Interaction among variant vascular endothelial growth factor (VEGF) and its receptor in relation to prostate cancer risk.

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 modulate susceptibility for prostate cancer, as previous demonstrated. This study evaluates the interplay among three highly variant genes (i.e., IL-10, TGFbetaR-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, TGFbetaR-1 and VEGF was analyzed using conventional logistic regression analysis (LR) models, multi-dimensionality reduction (MDR) and interaction 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 aggressive PCa. The presence of VEGF 2482T combined with VEGFR IVS6 + 54 loci were highly 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 = 0.04), respectively. CONCLUSION: These findings suggest the inheritance of VEGF and VEGFR IVS6 + 54 sequence variants may jointly modify PCa susceptibility through their influence on angiogenesis. Larger sub-population studies are needed to validate these findings and evaluate whether the VEGF-VEGR axis may serve as predictors of disease prognosis and ultimately clinical response to available treatment strategies.

Angiogenesis-associated sequence variants relative to breast cancer recurrence and survival.

INTRODUCTION: 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-ß1, VEGF, and their associated receptors as effective predictors of BrCA clinical outcomes. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

8q24 sequence variants in relation to prostate cancer risk among men of African descent: a case-control study.

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.

Examination of polymorphic glutathione S-transferase (GST) genes, tobacco smoking and prostate cancer risk among men of African descent: a case-control study.

BACKGROUND: Polymorphisms in glutathione 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 selected GST 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 GSTs (M1, T1, and P1) alone and combined with cigarette smoking on PCA susceptibility. METHODS: In order to evaluate the effects of GST 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 GSTM1 and GSTT1 gene deletions, GSTP1 105 Val and cigarette smoking on PCA risk. RESULTS: We observed a moderately significant association between risk among men possessing at least one variant GSTP1 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 GSTM1 (OR = 1.08; 95%CI = 0.65-1.82; p = 0.718) and GSTT1 (OR = 1.15; 95%CI = 0.66-2.02; p = 0.622) on PCA risk among all subjects. Although the GSTM1-GSTP1 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 GSTP1 Val marker. Notably, the GSTM1-GSTP1 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 GST SNPs and PCA. CONCLUSION: A moderately significant association was observed between PCA risk and men possessing at least one variant GSTP1 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 GSTP1 (Val/Val) and GSTM1 (*1/*1 + *1/*0) alleles. MDR analysis validated these findings; detecting GSTP1 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.

Validation of genome-wide prostate cancer associations in men of African descent.

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.