Polymorphisms of glutathione-S-transferase M1, T1, P1 and the risk of prostate cancer: a case-control study

<p>Abstract</p> <p>Background</p> <p>It has been suggested that polymorphisms in glutathione-<it>S</it>-transferases (GST) could predispose to prostate cancer through a heritable deficiency in detoxification pathways for environmental carcinogens. Yet, studies linking <it>GST </it>polymorphism and prostate cancer have so far failed to unambiguously establish this relation in patients. A retrospective study on healthy, unrelated subjects was conducted in order to estimate the population <it>GST </it>genotype frequencies in the Slovak population of men and compare our results with already published data (GSEC project-Genetic Susceptibility to Environmental Carcinogens). A further aim of the study was to evaluate polymorphisms in <it>GST </it>also in patients with prostate cancer in order to compare the evaluated proportions with those found in the control subjects.</p> <p>Methods</p> <p>We determined the <it>GST </it>genotypes in 228 healthy, unrelated subjects who attended regular prostate cancer screening between May 2005 and June 2007 and in 129 histologically verified prostate cancer patients. Analysis for the <it>GST </it>gene polymorphisms was performed by PCR and PCR-RFLP.</p> <p>Results</p> <p>We found that the <it>GST </it>frequencies are not significantly different from those estimated in a European multicentre study or from the results published by another group in Slovakia. Our results suggest that <it>Val/Val </it>genotype of <it>GSTP1 </it>gene could modulate the risk of prostate cancer, even if this association did not reach statistical significance. We did not observe significantly different crude rates of the <it>GSTM1 </it>and <it>GSTT1 </it>null genotypes in the men diagnosed with prostate cancer and those in the control group.</p> <p>Conclusion</p> <p>Understanding the contribution of <it>GST </it>gene polymorphisms and their interactions with other relevant factors may improve screening diagnostic assays for prostate cancer. We therefore discuss issues of study feasibility, study design, and statistical power, which should be taken into account in planning further trials.</p

Examination of polymorphic glutathione S-transferase (GST) genes, tobacco smoking and prostate cancer risk among Men of African Descent: A case-control study

<p>Abstract</p> <p>Background</p> <p>Polymorphisms in <it>glutathione S-transferase </it>(GST) genes may influence response to oxidative stress and modify prostate cancer (PCA) susceptibility. These enzymes generally detoxify endogenous and exogenous agents, but also participate in the activation and inactivation of oxidative metabolites that may contribute to PCA development. Genetic variations within selected <it>GST </it>genes may influence PCA risk following exposure to carcinogen compounds found in cigarette smoke and decreased the ability to detoxify them. Thus, we evaluated the effects of polymorphic <it>GSTs </it>(<it>M1</it>, <it>T1</it>, and <it>P1</it>) alone and combined with cigarette smoking on PCA susceptibility.</p> <p>Methods</p> <p>In order to evaluate the effects of <it>GST </it>polymorphisms in relation to PCA risk, we used TaqMan allelic discrimination assays along with a multi-faceted statistical strategy involving conventional and advanced statistical methodologies (e.g., Multifactor Dimensionality Reduction and Interaction Graphs). Genetic profiles collected from 873 men of African-descent (208 cases and 665 controls) were utilized to systematically evaluate the single and joint modifying effects of <it>GSTM1 </it>and <it>GSTT1 </it>gene deletions, <it>GSTP1 </it>105 Val and cigarette smoking on PCA risk.</p> <p>Results</p> <p>We observed a moderately significant association between risk among men possessing at least one variant <it>GSTP1 </it>105 Val allele (OR = 1.56; 95%CI = 0.95-2.58; p = 0.049), which was confirmed by MDR permutation testing (p = 0.001). We did not observe any significant single gene effects among <it>GSTM1 </it>(OR = 1.08; 95%CI = 0.65-1.82; p = 0.718) and <it>GSTT1 </it>(OR = 1.15; 95%CI = 0.66-2.02; p = 0.622) on PCA risk among all subjects. Although the <it>GSTM1</it>-<it>GSTP1 </it>pairwise combination was selected as the best two factor LR and MDR models (p = 0.01), assessment of the hierarchical entropy graph suggested that the observed synergistic effect was primarily driven by the <it>GSTP1 </it>Val marker. Notably, the <it>GSTM1</it>-<it>GSTP1 </it>axis did not provide additional information gain when compared to either loci alone based on a hierarchical entropy algorithm and graph. Smoking status did not significantly modify the relationship between the <it>GST </it>SNPs and PCA.</p> <p>Conclusion</p> <p>A moderately significant association was observed between PCA risk and men possessing at least one variant <it>GSTP1 </it>105 Val allele (p = 0.049) among men of African descent. We also observed a 2.1-fold increase in PCA risk associated with men possessing the <it>GSTP1 </it>(Val/Val) and <it>GSTM1 </it>(*1/*1 + *1/*0) alleles. MDR analysis validated these findings; detecting <it>GSTP1 </it>105 Val (p = 0.001) as the best single factor for predicting PCA risk. Our findings emphasize the importance of utilizing a combination of traditional and advanced statistical tools to identify and validate single gene and multi-locus interactions in relation to cancer susceptibility.</p