Abstract 816: Genetic variants in the dopaminergic system and bladder cancer clinical outcomes

Bladder cancer is estimated to be the fourth most common cancer diagnosed and the eighth most common cancer related death in men in 2015. A hallmark of bladder cancer outcomes is the high rates of recurrence and progression in patients diagnosed with non-muscle invasive bladder cancer (NMIBC) and poor survival rates in those that have progressed to or are diagnosed with muscle invasive bladder cancer (MIBC). Because of the poor outcomes, research for predictors of clinical outcomes is necessary. Recent studies show that current depressive symptoms at time of bladder cancer diagnosis are associated with bladder cancer mortality. We are interested in investigating the genetic mechanism underlying this relationship. The dopaminergic pathway is of interest because of its associations with depression and smoking addiction (with smoking being the main risk factor for bladder cancer). Therefore we aimed to do a candidate pathway analysis examining 256 single nucleotide polymorphisms (SNPs) in 15 genes from the dopaminergic system. We analyzed the association of genetic variants with recurrence and progression in NMIBC patients (N = 497) and the association with survival in MIBC patients (N = 399). Overall, there were four SNPs with a p-value of less than 0.01associated with recurrence in NMIBC. The most significant variant being rs2797853 located in DBH under the recessive model (HR = 1.77, 95% CI: 1.28- 2.46. P = 0.0012). Eight polymorphisms had a statistically significant association with progression in NMIBC patients, with COMT: rs5993891 being the most significant variant showing an increased odds of bladder cancer progression (HR = 2.54, 95% CI: 1.50- 4.28, P = 0.0013). Interestingly, the variant rs174675 located in COMT (an enzyme responsible for degrading dopamine) was associated with an increased risk of recurrence (HR = 1.23, 95% CI: 1.01-1.49, P = 0.046) and progression (HR = 1.55, 95% CI: 1.13-2.12, P = 0.007). Finally, five SNPs were statistically significant for bladder cancer survival in MIBC patients. BDNF: rs2203877 was associated with a 71% increased risk of death (HR = 1.71, 95% CI: 1.25-2.34, P = 0.001). There was a significant difference in median survival time (MST). Those with the homozygous dominant or heterozygous genotype had a MST of 66.3 months and those with the homozygous recessive genotype had a MST of 31.8 months (P log-rank = 0.02). The variant rs2239395 in COMT was associated with an increased risk of progression (HR = 2.54, 95% CI: 1.49-4.34, P = 0.002) and death (HR = 1.63, 95% CI: 1.05-2.53, P = 0.041). In addition to validation studies that are underway, the next steps include analyzing the association between these factors and BMI (a factor associated with depression, the dopamine system, and bladder cancer). The results of this study have the potential to contribute to identifying bladder cancer patients who may have poor clinical outcomes as well as the development of interventions that may improve outcomes. Citation Format: Jeanne A. Pierzynski, Yuanquing Ye, Alma Rodriguez, Michelle A.T. Hildebrandt, Ashish M. Kamat, Colin P.N. Dinney, Xifeng Wu. Genetic variants in the dopaminergic system and bladder cancer clinical outcomes. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 816.