Abstract 10: Interaction between obesity and variants in angiogenesis-related genes and prostate cancer aggressiveness.
Authors: Amankwah Ernest K. , Lin Hui-Yi , Sellers Thomas A. , Park Hyun , Radlein Selina , Pow-Sang Julio , Hakam Ardeshir , Qu Xiaotao , Tsai Ya-Yu , Park Jong 
Published: August 2013

Introduction: Angiogenesis has been associated with Gleason score, tumor stage, progression, metastasis and survival in prostate cancer. Furthermore, obesity has been associated with aggressive prostate cancer in most studies. However, the effect of the interaction between variants in genes in the angiogenesis pathway and obesity on the risk of aggressive prostate cancer is not well studied. We hypothesized that (i) variants in angiogenesis-related genes will associate with prostate cancer aggressiveness and (ii) obesity will modify the association between the variants and prostate cancer aggressiveness.

Methods: We conducted a two-stage analysis in two independent study populations to evaluate the role of variants in the angiogenesis pathway and their interaction with body mass index (BMI, as a measure of obesity) on prostate cancer aggressiveness. In our discovery stage, we compared genotype frequencies of 2,177 SNPs in 161 angiogenesis-related genes between 659 aggressive and 492 non-aggressive cases derived from existing Cancer Genetic Markers of Susceptibility (CGEMS) prostate cancer genome-wide association study data. In the replication stage, we attempted to validate initial findings from the discovery stage in a historical cohort of 437 aggressive and 603 non-aggressive prostate cancer patients treated at the Moffitt Cancer Center from 1986 to 2003. In both data sets, aggressive disease was defined as a Gleason score≥7 or stage≥III (all others were considered non-aggressive) and obesity was defined as BMI≥30kg/m2 (all others were considered non-obese). Associations between aggressive prostate cancer and individual SNPs were evaluated using logistic regression models to estimate odds ratios (OR) and 95% confidence intervals (95%CI). We evaluated cumulative effects of validated SNPs by summing the number of risk alleles (risk score) for each subject in the replication dataset. Interactions between validated SNPs and obesity were evaluated in the replication dataset using logistic regression models that included a product term for the ordinal coding of genotype and a binary obesity variable, as well as main effects of these variables. Associations at SNPs with statistically significant interactions were then stratified by obesity.

Results: In the discovery dataset, 279 SNPs in 75 angiogenesis related-genes had a raw p-value &lt; 0.05. Among these 279 SNPs, 160 (57.3%) had data available in the replication dataset. Four of these SNPs (COL4A3 rs10498214, PDGFD rs488753, COL4A3 rs6436661 and ELK3 rs2268509) were significantly associated with aggressive disease in the replication dataset. A meta-analysis of the two datasets revealed an increased risk for COL4A3 rs10498214 (OR=1.58, 95%CI=1.17-2.13), PDGFD rs488753 (OR=1.46, 95%CI=1.14-1.87) and ELK3 rs2268509 (OR=1.41, 95%CI=1.17-1.70) and a reduced risk for COL4A3 rs6436661 (OR=0.73, 95%CI=0.59-0.90). In risk score analyses, patients carrying 5-8 (OR=1.63, 95%CI=1.20-2.21, P=0.007), but not 4 (OR=1.31, 95%CI=0.95-1.81, P=0.86), risk alleles of these four SNPs had a significant increased risk for aggressive disease compared to patients carrying 0-3 risk alleles. We observed an increased risk of aggressive disease for obese cases (OR=1.35, 95%CI=1.02-1.80, P=0.039) compared to non-obese cases and a statistically significant interaction between COL4A3 rs10498214 and obesity (Pinteraction=0.0098). The per minor allele (rs10498214) risk for aggressive prostate cancer increased among obese cases (OR=1.79, 95%CI=1.24-2.58, P=0.002), but not non-obese cases (OR=0.97, 95%CI=0.75-1.24, P=0.78).

Conclusion: Our findings suggest that angiogenesis gene variants influence the risk of aggressive prostate cancer and obesity may modify this association. Further studies are warranted to validate these initial findings.

Citation Format: Ernest K. Amankwah, Hui-Yi Lin, Thomas A. Sellers, Hyun Park, Selina Radlein, Julio Pow-Sang, Ardeshir Hakam, Xiaotao Qu, Ya-Yu Tsai, Jong Park. Interaction between obesity and variants in angiogenesis-related genes and prostate cancer aggressiveness. [abstract]. In: Proceedings of the AACR Special Conference on Post-GWAS Horizons in Molecular Epidemiology: Digging Deeper into the Environment; 2012 Nov 11-14; Hollywood, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2012;21(11 Suppl):Abstract nr 10.