Supplemental Table 3 displays the interaction between candidate markers and ever or cumulative toluene and xylene exposure and risk of bladder cancer, common referent.

Supplemental Table 5 shows the interaction between genetic variants and smoking status, common referent.

Supplemental Table 2 shows the interaction between GWAS markers and ever or cumulative toluene and xylene exposure and risk of bladder cancer, common referent.

Supplemental Table 6 displays the associations between ever solvent exposure and risk of bladder cancer, stratified by the 24-marker bladder cancer polygenic risk score (PRS).

Supplemental Table 1 displays the odds ratios for the association between solvents and bladder cancer in the subset with genetic information.

Supplemental Table 4 shows the interaction between rs72826305 (CASC15/LOC105374970), rs2896518 (FGFR3), GSTT1, and rs2070676 (CYP2E1) and ever or cumulative solvent exposure and risk of bladder cancer, stratified.

OBJECTIVES:We modified an existing job-exposure matrix (CANJEM) to estimate the combined exposure to benzene, toluene, and xylene, which are highly correlated (hereafter, BTX), and integrated subject-specific occupational information to assess BTX exposure for participants in a bladder cancer case-control study. METHODS:We linked CANJEM to the lifetime occupational histories of subjects in a population-based case-control study of bladder cancer. We derived CANJEM-based estimates of the probability, intensity, and frequency of BTX exposure by assigning the highest rating observed among the benzene, toluene, and xylene CANJEM metrics. We used subject-specific exposure information in the occupational histories and exposure-oriented modules to refine the CANJEM-based BTX metrics when confirmatory exposure information was identified (hereafter, hybrid BTX metrics). We compared agreement between the CANJEM-based and hybrid BTX metrics at the job- and subject-level using kappa for the ordinal probability metrics and Spearman correlation for the continuous intensity and cumulative exposure metrics. RESULTS:The hybrid BTX approach increased 7% and decreased 5% of the CANJEM-based BTX probability ratings at the job-level and 16% and 7% at the subject-level, respectively. The CANJEM-based and hybrid BTX metrics identified 3.2% and 6.8% of the job records and 13% and 24% of the subjects as having a high probability of BTX exposure, respectively. The BTX-exposed subjects identified through the hybrid approach generally had lower cumulative exposures than those identified solely using CANJEM. CANJEM-based and hybrid BTX metrics had moderate agreement at the subject-level (probability: kappa = 0.62; cumulative metrics, Spearman correlation = 0.61). CONCLUSIONS:Supplementing a JEM with subject-specific exposure information identified within-job exposure heterogeneity that was not captured by using only a JEM.

Table S4: Top recurrent mutations in FGFR3 and PIK3CA within NMIBC (1,573 patients) and MIBC (1,243 patients)

Supplementary Table S1 shows urine pH and risk of bladder cancer among ever-smokers.

Supplementary Table S2 shows urine pH and bladder cancer risk stratified by never-, former-, and current-smokers.

Ever diesel and nitro-PAH signatures adjusted for smoking

REC and nitro-PAH signatures in New England

Table S5: Associations between driver mutations in BC and common risk factors

specific TP53 mutations and ever diesel

Table S7: Relationship of PyV status with FGFR3/PIK3CA-mutation status and cigarette smoking

The New England Bladder Cancer Study 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. In this study, 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 the ORs, 95% confidence intervals, and P values for multiplicative interaction in 1,182 cases and 1,408 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% confidence interval, 1.28-5.12) compared with 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.Prevention Relevance: Our findings suggest that bladder cancer risk is higher among those exposed to BTX-containing solvents who also harbor common genetic polymorphisms associated with bladder cancer. The joint contribution of genetics and occupational exposures may play an important role in the etiology of bladder cancer.

Table S3: Positivity of virus transcript detection in bladder tumors from UROMOL

Figure S1: Molecular characterization of BKPyV in NMIBC tumors and HBLAK cells

Supplementary Table S3 shows spot urine pH categorized into ≤6.0 and >6.0 and bladder cancer risk, stratified by smoking status.