Carcinogenesis Advance Access published online on June 29, 2005
Carcinogenesis, doi:10.1093/carcin/bgi171
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1 Department of Gastrointestinal Medical Oncology, The University of Texas, M.D. Anderson Cancer Center, 1515 Holcombe Blvd. Houston, TX 77030
* To whom correspondence should be addressed. To test the hypothesis that genetic variation in the metabolism of tobacco carcinogens, such as aromatic amines (AA) and heterocyclic amines (HCA), contributes to pancreatic cancer, we have examined genetic polymorphisms of three key enzymes, i.e. cytochrome P450 1A2 (CYP1A2) and N-acetyltransferase 1 and 2 (NAT1 and NAT2), in a hospital-based case-control study of 365 patients with pancreatic adenocarcinoma and 379 frequency-matched healthy controls. Genotypes were determined using PCR-restriction fragment length polymorphism (RFLP) and Taqman methods. Smoking information was collected by personal interview. Adjusted odds ratio (AOR) and 95% confidence interval (CI) was estimated by unconditional multivariate logistic regression analysis. We found that the NAT1 "rapid" alleles were associated with a 1.5-fold increased risk of pancreatic cancer (95% CI: 1.0 - 2.1) with adjustment of potential confounders. This effect was more prominent among never smokers (AOR: 2.4, 95% CI: 1.4-4.3) and females (AOR: 1.8, 95% CI: 1.0-3.1). Some genotypes were significantly associated with increased risk for pancreatic cancer among smokers, especially heavy smokers (> 20 pack years). For example, heavy smokers with the CYP1A2*1D (T-2467delT) delT, CYP1A2*1F(A-163C) C allele, NAT1 "rapid" or NAT2 "slow" alleles had an AOR (95% CI) of 1.4 (0.7-2.3), 1.9 (1.1-3.4), 3.0 (1.6-5.4) and 1.5 (0.8-2.6), respectively, compared with never smokers carrying the non at-risk alleles. These effects were more prominent in females than in males. The corresponding AOR (95% CI) was 3.1 (1.0-8.0), 3.8 (1.5-10.1), 4.5 (1.6-12.7), and 2.0 (0.8-5.1) for females versus 1.0 (0.4-1.9), 1.1 (0.5-2.4), 2.1 (1.0-4.6) and 1.1 (0.5-2.6) for males. A significant synergistic effect of CYP1A2*1F C allele and NAT1" rapid" alleles on the risk for pancreatic cancer was also detected among never smokers (AOR: 2.9, 95% CI: 1.2-6.9) and among females (AOR: 2.5, 95% CI: 1.1-5.7). These data suggest that polymorphisms of the CYP1A2 and NAT1 genes modify the risk of pancreatic cancer. 1 Supported by National Institutes of Health (NIH) grants CA98380 (to D.L.) and CA34627 (to D.W.H.), National Institute of Environmental Health Sciences center grant P30 ES07784, NIH cancer center core grant CA16672, and a research grant from The University of Texas M. D. Anderson Cancer Center.
Received April 7, 2005
Revised June 16, 2005
Accepted June 21, 2005
MOLECULAR EPIDEMIOLOGY AND CANCER PREVENTION
Polymorphisms of cytochrome P4501A2 and N-acetyltransferase genes, smoking, and risk of pancreatic cancer1
2 Department of Pharmacology and Toxicology and Brown Cancer Center, University of Louisville School of Medicine, Louisville, KY 40292
3 Department of Epidemiology, The University of Texas, M.D. Anderson Cancer Center, 1515 Holcombe Blvd. Houston, TX 77030
4 Department of Surgical Oncology, The University of Texas, M.D. Anderson Cancer Center, 1515 Holcombe Blvd. Houston, TX 77030
Donghui Li, E-mail: dli{at}mdanderson.org
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