997

DNA Repair and Other Biomarkers Associated with Cancer Risk and Outcomes

Urinary levels of tobacco-specific nitrosamine metabolites in relation to lung cancer development in two prospective cohorts of cigarette smokers

Sunday, Apr 19, 2009, 1:00 PM - 5:00 PM

Hall B-F, Poster Section 4

4

1

Highly-Rated Poster Presentation

Jian-Min Yuan, Woon-Puay Koh Koh, Sharon E. Murphy, Yunhua Fan, Renwei Wang, Steven G. Carmella, Shaomei Han, Latie Wickham, Yu-Tang Gao, Mimi C. Yu, Stephen S. Hecht. University of Minnesota, Minneapolis, MN, National University of Singapore, Singapore, Singapore, Shanghai Cancer Institute, Shanghai, China

Background: 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) and its glucuronides (sum of which is denoted as total NNAL) are metabolites of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). NNK and NNAL induce lung cancer in laboratory animals. Epidemiologic data directly linking NNK to lung cancer in humans are lacking. Methods: We prospectively examined the association between total NNAL, a validated marker for NNK, in prediagnostic urines and risk of lung cancer development among current smokers of two large population-based cohort studies - The Shanghai Cohort Study and The Singapore Chinese Health Study. The Shanghai Cohort Study enrolled 18,244 men aged 45-64 yr in Shanghai, China during 1/1/86 - 9/30/89 and the Singapore Chinese Health Study enrolled 63,257 Chinese men and women aged 45-74 yr in Singapore during 4/1/93 - 7/31/99. In addition to in-person interviews for cigarette smoking, dietary and other lifestyle factors, we collected blood and urine samples from more than 50,000 consented cohort participants. All biospecimens have been stored at ultra-low temperature since their collections. Both cohorts have been actively and passively followed for cancer and death occurrences since inception. We conducted within the two cohorts a nested case-control study involving 246 cases of incident lung cancer and 245 cohort controls of current smokers who were individually matched to the index cases by age, gender, and date of urine collection. Total NNAL and total cotinine in prediagnostic urines of all cases and controls were quantified by gas chromatography (GC)-nitrosamine selective detection and GC-mass spectrometry, respectively. The relative risk and its 95% confidence interval (CI) for lung cancer with elevated levels of urinary total NNAL was estimated using a logistic regression method. Results: Urinary levels of total NNAL were significantly associated with risk of lung cancer in a dose-dependent manner. Relative to the lowest tertile, risk associated with the 2^nd and 3^rd tertiles of total NNAL were 1.43 (95% CI 0.86-2.37) and 2.11 (95% CI 1.25-3.54), respectively (P for trend=0.005) after adjustment for self-reported smoking history and urinary total cotinine. Smokers in the highest tertiles of urinary total NNAL and total cotinine exhibited a 8.5-fold (95% CI 3.7-19.5) increased risk for lung cancer relative to smokers with comparable smoking history but possessing the lowest tertiles of urinary total NNAL and total cotinine.
Conclusion: Findings of the present study directly link NNK exposure to lung cancer development in humans. Total NNAL and total cotinine in urine are important predictors of lung cancer in smokers beyond the predictive indices of smoking intensity and duration. These two non-invasive biomarkers can serve as the starting point of an individual-based, predictive model for lung cancer risk in a smoker.