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Cancer Epidemiology, Biomarkers & Prevention
Cancer Epidemiology, Biomarkers & Prevention
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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

Carla J. Gallagher, Joshua E. Muscat, Amy N. Hicks, Yan Zheng, Anne-Marie Dyer, Gary A. Chase, John Richie and Philip Lazarus
Carla J. Gallagher
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Joshua E. Muscat
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Amy N. Hicks
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Yan Zheng
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Anne-Marie Dyer
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Gary A. Chase
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John Richie
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Philip Lazarus
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DOI: 10.1158/1055-9965.EPI-06-0823 Published April 2007
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Abstract

4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone is a potent and abundant procarcinogen found in tobacco smoke, and glucuronidation of its major metabolite, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), by UDP-glucuronosyltransferases (UGT) including UGT2B17 is an important mechanism for 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone detoxification. Both copies of the UGT2B17 gene are deleted in ∼10% of Whites and the deletion is associated with a reduction in NNAL glucuronidation activity in vitro. In this study, we examined the effects of the UGT2B17 deletion (0/0) on NNAL glucuronidation rates in a sample of 82 healthy cigarette smokers and further examined its effects on lung cancer risk in a separate case-control study. In the healthy smokers study, a lower urinary ratio of NNAL-glucuronide to NNAL was observed in women with the UGT2B17 deletion (0/0) as compared with women with either the wild-type or heterozygous genotypes (P = 0.058). There were no significant differences in this ratio by genotype in men (P = 0.597). In the case-control study of 398 lung cancer patients and 697 community controls, the UGT2B17 deletion (0/0) was associated with a significant increase in risk of lung cancer in women (odds ratio, 2.0; 95% confidence interval, 1.01-4.0). The risk for the subset of women with lung adenocarcinoma was 2.8 (95% confidence interval, 1.2-6.3). The deletion was not associated with other lung histologic types in women and was not associated with the risk for any lung histologic types in men. The association of the UGT2B17 deletion with increased lung adenocarcinoma in women is consistent with its association with decreased NNAL glucuronidation rates in women and with studies showing that NNAL is a selective inducer of lung adenocarcinoma in experimental animals. (Cancer Epidemiol Biomarkers Prev 2007;16(4):823–8)

  • Polymorphisms in carcinogen metabolism and cancer risk
  • Genotype-phenotype correlations
  • Tobacco
  • Lung cancer

Footnotes

  • ↵3 http://www.ncbi.nlm.nih.gov/BLAST/

  • Grant support: USPHS grants P01-CA68384 (P. Lazarus), R01-DE13158 (P. Lazarus), and K07-CA104231 (J.E. Muscat) from the NIH, and a formula grant under the Pennsylvania Department of Health's Health Research Formula Funding Program (State of PA, Act 2001-77—part of the PA Tobacco Settlement Legislation; P. Lazarus).

  • The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

    • Accepted January 19, 2007.
    • Received October 3, 2006.
    • Revision received December 6, 2006.
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Cancer Epidemiology Biomarkers & Prevention: 16 (4)
April 2007
Volume 16, Issue 4
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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
Carla J. Gallagher, Joshua E. Muscat, Amy N. Hicks, Yan Zheng, Anne-Marie Dyer, Gary A. Chase, John Richie and Philip Lazarus
Cancer Epidemiol Biomarkers Prev April 1 2007 (16) (4) 823-828; DOI: 10.1158/1055-9965.EPI-06-0823

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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
Carla J. Gallagher, Joshua E. Muscat, Amy N. Hicks, Yan Zheng, Anne-Marie Dyer, Gary A. Chase, John Richie and Philip Lazarus
Cancer Epidemiol Biomarkers Prev April 1 2007 (16) (4) 823-828; DOI: 10.1158/1055-9965.EPI-06-0823
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