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Clinical Cancer Research 13, 2526-2532, April 15, 2007. doi: 10.1158/1078-0432.CCR-06-2293
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Cancer Prevention

Polymorphisms of MTHFD, Plasma Homocysteine Levels, and Risk of Gastric Cancer in a High-Risk Chinese Population

Lina Wang1, Qiao Ke1, Wensen Chen1, Jianming Wang2, Yongfei Tan3, Yan Zhou3, Zhaolai Hua2, Weiliang Ding3, Juying Niu1, Jing Shen1, Zuofeng Zhang4, Xinru Wang1, Yaochu Xu1 and Hongbing Shen1

Authors' Affiliations: 1 Department of Epidemiology and Biostatistics, Institute of Toxicology, Nanjing Medical University, Nanjing, China; 2 Yang-zhong Cancer Institute, Yang-zhong City, Jiangsu Province, China; 3 Yi-xing People's Hospital, Yi-xing City, Jiangsu Province, China; and 4 Department of Epidemiology, School of Public Health, University of California, Los Angeles

Requests for reprints: Hongbing Shen, Department of Epidemiology and Biostatistics, Nanjing Medical University, 140 Hanzhong Road, Nanjing 210029, China. Phone: 86-25-868-62756; Fax: 86-25-868-62756; E-mail: hbshen{at}njmu.edu.cn.


   Abstract
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Materials and Methods
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Purpose: Accumulative evidence suggests that folate has a protective effect on gastric cancer. The methylenetetrahydrofolate dehydrogenase (MTHFD) plays an important role in folate and homocysteine metabolisms, and polymorphisms of MTHFD may result in disturbance of the folate-mediated homocysteine pathway. The aim of this study is to test the hypothesis that genetic variants of MTHFD and plasma homocysteine levels are associated with risk of gastric cancer and modulated by genotypes of methylenetetrahydrofolate reductase (MTHFR).

Experimental Design: We genotyped G1958A and T401C in MTHFD and C677T in MTHFR and detected total plasma homocysteine (tHcy) levels in a case-control study of 589 gastric cancer cases and 635 cancer-free controls in a high-risk Chinese population.

Results: The variant genotypes of MTHFD 1958AA and 401CC were associated with a significantly increased risk of gastric cancer [adjusted odds ratio (OR), 2.05; 95% confidence interval (95% CI), 1.34-3.13 for 1958AA; adjusted OR, 1.43; 95% CI, 1.14-1.80 for 401CC] compared with 1958GG/GA and 401TT/TC genotypes, respectively. Both of the effects were more evident in the subjects carrying MTHFR 677CT/TT genotypes. The average tHcy level was significantly higher in gastric cancer cases than in controls (P < 0.01), and the upper quartile of tHcy (>13.6 µmol/L) was associated with an 82% significantly increased risk of gastric cancer, compared with the lowest quartile of tHcy (≤8.0 µmol/L; adjusted OR, 1.82; 95% CI, 1.20-2.75).

Conclusions: The strong associations between MTHFD variants and the plasma tHcy levels and gastric cancer risk suggest, for the first time, a possible gene-environment interaction between genetic variants of folate-metabolizing genes and high tHcy levels in gastric carcinogenesis.

Gastric cancer remains the second most common cause of cancer-related deaths in the world (1, 2). It was estimated that 933,937 gastric cancer cases occurred worldwide and 392,938 cases (42%) in China in 2002 (3). The crude mortality rate of gastric cancer in China was 25.2 per 100,000, which accounted for almost one fourth of total cancer deaths during 1990 to 1992 (4). Epidemiologic studies have shown that less consumption of vegetables and fruits is associated with increased risk of gastric cancer (5, 6). Folate is one of the important constituents in fruits and vegetables, and low folate intake has been associated with an increased risk for a number of gastrointestinal cancers (7), including gastric cancer (8). Recently, two intervention studies provided strong evidence on the chemopreventive effect of folic acid on gastric cancer in both animal models (9) and human population (10).

