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Grant Details

Grant Number: 3P01CA068384-08S1 Interpret this number
Primary Investigator: Lazarus, Philip
Organization: Pennsylvania State University
Project Title: Tobacco and Cancer Risk-Dose, Metabolism and Genetics
Fiscal Year: 2005
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Abstract

Studies from our group and others have demonstrated that the risk for tobacco-related cancers differs by race, gender and type of tobacco product consumed. These important public health differences cannot be fully explained by existing patterns of tobacco consumption. We hypothesize that risk is related to the type of cigarette smoked (e.g., low versus medium yield of carcinogens), the manner in which an individual's smoking habit regulates the dosage that reaches the lungs, metabolic capacity to activate and detoxify smoke-borne carcinogens, and susceptibility to cancer related to genetic factors that may affect metabolism or DNA repair. During the first three years of the study, the program focused on epidemiology, dosage and biomarkers of dose, and metabolic pathways of carcinogen activation and detoxification. In the coming period, the former Project (epidemiology) will be replaced by an epidemiological core facility (Core C) to provide appropriate study subjects for the two continuing projects and one new project. The current Project (Dosimetry of Lung and Bladder Cancer Risk among Cigarette Smokers) is about how smoking behavior affects the "delivered" carcinogen dose, and in turn how dose is related to biomarkers of carcinogen metabolites. Project (Metabolic Epidemiology of Tobacco-Related Cancers in Black and White Americans) is a study of differences between African Americans and Caucasians in metabolic activation and/or detoxification of an array of carcinogens derived from cigarette smoking, such as NNK (a potent lung carcinogen) and 4-aminobiphenyl (a bladder carcinogen). It utilizes metabolic and molecular techniques to study pathways of activation of tobacco-derived nitrosamines related to lung cancer, which is higher in African Americans compared to Caucasians, as well as detoxification of aromatic amines involved in bladder cancer, the rate of which is lower. Project (UDP Glucuronosyltransferases, Detoxification of NNK and Lung Cancer Risk) focuses on a family of detoxification enzymes that may be related to individual risk for developing lung or bladder cancer, and for which genetic polymorphisms exist that might explain variation in cancer risk. A broader understanding of these factors, both individually and comprehensively, will contribute greatly to our understanding of the causes of tobacco-related cancers in a way that can help improve our prevention strategies. The investigators are leaders in their respective fields with a strong history of collaboration. The program is supported by an Administrative Core with an Advisory Board of distinguished scientists and a community representative, by a Biostatistics and Computing Core Facility to provide efficient data management and statistical support, and by an Epidemiology Core Facility to manage accrual of subjects, interviews, acquisition of buccal cells, urine, and blood for biomarker assays, and pathological review.

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Publications

A functional trinucleotide repeat polymorphism in the 5'-untranslated region of the glutathione biosynthetic gene GCLC is associated with increased risk for lung and aerodigestive tract cancers.
Authors: Nichenametla SN, Muscat JE, Liao JG, Lazarus P, Richie JP Jr
Source: Mol Carcinog, 2013 Oct;52(10), p. 791-9.
EPub date: 2012 May 18.
PMID: 22610501
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Menthol smoking in relation to time to first cigarette and cotinine: results from a community-based study.
Authors: Muscat JE, Liu HP, Stellman SD, Richie JP Jr
Source: Regul Toxicol Pharmacol, 2012 Jun;63(1), p. 166-70.
EPub date: 2012 Apr 2.
PMID: 22487419
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The nicotine dependence phenotype, time to first cigarette, and larynx cancer risk.
Authors: Muscat JE, Liu HP, Livelsberger C, Richie JP Jr, Stellman SD
Source: Cancer Causes Control, 2012 Mar;23(3), p. 497-503.
EPub date: 2012 Feb 25.
PMID: 22367700
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Nicotine dependence phenotype and lung cancer risk.
Authors: Muscat JE, Ahn K, Richie JP Jr, Stellman SD
Source: Cancer, 2011 Dec 1;117(23), p. 5370-6.
EPub date: 2011 Aug 8.
PMID: 21826644
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Nicotine dependence phenotype, time to first cigarette, and risk of head and neck cancer.
