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Background: Genome-wide association studies (GWAS) have identified numerous prostate cancer susceptibility alleles, but these loci have been identified primarily in men of European descent. There is limited information about the role of these loci in men of African descent.Methods: We identified 7,788 prostate cancer cases and controls with genotype data for 47 GWAS-identified loci.Results: We identified significant associations for SNP rs10486567 at JAZF1, rs10993994 at MSMB, rs12418451 and rs7931342 at 11q13, and rs5945572 and rs5945619 at NUDT10/11. These associations were in the same direction and of similar magnitude as those reported in men of European descent. Significance was attained at all reported prostate cancer susceptibility regions at chromosome 8q24, including associations reaching genome-wide significance in region 2.Conclusion: We have validated in men of African descent the associations at some, but not all, prostate cancer susceptibility loci originally identified in European descent populations. This may be due to the heterogeneity in genetic etiology or in the pattern of genetic variation across populations.Impact: The genetic etiology of prostate cancer in men of African descent differs from that of men of European descent. Cancer Epidemiol Biomarkers Prev; 20(1); 23–32. ©2011 AACR.

Supplementary Materials from Validation of Genome-Wide Prostate Cancer Associations in Men of African Descent

Breast cancer (BrCA) risk stratification using clinico-pathological biomarkers helps improve disease prognosis prediction. However, disease recurrence rates remain unfavorable and individualized clinical management strategies are needed. Consequently, we evaluated the influence of 14 sequence variants detected in IL-10, TGF-β1, VEGF, and their associated receptors as effective predictors of BrCA clinical outcomes.Tumor DNA samples collected from 441 BrCA patients were genotyped using TaqMan-PCR. Most selected targets alter cytokine serum/plasma levels or signaling pathways. Relationships between genetic profiles and recurrence as well as disease-related mortality were evaluated using cumulative incidence curves and competing risk regression models.The VEGF(-2578)C allele was associated with a 1.3- to 1.6-fold increase in BrCA recurrence (HR(trend) = 1.28; 95% CI = 0.96-1.72) and disease-related mortality (HR(trend) = 1.56; 95% CI = 0.93-2.56). Although this marker was marginally significant relative to BrCA outcomes, there were substantial gains in the 5- and 8-year predictive accuracy compared to standard prognostic indicators. Among ER(+)/PR(+) status patients, there was a significant impact of the VEGF(-2578)CC genotype on disease recurrence and predictive accuracy.Our findings suggest inheritance of the VEGF(-2578)C allele could serve as an independent prognostic indicator of BrCA prognosis. The VEGF(-2578) marker may have clinical implications among a subset of ER(+)/PR(+) patients with an aggressive phenotype. Because the VEGF(-2578)C allele is linked to high VEGF expression, this cytokine is a potential prognostic and targeted clinical management tool.

BACKGROUND. Prostate cancer (PCa) incidence and mortality are disproportionately high among African-American (AA) men. Its detection and perhaps its disparities could be improved through the identification of genetic susceptibility biomarkers within essential biological pathways. Interactions among highly variant genes, central to angiogenesis, may modulatesusceptibilityforprostate cancer,aspreviousdemonstrated.Thisstudyevaluatesthe interplay among three highly variant genes (i.e., IL-10, TGFbR-1, VEGF), their receptors and their influence on PCa within a case-control study consisting of an under-served population. METHODS. This study evaluated single gene and joint modifying effects on PCa risk in a case-control study comprised of 859 AA men (193 cases and 666 controls) using TaqMan qPCR. Interaction among polymorphic IL-10, TGFbR-1 and VEGF was analyzed using conventional logisticregressionanalysis(LR)models,multi-dimensionalityreduction(MDR)andinteraction entropy graphs. Symbolic modeling allowed validation of gene‐gene interaction findings identified by MDR. RESULTS. No significant single gene effects were demonstrated in relation to PCa risk. However, carriers of the VEGF 2482T allele had a threefold increase in the risk of developing aggressivePCa.ThepresenceofVEGF2482Tcombinedwith VEGFRIVS6 þ54lociwerehighly significant for the risk of PCa based on MDR and symbolic modeling analyses. These findings were substantiated by 1,000-fold cross validation permutation testing (P ¼0.04), respectively.

