硝化多环芳烃（Nitro-PAH）特征与暴露于柴油废气中的膀胱癌中的体细胞突变。
Nitrated Polycyclic Aromatic Hydrocarbon (Nitro-PAH) Signatures and Somatic Mutations in Diesel Exhaust-Exposed Bladder Tumors.
机构信息
Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Department of Health and Human Services, Bethesda, Maryland.
Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Department of Health and Human Services, Bethesda, Maryland.
出版信息
Cancer Epidemiol Biomarkers Prev. 2023 Jun 1;32(6):840-847. doi: 10.1158/1055-9965.EPI-22-1208.
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.
背景
柴油废气是一种复杂的混合物，包括多环芳烃（PAH）和硝化多环芳烃（硝基-PAH），其中许多是强诱变剂，可能是膀胱癌的致癌物质。为了探讨柴油暴露与膀胱癌发生之间的关系，我们研究了膀胱肿瘤中暴露与体细胞突变和突变特征之间的关系。
方法
对新英格兰膀胱癌研究中的膀胱肿瘤进行了靶向测序。使用 797 例病例和 1418 例对照的数据，采用两阶段多分类逻辑回归评估膀胱癌亚型之间的病因异质性和可吸入元素碳（REC）的定量、终生估计值，REC 是柴油暴露的替代物。泊松回归用于评估 REC 与突变特征之间的关系。
结果
我们观察到柴油-膀胱癌风险关系存在显著的异质性，与对照组相比，高级别、非肌肉浸润性 TP53 突变型肿瘤病例中存在强烈的正相关[最高三分位与未暴露组相比，4.8；95%置信区间（CI），2.2-10.5；Ptrend<0.001；P 异质性=0.002]。在肌肉浸润性肿瘤中，我们观察到柴油暴露与 1,6-二硝基芘（RR，1.93；95%CI，1.28-2.92）和 3-硝基苯甲酸（RR，1.97；95%CI，1.33-2.92）的硝基-PAH 特征之间存在正相关。
结论
基于肿瘤中 TP53 突变的存在，柴油废气与膀胱癌之间的关系存在异质性，进一步支持 PAH 暴露与致癌作用中 TP53 突变之间的联系。未来需要进行能够识别暴露肿瘤中硝基-PAH 特征的研究，以提供支持柴油与膀胱癌之间联系的人体数据。
影响
本研究为柴油废气引起的膀胱癌的病因学和可能机制提供了更多的见解。
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