• Asian Pacific Journal of Cancer Prevention
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• v.15 no.21
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• pp.9259-9264
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• 2014

Background: Previous studies concerning the association between the 5,10-methylenetetrahydrofolate reductase (MTHFR) C677T gene polymorphism with lung cancer in Asian populations have provided inconclusive findings. Aim: A meta-analysis was performed to investigate a more reliable association between MTHFR C677T polymorphism and lung cancer in Asians. Materials and Methods: A comprehensive search was conducted to identify all case-control studies of MTHFR polymorphisms and lung cancer in Asia, using odds ratios (ORs) with 95% confidence intervals (CIs) to assess the strength of any association. Results: Meta-analysis results suggested that the MTHFR C677T polymorphism contributed to an increased lung cancer risk in Asian populations (for T vs C: OR=1.11, 95%CI=1.0-1.23; for CT vs CC: OR= 1.1, 95%CI= 0.95-1.2 ; for TT+CT vs CC: OR=1.13, 95%CI=1.0-1.30; for TT vs CC: OR=1.25, 95%CI=1.01-1.30; for TT vs CT+CC: OR=1.16, 95%CI=1.0-1.36). Conclusions: MTHFR C677T polymorphism is significantly associated with lung cancer in Asians.

• Journal of Nutrition and Health
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• v.32 no.4
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• pp.376-383
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• 1999

The effects of $\beta$-carotene substitutionl for vitamin A and the chronic consumption of ethanol of ethanol on hepatic folate metabolism were studied it rats. The substitution of $\beta$-carotene for vitamin A depressed hepatic 10-formyl-tetreahydrofolate dehydrogenase(10-formyl-tetrahydrofolate : NADP oxidoreductase, E.C. 1.5. 1.6)activity to 65% of controls(p<0.001) and enhanced hepatic 5, 10-methy-lenetetrahydrofolate reductase(E. C. 6.3.3.2)activity by 56% with respect to control levels(p<0.001). Hepatic activity of 10-formyltertrahydrofolate dehydrogenase was depressed to about half that of control levels by ethanol administration to rats(36% ethanol diet, p<0.001). The activity of 5, 10-methyleneterahydrofolate reductase was not changed by ethanol consumption. The increased activity of 5, 10-methyleneterahydrofolate reductase and the decreased activity of 10-formyltetrahydrofolate dehydrogenase appeared to decrease the level of nonmethyl folate conezyme and the rate of one-carbon metabolism. Plasma homocysteine concentrations were significantly higher in rats fed ethanol(p<0.01) o $\beta$-carotene(p<0.001) than in controls, which suggests that increased activity of 5, 10-methylenetetrahydrofolate reductase can depress homocysteine metabolism. We concluded that dietary substitution of $\beta$-carotene for vitamin A or chronic administration of ethanol resulted in changes in the activity of hepatic folate-dependent enzymes, which could affect the distribution of folate derivatives, plasma homocysteine levels and one-carbon metabolism.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.15
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• pp.6333-6337
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• 2014

Background: In this case-control study, we aimed to investigate the relationship between the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and lung cancer. Materials and Methods: Total 200 individuals including 100 patients with lung cancer and 100 controls were analyzed. Genotyping of MTHFR C677T was performed using PCR and RFLP methods. Results: The majority of the patients were men and 90% were smokers. We found that the risk ratio for development of LC was 13-times higher in smokers compared with non-smokers between patient and control groups in our study (OR:13.5, 95%CI:6.27-29.04, p:0.0001). Besides, the risk ratio for development of LC was nine times higher in individuals with cancer history in their family than those without cancer history (OR:9.65, 95%CI: 2.79-33.36; p:0.0001). When genotype distributions and allele frequencies were analyzed in the study groups, no significant difference was apparent (${\chi}^2$:0.53, p=0.76). In addition, no correlation between genotypes of MTHFRC677T polymorphism and histological type of LC was found (${\chi}^2$:0.99, p=0.60). Conclusions: These results suggest that there was no association between the MTHFR C677T polymorphism and lung cancer in the Turkish population.

