Abstract 894: Genetic variations in the angiogenesis pathway modulate clinical outcomes of bladder cancer

Abstract

Abstract Bladder cancer is the fourth most common cancer in men in the United States. There is compelling evidence suggesting that a patient's genetic background contributes to bladder cancer clinical outcome. Angiogenesis is an essential process required for tumor development, growth, and metastasis. We hypothesized that genetic variations in the angiogenesis pathway may affect the overall survival of bladder cancer patients. We conducted a follow-up study of 397 non-muscle invasive and 320 muscle-invasive bladder cancer patients to systematically evaluate 458 single nucleotide polymorphisms (SNPs) in 24 angiogenesis pathway genes as predicators of prognosis and BCG response. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated by multivariate Cox proportional hazard regression adjusting for age, gender, stage, grade, and treatment regimen. In non-muscle invasive bladder cancer patients, no significant SNPs were identified after correction for multiple comparisons. When stratified by BCG treatment, variant KIT rs11735550 was significantly associated with recurrence in patients who did not receive BCG treatment (HR=2.84, 95%CI: 1.67-4.83). In muscle-invasive bladder cancer patients, variant FLT4 rs11750142, rs2447737, rs13168072, and rs11739750 genotypes, and wild-type rs11957360 were significantly associated with increased risk of dying. These SNPs are not in linkage disequilibrium suggesting that each one independently modulates survival. In addition, a significant gene dosage effect was observed for increased risk with increasing number of unfavorable genotypes (P for trend<0.001). Compared to the low-risk group (0-1 unfavorable genotypes), median-risk group (2-3 unfavorable genotypes) and high-risk group (4-5 unfavorable genotypes) showed 1.34- (95%CI: 0.86-2.11) and 2.60-fold (95%CI: 1.66-4.09) increased risk of dying, respectively. In Kaplan-Meier estimates, the low-, median-, and high-risk groups had significantly different median survival time (MST) of 81.9, 67.9, and 31.3 months, respectively (logrank P <0.01). These results support the hypothesis that genetic variations in the angiogenesis pathway modulate clinical outcomes for bladder cancer patients. These findings warrant further replication in independent populations, and could be useful in disease management and the development of targeted therapies for bladder cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 894.