Folic acid is essential for both the synthesis of nucleotide precursors of DNA and cellular methylation reactions and is therefore associated with gastric cancer risk. The genes that code for the enzymes involved in the folate metabolism pathway (e.g., 5,10-methylenetetrahydrofolate reductase, MTHFR) are obvious candidates for screening the genetic variants associated with gastric cancer. These important enzymes include MTHFR, thymidylate synthase (TS), methionine synthase reductase (MTRR), and methylenetetrahydrofolate dehydrogenase (MTHFD). MTHFR plays an important role in folate metabolism by catalyzing the reduction of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, which acts as a methyl group donor (11). The functional C677T polymorphism of the MTHFR (12) is associated with significantly lower folate levels in plasma and RBC (13, 14) and is associated consistently with increased risk of gastric cancer in different populations (15, 16). In addition, studies have shown that single nucleotide polymorphisms of TS and MTRR were also associated with gastric cancer in both Chinese (17–19) and Italian populations (20).

MTHFD is localized in chromosome 14 (14q24) and has coding domains with catalytic activities, which plays an indirect role in folate and homocysteine metabolism by providing some of the 5,10-methylenetetrahydrofolate pool (21). Examination of the primary structure of this protein revealed mutations in key residues required for dehydrogenase and cyclohydrolase activities (22). This monofunctional synthetase completes the pathway for the production of formate from formyltetrahydrofolate in the mitochondria in the model of mammalian one-carbon folate metabolism in embryonic and transformed cells (22). It has been reported that MTHFD single nucleotide polymorphisms were associated with serum folic acid and homocysteine levels in congenital heart disease families (23, 24), indicating its important roles in folate and homocysteine metabolism pathway.

Several potentially functional single nucleotide polymorphisms of MTHFD including G1958A [R653Q] (21) and T401C [R134K] (25) were identified from public databases and literature. The MTHFD G1958A polymorphism may result in disturbance of the folate-mediated homocysteine pathway and therefore may alter folate or homocysteine levels (23, 26). These two polymorphisms have been widely studied in birth defects in humans (23, 25, 27), and several studies were conducted in the associations between MTHFD polymorphisms and risk of breast cancer (28), colorectal cancer (29), and methotrexate sensitivity on acute lymphoblastic leukemia (30, 31). However, none have been conducted on gastric cancer.

In the present study, we hypothesized that genetic variants of MTHFD (G1958A and T401C) and plasma total homocysteine (tHcy) levels are associated with altered risk of gastric cancer and modulated by MTHFR genotypes. To test this hypothesis, we did genotyping analyses for these two single nucleotide polymorphisms of MTHFD as well as C677T of MTHFR in 589 gastric cancer patients and 635 frequency-matched cancer-free controls and measured plasma tHcy levels in those subjects with plasma available (306 gastric cancer cases and 615 controls) in a high-risk Chinese population. For MTHFR genotypes, because we previously found that the MTHFR C677T but not A1298C was associated with increased risk of gastric cancer, and because C677T was in close linkage disequilibrium with A1298C (15), therefore, we only genotyped MTHFR C677T in this study population.


   Materials and Methods
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Study population. This population-based case-control study consisted a total of 675 gastric cancer patients and 704 cancer-free population controls, which was approved by the institutional review board of Nanjing Medical University. The gastric cancer cases were consecutively recruited between January 2003 and July 2005 from Yang-Zhong and Yi-Xing, counties of high gastroesophageal cancer mortality, in Jiangsu Province, People's Republic of China. All the gastric cancer cases that consented to participate in the study and provided blood samples were newly identified incident patients and were histopathologically diagnosed with gastric adenocarcinoma, with a response rate of 89.4% (675 of 755). The population controls were selected from cancer-free individuals living in the same residential areas as the cases and were frequency matched to the cases on age (±5 years) and sex, and the response rate was 84.8% (704 of 830). Trained interviewers used a pre-tested questionnaire to determine demographic and lifestyle characteristics, such as sex, age, and related factors, including tobacco smoking, alcohol drinking, etc. After the interview, ~5-mL venous blood sample was collected from each subject, and the blood samples from the cases were taken as soon as the patients were diagnosed. Individuals that smoked once a day for over 1 year were defined as smokers, and those who consumed three or more alcoholic drinks per week for over 6 months were considered drinkers.

