Genomics of Smoking Exposure and Cessation: Lessons for Cancer Prevention and Treatment

Abstract

Tobacco use is the greatest preventable cause of cancer in the United States, accounting for almost one third of all cancerrelated deaths and 90% of deaths from lung cancer. Despite widespread knowledge of these risks, tobacco use prevalence rates are 20% in the United States and up to 30% to 50% in the developing world (1, 2). Nicotine, the addictive chemical in tobacco, produces a biological dependence (3), and therefore, even with the most efficacious medications available, only one in four smokers is able to maintain long-term abstinence (4). Persistent tobacco use is common even following a diagnosis of tobaccorelated cancer and is associated with poorer outcomes of radiation therapy and chemotherapy and with increased risk of second primary malignancies (5). Although smoking cessation is optimal, it may not be realistic for all patients. Therefore, it is essential to gain a better understanding of the cellular and molecular mechanisms through which tobacco exposure contributes to cancer pathogenesis and outcomes, and to develop targeted prevention and therapeutic approaches. Toward this end, a study reported by Gumus et al. (6) in this issue of the journal characterized gene expression profiles in the oral mucosa of smokers and nonsmokers and validated their findings by examining the in vitro effects of tobacco smoke condensate on gene expression in an oral leukoplakia cell line. Another related study also reported in this issue of the journal was conducted by Zhang et al. (7), who compared gene expression in cells obtained from bronchial brushes from never, current, and former smokers. Smoking effects on global gene expression were common across these studies. Certain genes (CYP1A1 and CYP1B1) that were up-regulated in buccal oral specimens of smokers were part of a larger group (CYP1A1, CYP1B1, ALDH3A1, NQO1, and AKR1C1) up-regulated following in vitro exposure to tobacco smoke condensate (6) and in the airway cells of smokers (7). Zhang and colleagues provide further in vivo evidence that many of these genes are down-regulated in persons who reported quitting smoking at least 1 year before the assessment (CYP1B1, AKR1C1, AKR1C2, AKR1B10 ,a ndALDH3A1). Many of these same genes were previously shown to be overexpressed in oral cancer cells exposed to tobacco smoke condensate (8), in bronchial epithelial cells of smokers, and in patients' non–small cell lung carcinoma cells (9, 10). The effects are also consistent with the effects of smoking on the airway transcriptome (11, 12). Taken together, these findings identify important tobacco smoke exposure response genes. The studies of Gumus et al. and Zhang et al. in this issue of the journal provide an elegant illustration of the value of cross-model (preclinical and clinical) validation in translational cancer prevention research.