Carcinogenesis Advance Access originally published online on November 4, 2004
Carcinogenesis 2005 26(2):403-409; doi:10.1093/carcin/bgh307
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Carcinogenesis vol.26 no.2 © Oxford University Press 2005; all rights reserved.
ARTICLE |
DNMT3B polymorphisms and risk of primary lung cancer
1 Cancer Research Institute, Kyungpook National University Hospital, Samduk 2Ga 50, Daegu, 700-412, Korea, 2 Department of Biochemistry and 3 Department of Internal Medicine, School of Medicine, Kyungpook National University, Dong In 2Ga 101, Daegu, 700-422, Korea, 4 Health Promotion Research Center, Kyungpook National University, Dong In 2Ga 101, Daegu, 700-422, Korea, 5 Department of Preventive Medicine, School of Medicine, Kyungpook National University, Dong In 2Ga 101, Daegu, 700-422, Korea and 6 Department of Obstetrics and Gynecology, School of Medicine, Kyungpook National University, Dong In 2Ga 101, Daegu, 700-422, Korea
7 To whom correspondence should be addressed Email: jaeyong{at}kyungpook.ac.kr
DNA-methyltransferase-3B (DNMT3B) plays an important role in the generation of aberrant methylation in carcinogenesis. Polymorphisms and haplotypes of the DNMT3B gene may influence DNMT3B activity on DNA methylation, thereby modulating the susceptibility to lung cancer. To test this hypothesis, we investigated the association of the –283T > C (from exon 1A transcription start site) and –579G > T (from exon 1B transcription start site) polymorphisms in DNMT3B promoter, and their haplotypes with the risk of lung cancer in a Korean population. The DNMT3B genotype was determined in 432 lung cancer patients and 432 healthy controls that were frequency-matched for age and sex. Individuals with at least one –283T allele were at a significantly decreased risk of adenocarcinoma (AC) and small cell carcinoma (SM) [adjusted odds ratio (OR) = 0.48, 95% confidence interval (CI) = 0.28–0.82, P = 0.007; and adjusted OR = 0.47, 95% CI = 0.24–0.93, P = 0.03, respectively] compared with those harboring a –283CC genotype. Individuals with at least one –579G allele were also at a significantly decreased risk of AC and SM (adjusted OR = 0.47, 95% CI = 0.28–0.81, P = 0.006; and adjusted OR = 0.51, 95% CI = 0.26–0.99, P = 0.048, respectively) compared with those having a –579TT genotype. The –283T allele was linked with the –579G allele, and haplotype –283T/–579G was associated with a significantly decreased risk of AC (adjusted OR = 0.48, 95% CI = 0.29–0.81, P = 0.006) as compared with haplotype –283C/–579T. In a promoter assay, carriage of the –283T allele showed a significantly lower promoter activity (
50%) compared with the –283C allele (P < 0.001), but the –579G > T polymorphism did not have an affect on the DNMT3B promoter activity. These results suggest that the DNMT3B –283T > C polymorphism influences DNMT3B expression, thus contributing to the genetic susceptibility to lung cancer.
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