Laboratory assays. Genomic DNA was isolated from leucocytes of venous blood by proteinase K digestion followed by phenol-chloroform extraction and ethanol precipitation. The PCR-RFLP assay was used to detect MTHFD G1958A and T401C polymorphisms. In brief, the primers of the G1958A polymorphism were 5'-CATTCCAATGTCTGCTCCAA-3' (forward) and 5'-GTTTCCACAGGGCACTCC-3' (reverse), which generated the 254-bp fragment. The primers of the T401C polymorphism were 5'-GGCGTACAAGGAATGAAAC-3' (forward) and 5'-GGATGTGGATGGGTAAGTG-3' (reverse), which generated the 225-bp fragment. The 20-µL PCR mixture contained ~50 ng of genomic DNA, 12.5 pmol of each primer, 0.1 mmol/L each deoxynucleotide triphosphate, 1x PCR buffer (50 mmol/L KCl, 10 mmol/L Tris-HCl, and 0.1% Triton X-100), 1.5 mmol/L MgCl2, and 1.0 unit of Taq polymerase. The PCR profile for the G1958A polymorphism consisted of an initial melting step of 95°C for 5 min; 35 cycles of 95°C for 30 s, 57°C for 40 s, and 72°C for 40 s; and a final extension step of 72°C for 10 min. As for the T401C polymorphism, a similar PCR profile with an annealing temperature of 48°C was used. The two fragments were then digested by HpaII and BsmAI (New England BioLabs, Beverly, MA), respectively. For the G1958A variant, the expected fragment sizes were 170 and 84 bp for the HpaII restriction site. For the T401C variant, the 401T allele produced two fragments of 180 and 45 bp, and the 401C allele produced three fragments of 131, 49, and 45 bp digested by BsmAI. Both digestion products were separated on a 3% agarose gel at 80 V for 40 min and stained with ethidium bromide. Genotyping failed for the two loci in 86 cases (12.7%) and 69 controls (9.8%) due to DNA quality or quantity, and these samples were excluded in further analyses. Therefore, 589 gastric cancer cases and 635 controls were included in the final genotyping analyses.

Genotyping was done without knowing the subjects' case and control status, and approximately equal numbers of cases and controls were assayed in each 96-well PCR plate with a positive control of a DNA sample with known heterozygous genotype. If a consensus on the tested genotype was not reached, two research assistants independently did the repeated assays to achieve 100% concordance. The PCR-RFLP assay was also used to genotype the MTHFR C677T polymorphism as we previously reported (15).

Among the recruited subjects, we had plasma samples available with good quality for 306 gastric cancer cases and 615 controls, and we then detected plasma tHcy concentrations for these subjects. The plasma tHcy concentration was measured with enzymatic biochemical assay of homocysteine on microtiter plates using crude lysate containing recombinant methionine {gamma}-lyase (32) according to the manufacturer's instructions (Jei Daniel Biotech Co. Ltd., Taiwan, China).

Statistical analyses. Differences in demographic characteristics, selected variables, frequencies of the genotypes of MTHFD polymorphisms, and plasma tHcy levels between the cases and controls were evaluated using the {chi}2 or Student's t test. The associations between the G1958A and T401C genotypes and risk of gastric cancer were estimated by estimating adjusted odds ratios (OR) and their 95% confidence intervals (95% CI) from logistic regression analyses, with the adjustment for age, sex, cigarette smoking, and alcohol drinking. Dummy variables of the quartile of plasma tHcy levels were created to calculate the ORs and 95% CIs (with the lowest quartile as the reference category) as an estimate of the relative risk in the logistic regression analyses. The Hardy-Weinberg equilibrium was tested by a goodness-of-fit {chi}2 test to compare the observed genotype frequencies with the expected ones among control subjects. Linkage disequilibrium was estimated using the EM algorithm available online.5 All of the statistical analyses were done with Statistical Analysis System software (v.9.1.3e; SAS Institute, Cary, NC).


