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Int J Mol Epidemiol Genet 2010;1(1):295-309.
Original Article
Interaction of CYP1B1, cigarette-smoke carcinogen metabolism, and lung
cancer risk
Timothy R. Church, Majda Haznadar, Mindy S. Geisser, Kristin E. Anderson, Neil E. Caporaso, Chap Le, Salwan B. Abdullah,
Stephen S. Hecht, Martin M. Oken, Brian Van Ness
Divisions of Environmental Health Sciences, Epidemiology and Community Health, and Biostatistics, University of Minnesota
School of Public Health, Institute of Human Genetics, Masonic Cancer Center, University of Minnesota, and Division of
Hematology and Oncology, Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, USA; and
Genetic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland,
USA.
Received May 26, 2010; accepted August 1, 2010; available online August 5, 2010
Abstract: A previously published case-control study nested in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening
Trial found a significant relationship of serum levels of total NNAL (4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol and its
glucuronides) to prospective lung cancer risk. The present paper examines this relationship in the context of single-nucleotide
polymorphisms (SNPs) in genes important in the metabolism of tobacco smoke carcinogens. DNA was extracted from the
subjects’ lymphocytes and analyzed for SNPs in 11 locations on four genes related to tobacco carcinogen metabolism. Logistic
regressions on case-control status were used to estimate main effects of SNPs and biomarkers and their interactions
adjusting for potential confounders. Of the 11 SNPs, only one, in CYP1B1, significantly interacted with total NNAL affecting risk
for lung cancer. At low NNAL levels, the variant appeared protective. However, for those with the minor variant, the risk for lung
cancer increased with increasing NNAL five times as rapidly compared to those without it, so that at high NNAL levels, this SNP’
s protection disappears. Analyzing only adenocarcinomas, the effect of the variant was even stronger, with the risk of cancer
increasing six times as fast. A common polymorphism of CYP1B1 may play a role in the risk of NNK, a powerful lung
carcinogen, in the development of lung cancer in smokers. (IJMEG1005002).
Keywords: Smoking, biomarkers, single nucleotide polymorphism, SNP, genetics
Full Text PDF
Address all correspondence to:
Timothy R. Church
420 Delaware Street Southeast
Room 1260, MMC 807
Minneapolis, Minnesota 55455
Tel: 612-625-9091, Fax: 612-624-3370
E-mail: trc@cccs.umn.edu
and
Majda Haznadar
Genetics and Cell Development
Room 6-160 JacH
321 Church St SE
Minneapolis, MN 55455
Tel: 612-624-9663, Fax: 612-624-4294
E-mail: hazna001@umn.edu
Original Article
Interaction of CYP1B1, cigarette-smoke carcinogen metabolism, and lung
cancer risk
Timothy R. Church, Majda Haznadar, Mindy S. Geisser, Kristin E. Anderson, Neil E. Caporaso, Chap Le, Salwan B. Abdullah,
Stephen S. Hecht, Martin M. Oken, Brian Van Ness
Divisions of Environmental Health Sciences, Epidemiology and Community Health, and Biostatistics, University of Minnesota
School of Public Health, Institute of Human Genetics, Masonic Cancer Center, University of Minnesota, and Division of
Hematology and Oncology, Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, USA; and
Genetic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland,
USA.
Received May 26, 2010; accepted August 1, 2010; available online August 5, 2010
Abstract: A previously published case-control study nested in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening
Trial found a significant relationship of serum levels of total NNAL (4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol and its
glucuronides) to prospective lung cancer risk. The present paper examines this relationship in the context of single-nucleotide
polymorphisms (SNPs) in genes important in the metabolism of tobacco smoke carcinogens. DNA was extracted from the
subjects’ lymphocytes and analyzed for SNPs in 11 locations on four genes related to tobacco carcinogen metabolism. Logistic
regressions on case-control status were used to estimate main effects of SNPs and biomarkers and their interactions
adjusting for potential confounders. Of the 11 SNPs, only one, in CYP1B1, significantly interacted with total NNAL affecting risk
for lung cancer. At low NNAL levels, the variant appeared protective. However, for those with the minor variant, the risk for lung
cancer increased with increasing NNAL five times as rapidly compared to those without it, so that at high NNAL levels, this SNP’
s protection disappears. Analyzing only adenocarcinomas, the effect of the variant was even stronger, with the risk of cancer
increasing six times as fast. A common polymorphism of CYP1B1 may play a role in the risk of NNK, a powerful lung
carcinogen, in the development of lung cancer in smokers. (IJMEG1005002).
Keywords: Smoking, biomarkers, single nucleotide polymorphism, SNP, genetics
Full Text PDF
Address all correspondence to:
Timothy R. Church
420 Delaware Street Southeast
Room 1260, MMC 807
Minneapolis, Minnesota 55455
Tel: 612-625-9091, Fax: 612-624-3370
E-mail: trc@cccs.umn.edu
and
Majda Haznadar
Genetics and Cell Development
Room 6-160 JacH
321 Church St SE
Minneapolis, MN 55455
Tel: 612-624-9663, Fax: 612-624-4294
E-mail: hazna001@umn.edu
