Lung cancer is the leading cause of cancer-related deaths worldwide. Lung cancer in nonsmokers is the seventh leading cause of cancer deaths worldwide and the proportion of lung cancer in never smokers is expected to increase as successful smoking prevention and cessation programs are implemented. In Pennsylvania, the adjusted rates of lung cancer incidence for Philadelphia is almost double that of rural areas in PA. If smoking was the only cause of lung cancer, these incidence rates should be the same suggesting that other environmental exposures may contribute. Polycyclic aromatic hydrocarbons (PAH) are ubiquitous environmental pollutants and are elevated in urban areas. PAHs, including the prototypical benzo[a]pyrene, are activated by several pathways (involving P450 and AKR enzymes) to electrophiles that can cause DNA lesions and initiate lung cancer. Studies outside US showed a positive correlation between PAH levels in non-smokers urine and lung cancer risk. Alterations in different metabolic pathways following PAH exposure in cell and animal models, suggest that dysregulation of plasma metabolomics may provide potential biomarkers of PAH effect. Metabolomics biomarkers have been identified in lung cancer and other cancer types. Identification of cancer-associated mutations in genes encoding enzymes with significant roles in cellular metabolism lead to oncometabolites (small-molecule components of normal metabolism whose accumulation causes signaling dysregulation to establish a milieu that initiates carcinogenesis) being quantified in different cancer types. In non-small cell lung cancer (NSCLC) cases, several biomarkers were able to discriminate NSCLC cases from healthy controls. Significant associations between specific plasma metabolites and the pathological type or stage of NSCLC were also observed. These findings suggest that metabolomics (by identifying oncometabolites) can serve as a potential tool to predict NSCLC disease stage and select lung cancer patients for precision treatment. We tested the hypothesis that PAHs are major modifiers of NSCLC risk in never-smokers by generating PAH-associated metabolic profiles and metabolomics profiles from plasma in never smokers with NSCLC and compare these levels in matched controls. The levels of the dysregulated metabolomic biomarkers were correlated with individual PAH-metabolites, to determine if they confer excess risk to NSCLC.

Environmental polycyclic aromatic hydrocarbons and risk of lung cancer in never smokers

2019 Fall National Meeting

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