Authors: Muscat JE, Ahn K, Richie JP Jr, Stellman SD
Source: Cancer, 2011 Dec 1;117(23), p. 5377-82.
EPub date: 2011 Aug 8.
PMID: 21826643
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Association of selenium status and blood glutathione concentrations in blacks and whites.
Authors: Richie JP Jr, Muscat JE, Ellison I, Calcagnotto A, Kleinman W, El-Bayoumy K
Source: Nutr Cancer, 2011;63(3), p. 367-75.
PMID: 21462082
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A GAG trinucleotide-repeat polymorphism in the gene for glutathione biosynthetic enzyme, GCLC, affects gene expression through translation.
Authors: Nichenametla SN, Lazarus P, Richie JP Jr
Source: FASEB J, 2011 Jul;25(7), p. 2180-7.
EPub date: 2011 Mar 28.
PMID: 21444626
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A comparison of creatinine vs. specific gravity to correct for urinary dilution of cotinine.
Authors: Muscat JE, Liu A, Richie JP Jr
Source: Biomarkers, 2011 May;16(3), p. 206-11.
EPub date: 2011 Feb 3.
PMID: 21288164
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Glucuronidation genotypes and nicotine metabolic phenotypes: importance of functional UGT2B10 and UGT2B17 polymorphisms.
Authors: Chen G, Giambrone NE Jr, Dluzen DF, Muscat JE, Berg A, Gallagher CJ, Lazarus P
Source: Cancer Res, 2010 Oct 1;70(19), p. 7543-52.
EPub date: 2010 Sep 28.
PMID: 20876810
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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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International Lung Cancer Consortium: coordinated association study of 10 potential lung cancer susceptibility variants.
Authors: Truong T, Sauter W, McKay JD, Hosgood HD 3rd, Gallagher C, Amos CI, Spitz M, Muscat J, Lazarus P, Illig T, Wichmann HE, Bickeböller H, Risch A, Dienemann H, Zhang ZF, Naeim BP, Yang P, Zienolddiny S, Haugen A, Le Marchand L, Hong YC, Kim JH, Duell EJ, Andrew AS, Kiyohara C, Shen H, Matsuo K, Suzuki T, Seow A, Ng DP, Lan Q, Zaridze D, Szeszenia-Dabrowska N, Lissowska J, Rudnai P, Fabianova E, Constantinescu V, Bencko V, Foretova L, Janout V, Caporaso NE, Albanes D, Thun M, Landi MT, Trubicka J, Lener M, Lubinski J, EPIC-lung, Wang Y, Chabrier A, Boffetta P, Brennan P, Hung RJ
Source: Carcinogenesis, 2010 Apr;31(4), p. 625-33.
EPub date: 2010 Jan 27.
PMID: 20106900
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UDP-glucuronosyltransferase 1A10: activity against the tobacco-specific nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol, and a potential role for a novel UGT1A10 promoter deletion polymorphism in cancer susceptibility.
Authors: Balliet RM, Chen G, Dellinger RW, Lazarus P
Source: Drug Metab Dispos, 2010 Mar;38(3), p. 484-90.
EPub date: 2009 Dec 9.
PMID: 20007297
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Time to first cigarette after waking predicts cotinine levels.
Authors: Muscat JE, Stellman SD, Caraballo RS, Richie JP Jr
Source: Cancer Epidemiol Biomarkers Prev, 2009 Dec;18(12), p. 3415-20.
PMID: 19959690
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Functional characterization of low-prevalence missense polymorphisms in the UDP-glucuronosyltransferase 1A9 gene.
Authors: Olson KC, Dellinger RW, Zhong Q, Sun D, Amin S, Spratt TE, Lazarus P
Source: Drug Metab Dispos, 2009 Oct;37(10), p. 1999-2007.
EPub date: 2009 Jul 9.
PMID: 19589876
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Effects of menthol on tobacco smoke exposure, nicotine dependence, and NNAL glucuronidation.
Authors: Muscat JE, Chen G, Knipe A, Stellman SD, Lazarus P, Richie JP Jr
Source: Cancer Epidemiol Biomarkers Prev, 2009 Jan;18(1), p. 35-41.
PMID: 19124478
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Association between haplotypes of manganese superoxide dismutase (SOD2), smoking, and lung cancer risk.
