Abstract 2615: Genetic variations in angiogenesis-related genes in prostate cancer recurrence

Abstract

Abstract Introduction: Prostate cancer is the most common cancer and the second leading cause of cancer death in American men. Among patients who have a radical prostatectomy, ∼30% will have disease recurrence. Currently, the level of prostate specific antigen (PSA), clinical stage (TNM) and tumor grade (Gleason score) are used to estimate prognosis and inform treatment modalities. Although these are extremely useful, additional biomarkers are needed to better predict outcome. Angiogenesis has been associated with Gleason score, tumor stage, progression, metastasis and survival in prostate cancer. We hypothesized that single nucleotide polymorphisms (SNPs) in genes in the angiogenesis pathway may be associated with prostate cancer recurrence. Methods: In a historical cohort of 1061 prostatectomy cases treated at the Moffitt Cancer Center from 1986 to 2003, we identified 311 recurrent cases and 750 non-recurrent cases. A recurrent case was defined by either an elevated PSA level after surgical treatment, clinical metastasis or disease specific death. All other patients were categorized as non-recurrent. We compared genotype frequencies of 2,981 SNPs in 547 angiogenesis genes between the two groups. Genotyping was performed using the Illumina GoldenGate assay and associations between recurrence-free survival and individual SNPs were evaluated using competing Cox regression models to estimate hazard ratios (HR) and 95% confidence intervals (95%CI) under three inheritance models (dominant, recessive and log-additive model). For each SNP, the minimum P-value among all tested inheritance models was selected. We calculated q-values to estimate false discovery rates. Results: The mean age at diagnosis of the study subjects was 59.7 (SD=7.5) years. The recurrence rate was 29.3% with a median recurrence-free survival of 200.8 (range=179.0-241.9) months. A total of 91 SNPs in 56 angiogenesis genes had raw P-values less than 0.01 and q-values less than 3%. We found associations for several families of genes that have been previously associated with aggressiveness and/or survival of prostate cancer, such as cadherins (CDH,11 SNPs), fibroblast growth factor and its receptor (FGF/FGFR, 6 SNPs), insulin-like growth factor and its receptor (IGF/IGFR, 3 SNPs), interleukins (IL, 5 SNPs), metalloproteinases (MMP, 3 SNPs) and thrombospondin (THBS, 4 SNPs). The most significant association was observed for rs889730 in CDH13 (HR= 0.69, 95%CI=0.58-0.83, P=0.000057, additive model). CDH13 contributes to promotion of tumor neovascularization, but down regulation has been associated with a poor outcome in prostate cancer. Conclusion: Data from this comprehensive study of angiogenesis genes and prostate cancer suggests that variants in angiogenesis-related genes may influence prostate cancer recurrence after radical prostatectomy. Further studies are warranted to confirm these preliminary findings. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2615. doi:1538-7445.AM2012-2615