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L. Le Marchand
ED01 - Biology of Lung Cancer (ID 263)
- Event: WCLC 2016
- Type: Education Session
- Track: Biology/Pathology
- Presentations: 1
ED01.02 - Tobacco Carcinogens and Lung Cancer Susceptibility (ID 6422)
11:00 - 12:30 | Author(s): L. Le Marchand
While cigarette smoking is clearly the major cause of lung cancer, only 11% of female and 24% of male lifetime smokers will get lung cancer by age 85 or greater, and this relatively small percentage is not due to competing causes of death from smoking (1) The major goal of the research approach discussed in this presentation is to identify individuals who are highly susceptible to the carcinogenic effects of cigarette smoke. These individuals would be candidates for intensive lung cancer surveillance and screening, increasing the probability of detection of a tumor at an early stage. We are not proposing methods for early detection of tumors such as the identification of metabolites or proteins characteristic of lung tumors, but rather early identification of susceptible individuals. While there are already algorithms relating various parameters to lung cancer susceptibility, they are mostly retrospective in nature, with pack-years of cigarette smoking being a major prognostic factor (2,3). Thus, these algorithms are typically applied to subjects who are older, when the process may be more advanced. Our ultimate goal is to develop a risk model that is prospective in nature. Overall, there would be a greater probability of success if one could identify high risk individuals early in the carcinogenic process. Even if this were effective in only 10% of tobacco users, the outcome could be prevention of more than 15,000 lung cancer deaths per year in the U.S. alone and massive financial savings. Among the more than 7,000 identified chemical compounds in cigarette smoke, there are 72 fully characterized carcinogens among which at least 20 are known to cause lung tumors in laboratory animals (4,5). Important among the lung carcinogens are polycyclic aromatic hydrocarbons (PAH) such as benzo[a]pyrene, tobacco-specific nitrosamines such as 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), and volatiles such as 1,3-butadiene. Other related volatile compounds that may contribute to the carcinogenic process include acrolein, crotonaldehyde, and benzene. Perhaps the most important compound in tobacco smoke is nicotine – while not a carcinogen, it is the addictive constituent of smoke that causes people to continue to inhale this incredibly unhealthy mixture. In pursuit of our goal of identifying smokers susceptible to lung cancer, we have focused on several tobacco smoke toxicant and carcinogen parent substances and metabolites in urine (6). Thus, we and others have developed and applied analytically validated mass spectrometric methods for total nicotine equivalents (the sum of nicotine and six metabolites: nicotine glucuronide, cotinine, cotinine glucuronide, 3′-hydroxycotinine and its glucuronide, and nicotine-N-oxide); total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), a metabolite of NNK; phenanthrene tetraol (PheT) and 3-hydroxyphenanthrene (3-PheOH), metabolites of a representative PAH; S-phenylmercapturic acid (SPMA), a metabolite of the carcinogen benzene; 3-hydroxypropylmercapturic acid (HPMA), a metabolite of acrolein; and 3-hydroxy-1-methylpropylmercapturic acid (HMPMA), a metabolite of crotonaldehyde. We have collaborated with epidemiologists to evaluate the relationship of these urinary metabolites to cancer, as determined in prospective cohort studies. These studies collect and store bio-samples from large numbers of healthy subjects, then follow the subjects until sufficient numbers of cancer cases occur for statistical analysis. Samples from the cases and matched controls without cancer are retrieved from biorepositories and analyzed for specific biomarkers. The results of these studies have been reviewed (7,8). In summary, statistically significant relationships of urinary total cotinine (cotinine plus its glucuronide, the major metabolite of nicotine), total NNAL, and PheT with lung cancer risk were observed among male smokers in Shanghai. Urinary total cotinine and total NNAL were related to lung cancer risk in a study of male and female smokers in Singapore, and total NNAL in serum was related to lung cancer risk in a study of male and female smokers in the U.S. (7,8). Levels of urinary SPMA , HPMA, and HMPMA were not independently related to lung cancer in the Shanghai study. These results