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

描述（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毁灭性疾病。虽然OSCC最常见于烟草使用者，但也有许多烟草使用者没有发生癌。迄今为止，导致一些烟草使用者患上OSCC而另一些则没有的因素研究很少。从理论上讲，一些吸烟者在暴露于致癌物中时更容易患癌症。这可能是由于烟草的使用方式、致癌物的先天代谢或排泄改变所致。通过诊断前的临床监测，确定那些最有可能发生OSCC的吸烟者将有很大的好处。拟议的研究项目旨在确定患有和不患有OSCC的吸烟者之间的差异，作为了解吸烟者患癌的致癌作用和风险的一种方法。更好地了解烟草致癌物暴露程度和代谢的一种方法是研究烟草致癌物暴露标记物。可以在尿液中检测烟草致癌物质暴露标记物的水平，以确定剂量、暴露和代谢模式。本提案的目的是通过病例对照研究确定哪些烟草致癌物质暴露标记物与烟草诱导的OSCC最相关。病例将由患有OSCC的吸烟者组成，对照组将是没有OSCC的吸烟者。我们将研究的暴露标记是4-（甲基亚硝胺）-1-（3-吡啶基）-1-丁酮（NNK）， N'-亚硝基sonornicotine (NNN)， 1-羟基芘和可替宁。此外，我们还将研究DNA加合物在口腔鳞状细胞中的形成。鉴于DNA加合物可导致突变并最终导致癌症，研究它们在OSCC患者中的分布代表了一项独特的努力，以确定吸烟诱导的OSCC的致癌途径。我们的中心假设是，与没有OSCC的吸烟者相比，患有OSCC的吸烟者在口腔鳞状细胞中有更高的尿暴露标志物水平和更高的致突变DNA加合物形成。该提案还包括对主要研究者的全面指导和培训计划。培训计划的各个方面包括流行病学、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、数据分析和资助方面的广泛培训。本申请中提出的指导的最终目标是最终由主要研究者建立一个独立的研究计划。总之，本提案旨在确定烟草致癌物质暴露标志物和DNA加合物在OSCC吸烟者中升高。这将形成理解烟草相关致癌作用和OSCC风险的基础，并指导我们未来在这一领域的调查。

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.