DNA Damage Biomarkers for Carcinogenesis Related to Tobacco Product Use

Tobacco product use is a well-established risk factor for not only lung cancer but also head and neck cancer. Compounds present in both unburned and combusted tobacco generate a broad spectrum of DNA damage. Tobacco use also results in local inflammatory responses, elevating oxidative stress levels that further contribute to DNA damage generation. This increased DNA damage burden results in higher mutation rates and other cellular changes, inducing the so-called field carcinogenesis effect in exposed tissues of the lung and oral cavity that promotes dysplasia and malignancies in these tissues. DNA damage accumulation and alteration of normal DNA damage responses (DDRs) over time have also been associated with chronic tobacco use, and would hypothetically serve as biomarkers related not only to exposure but also to cancer susceptibility. Furthermore, such alterations in DDRs in tumor cells may affect outcomes following radiation or chemotherapeutic treatments employed to treat either lung or head and neck cancers. Hypothetically, analysis of tissues exposed to tobacco carcinogens would informative regarding ongoing carcinogenic processes, including generation and accumulation of DNA damage (and mutations) as well as induction and alteration of key DDRs. However, sampling of lung tissue exposed to tobacco carcinogens is not practical. In contrast, routine sampling of epithelia in the oral cavity is non-invasive and relatively easy, and should be informative regarding oral exposure and as a surrogate for lung epithelia. The proposed studies would establish the relationships between exposure to tobacco carcinogens, DNA damage generation and DDR using oral epithelial and head and neck cancer cell models, and investigate these parameters in oral epithelial (buccal) cells obtained from human subjects without or with immediate and chronic exposure to tobacco smoke. In parallel, we also will initiate collection and storage of buccal cells from head and neck cancer patients to facilitate, in future studies, analysis of our biomarkers in these samples and their comparison to tumor cell tissues for the purposes of informing cancer etiology and treatment. The proposed research brings together an investigative team of basic researchers and head and neck (and lung) cancer clinicians to 1) elucidate the relationships between exposure, DNA damage burden, and key DDR biomarkers and 2) apply this knowledge towards understanding of the etiology of head and neck as well as lung cancers and the responses of these malignancies to radiation and chemotherapeutic treatments. Furthermore, results achieved from these experiments will provide the basis to obtain broader (R01/R21) funding to further explore and establish these relationships in basic and translational studies and to employ our DNA damage and DDR biomarker analyses for analyzing the toxicity and carcinogenicity of emerging tobacco products (including e-cigarettes) to inform their future regulation. Importantly, the FDA (in collaboration with NIH) is devoting substantial resources to support research in tobacco regulatory science.