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Grant Details

Grant Number: 5R01CA129534-06 Interpret this number
Primary Investigator: Yuan, Jian-Min
Organization: University Of Pittsburgh At Pittsburgh
Project Title: Biomarkers of Nnk in Prediction of Lung Cancer Development in Smokers
Fiscal Year: 2013
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Abstract

DESCRIPTION (provided by applicant): Lung cancer is the leading cause of cancer death in the United States and worldwide. Cigarette smoking causes approximately 90 percent of lung cancer. However, approximately only 15 percent of lifelong smokers develop lung cancer over their lifetimes. The variation in the susceptibility to lung cancer among smokers not only depends on their exposure to tobacco carcinogens, but also upon genetic, dietary, and other environmental factors. Tobacco- specific nitrosamines (i.e., NNK) in cigarette smoke is among the most important carcinogens that cause lung cancer in humans. The proposed study is to assess the role of validated urinary biomarkers for the uptake and metabolism of NNK in prediction of lung cancer development among current smokers. The proposed study will utilize two established residential cohorts of Chinese. The Shanghai Cohort Study enrolled 18,244 men aged 45-64 years in Shanghai, China, during 1986-89. The Singapore Chinese Health Study enrolled 27,959 men and 35,298 women aged 45-74 years during 1993-98. At recruitment, all cohort members provided detailed dietary and medical histories. Blood and urine specimens were collected from all Shanghai cohort members and about 60 percent of Singapore cohort members. The cohorts have been followed for the occurrence of cancer and death through routine ascertainment approaches. By the end of 2012, a total of 1317 incident lung cancer cases will be expected in the two cohorts. An equal number of controls will be randomly chosen among the two cohorts for proposed studies. We will measure the concentrations of NNAL and NNAL-Glucs (NNK metabolites), total nicotine equivalents (i.e., the sum of nicotine, cotinine, trans-32-hydroxycotinine and their corresponding glucuronides), and total isothiocyanates in urine, and beta-cryptoxanthin and other dietary antioxidants in serum on all study subjects. Genetic polymorphisms in NNK- and nicotine-metabolizing genes also will be determined. The specific aims are (1) to determine if total NNAL and NNAL-Glucs:NNAL ratio in prediagnostic urines differ between those who develop lung cancer and those who remain free of cancer, but are otherwise comparable in terms of age, gender, date of study enrollment, smoking status, intensity and duration over lifetime, and urinary total nicotine equivalents; and (2) to determine if genetic polymorphisms in NNK- and nicotine-metabolizing genes and dietary factors modify the association between NNK biomarkers and development of lung cancer. The ultimate goal of the proposed research is the development of an effective set of non-invasive, predictive markers of lung cancer development that allow for the identification, among smokers, of the relatively small fraction of individuals who are at very high risk for lung cancer. People with high risk for lung cancer could be closely followed for early detection of lung cancer and encouraged to change their lifestyles, e.g., quitting smoking. In addition, chemopreventive agents, if available, could be prescribed to high-risk people for protection against lung cancer development.

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Publications

Urinary tobacco smoke-constituent biomarkers for assessing risk of lung cancer.
Authors: Yuan JM, Butler LM, Stepanov I, Hecht SS
Source: Cancer Res, 2014 Jan 15;74(2), p. 401-11.
EPub date: 2014 Jan 9.
PMID: 24408916
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Impact of postdiagnosis smoking on long-term survival of cancer patients: the Shanghai cohort study.
Authors: Tao L, Wang R, Gao YT, Yuan JM
Source: Cancer Epidemiol Biomarkers Prev, 2013 Dec;22(12), p. 2404-11.
PMID: 24319070
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Tobacco-specific N-nitrosamine exposures and cancer risk in the Shanghai Cohort Study: remarkable coherence with rat tumor sites.
Authors: Stepanov I, Sebero E, Wang R, Gao YT, Hecht SS, Yuan JM
Source: Int J Cancer, 2014 May 15;134(10), p. 2278-83.
EPub date: 2013 Nov 18.
PMID: 24243522
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Urinary metabolites of a polycyclic aromatic hydrocarbon and volatile organic compounds in relation to lung cancer development in lifelong never smokers in the Shanghai Cohort Study.
Authors: Yuan JM, Butler LM, Gao YT, Murphy SE, Carmella SG, Wang R, Nelson HH, Hecht SS
Source: Carcinogenesis, 2014 Feb;35(2), p. 339-45.
EPub date: 2013 Oct 22.
PMID: 24148823
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Tobacco smoke biomarkers and cancer risk among male smokers in the Shanghai Cohort Study.
Authors: Hecht SS, Murphy SE, Stepanov I, Nelson HH, Yuan JM
Source: Cancer Lett, 2012 Jul 20;null, p. null.
EPub date: 2012 Jul 20.
PMID: 22824243
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Urinary levels of volatile organic carcinogen and toxicant biomarkers in relation to lung cancer development in smokers.
Authors: Yuan JM, Gao YT, Wang R, Chen M, Carmella SG, Hecht SS
Source: Carcinogenesis, 2012 Apr;33(4), p. 804-9.
EPub date: 2012 Jan 31.
PMID: 22298640
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Urinary levels of cigarette smoke constituent metabolites are prospectively associated with lung cancer development in smokers.
Authors: Yuan JM, Gao YT, Murphy SE, Carmella SG, Wang R, Zhong Y, Moy KA, Davis AB, Tao L, Chen M, Han S, Nelson HH, Yu MC, Hecht SS
Source: Cancer Res, 2011 Nov 1;71(21), p. 6749-57.
EPub date: 2011 Oct 25.
PMID: 22028322
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Urinary levels of the tobacco-specific carcinogen N'-nitrosonornicotine and its glucuronide are strongly associated with esophageal cancer risk in smokers.
Authors: Yuan JM, Knezevich AD, Wang R, Gao YT, Hecht SS, Stepanov I
Source: Carcinogenesis, 2011 Sep;32(9), p. 1366-71.
EPub date: 2011 Jul 6.
PMID: 21734256
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Applying tobacco carcinogen and toxicant biomarkers in product regulation and cancer prevention.
Authors: Hecht SS, Yuan JM, Hatsukami D
Source: Chem Res Toxicol, 2010 Jun 21;23(6), p. 1001-8.
PMID: 20408564
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