   Results
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 Materials and Methods
 Results
Discussion
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Characteristics of the study population. Selected characteristics of the 589 gastric cancer cases and 635 cancer-free controls are summarized in Table 1 . The frequency matching on age and sex between the cases and controls was adequate as suggested by the {chi}2 test. As indicated in Table 1, the mean age was 60.6 ± 9.4 years for cases and 59.8 ± 10.3 years for controls (P = 0.126). There were slightly more men in the cases (68.4%) than in the controls (66.6%; P = 0.503). In addition, there were significantly more alcohol drinkers among the gastric cancer cases than among the controls (P = 0.043), but no difference for smokers was found between the two groups (P = 0.907). The mean level of plasma tHcy of gastric cancer cases was significantly higher than that of controls (P = 0.003), and there were significantly more cases than controls with low amount of tHcy (≤15.0 µmol/L; P = 0.005; Table 1).


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  		Table 1. Distributions of selected variables in gastric cancer cases and cancer-free controls

 
Associations among MTHFD polymorphisms, tHcy levels, and risk of gastric cancer. The MTHFD G1958A and T401C genotype distributions in the cases and controls are shown in Table 2 . The genotype frequencies of the MTHFD G1958A polymorphism among the cases were 57.9%, 30.7%, and 11.4% for the 1958GG, GC, and AA genotypes, respectively (58.6%, 35.7%, and 5.7% among the controls, respectively). The overall difference was statistically significant (P = 0.001). Similarly, the frequency of MTHFD 401TT, CT, and CC genotypes were 10.5%, 44.5%, and 45.0% among the gastric cancer cases and 15.0%, 49.0%, and 36.0% among the controls, respectively; the overall difference was also statistically significant (P = 0.002). The observed genotype frequencies for these two polymorphisms were in Hardy-Weinberg equilibrium in the controls (P = 0.859 for the G1958A and P = 0.526 for the T401C), and linkage disequilibrium analyses showed that the G1958A and T401C loci of MTHFD were not in linkage disequilibrium (D' = 0.380, r2 = 0.027).


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  		Table 2. Logistic regression analyses of associations between MTHFD G1958A T401C polymorphisms and plasma tHcy levels and risk of gastric cancer

 
Logistic regression analyses revealed that the MTHFD 1958AA variant genotype instead of the 1958GA heterozygote was associated with a significantly increased risk of gastric cancer (adjusted OR, 1.93; 95% CI, 1.25-2.98 for 1958AA and adjusted OR, 0.85; 95% CI, 0.67-1.09 for 1958GA, respectively), compared with the 1958GG wild-type homozygote (Table 2). In the recessive model, the 1958AA variant homozygote was associated with a 2.05-fold significantly increased risk of gastric cancer compared with the 1958GG/GA genotypes (adjusted OR, 2.05; 95% CI, 1.34-3.13). Similarly, for the MTHFD T401C polymorphism, the 401CC genotype was associated with a significantly increased risk of gastric cancer (adjusted OR, 1.74; 95% CI, 1.21-2.52) compared with the 401TT genotype, whereas the 401CT heterozygote was not associated with a significantly increased risk (adjusted OR, 1.28; 95% CI, 0.90-1.85). This effect was also evident in the recessive model, and the 401CC genotype was associated with a 43% increased risk of gastric cancer compared with 401TT/CT genotypes (adjusted OR, 1.43; 95% CI, 1.14-1.80).

The associations between plasma tHcy levels and risk of gastric cancer were also evaluated by unconditional logistic regression analyses. As shown in Table 2, when the control median tHcy level (10.2 µmol/L) was used as the cutoff value for calculating the ORs, 58.2% (178 of 306) of the cases were above this median level. The plasma tHcy level above the control median level was associated with a 35% increased risk of gastric cancer after adjustment for age, sex, smoking status, and alcohol consumption (adjusted OR, 1.35; 95% CI, 1.02-1.79). In addition, when the control quartiles of tHcy were used to categorize risk, a significant dose-response relationship between increasing plasma tHcy and elevated risk of gastric cancer was evident (OR, 1.50, 1.55, and 1.82 for the second, third, and fourth quartiles of tHcy, respectively; Ptrend < 0.01) after adjustment for the same variables above (Table 2).

