Abstract 861: Diesel engine exhaust is associated with TP53 mutations and high-risk non-muscle invasive bladder cancer

Abstract

Abstract Background: Second to cigarette smoking, occupational exposures are a leading risk factor for the development of bladder cancer. Occupational exposure to diesel exhaust in particular has been linked to increased bladder cancer risk in several epidemiologic studies. To provide insight into possible mechanisms that influence this association, we examined the relationship between diesel exhaust and somatic mutations in bladder tumors. Methods: Targeted sequencing of frequently mutated genes in bladder cancer was conducted in formalin-fixed paraffin-embedded bladder tumors from a population-based case-control study in New England. Lifetime occupational histories combined with exposure-oriented questions were used to estimate cumulative exposure to respirable elemental carbon (REC), a primary index for diesel exhaust. REC exposure was modeled both continuously (per 100 μg/m3-yrs) and categorically (by tertiles). Two-stage polytomous logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) to evaluate etiologic heterogeneity by tumor subtypes using data on 797 cases and 1,418 controls. Results: We observed significant heterogeneity in the relationship between diesel exhaust and risk of bladder cancer by TP53 mutation status (p-heterogeneity=0.013). When comparing patients with TP53+ tumors to controls, there was a strong association with increasing cumulative REC exposure (ORTertile 1 vs. Unexposed=1.4, 95% CI=0.7, 2.8; ORTertile 2 vs. Unexposed=1.3, 95% CI=0.6, 2.7; ORTertile 3 vs. Unexposed=2.8, 95% CI=1.4, 5.7; p-trend=0.003), while there was no apparent association between cumulative REC exposure and bladder cancer among patients with wild-type TP53 tumors (p-trend=0.603). Subtype analyses that incorporate clinical features (stage: non-muscle invasive/muscle-invasive and grade: low-grade/high-grade) with TP53 mutation, also indicate etiologic heterogeneity in the relationship between diesel exhaust and bladder cancer (p-het=0.002), with the strongest association observed between increasing cumulative REC and risk of bladder cancer among cases with non-muscle invasive, high-grade tumors (including carcinoma in situ) with TP53 mutations (OR per 100 μg/m3-yrs =1.14, 95% CI=1.00, 1.29). Conclusions: Our results suggest that diesel engine exhaust may influence bladder cancer risk by impacting the cell cycle, especially among patients with high-risk non-muscle invasive tumors that are more likely to progress to invasive disease. More work will be needed to understand the impact of diesel-generated oxidative stress on tumor suppressor genes like TP53 and cell cycle regulation in the development of bladder cancer. Citation Format: Nicole Gonzalez, Nina Rao, Michael Dean, Ludmila Prokunina-Olsson, Dalsu Baris, Molly Schwenn, Alison Johnson, Nathaniel Rothman, Debra Silverman, Stella Koutros. Diesel engine exhaust is associated with TP53 mutations and high-risk non-muscle invasive bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 861.