Authors: Gallagher CJ, Ahn K, Knipe AL, Dyer AM, Richie JP Jr, Lazarus P, Muscat JE
Source: Free Radic Biol Med, 2009 Jan 1;46(1), p. 20-4.
EPub date: 2008 Sep 27.
PMID: 18930810
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Comparison of CYP1A2 and NAT2 phenotypes between black and white smokers.
Authors: Muscat JE, Pittman B, Kleinman W, Lazarus P, Stellman SD, Richie JP Jr
Source: Biochem Pharmacol, 2008 Oct 1;76(7), p. 929-37.
EPub date: 2008 Jul 25.
PMID: 18703023
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Blood iron, glutathione, and micronutrient levels and the risk of oral cancer.
Authors: Richie JP Jr, Kleinman W, Marina P, Abraham P, Wynder EL, Muscat JE
Source: Nutr Cancer, 2008;60(4), p. 474-82.
PMID: 18584481
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Inhibition of caspase-3 activity and activation by protein glutathionylation.
Authors: Huang Z, Pinto JT, Deng H, Richie JP Jr
Source: Biochem Pharmacol, 2008 Jun 1;75(11), p. 2234-44.
EPub date: 2008 Feb 29.
PMID: 18395187
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Identification of a prevalent functional missense polymorphism in the UGT2B10 gene and its association with UGT2B10 inactivation against tobacco-specific nitrosamines.
Authors: Chen G, Dellinger RW, Gallagher CJ, Sun D, Lazarus P
Source: Pharmacogenet Genomics, 2008 Mar;18(3), p. 181-91.
PMID: 18300939
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Glucuronidation of tobacco-specific nitrosamines by UGT2B10.
Authors: Chen G, Dellinger RW, Sun D, Spratt TE, Lazarus P
Source: Drug Metab Dispos, 2008 May;36(5), p. 824-30.
EPub date: 2008 Jan 31.
PMID: 18238858
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The UGT2B17 gene deletion polymorphism and risk of prostate cancer. A case-control study in Caucasians.
Authors: Gallagher CJ, Kadlubar FF, Muscat JE, Ambrosone CB, Lang NP, Lazarus P
Source: Cancer Detect Prev, 2007;31(4), p. 310-5.
PMID: 17935910
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Glucuronidation of nicotine and cotinine by UGT2B10: loss of function by the UGT2B10 Codon 67 (Asp>Tyr) polymorphism.
Authors: Chen G, Blevins-Primeau AS, Dellinger RW, Muscat JE, Lazarus P
Source: Cancer Res, 2007 Oct 1;67(19), p. 9024-9.
PMID: 17909004
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Glucuronidation of PhIP and N-OH-PhIP by UDP-glucuronosyltransferase 1A10.
Authors: Dellinger RW, Chen G, Blevins-Primeau AS, Krzeminski J, Amin S, Lazarus P
Source: Carcinogenesis, 2007 Nov;28(11), p. 2412-8.
EPub date: 2007 Jul 17.
PMID: 17638922
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The UDP-glucuronosyltransferase 2B17 gene deletion polymorphism: sex-specific association with urinary 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol glucuronidation phenotype and risk for lung cancer.
Authors: Gallagher CJ, Muscat JE, Hicks AN, Zheng Y, Dyer AM, Chase GA, Richie J, Lazarus P
Source: Cancer Epidemiol Biomarkers Prev, 2007 Apr;16(4), p. 823-8.
PMID: 17416778
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Gender differences relative to smoking behavior and emissions of toxins from mainstream cigarette smoke.
Authors: Melikian AA, Djordjevic MV, Hosey J, Zhang J, Chen S, Zang E, Muscat J, Stellman SD
Source: Nicotine Tob Res, 2007 Mar;9(3), p. 377-87.
PMID: 17365769
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Characterization of tamoxifen and 4-hydroxytamoxifen glucuronidation by human UGT1A4 variants.
Authors: Sun D, Chen G, Dellinger RW, Duncan K, Fang JL, Lazarus P
Source: Breast Cancer Res, 2006;8(4), p. R50.
PMID: 16884532
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Importance of UDP-glucuronosyltransferase 1A10 (UGT1A10) in the detoxification of polycyclic aromatic hydrocarbons: decreased glucuronidative activity of the UGT1A10139Lys isoform.