In the stratification analyses between the two variants and gastric cancer, the MTHFD 1958AA genotype was associated with a 2.6-fold significantly increased risk of gastric cancer among subjects carrying the 401TT/CT genotype (adjusted OR, 2.60; 95% CI, 1.34-5.02) compared with subjects with the 1958GG/GA genotype. Meanwhile, we found that among the subgroup carrying MTHFR variant genotypes 677CT/TT, the MTHFD 1958AA genotype was associated with a more significantly increased risk of gastric cancer compared with the 1958GG/AA genotypes (adjusted OR, 2.20; 95% CI, 1.27-3.82), and the MTHFD 401CC genotype was associated with a 48% increased risk of gastric cancer compared with 401TT/TC genotypes (adjusted OR, 1.48; 95% CI, 1.12-1.97; Table 3 ).


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  		Table 3. Stratified analyses between MTHFD G1958A T401C polymorphisms and gastric cancer risk by MTHFD T401C and MTHFR C677T genotypes

 
Stratification analyses of MTHFD G1958A and T401C polymorphisms and risk of gastric cancer. Further stratification analyses based on the recessive models are shown in Table 4 . A significantly increased risk of gastric cancer associated with the MTHFD 1958AA genotype was evident among men (adjusted OR, 2.40; 95% CI, 1.44-3.97), subjects ages 60 years and older (adjusted OR, 2.23; 95% CI, 1.26-3.94), smokers (adjusted OR, 3.16; 95% CI, 1.61-6.21), and nondrinkers (adjusted OR, 2.34; 95% CI, 1.39-3.95), compared with the 1958GG/GA genotype. For the T401C variant, the risk effects of 401CC versus 401TT/CT were significant in men (adjusted OR, 1.54; 95% CI, 1.16-2.04), smokers (adjusted OR, 1.59; 95% CI, 1.10-2.31), nondrinkers (adjusted OR, 1.35; 95% CI, 1.01-1.80), and relatively younger subjects (<60 years; adjusted OR, 1.54; 95% CI, 1.09-2.19). Interestingly, in the subgroup with high plasma tHcy levels, the 401CC genotype was associated with an 84% increased risk of gastric cancer compared with 401TT/TC genotypes (adjusted OR, 1.84; 95% CI, 1.00-3.40).


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  		Table 4. Stratified analyses between MTHFD G1958A and T401C polymorphisms and gastric cancer risk by sex, age, smoking status, alcohol consumption, Helicobacter pylori infection status, and plasma tHcy level

 

   Discussion
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 Abstract
 Materials and Methods
 Results
 Discussion
References
 
In this population-based case-control study, we investigated the associations between MTHFD G1958A and T401C polymorphisms and plasma tHcy levels and gastric cancer risk in a high-risk Chinese population. We found that the variant genotypes of MTHFD 1958AA and 401CC were associated with a significantly increased risk of gastric cancer compared with their wild-type genotypes, respectively. In addition, the 1958AA genotype was significantly associated with a 2.6-fold increased risk of gastric cancer in subjects carrying 401TT/CT genotypes. The associations between MTHFD 1958AA and 401TT and risk of gastric cancer were more evident in the subjects carrying MTHFR 677CT/TT variant genotypes. Furthermore, the average plasma tHcy level was significantly higher in gastric cancer cases than in controls (P < 0.01). These findings support our hypothesis that these two polymorphisms in MTHFD genes may play a role in the etiology of gastric carcinogenesis and modulate the risk of gastric cancer associated with folate and homocysteine metabolism.

A number of epidemiologic studies, including those conducted in China, have consistently indicated an inverse association between the consumption of vegetables and fruits, major sources of folate, and risk of gastroesophageal cancers (33, 34). Genes involved in the folate metabolism pathway were investigated as candidates for the associations between genetic polymorphisms and susceptibility to gastric cancer. For example, MTHFR was a critical enzyme for intracellular folate homeostasis and metabolism. The MTHFR C677T polymorphism, resulting in a "thermolabile" variant of the enzyme (35), was associated with an increased risk of hyperhomocysteinemia and lower levels of folate in plasma and RBC (14). A recent meta-analysis of MTHFR C677T variant and risk of gastric cancer provided a consistent view on the effect of this variant on gastric carcinogenesis (36). In addition to MTHFR, TS and reduced folate carrier (RFC1) genes also showed significant associations with gastric cancer as previously reported (15, 18, 37).