• Asian Pacific Journal of Cancer Prevention
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• v.13 no.2
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• pp.569-573
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• 2012

Early diagnosis and better prognosis of ovarian cancer is still a challenge. Besides environmental risk factors, genetic factors have established a role in pathogenesis of ovarian cancer. Methods: A case-control and a prospective study design conducted in 224 ovarian cancer patients and 432 controls in Chinese population. MTHFR C677T genotyping was done by PCR-RFLP. Results: Patients with ovarian cancer is associated with a higher less number of delivery and less frequent oral contraceptive use. When potential confounding factors adjusted logistic regression analysis between cases and controls were performed, significant association was obtained for 677T/T genotype and ovarian cancer (OR=3.13, 95% CI=1.59-5.72). Cox regression survival analysis showed individuals carrying T/T genotype had significantly increased HR for death in ovarian cancer patients (HR=2.86, 95% CI=1.27-7.93). In conclusion, we observed that the MTHFR C677T polymorphism is associated with the susceptibility and survival of ovarian cancer in Chinese population.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.19
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• pp.8245-8250
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• 2014

Previous studies investigating the association between 5,10-methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms and colon cancer risk have generated conflicting results. The aim of our meta-analysis was to clarify the precise association. A systematic literature search was conducted to identify all relevant studies. Pooled odds ratio (ORs) with 95% confidence interval (CI) were used to estimate the strength of the association. In this meta-analysis, a total of 13 articles, involving 5,386 cases and 8,017 controls met the inclusion criteria. Overall, a significant association was found between colon cancer risk and the MTHFR C667 polymorphism (TT vs CC+CT: OR=0.79; 95%CI=0.65-0.96; p=0.017). Stratification by ethnicity revealed that MTHFRC667 was associated with colon cancer risk in the non-Asian group (TT vs CC+CT:OR=0.77, 95%CI=0.68-0.89, p=0.000; TT vs CC: OR=0.84, 95%CI=0.73-0.97, p=0.016). Stratification by source of control indicated that MTHFR C667 also correlated with colon cancer risk in the population-based subgroup (TT vs CC: OR=0.85, 95%CI=0.74-0.97, p=0.017; TT vs CC+CT: OR=0.78, 95%CI=0.68-0.89, p=0.000) and hospital-based subgroup (TT vs CC+CT: OR=0.65, 95%CI=0.49-0.86, p=0.003). However, risk was significantly increased for MTHFR A1298C polymorphisms and colon cancer risk in hospital-based studies (C vs A: OR=1.52, 95%CI=1.26-1.83, p=0.000; CC+AC vs AA: OR=1.93, 95%CI=1.47-2.49, p=0.000) but reduced in population-based studies (CC vs AA: OR=0.83, 95%CI=0.70-0.99, p=0.042). In conclusion, the results of our meta-analysis suggest that the MTHFR C667 polymorphism is associated with reduced colon cancer risk, especially for non-Asian populations.

• Korean Journal of Clinical Oncology
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• v.9 no.2
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• pp.80-86
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• 2013

Purpose: Hypermethylation of human mut L homologue 1 (hMLH1) promoter region is known to cause sporadic microsatellite instability (MSI) colorectal cancers. 5,10-methylenetetrahydrofolate reductase (MTHFR) is the key enzyme in folate metabolism, acting as a methyl donor for DNA methylation. In this study, we investigate whether the polymorphism of MTHFR 677C>T plays a role in the alteration of the promoter-specific hypermethylation, predisposing to MSI colorectal cancers. Methods: Total of 487 sporadic colorectal cancer patients in CHA Bundang Medical Center were collected. MSI was identified when two or more are positive among five microsatellite markers (BAT25, BAT26, D17S250, D5S346, D2S123). The others were classified as microsatellite stable (MSS). Polymorphism of MTHFR 677C>T was genotyped by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Results: MSI was observed in 65 of 487 patients (12.73%). MSI colorectal cancers showed similar clinicopathological features with previously reported; younger age onset, right-sided preponderance, mucinous and poorly differentiated histology, lower stage, fewer lymph node metastases than MSS tumors (each P<0.05). The frequency of MTHFR 677TT genotype was 17.7% in the MSI group higher than 14.6% in the MSS group (P=0.17). Although not statistically significant, compared to the MTHFR 677CC referent, MTHFR 677 CT+TT genotype was more likely to have MSI than MSS (odds ratio, 1.81; 95% confidence interval, 0.94 to 3.68; P=0.06). Conclusion: This study demonstrated higher frequency of MTHFR 677TT genotype in MSI colorectal cancers. Furthermore, individuals with MTHFR 677CT+TT variant type might potentially develop MSI rather than MSS colorectal cancers.