Authors: Dellinger RW, Fang JL, Chen G, Weinberg R, Lazarus P
Source: Drug Metab Dispos, 2006 Jun;34(6), p. 943-9.
EPub date: 2006 Mar 1.
PMID: 16510539
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Genotype-phenotype correlation between the polymorphic UGT2B17 gene deletion and NNAL glucuronidation activities in human liver microsomes.
Authors: Lazarus P, Zheng Y, Runkle EA, Muscat JE, Wiener D
Source: Pharmacogenet Genomics, 2005 Nov;15(11), p. 769-78.
PMID: 16220109
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An extremely compensatible cigarette by design: documentary evidence on industry awareness and reactions to the Barclay filter design cheating the tar testing system.
Authors: Kozlowski LT, Dreschel NA, Stellman SD, Wilkenfeld J, Weiss EB, Goldberg ME
Source: Tob Control, 2005 Feb;14(1), p. 64-70.
PMID: 15735303
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Enhanced protein glutathiolation and oxidative stress in cigarette smokers.
Authors: Muscat JE, Kleinman W, Colosimo S, Muir A, Lazarus P, Park J, Richie JP Jr
Source: Free Radic Biol Med, 2004 Feb 15;36(4), p. 464-70.
PMID: 14975449
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Correlation between the UDP-glucuronosyltransferase (UGT1A1) TATAA box polymorphism and carcinogen detoxification phenotype: significantly decreased glucuronidating activity against benzo(a)pyrene-7,8-dihydrodiol(-) in liver microsomes from subjects with the UGT1A1*28 variant.
Authors: Fang JL, Lazarus P
Source: Cancer Epidemiol Biomarkers Prev, 2004 Jan;13(1), p. 102-9.
PMID: 14744740
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Characterization of N-glucuronidation of the lung carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) in human liver: importance of UDP-glucuronosyltransferase 1A4.
Authors: Wiener D, Doerge DR, Fang JL, Upadhyaya P, Lazarus P
Source: Drug Metab Dispos, 2004 Jan;32(1), p. 72-9.
PMID: 14709623
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Detection of UGT1A10 polymorphisms and their association with orolaryngeal carcinoma risk.
Authors: Elahi A, Bendaly J, Zheng Z, Muscat JE, Richie JP Jr, Schantz SP, Lazarus P
Source: Cancer, 2003 Aug 15;98(4), p. 872-80.
PMID: 12910533
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Protein glutathiolation in human blood.
Authors: Kleinman WA, Komninou D, Leutzinger Y, Colosimo S, Cox J, Lang CA, Richie JP Jr
Source: Biochem Pharmacol, 2003 Mar 1;65(5), p. 741-6.
PMID: 12628487
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Glucuronidation: an important mechanism for detoxification of benzo[a]pyrene metabolites in aerodigestive tract tissues.
Authors: Zheng Z, Fang JL, Lazarus P
Source: Drug Metab Dispos, 2002 Apr;30(4), p. 397-403.
PMID: 11901093
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Tobacco carcinogen-detoxifying enzyme UGT1A7 and its association with orolaryngeal cancer risk.
Authors: Zheng Z, Park JY, Guillemette C, Schantz SP, Lazarus P
Source: J Natl Cancer Inst, 2001 Sep 19;93(18), p. 1411-8.
PMID: 11562393
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Status of glutathione and other thiols and disulfides in human plasma.
Authors: Kleinman WA, Richie JP Jr
Source: Biochem Pharmacol, 2000 Jul 1;60(1), p. 19-29.
PMID: 10807941
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Role of polymorphisms in codons 143 and 160 of the O6-alkylguanine DNA alkyltransferase gene in lung cancer risk.
Authors: Kaur TB, Travaline JM, Gaughan JP, Richie JP Jr, Stellman SD, Lazarus P
Source: Cancer Epidemiol Biomarkers Prev, 2000 Mar;9(3), p. 339-42.
PMID: 10750675
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Doses of nicotine and lung carcinogens delivered to cigarette smokers.
Authors: Djordjevic MV, Stellman SD, Zang E
Source: J Natl Cancer Inst, 2000 Jan 19;92(2), p. 106-11.
PMID: 10639511
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