Tobacco carcinogens as markers of exposure, carcinogenesis and risk in oral cance

描述(由申请人提供)：口腔鳞状细胞癌(OSCC)是一种与烟草使用密切相关的破坏性疾病。虽然OSCC最常发生在吸烟者身上，但也有许多吸烟者没有患上癌症。到目前为止，导致一些烟草使用者患上OSCC的因素，而另一些人没有，研究得很少。可以从理论上推断，一些吸烟者在接触致癌物质时，天生更容易患癌症。这可能是由于烟草的使用模式、致癌物的先天新陈代谢或排泄物的改变。通过诊断前的临床监测，确定哪些吸烟者最有可能患上口腔鳞状细胞癌，将会有很大的好处。这项拟议的研究项目旨在确定患有口腔鳞状细胞癌和不患有口腔鳞癌的吸烟者之间的差异，以此作为一种方法来了解那些患有癌症的吸烟者的致癌作用和风险。要更好地了解烟草致癌物的暴露程度和代谢，一种方法是通过研究烟草致癌物暴露标志物。可以检测尿液中烟草致癌物质暴露标志物的水平，以确定剂量、暴露和新陈代谢模式。这项建议的目的是通过一项病例对照研究，确定哪些烟草致癌暴露标志物与烟草引起的口腔鳞癌最相关。病例将由患有口腔鳞状细胞癌的吸烟者组成，对照病例将由没有口腔鳞癌的吸烟者组成。我们将研究的暴露标记物是烟碱(4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone，NNK)、N‘-亚硝基烟碱(N’-NitrosonorNicotine，NNN)、1-羟基苯和可替宁(Cotinine)。此外，我们还将研究口腔鳞状细胞中DNA加合物的形成。鉴于DNA加合物可以导致突变并最终导致癌症，研究它们在口腔鳞癌患者中的分布是确定吸烟诱导的口腔鳞癌致癌途径的独特努力。我们的中心假设是，与没有口腔鳞癌的吸烟者相比，患有口腔鳞癌的吸烟者将有更高的尿液暴露标志物水平和更高的口腔鳞状细胞DNA加合物突变形成。该提案还包括一项针对主要调查员的全面指导和培训计划。培训计划的内容包括流行病学、生物统计学和数据分析方面的教学指导，以及项目导师在实验室技术、研究设计、数据分析和赠款方面的广泛培训。本申请中提出的指导的最终目标是最终由主要研究人员建立一个独立的研究计划。综上所述，这项建议试图确定烟草致癌暴露标志物和DNA加合物在患有口腔鳞癌的吸烟者中升高。这将为了解烟草在口腔鳞状细胞癌中的致癌作用和风险奠定基础，并指导我们未来在这一领域的研究。

DESCRIPTION (provided by applicant): Squamous cell carcinoma of the oral cavity (OSCC) is a devastating disease that is strongly associated with tobacco use. While OSCC most commonly occurs in tobacco users, there are many tobacco users who do not develop carcinoma. The factors that cause some tobacco users to develop OSCC, while others do not, are poorly studied to date. It can be theorized that some smokers are inherently more susceptible to developing carcinoma when exposed to carcinogens. This may be due to patterns of tobacco use, innate metabolism of carcinogens, or altered excretion. Identifying those smokers who are most at-risk for the development of OSCC would have great benefit through pre-diagnosis clinical surveillance. The proposed research project aims to identify differences between smokers with and without OSCC as a method to understand carcinogenesis and risk in those cigarette smokers who develop carcinoma. One approach to better understand the extent of exposure to, and metabolism of, tobacco carcinogens is through the study of tobacco carcinogen exposure markers. Levels of tobacco carcinogen exposure markers can be assayed in the urine to identify patterns of dose, exposure and metabolism. The objective of this proposal is to determine which tobacco carcinogen exposure markers are most associated with tobacco-induced OSCC through a case-control study. Cases will consist of smokers with OSCC and controls will be smokers who do not have OSCC. The exposure markers we will study are 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), N'- nitrosonornicotine (NNN), 1-hydroxypyrene and cotinine. In addition, we will also study the formation of DNA adducts in buccal squamous cells. Given that DNA adducts can lead to mutagenesis and eventually carcinoma, investigating their distribution in OSCC patients represents a unique effort to identify carcinogenic pathways in smoking-induced OSCC. Our central hypothesis is that smokers with OSCC will have higher urinary exposure marker levels and higher mutagenic DNA adduct formation in oral squamous cells than smokers without OSCC. This proposal also includes a comprehensive mentoring and training plan for the primary investigator. Aspects of the training plan include didactic instruction in epidemiology, biostatistics and data analysis in addition to extensive training by the project mentors in laboratory techniques, study design, data analysis and grantsmanship. The ultimate goal of the mentoring proposed in this application is the eventual establishment of an independent research program by the primary investigator. In summary, this proposal seeks to identify tobacco carcinogen exposure markers and DNA adducts that are elevated in smokers with OSCC. This will form the foundation of an understanding of tobacco associated carcinogenesis and risk in OSCC and direct our future investigations in this area.