Introduction Occupational diesel exhaust exposure has been linked to increased bladder cancer risk in epidemiologic studies, but few explore mechanistic links.

Objectives We examined the relationship between diesel exhaust exposure and somatic mutations and mutational signatures in bladder tumors.

Methods Targeted sequencing was conducted in bladder tumors from the New England Bladder Cancer Study (NEBCS), a population-based case-control study. Using data on 797 cases and 1,418 controls, two-stage polytomous logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) to evaluate etiologic heterogeneity between bladder cancer subtypes and quantitative estimates of respirable elemental carbon. Poisson regression was used to evaluate associations between REC and mutational signatures including those from nitro-polycyclic aromatic hydrocarbons (nitro-PAHs) in the NEBCS and in publicly available whole-genome sequencing bladder cancer dataset from The Cancer Genome Atlas Project (TCGA) (N=412).

Results We observed significant heterogeneity in the diesel-bladder cancer risk relationship, with a strong positive association predominantly among cases with high-grade, non-muscle invasive TP53-mutated tumors compared to controls (ORTertile3vsUnexposed = 4.8, 95% CI=2.2,10.5; p-trend T mutations at CpG dinucleotides (Relative Risk (RR)=1.47, 95% CI=1.38,1.57). In muscle-invasive tumors, we also observed a positive association between diesel exposure and the diesel-associated nitro-PAH signatures of 1,6-dintropyrene (RR=1.93, 95% CI=1.28,2.92) and 3-nitrobenzoic acid (RR=1.97, 95% CI=1.33,2.92) in pooled analyses of NEBCS and TCGA.

Conclusion The relationship between diesel exhaust and bladder cancer was heterogeneous based on the presence of TP53 mutations in tumors. Assessing the impact of diesel exhaust exposure at CpG dinucleotides and any resultant transcriptional changes in bladder tumors may be valuable considering the wealth of data linking particulate exposures to altered DNA methylation. Future studies that can identify nitro-PAH signatures in tumors are of interest to support the findings generated here.