, both the polymorphisms- rs13347 and rs353639 had no effect on breast cancer susceptibility

Total PSA and free PSA in patients with severe liver dysfunction

Objectives: To evaluate the effect of liver diseases in patients, on serum free prostate specific antigen (JPSA) levels, total prostate specific antigen (tPSA) levels and fPSA/tPSA ratios. Methods: Serum concentrations of total and free as well as JPSA/tPSA were determined in 20 men with histologi-cally confirmed liver cirrhosis, 15 men with chronic hepa-titis and 20 healthy men. Results: The serum levels of total PSA in liver cirrhosis as well as in chronic hepatitis were significantly lower than those observed in control. Free PSA remained unchanged. Conclusions: Our study suggests that despite severe liver dysfunction the tPSA, fPSA as well as the ratio of fPSA/ tPSA were not elevated as it was hypothesized that liver impairment might affect the PSA levels, as liver is a site for PSA metabolism