Background: Genome-wide association studies (GWAS) have identified numerous prostate cancer susceptibility alleles, but these loci have been identified primarily in men of European descent. There is limited information about the role of these loci in men of African descent. Methods: We identified 7,788 prostate cancer cases and controls with genotype data for 47 GWAS-identified loci. Results: We identified significant associations for SNP rs10486567 at JAZF1, rs10993994 at MSMB, rs12418451 and rs7931342 at 11q13, and rs5945572 and rs5945619 at NUDT10/11. These associations were in the same direction and of similar magnitude as those reported in men of European descent. Significance was attained at all reported prostate cancer susceptibility regions at chromosome 8q24, including associations reaching genome-wide significance in region 2. Conclusion: We have validated in men of African descent the associations at some, but not all, prostate cancer susceptibility loci originally identified in European descent populations. This may be due to the heterogeneity in genetic etiology or in the pattern of genetic variation across populations. Impact: The genetic etiology of prostate cancer in men of African descent differs from that of men of European descent. Cancer Epidemiol Biomarkers Prev; 20(1); 23–32. ©2011 AACR.

Background Human chromosome 8q24 has been implicated in prostate tumorigenesis. Methods Consequently, we evaluated seven 8q24 sequence variants relative to prostate cancer (PCA) in a case-control study involving men of African descent. Genetic alterations were detected in germ-line DNA from 195 incident PCA cases and 531 controls using TaqMan polymerase chain reaction (PCR). Results Inheritance of the 8q24 rs16901979 T allele corresponded to a 2.5-fold increase in the risk of developing PCA for our test group. These findings were validated using multifactor dimensionality reduction (MDR) and permutation testing (p = 0.038). The remaining 8q24 targets were not significantly related to PCA outcomes. Conclusions Although compelling evidence suggests that the 8q24 rs16901979 locus may serve as an effective PCA predictor, our findings require additional evaluation in larger studies.

BACKGROUND Recent reports hypothesize that multiple variant DNA repair gene interactions influence cancer susceptibility. However, studies identifying high-risk cancer-related genes use single gene approaches that lack the statistical rigor to model higher order interactions. METHODS To address this issue, we systematically evaluated individual and joint modifying effects of commonly studied polymorphic base and nucleotide excision repair genes relative to prostate cancer (PCA) risk using conventional logistic regression models and multifactor dimensionality reduction (MDR). We hypothesized that inheriting two or more compromised DNA repair loci may increase PCA risk due to altered gene product function. Six genetic alterations were evaluated using germ-line DNA samples from 208 PCA cases and 665 disease-free controls via TaqMan polymerase chain reaction. RESULTS With the exception of XPD 312, no association existed between individual DNA repair single-nucleotide polymorphisms (SNPs) and PCA. Individuals with the XPD 312 Asn/Asn genotype had an 8.6-fold increase in risk (OR = 8.59; 95% CI = 1.81–40.66). We did not observe any significant single gene or gene–gene interactions based on MDR modeling. CONCLUSIONS Our findings emphasize the importance of utilizing a combination of traditional and advanced statistical tools to identify and validate single gene and multilocus interactions in relation to cancer susceptibility. Prostate 70: 113–119, 2010. ©2009 Wiley-Liss, Inc.

BackgroundPolymorphisms inglutathione S-transferase(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 selectedGSTgenes 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 polymorphicGSTs(M1,T1, andP1) alone and combined with cigarette smoking on PCA susceptibility.MethodsIn order to evaluate the effects ofGSTpolymorphisms 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 ofGSTM1andGSTT1gene deletions,GSTP1105 Val and cigarette smoking on PCA risk.ResultsWe observed a moderately significant association between risk among men possessing at least one variantGSTP1105 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 amongGSTM1(OR = 1.08; 95%CI = 0.65-1.82; p = 0.718) andGSTT1(OR = 1.15; 95%CI = 0.66-2.02; p = 0.622) on PCA risk among all subjects. Although theGSTM1-GSTP1pairwise 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 theGSTP1Val marker. Notably, theGSTM1-GSTP1axis 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 theGSTSNPs and PCA.ConclusionA moderately significant association was observed between PCA risk and men possessing at least one variantGSTP1105 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 theGSTP1(Val/Val) andGSTM1(*1/*1 + *1/*0) alleles. MDR analysis validated these findings; detectingGSTP1105 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.