Solvent exposure, genetic susceptibility, and risk of bladder cancer.

The New England Bladder Cancer Study (NEBCS) has recently reported an increased bladder cancer risk with occupational exposure to mononuclear aromatic organic solvents, including exposure to benzene, toluene, and xylene and their combination BTX. However, the mechanisms by which BTX influence bladder cancer are unclear. Here, we evaluated the interaction between BTX and genetic markers in known bladder cancer susceptibility loci and in variants shown to impact the metabolism of these solvents. We used multivariate logistic regression to calculate odds ratios (ORs), 95% confidence intervals (CIs) and p-values for multiplicative interaction in 1182 cases and 1408 controls from a population-based case-control study from New England. Lifetime occupational exposure to benzene, toluene, xylene, and BTX were assessed using occupational histories and exposure-oriented modules in conjunction with a job-exposure matrix. Buccal cells from mouthwash samples were used to conduct genotyping. Subjects with the highest cumulative exposure to benzene and who carried a risk allele in rs72826305 (CASC15) had an increased risk of bladder cancer (OR= 2.56, 95% CI: 1.28-5.12) compared to those never exposed with no risk alleles (p-interaction=0.03). Additional suggestive joint effects with benzene were evident for those carrying genetic risk variants in FGFR3 (p-value =0.01) and GSTT1 (p-interaction =0.007). Bladder cancer risk is higher among those exposed to BTX-containing solvents who also harbor common variants in CASC15, FGFR3 and GSTT1, adding to the evidence of a plausible link between these exposures and bladder cancer risk.