Abstract
BackgroundCigarette smoking is an established risk factor of lung cancer development while the current epidemiological evidence is suggestive of an increased lung cancer risk associated with alcohol consumption. Dietary folate, which is present in a wide range of fresh fruits and vegetables, may be a micronutrient that has a beneficial impact on lung carcinogenesis. Methylenetetrahydrofolate reductase (MTHFR) plays a crucial role in regulating folate metabolism, which affects both DNA synthesis/repair and methylation. We examined if smoking or alcohol consumption modify associations between MTHFR polymorphisms and lung cancer risk.MethodsWe evaluated the role of the MTHFR C677T (rs1801133) and A1298C (rs1801131) polymorphisms in a case-control study comprised of 462 lung cancer cases and 379 controls in a Japanese population. Logistic regression was used to assess the adjusted odds ratios (OR) and 95% confidence intervals (95% CI).ResultsThe TT genotype of the C677T polymorphism was significantly associated with an increased risk of lung cancer (OR = 2.27, 95% CI = 1.42 - 3.62, P < 0.01) while the A1298C polymorphism was not associated with lung cancer risk. The minor alleles of both polymorphisms behaved in a recessive fashion. The highest risks were seen for 677TT-carriers with a history of smoking or excessive drinking (OR = 6.16, 95% CI = 3.48 - 10.9 for smoking; OR = 3.09, 95% CI = 1.64 - 5.81 for drinking) compared with C-carriers without a history of smoking or excessive drinking, but no interactions were seen. The 1298CC genotype was only associated with increased risk among non-smokers (P < 0.05), and smoking was only associated with increased risks among 1298A-carriers (P < 0.01), but no significant interaction was seen. There was a synergistic interaction between the A1298C polymorphism and drinking (P < 0.05). The highest risk was seen for the CC-carriers with excessive drinking (OR = 7.24, 95% CI = 1.89 - 27.7) compared with the A-carriers without excessive drinking).ConclusionsThe C677T polymorphism was significantly associated with lung cancer risk. Although the A1298C polymorphism was not associated with lung cancer risk, a significant interaction with drinking was observed. Future studies incorporating data on folate intake may undoubtedly lead to a more thorough understanding of the role of the MTHFR polymorphisms in lung cancer development.
Highlights
Cigarette smoking is an established risk factor of lung cancer development while the current epidemiological evidence is suggestive of an increased lung cancer risk associated with alcohol consumption
The importance of the Methylenetetrahydrofolate reductase (MTHFR) enzyme in cancer susceptibility arises from its involvement in two pathways of folate metabolism. 5,10-methylene THF is required for DNA synthesis and DNA repair, and 5-methyl THF is the methyl donor for regeneration of methionine from homocysteine for subsequent methylation reactions [11,12]
The TT genotype of the C677T polymorphism was significantly associated with an increased risk of lung cancer compared with the CT (AC) and TT (CC) genotype
Summary
Cigarette smoking is an established risk factor of lung cancer development while the current epidemiological evidence is suggestive of an increased lung cancer risk associated with alcohol consumption. Cigarette smoking is the primary risk factor for lung cancer, approximately one in 10 smokers develops lung cancer in their lifetime indicating an interindividual variation in susceptibility to tobacco smoke [2]. Other factors such as dietary factors may play an important role in the etiology of lung cancer. Candidate susceptibility genes for lung cancer have been extensively studied, with most of the work focusing on mechanistically plausible polymorphisms in genes coding for enzymes involved in the activation, detoxification and repair of damage caused by tobacco smoke. It is probable that the decreased availability of 5-methyl THF for DNA methylation is the crucial mechanism behind the expected increased risk of lung cancer in subjects with the genotypes related to low MTHFR activity
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