Nitrated Polycyclic Aromatic Hydrocarbon (Nitro-PAH) Signatures and Somatic Mutations in Diesel Exhaust-Exposed Bladder Tumors

Abstract

Background: Diesel exhaust is a complex mixture, including polycyclic aromatic hydrocarbons (PAH) and nitrated PAHs (nitro-PAH), many of which are potent mutagens and possible bladder carcinogens. To explore the association between diesel exposure and bladder carcinogenesis, we examined the relationship between 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. Using data on 797 cases and 1,418 controls, two-stage polytomous logistic regression was used to evaluate etiologic heterogeneity between bladder cancer subtypes and quantitative, lifetime estimates of respirable elemental carbon (REC), a surrogate for diesel exposure. Poisson regression was used to evaluate associations between REC and mutational signatures.

Results: We observed significant heterogeneity in the diesel-bladder cancer risk relationship, with a strong positive association among cases with high-grade, nonmuscle invasive TP53-mutated tumors compared with controls [ORTop Tertile vs.Unexposed, 4.8; 95% confidence interval (CI), 2.2-10.5; Ptrend < 0.001; Pheterogeneity = 0.002]. In muscle-invasive tumors, we observed a positive association between diesel exposure and the 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).

Conclusions: The relationship between diesel exhaust and bladder cancer was heterogeneous based on the presence of TP53 mutations in tumors, further supporting the link between PAH exposure and TP53 mutations in carcinogenesis. Future studies that can identify nitro-PAH signatures in exposed tumors are warranted to add human data supporting the link between diesel and bladder cancer.

Impact: This study provides additional insight into the etiology and possible mechanisms related to diesel exhaust-induced bladder cancer.

Figure 1.. Plots of signature profiles in the New England Bladder Cancer Study.

They include the four major mutational signatures (COSMIC signature 1, APOBEC-mediated signatures 2 and 13, and 5*/ERCC2 signature) and the four mutational signatures for nitro-PAHs (1,6-dinitropyrene (1,6-DNP), 1,8-dinitropyrene (1,8-DNP), 3-nitrobenzoic acid (3-NBA), and 6-nitrochysene). The x-axis denotes the 5’ and 3’ nucleotides for each substitution type (e.g., A[T>C]C, thymine to cytosine substitution with 5’ adenine and 3’ cytosine).