• Clinical and Experimental Reproductive Medicine
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• v.29 no.3
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• pp.215-222
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• 2002

Objective : Previous studies have suggested that hyperhomocysteinemia and methylenetetrahydrofolate reductase (MTHFR C677T) mutations are associated with increased risk of recurrent spontaneous abortion (RSA). Recently, a second site polymorphism in MTHFR, 1298A-->C, which changes a glutamic acid into an alanine residue, was shown to be associated with a decreased enzyme activity. We tested whether the variant alleles of MTHFR C677T and A1298C are risk factor (biomarker) for RSA. Materials and Methods: We analyzed DNA from a case-control study in the Korean DNA was extracted from blood samples of 118 patients with RSA and 123 healthy fertile patients as the controls. MTHFR variant alleles were determined by a PCR-restriction fragment length polymorphism assay. Results: We found no evidence for an association between 677TT genotype and risk of RSA (OR=1.95, 95% CI=$0.84{\sim}4.50$, p=0.12). However, the MTHFR 1298AC (OR=0.36, 95% CI=$0.20{\sim}0.63$, p=0.0004) and 1298AC+CC (OR=0.35, 95% CI=$0.20{\sim}0.61$, p=0.0002) genotypes were lower among 118 RSA cases compared with 123 controls, conferring a 2.8-fold decrease in risk of RSA, respectively. Moreover, the combined genotypes of MTHFR 677CC/1298AC (OR=0.30, 95% CI=$0.10{\sim}0.88$, p=0.029) and 677CT/1298AC (OR=0.77, 95% CI=$0.60{\sim}0.99$, p=0.043) also showed significantly lower risk than those with MTHFR 677CC/1298AA type. Conclusion: MTHFR 1298AC, MTHFR 677CC/1298AC and 677CT/1298AC genotypes may represent genetic markers for the protection of RSA at least in Korean women.

• Asian Pacific Journal of Cancer Prevention
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• v.13 no.8
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• pp.3763-3766
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• 2012

Background: Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme in the metabolism of folate, and the role of the MTHFR C677T polymorphism in pancreatic carcinogenesis is still controversial. Methods: A literature search was performed using Pubmed and CNKI databases for published studies through May 2012. We performed a meta-analysis of all relevant case-control studies that examined the association between MTHFR C677T polymorphism and pancreatic cancer risk. Results: Finally, 9 individual case-control studies with a total of 1,299 pancreatic cancer cases and 2,473 controls were included into this meta-analysis. Results: This metaanalysis showed there was an obvious association between MTHFR C677T polymorphism and pancreatic cancer risk in East Asians (for allele model, OR = 1.67, 95%CI 1.11-2.51; For homozygote model, OR = 2.77, 95%CI 1.40-5.48; for recessive model, OR = 1.96, 95%CI 1.54-2.50; for dominant model, OR = 2.11, 95%CI 1.01-4.41). However, no significant association was found in Caucasians. Conclusions: The MTHFR C677T polymorphism is associated with pancreatic cancer risk, and a race-specific effect may exist in this association. More studies with a larger sample size are needed to further clarify this association.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.8
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• pp.3101-3109
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• 2015

Background: Methylenetetrahydrofolate reductase (MTHFR) is involved in amino acid synthesis and DNA function. Two common polymorphisms are reported, C677T and A1298C, that are implicated in a number of human diseases, including cancer. Objective: The association between MTHFR C677T and A1298C genotype and haplotype frequencies in risk for lung cancer (LC) was investigated in the Jordanian population. Materials and Methods: A total of 98 LC cases were studied for MTHFR C677T and A1298C polymorphisms, compared to 89 controls taken from the general population, employing the PCR-RFLP technique. Results: The frequency of the genotypes of MTHFR C677T among Jordanians was: CC, 59.6%, CT, 33%; and TT, 7.4% among LC cases and 49.4%, 40.2% and 10.3% among controls. No significant association was detected between genetic polymorphism at this site and LC. At MTHFR A12987C, the genotype distribution was AA, 29.5%; AC, 45.3%, and CC 25.3% among LC cases and 36.8%, 50.6% and 12.6% among controls. Carriers of the CC genotype were more likely to have LC (OR=2.5; 95%CI: 1.04-6; p=0.039) as compared to AA carriers. Smokers and males with the CC genotype were 9.9 and 6.7 times more likely to have LC, respectively ($OR_{smokers}=9.9$; 95%CI: 1.2-84.5, p=0.018; $OR_{men}=6.6$; 95%CI: 1.7-26.2, p=0.005). Haplotype analysis of MTHFR polymorphism at the two loci showed differential distribution of the CC haplotype (677C-1298C) between cases and controls. The CC haplotype was associated with an increased risk for lung cancer (OR=1.6; 95% CI: 1.03-2.4, p=0.037). Conclusions: The genetic polymorphism of MTHFR at 1298 and the CC haplotype (risk is apparently lower with the C allele at position 677) may modulate the risk for LC development among the Jordanian population. Risk associated with the 1298C allele is increased in smokers and in males. The results indicate that a critical gene involved in folate metabolism plays a modifying role in lung cancer risk, at least in the Jordanian population.

