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.

Public Health Relevance

Oral squamous cell carcinoma (OSCC) is a disease that threatens all tobacco users. Our research will investigate carcinogenesis and risk profiles for the development of OSCC in smokers through examination of urine and oral cells. We feel this work has the potential to improve our understanding of tobacco-induced carcinogenesis, identify those at highest risk for developing OSCC requiring surveillance, provide guidance for future mechanistic studies in this field, and generate data supporting federal regulation of tobacco constituents.

National Institute of Health (NIH)
National Institute of Dental & Craniofacial Research (NIDCR)
Mentored Patient-Oriented Research Career Development Award (K23)
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NIDR Special Grants Review Committee (DSR)
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King, Lynn M
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University of Minnesota Twin Cities
Schools of Medicine
United States
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Khariwala, Samir S; Hatsukami, Dorothy K; Stepanov, Irina et al. (2018) Patterns of Tobacco Cessation Attempts and Symptoms Experienced Among Smokers With Head and Neck Squamous Cell Carcinoma. JAMA Otolaryngol Head Neck Surg 144:477-482
Jethwa, Ashok R; Khariwala, Samir S (2017) Tobacco-related carcinogenesis in head and neck cancer. Cancer Metastasis Rev 36:411-423
Nollen, Nicole L; Mayo, Matthew S; Clark, Lauren et al. (2017) Tobacco toxicant exposure in cigarette smokers who use or do not use other tobacco products. Drug Alcohol Depend 179:330-336
Khariwala, Samir S; Ma, Bin; Ruszczak, Chris et al. (2017) High Level of Tobacco Carcinogen-Derived DNA Damage in Oral Cells Is an Independent Predictor of Oral/Head and Neck Cancer Risk in Smokers. Cancer Prev Res (Phila) 10:507-513
Jain, Vipin; Garg, Apurva; Parascandola, Mark et al. (2017) Analysis of Alkaloids in Areca Nut-Containing Products by Liquid Chromatography-Tandem Mass Spectrometry. J Agric Food Chem 65:1977-1983
Ma, Bin; Ruszczak, Chris; Jain, Vipin et al. (2016) Optimized Liquid Chromatography Nanoelectrospray-High-Resolution Tandem Mass Spectrometry Method for the Analysis of 4-Hydroxy-1-(3-pyridyl)-1-butanone-Releasing DNA Adducts in Human Oral Cells. Chem Res Toxicol 29:1849-1856
Khariwala, Samir S; Le, Bin; Pierce, Brendan H G et al. (2016) Antibiotic Use after Free Tissue Reconstruction of Head and Neck Defects: Short Course vs. Long Course. Surg Infect (Larchmt) 17:100-5
Balbo, Silvia; Juanes, Rita Cervera; Khariwala, Samir et al. (2016) Increased levels of the acetaldehyde-derived DNA adduct N 2-ethyldeoxyguanosine in oral mucosa DNA from Rhesus monkeys exposed to alcohol. Mutagenesis 31:553-8
de la Garza, Gabriel; Militsakh, Oleg; Panwar, Aru et al. (2016) Obesity and perioperative complications in head and neck free tissue reconstruction. Head Neck 38 Suppl 1:E1188-91
Liu, C Carrie; Jethwa, Ashok R; Khariwala, Samir S et al. (2016) Sensitivity, Specificity, and Posttest Probability of Parotid Fine-Needle Aspiration: A Systematic Review and Meta-analysis. Otolaryngol Head Neck Surg 154:9-23

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