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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 ( approximately 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.

Angiogenesis is an essential process in the development, growth, and metastasis of malignant tumors including lung cancer. DNA sequence variations in the vascular endothelial growth factor (VEGF) gene may lead to altered VEGF production and/or activity, thereby causing interindividual differences in the susceptibility to lung cancer via their actions on the pathways of tumor angiogenesis. To test this hypothesis, we investigated the potential association between three VEGF polymorphisms (À À460T > C, +405C > G, and 936C > T)/haplotypes and the risk of lung cancer in a Korean population. VEGF genotypes were determined in 432 lung cancer patients and 432 healthy controls that were frequency matched for age and sex. VEGF haplotypes were predicted using Bayesian algorithm in the phase program. Compared with the combined +405 CC and CG genotype, the +405 GG genotype found associated with a significantly decreased risk of small cell carcinoma [SCC; adjusted odds ratio (OR), 0.36; 95% confidence interval (95% CI), 0.17-0.78]. The 936 CT genotype and the combined 936 CT and TT genotype were also associated with a significantly decreased risk of SCC compared with the 936 CC genotype (adjusted OR, 0.47; 95% CI, 0.26-0.85 and adjusted OR, 0.44; 95% CI, 0.24-0.80, respectively). Haplotype CGT was associated with a significantly decreased risk of SCC (adjusted OR, 0.39; 95% CI, 0.18-0.87), whereas haplotype TCC conferred a significantly increased risk of SCC (adjusted OR, 1.63; 95% CI, 1.14-2.33). None of the VEGF polymorphisms studied significantly influenced the susceptibility to lung cancer except SCC. However, haplotypes TCT and TGT were significantly associated with the risk of overall lung cancer, respectively (adjusted OR, 0.38; 95% CI, 0.25-0.60 and adjusted OR, 3.94; 95% CI, 2.00-7.76, respectively). These effects of haplotypes TCT and TGT on lung cancer risk were observed in three major histologic types of lung cancer. These results suggest that the VEGF gene may be contribute to an inherited predisposition to lung cancer.

DNA repair plays a critical role in protecting the genome from insults of cancer-causing agents, such as those found in tobacco smoke. Therefore, reduced DNA repair capacity can increase the susceptibility to smoking-related cancers. Recently, several polymorphisms have been identified in the xeroderma pigmentosum group G (XPG) gene, and it is possible that these polymorphisms may affect the DNA repair capacity, thereby modulating cancer susceptibility. We investigated the relationship between the His1104Asp polymorphism in the XPG gene and the risk of lung cancer. The study population consisted of 310 lung cancer patients and 311 healthy controls who were frequency (1:1) matched based on age and sex. The Asp/Asp genotype was more frequent in the controls (28.9%) than in the cases (18.7%) and associated with a significantly decreased risk of lung cancer [adjusted odds ratio (OR) = 0.54, 95% confidence interval (CI) = 0.37-0.80] when the combined His/His and His/Asp genotype was used as the reference. The protective effect of the Asp/Asp genotype against lung cancer was statistically significant in the older subjects (adjusted OR = 0.51, 95% CI = 0.37-0.80), males (adjusted OR = 0.54, 95% CI = 0.35-0.83), and lighter smokers (adjusted OR = 0.48, 95% CI = 0.25-0.94) in a stratification analysis. When the lung cancers were analyzed by histologic type, the Asp/Asp genotype was associated with a significantly decreased risk of squamous cell carcinoma (adjusted OR = 0.55, 95% CI = 0.34-0.88) and small cell lung cancer (adjusted OR = 0.44, 95% CI = 0.20-0.97), but non-significant decreased risk of adenocarcinoma (adjusted OR = 0.64, 95% CI = 0.36-1.12). These results suggest that the XPG codon 1104 polymorphism contributes to genetic susceptibility to lung cancer.

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