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

Interaction among apoptosis-associated sequence variants and joint effects on aggressive prostate cancer

<p>Abstract</p> <p>Background</p> <p>Molecular and epidemiological evidence demonstrate that altered gene expression and single nucleotide polymorphisms in the apoptotic pathway are linked to many cancers. Yet, few studies emphasize the interaction of variant apoptotic genes and their joint modifying effects on prostate cancer (PCA) outcomes. An exhaustive assessment of all the possible two-, three- and four-way gene-gene interactions is computationally burdensome. This statistical conundrum stems from the prohibitive amount of data needed to account for multiple hypothesis testing.</p> <p>Methods</p> <p>To address this issue, we systematically prioritized and evaluated individual effects and complex interactions among 172 apoptotic SNPs in relation to PCA risk and aggressive disease (i.e., Gleason score ≥ 7 and tumor stages III/IV). Single and joint modifying effects on PCA outcomes among European-American men were analyzed using statistical epistasis networks coupled with multi-factor dimensionality reduction (SEN-guided MDR). The case-control study design included 1,175 incident PCA cases and 1,111 controls from the prostate, lung, colo-rectal, and ovarian (PLCO) cancer screening trial. Moreover, a subset analysis of PCA cases consisted of 688 aggressive and 488 non-aggressive PCA cases. SNP profiles were obtained using the NCI Cancer Genetic Markers of Susceptibility (CGEMS) data portal. Main effects were assessed using logistic regression (LR) models. Prior to modeling interactions, SEN was used to pre-process our genetic data. SEN used network science to reduce our analysis from > 36 million to < 13,000 SNP interactions. Interactions were visualized, evaluated, and validated using entropy-based MDR. All parametric and non-parametric models were adjusted for age, family history of PCA, and multiple hypothesis testing.</p> <p>Results</p> <p>Following LR modeling, eleven and thirteen sequence variants were associated with PCA risk and aggressive disease, respectively. However, none of these markers remained significant after we adjusted for multiple comparisons. Nevertheless, we detected a modest synergistic interaction between <it>AKT3 rs2125230-PRKCQ rs571715 </it>and disease aggressiveness using SEN-guided MDR (p = 0.011).</p> <p>Conclusions</p> <p>In summary, entropy-based SEN-guided MDR facilitated the logical prioritization and evaluation of apoptotic SNPs in relation to aggressive PCA. The suggestive interaction between <it>AKT3-PRKCQ </it>and aggressive PCA requires further validation using independent observational studies.</p

Multi-institutional prostate cancer study of genetic susceptibility in populations of African descent.

International audienceProstate cancer disparities have been reported in men of African descent who show the highest incidence, mortality, compared with other ethnic groups. Few studies have explored the genetic and environmental factors for prostate cancer in men of African ancestry. The glutathione-S-transferases family conjugates carcinogens before their excretion and is expressed in prostate tissue. This study addressed the role of GSTM1 and GSTT1 deletions on prostate cancer risk in populations of African descent. This multi-institutional case-control study gathered data from the Genetic Susceptibility to Environmental Carcinogens (GSEC) database, the African-Caribbean Cancer Consortium (AC3) and Men of African Descent and Carcinoma of the Prostate Consortium (MADCaP). The analysis included 10 studies (1715 cases and 2363 controls), five in African-Americans, three in African-Caribbean and two in African men. Both the GSTM1 and the GSTT1 deletions showed significant inverse associations with prostate cancer [odds ratio (OR): 0.90, 95% confidence interval (CI) 0.83-0.97 and OR 0.88, 95% CI: 0.82-0.96, respectively]. The association was restricted to Caribbean and African populations. A significant positive association was observed between GSTM1 deletion and prostate cancer in smokers in African-American studies (OR: 1.28, 95% CI: 1.01-1.56), whereas a reduced risk was observed in never-smokers (OR: 0.66, 95% CI: 0.46-0.95). The risk of prostate cancer increased across quartiles of pack-years among subjects carrying the deletion of GSTM1 but not among subjects carrying a functional GSTM1. Gene-environment interaction between smoking and GSTM1 may be involved in the etiology of prostate cancer in populations of African descent