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Grant Details

Grant Number: 5R01CA085997-05 Interpret this number
Primary Investigator: Le Marchand, Loic
Organization: University Of Hawaii At Manoa
Project Title: Genes, Diet and Carcinogen Activation in Smokers
Fiscal Year: 2004
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Abstract

DESCRIPTION (Adapted from the Applicant's Abstract): This research will investigate genetic and dietary influences on the Phase I metabolism of tobacco smoke carcinogens and on lung cancer risk. Based on recent findings, we hypothesize that, in smokers: 1) polycyclic aromatic hydrocarbons (PAHs) in tobacco smoke are the primary cause of squamous cell carcinoma of the lung, whereas nitrosamines in tobacco are the primary cause of lung adenocarcinoma; 2) the metabolic activation of PAHs is mainly carried out by CYPIA1, with more minor roles for CYP3A4 and CYP1B 1, and the activation of tobacco-specific nitrosamines (TSNAs) is mainly carried out by CYP2E1, CYPlA2 and CYP2A6; and 3) the activation of these carcinogens is modified by polymorphic genes and dietary inhibitors/inducers. We will use genomic DNA samples from a completed case-control study of lung cancer among Japanese, Caucasians and Hawaiians (341 cases, 456 controls) to test the independent and joint associations of these polymorphisms with lung cancer risk. We will also conduct a cross-sectional study (n=600) among Japanese, Hawaiian and Caucasian smokers participating in our Multiethnic Cohort Study to test associations of: 1) urinary NNAL (the main metabolite of NNK) and TSNA globin adducts with the high activity genotypes for CYP2E1, CYIA2 and/or CYP2A6; 2) urinary total 1-hydroxypyrene and levels of PAH DNA adducts in circulating lymphocytes with the high activity genotypes for CYPIAI, AhR and CYPIBI; and 3) intake and urinary levels of phytochemicals (specific flavonoids, total isothiocyanates) and plasma levels of micronutrients with these markers of activation. Finally, two feeding studies (n=50 each) will use a randomized cross-over design to test the effect of selected foods on markers of PAH or TSNA metabolism and on metabolizing enzymes in smokers with high and low activity genotypes. The elucidation of the main enzymes responsible for carcinogen activation and of the impact of dietary factors on these enzymes would have important implications for cancer prevention.

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Publications

Replication of lung cancer susceptibility loci at chromosomes 15q25, 5p15, and 6p21: a pooled analysis from the International Lung Cancer Consortium.
Authors: Truong T, Hung RJ, Amos CI, Wu X, Bickeböller H, Rosenberger A, Sauter W, Illig T, Wichmann HE, Risch A, Dienemann H, Kaaks R, Yang P, Jiang R, Wiencke JK, Wrensch M, Hansen H, Kelsey KT, Matsuo K, Tajima K, Schwartz AG, Wenzlaff A, Seow A, Ying C, Staratschek-Jox A, Nürnberg P, Stoelben E, Wolf J, Lazarus P, Muscat JE, Gallagher CJ, Zienolddiny S, Haugen A, van der Heijden HF, Kiemeney LA, Isla D, Mayordomo JI, Rafnar T, Stefansson K, Zhang ZF, Chang SC, Kim JH, Hong YC, Duell EJ, Andrew AS, Lejbkowicz F, Rennert G, Müller H, Brenner H, Le Marchand L, Benhamou S, Bouchardy C, Teare MD, Xue X, McLaughlin J, Liu G, McKay JD, Brennan P, Spitz MR
Source: J Natl Cancer Inst, 2010 Jul 7;102(13), p. 959-71.
EPub date: 2010 Jun 14.
PMID: 20548021
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Smokers with the CHRNA lung cancer-associated variants are exposed to higher levels of nicotine equivalents and a carcinogenic tobacco-specific nitrosamine.
Authors: Le Marchand L, Derby KS, Murphy SE, Hecht SS, Hatsukami D, Carmella SG, Tiirikainen M, Wang H
Source: Cancer Res, 2008 Nov 15;68(22), p. 9137-40.
PMID: 19010884
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Design considerations for genomic association studies: importance of gene-environment interactions.
Authors: Le Marchand L, Wilkens LR
Source: Cancer Epidemiol Biomarkers Prev, 2008 Feb;17(2), p. 263-7.
PMID: 18268108
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Pooled analysis of the CYP1A1 exon 7 polymorphism and lung cancer (United States).
Authors: Le Marchand L, Guo C, Benhamou S, Bouchardy C, Cascorbi I, Clapper ML, Garte S, Haugen A, Ingelman-Sundberg M, Kihara M, Rannug A, Ryberg D, Stücker I, Sugimura H, Taioli E
Source: Cancer Causes Control, 2003 May;14(4), p. 339-46.
PMID: 12846365
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Cancer preventive effects of flavonoids--a review.
Authors: Le Marchand L
Source: Biomed Pharmacother, 2002 Aug;56(6), p. 296-301.
PMID: 12224601
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Association of the hOGG1 Ser326Cys polymorphism with lung cancer risk.
Authors: Le Marchand L, Donlon T, Lum-Jones A, Seifried A, Wilkens LR
Source: Cancer Epidemiol Biomarkers Prev, 2002 Apr;11(4), p. 409-12.
PMID: 11927502
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Etiologic research on lung cancer in Hawaii: the roles of smoking, phytochemicals and metabolic genes.
Authors: Le Marchand L
Source: Hawaii Med J, 2001 Dec;60(12), p. 325-6.
PMID: 11836972
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