MTHFD is one of the important enzymes that are involved in folate metabolism, which is a reverse process of MTHFR, and was extensively studied in birth defects (25). The MTHFD protein is far removed from the region providing for the methenyltetrahydrofolate cyclohydrolase and MTHFD activities (38). The G1958A polymorphism lies in the 10-formyltetrahydrofolate synthetase domain of MTHFD. This residue is also an arginine in rats, mice, and some fungal orthologues, but it is a lysine in other species (including numerous prokaryotes, insects, plants, and fungi). This cross-kingdom conservation suggests that the replacement of this amino acid by a glutamine may have direct functional consequences. It has been shown that this amino acid substitution was associated with serum folic acid and homocysteine levels in congenital heart disease families (23, 24). The MTHFD T401C lies within the dehydrogenase/cyclohydrolase domain of the enzyme, but this arginine residue is not conserved in other species and is a lysine in rats and a glutamic acid in yeast (25). The MTHFD G1958A and T401C may result in disturbance of the folate-mediated homocysteine pathway together with MTHFR C677T; therefore, they may be functional in carcinogenesis.

Stratified analyses in this study indicated that the significantly increased risk of gastric cancer associated with MTHFD 1958AA or 401CC genotypes was more evident among men, smokers, nondrinkers, and individuals with high plasma tHcy levels; however, we did not find any evidence for significant interactions between MTHFD polymorphisms and these risk factors. The associations from subgroups might suggest a potential joint effect between the established risk factors and genetic polymorphisms. Another possibility is that the results from the stratification analyses were due to chance because of the type I error related to the small sample size in the subgroups.

Accumulative evidences suggest that hyperhomocysteinemia (elevated tHcy in blood circulation) might be a risk factor for carcinogenesis (39, 40). Several studies reported that hyperhomocysteinemia were associated with increased risk of cervical (41), lung (42), head and neck squamous cell carcinoma (43), and acute lymphoblastic leukemia (44), but not with colorectal cancer (45). In the present study, we also showed that high plasma tHcy was associated with significantly increased risk of gastric cancer in this high-risk Chinese population. The mean level of plasma tHcy of Chinese controls in our study was 11.5 ± 6.2 µmol/L, which was very close to that of the subjects from Northern Sweden (11.4 [9.6-13.8] µmol/L; ref. 45), lower than that of Finlanders (13.4 ± 7.0 µmol/L; ref. 42), and slightly higher than that of Turkey population (10.45 ± 5.67 µmol/L; ref. 46). In addition, we also found that the risk effect associated with MTHFD 401CC genotype was significantly more evident in the subjects with high plasma tHcy levels, suggesting that polymorphisms of MTHFD may modulate the folate and homocysteine metabolisms.

In conclusion, we observed, for the first time, that the MTHFD G1958A and T401C polymorphisms and high plasma tHcy levels were strongly associated with risk of gastric cancer in a high-risk Chinese population. However, the primary shortcoming of this study is the lack of data on detailed dietary intake of folate and direct plasma or erythrocyte folate levels, although the plasma tHcy levels may partially represent the dietary intake of folate. Because the effect of genetic variations in folate metabolic genes on cancer risk depends on folate intake status, our study might underestimate the risk of the presence of low dietary folate intake and could not evaluate possible gene-nutrient interactions (47, 48). Larger studies incorporating information on dietary folate intake and other potential exposure variables are needed to verify these findings, in which potential gene-gene and gene-environmental interactions on gastric cancer risk could be further examined.


   Footnotes
 
Grant support: National Natural Science Foundation of China grants 30671814 and 30571605 and Jiangsu Natural Science Foundation grant BK2005143.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

5 http://linkage.rockefeller.edu/soft Back

Received 9/14/06; revised 1/21/07; accepted 1/26/07.


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L Peyrin-Biroulet, J.-L. Gueant, A M C Rocha, G A Rocha, M C A Marino, and D M M Queiroz
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