Single Nucleotide Polymorphisms in Genes of One-Carbon Metabolism Pathway and Bladder Cancer Survival

Abstract

One-carbon metabolism pathway plays an important role in carcinogenesis through its involvement in DNA methylation and biosynthesis. Epidemiologic studies have indicated the associations between genetic polymorphisms in this pathway and the susceptibility of various cancers, including bladder cancer. However, few studies have focused on their associations with bladder cancer prognosis. Using follow-up data from 249 bladder cancer patients who have been treated at the Memorial Sloan-Kettering Cancer Center from 1993 to 1997, we investigated the associations between survival time of bladder cancer patients and single nucleotide polymorphisms (SNPs) involved in the one-carbon metabolism pathway. Epidemiologic data were collected by trained interviewers. Genotyping of seven SNPs in methylenetetrahydrofolate reductase (MTHFR), methionine synthase (MTR), methionine synthase reductase (MTRR), DNA methyltransferase 1 (DNMT1), and aldehyde dehydrogenase 2 (ALDH2) genes was performed using SNPlex and Taqman assays (Applied Biosystems) with DNA isolated from blood samples collected at time-of-interview. Survival curves were estimated using the Kaplan-Meier method, and differences in distributions were evaluated by log-rank tests and Cox proportional hazards models. Overall, no obvious associations were observed between the studied SNPs and all-cause mortality among bladder cancer patients after adjustment on age, gender, race/ethnicity, smoking status, and tumor stage. However, after stratification on smoking status, increased survival time was found among ever-smoked carriers of MTRR rs1532268 and rs1801394 variant allele, with adjusted HRs of 0.65 (95% CI = 0.45–0.95) and 0.65 (95% CI = 0.43–0.98), respectively. Increased survival time was also observed among never smokers with ALDH2 rs2238151 C/T or T/T genotypes, compared to those with the C/C genotype (HR = 0.23, 95% CI = 0.06–0.90). Our findings suggest that smoking may interact with one-carbon metabolism pathway related genetic polymorphisms on survival among bladder cancer patients. Future studies with larger sample sizes are needed to confirm the associations.