• Journal of Gastric Cancer
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• v.5 no.1
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• pp.10-15
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• 2005

Purpose: Recently the role of vitamins, folate in particular, has been emphasized in the maintenance of health. Folate deficiency is known to give rise to developmental delay, immature vascular disease, neural tube defect, acute leukemia, atherosclerotic vascular disease, delivery defects, breast cancer, and particularly gastrointestinal neoplasia. Methylenetetrahydrofolate reductase (MTHFR) is an essential enzyme in folate metaboism, and influences DNA synthesis and DNA methylation. Generally, folate deficiency is associated with gastrointestinal neoplasms. The amino-acid- changing and enzyme-activity-reducing nucleotide polymorphism (766C$\rightarrow$T/ Ala222Val) has been described in the MTHFR polymorphism and leads to low enzyme activity that may reduce the capacity of DNA methylation and possibly uracil mis-incorporation into DNA. These processes may be critical in the oncogenic transformation of human cells, especially in colorectal carcinomas. We investigated the relationship between the MTHFR polymorphism in gastric cancer and the tumor site, the smoking history, and the alcoholic history. Materials and Methods: Ninety-six (96) individuals with gastric cancer and 287 healthy persons were analyzed. Blood sampling was performed, PCR-RFLP was analyzed, and MTHFR polymorphism genotypes of C/C, C/T, and T/T were obtained and analyzed statistically for their correlation. Results: In the gastric cancer group there were 69 ($72\%$) males and 27 ($28\%$) females. There were also 58 cases ($60\%$) involving the gastric lower body, 20 cases ($21\%$) the gastric mid-body, and 18 cases ($19\%$) the gastric upper body. In the control group there were 169 ($59\%$) males and 118 ($41\%$) females. Among the gastric cancer, 56 ($61\%$) smoking patients, 40 ($39\%$) non-smoking patients, 45($47\%$) alcoholic patients, 51 ($53\%$) non-alcoholic patients. In the gastric cancer group, MTHER polymorphisms were C/C in 18 ($19\%$) cases, C/T in 59 ($61\%$) cases, T/T in 19 ($20\%$) cases. In the control group polymorphisms were C/C 116 ($40\%$) cases, C/T 103 ($36\%$) cases, and T/T 68 ($24\%$) cases (P=0.045). In cases of lower gastric body cancer, polymorphisms were C/C in 16 ($24\%$) C/C in 16 ($24\%$) cases and C/T or T/T in 42 ($72\%$) cases. In cases of upper and mid-body cancer, polymorphisms were C/C in 2 ($5\%$) cases and C/T or T/T 36 ($95\%$) cases (P=0.006). In the non-smoking patient group, polymorphisms were C/C in 5 (12%) cases and C/T or T/T in 35 ($88\%$) cases. In the smoking patient group, C/C in 13 ($23\%$) cases and C/T or T/T in 43 ($77\%$) cases (P=0.189). In the non-alcoholic patient group, polymorphisms were C/C in 6 ($12\%$) cases and C/T or T/T in 45 ($88\%$) cases. In the alcoholic patient group, polymorphisms were C/C in 12 ($26\%$) cases and C/T or T/T in 33 ($74\%$) cases (P=0.063) Conclusion: MTHFR polymorphisms are associated with gastric cancer and tumor site, but not with smoking and alcohol drinking.