indicate that total cotinine, total NNAL, and PheT are possible biomarkers of lung cancer risk. We are also collaborating with scientists from the Multiethnic Cohort study, a prospective cohort study investigating the association of genetic and lifestyle factors with chronic diseases in a population with diverse ethnic backgrounds. They have reported that, for the same number of cigarettes smoked, and particularly at lower levels of smoking, African Americans and Native Hawaiians have a higher risk for lung cancer than Whites while Latinos and Japanese Americans have a lower risk (9). We are investigating the mechanistic basis for these remarkable differences. We analyzed urine samples from 300-700 subjects per group for total nicotine equivalents, total NNAL, PheT, 3-PheOH, SPMA, HPMA, and HMPMA. The results demonstrated that African Americans, although smoking fewer cigarettes per day than any of the other groups except Latinos, had significantly higher levels of total nicotine equivalents, total NNAL, PheT, 3-PheOH, and SPMA compared to Whites while Japanese Americans had significantly lower levels of most of these biomarkers than Whites. The relatively low level of urinary total nicotine equivalents in the Japanese American smokers was related to a high prevalence of CYP2A6 polymorphisms in this group (10). CYP2A6 is the primary catalyst of nicotine metabolism and the CYP2A6 alleles common in Japanese Americans code for low activity and non-functional enzyme. Therefore, Japanese Americans on the average have more unchanged nicotine circulating and will not need to obtain as much nicotine per cigarette. The biomarker profiles of Native Hawaiians and Latinos did not clearly relate to their relative lung cancer risks, but Native Hawaiians had high levels of the acrolein biomarker HPMA compared to other groups while those of Latinos were low. These results provide important new data pertinent to the relatively high risk of African Americans and the lower risk of Japanese Americans for lung cancer. Collectively, our results support the use of urinary nicotine metabolites, total NNAL, and PheT as biomarkers of lung cancer risk in cigarette smokers. Further studies are required to produce a reliably predictive algorithm for lung cancer susceptibility in cigarette smokers. These studies are likely to require the analysis of DNA adduct levels and to incorporate genetic and epigenetic information. Reference List 1. International Agency for Research on Cancer (2004) Tobacco Smoke and Involuntary Smoking. In IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, vol. 83 pp 174-176, IARC, Lyon, FR. 2. Tammemagi, C. M., Pinsky, P. F., Caporaso, N. E., Kvale, P. A., Hocking, W. G., Church, T. R., Riley, T. L., Commins, J., Oken, M. M., Berg, C. D., and Prorok, P. C. (2011) Lung cancer risk prediction: prostate, lung, colorectal and ovarian cancer screening trial models and validation. J. Natl. Cancer Inst. 103, 1058-1068. 3. Weissfeld, J. L., Lin, Y., Lin, H. M., Kurland, B. F., Wilson, D. O., Fuhrman, C. R., Pennathur, A., Romkes, M., Nukui, T., Yuan, J. M., Siegfried, J. M., and Diergaarde, B. (2015) Lung cancer risk prediction using common SNPs located in GWAS-identified susceptibility regions. J Thorac. Oncol. 4. Hecht, S. S. (1999) Tobacco smoke carcinogens and lung cancer. J. Natl. Cancer Inst. 91, 1194-1210. 5. Rodgman, A. and Perfetti, T. (2009) The Chemical Components of Tobacco and Tobacco Smoke. CRC Press, Boca Raton, FL. 6. Hecht, S. S., Yuan, J.-M., and Hatsukami, D. K. (2010) Applying tobacco carcinogen and toxicant biomarkers in product regulation and cancer prevention. Chem. Res. Toxicol. 23, 1001-1008. 7. Yuan, J. M., Butler, L. M., Stepanov, I., and Hecht, S. S. (2014) Urinary tobacco smoke-constituent biomarkers for assessing risk of lung cancer. Cancer Res. 74, 401-411. 8. Hecht, S. S., Murphy, S. E., Stepanov, I., Nelson, H. H., and Yuan, J.-M. (2012) Tobacco smoke biomarkers and cancer risk among male smokers in the Shanghai Cohort Study. Cancer Lett. 334, 34-38. 9. Haiman, C. A., Stram, D. O., Wilkens, L. R., Pike, M. C., Kolonel, L. N., Henderson, B. E., and Le Marchand, L. (2006) Ethnic and racial differences in the smoking-related risk of lung cancer. N. Engl. J. Med. 354, 333-342. 10. Park, S.-L., Tiirikainen, M., Patel, Y., Wilkens, L. R., Stram, D. O., Le Marchand, L., and Murphy, S. E. (2016) Genetic determinants of CYP2A6 activity across racial/ethnic groups with different risk of lung cancer and effect on their smoking behavior. Carcinogenesis in press.
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