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Nicotine metabolism and predicting lung cancer risk in African Americans

Institution: University of Southern California
Investigator(s): Sungshim Park, Ph.D.
Award Cycle: 2017 (Cycle 26) Grant #: 26IR-0001 Award: $496,005
Subject Area: Early Diagnosis of Tobacco-Related Cancer
Award Type: High Impact Research Project Award

Initial Award Abstract

Lung cancer is the most common cancer and the leading cause of cancer-related deaths. African Americans are more vulnerable to the disease than many other racial/ethnic groups, such as whites. Tobacco smoking is the primary cause of lung cancer. Nicotine, a compound in tobacco, is the primary addictive component. In smokers, the majority of nicotine is metabolized by an enzyme called cytochrome P450 2A6 (CYP2A6). CYP2A6 may influence lung cancer risk because it influences how individuals smoke. For instance, individuals who have slower enzyme levels, have been also found to have on average higher levels of nicotine in their system. These individuals may smoke less and are therefore, exposed to fewer smoking-related carcinogens and expected to have a lower risk of lung cancer. Our research group has found that the CYP2A6 activity biomarker, measured from non-invasive tissue, such as blood or urine, is a potential biomarker for tobacco-related lung cancer risk. This would help to better identify those at greater risk of disease for screening recommendations. However, because of many limitations, it is not easy measure this biomarker in former smokers (who are most of the lung cancer cases). Genetics to serve as a proxy biomarker could be solution; however, because the genetic sequence of this gene is very similar to those of neighboring genes, accurate genotyping is also a challenge. This study proposes a solution to these limitations by improving genotyping accuracy so that genetic variants could serve as a practical and efficient proxy to the CYP2A6 activity biomarker. This study will be conducted in African Americans, because, when compared to whites, they are particularly vulnerable to lung cancer. Also, they have greater genomic variation, which may help to make this research more generalizable to other populations. This study will first accurately genotype CYP2A6 in African Americans through deep sequencing the genetic region. Second, we will identify which genetic variants are most associated with CYP2A6 activity. The strongest associated variants will be compiled to create a predicted CYP2A6 activity score. This score will serve as a proxy for the CYP2A6 activity biomarker. Lastly, we will evaluate the association for the predicted CYP2A6 activity score with tobacco-related lung cancer risk in 349 African American ever smokers. The successful completion of these study aims will allow for the construction of a practical and efficient proxy for CYP2A6. This will increase the utility of CYP2A6 as a biomarker in tobacco-related lung cancer risk prediction. It will also to help to identify individuals who are at highest risk of lung cancer so that they can be recommended for lung cancer screening for early disease detection and improve survival from this disease.