Polymorphisms in folate metabolic genes and lung cancer risk in Xuan Wei, China
Introduction
Lung cancer is the leading cause of death from cancer worldwide with an estimated mortality of 31.43 for men and 9.53 for women per 100,000 in 2000 [1]. Tobacco smoking is the major attributable risk factor for the high prevalence of lung cancer across the world [2]. The lung cancer mortality rate in rural Xuan Wei County, Yunnan Province, is among the highest in China and is eight times the Chinese national average for women and four times the national average for men [3]. Although few women compared to men smoke in Xuan Wei, the mortality rates from lung cancer are similar between the sexes (27.7 and 25.3 per 100,000 for males and females, respectively). The extensive use of smoky coal indoors without adequate ventilation has been shown to cause the high incidence of lung cancer in this population and accounts for more than 90% of lung cancer cases for both men and women [3], [4]. Local smoky coal is a low-sulfur (0.2%), medium-volatile, bituminous coal and is used for cooking and heating in homes without chimneys [3]. During the burning of smoky coal, the indoor air concentration of particulate matter and extractable organic matter can reach as high as 24.4 and 17.6 mg/m3, respectively [3], and the corresponding concentrations of benzo(a)pyrene, an indicator of PAHs, can reach as high as 19.3 μg/m3 [5], which is comparable to exposure levels experienced by coke oven workers.
Folate, which is unsynthesizable by human cells, is considered to be a potential protective agent against cancer and is one of the components of fruits and vegetables [6]. Although not all epidemiologic studies have agreed [7], [8], accumulating evidence suggests that reduced folate intake is a risk factor for lung cancer [9], [10], [11], [12]. Folate, via its chemically reduced form tetrahydrofolate, is essential for the transfer of one-carbon units in the de novo synthesis of nucleotides. Reduced levels of N5,N10-methylenetetrahydrofolate lead to decreased synthesis of thymidylate from deoxyuridylate and consequently increase uracil misincorporation into DNA [13]. If not properly repaired, the misincorporation of uracil into DNA can cause DNA damage and chromosomal breaks [13]. In addition, folate is essential for maintaining normal DNA methylation patterns. Both global hypomethylation and hypermethylation of select CpG islands are thought to contribute to the pathogenesis of cancer [14]. Hypermethylation of CpG islands in the promoter regions of genes leads to transcriptional silencing, and hypermethylation of tumor suppressor genes and other genes involved in cell cycle control is thought to contribute to carcinogenesis. Several genes, including CDKN2A and MGMT, have been found to be hypermethylated in lung cancer tumors [15], suggesting that DNA methylation plays an important role in the pathogenesis of lung cancer. Through de novo DNA synthesis and methylation, folate is involved in DNA repair and low dietary folate intake was found to be associated with suboptimal DNA repair capacity [16].
Insufficient dietary folate intake is not the only reason for folate depletion. Tissue-specific folate concentration, varying distribution and aberrant function of co-enzymes in folate metabolism may play roles in maintaining the normal physical function of folate. Variants in at least two genes involved in folate metabolism have been shown to be associated with altered DNA methylation patterns [17]. In addition, a common polymorphism in the MTHFR gene, which converts N5,N10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, has been found to lead to decreased enzymatic activity [18] and a shift in the tetrahydrofolate distribution [19]. Other genes involved in the metabolism of folate may also alter the distribution of folate and DNA methylation patterns.
Folate deficiency is a worldwide problem, especially in developing countries where people have less vitamin supplements and fortified food. It is a common but less realized health problem in the Chinese population [20], [21], [22], where the incidence of congenital neural tube defects is among the highest in the world [23], [24]. Lack of adequate folate nutrition is thought to be a problem in Xuan Wei, because unfavorable economic conditions and lack of fresh fruits and vegetables make it difficult for people living in Xuan Wei to obtain good food sources of folate [4]. With reduced levels of folate, differences in folate metabolism could have a dramatic impact on the physiologic roles of folate in the body. Since genetic polymorphisms in folate metabolic genes may modify the ability of folate to protect against lung cancer, we studied the relationship between genetic polymorphisms of 12 folate metabolic genes (23 single nucleotide polymorphisms (SNPs)) and lung cancer risk in Xuan Wei, China.
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Study population
This was a population-based case-control study of lung cancer in Xuan Wei. Details of the study are described elsewhere [25]. A total of 122 newly diagnosed lung cancer cases and 1:1 individually matched controls were selected from March 1995 through March 1996. Matching conditions included sex, age (±2 years), village, and type of fuel currently used for cooking and home heating. The criteria for inclusion as a lung cancer case were positive histology or cytology results (105 cases, 86.1%) or
Results
Demographic features, including age, sex, ethnicity, education level, household income, dwelling type, and type of fuel source, were comparable between 122 case and 122 controls (Table 1). Smoky coal use but not smoking was associated with an increased risk of lung cancer, which is consistent with previous studies in Xuan Wei [28]. Twenty-three SNPs in twelve genes were genotyped in the study population. With the exception of GGH −353G > T (P = 0.01), FPGS Ex15 −260 C > T (P = 0.03), MTHFD2 IVS1 +3323 T
Discussion
Accumulating research results suggest that low levels of folate and elevated homocysteine levels confer increased risk of multiple age-related diseases consistent with its crucial physiological functions [12], [29]. Folate is thought to be important in preventing lung cancer because of its roles in DNA synthesis and DNA methylation and some evidence suggests that the protective effect of folate against lung cancer is more evident in heavy smokers [10], [11], [12]. The folate pathway may be
Conflict of interest
All the authors have not been paid for the work. This article is not in conflict with financial interests of any organization.
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