• Asian Pacific Journal of Cancer Prevention
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• v.16 no.18
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• pp.8093-8100
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• 2016

Background: Genetic and environmental factors play important roles in pathogenesis of digestive tract cancers like those in the esophagus, stomach and colorectum. Folate deficiency and methylenetetrahydrofolate reductase (MTHFR) as an important enzyme of folate and methionine metabolism are considered crucial for DNA synthesis and methylation. MTHFR variants may cause genomic hypomethylation, which may lead to the development of cancer, and MTHFR gene polymorphisms (especially C677T and A1298C) are known to influence predispositions for cancer development. Several case control association studies of MTHFR C677T polymorphisms and colorectal cancer (CRC) have been reported in different populations with contrasting results, possibly reflecting inadequate statistical power. Aim: The present meta-analysis was conducted to investigate the association between the C677T polymorphism and the risk of colorectal cancer. Materials and Methods: A literature search of the PubMed, Google Scholar, Springer link and Elsevier databases was carried out for potential relevant articles. Pooled odds ratio (OR) with corresponding 95 % confidence interval (95 % CI) was calculated to assess the association of MTHFR C677T with the susceptibility to CRC. Cochran's Q statistic and the inconsistency index (I2) were used to check study heterogeneity. Egger's test and funnel plots were applied to assess publication bias. All statistical analyses were conducted by with MetaAnalyst and MIX version 1.7. Results: Thirty four case-control studies involving a total of 9,143 cases and 11,357 controls were retrieved according to the inclusion criteria. Overall, no significant association was found between the MTHFR C677T polymorphism and colorectal cancer in Asian populations (for T vs. C: OR=1.03; 95% CI= 0.92-1.5; p= 0.64; for TT vs CC: OR=0.88; 95%CI= 0.74-1.04; p= 0.04; for CT vs. CC: OR = 1.02; 95%CI= 0.93-1.12; p=0.59; for TT+ CT vs. CC: OR=1.07; 95%CI= 0.94-1.22; p=0.87). Conclusions: Evidence from the current meta-analysis indicated that the C677T polymorphism is not associated with CRC risk in Asian populations. Further investigations are needed to offer better insight into any role of this polymorphism in colorectal carcinogenesis.

• Asian Pacific Journal of Cancer Prevention
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• v.14 no.9
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• pp.5189-5192
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• 2013

Aim: We aimed to investigate the associations of dietary intake of folate, vitamin $B_6$ and $B_{12}$ and MTHFR genotype with breast cancer in a Chinese population. Methods: A matched case-control study was conducted, and 435 patients with newly diagnosed and histologically confirmed breast cancer and 435 controls were collected. The folate intake, vitamin $B_6$ and vitamin $B_{12}$ were calculated, and MTHFR C665T, C677T and A1298C were analyzed by PCR-RFLP. Results: We found vitamin $B_{12}$ was likely to reduce the risk of breast cancer, and MTHFR 665TT was associated with increased risk of breast cancer. Folate intake, vitamin $B_{12}$ intake and variants of MTHFR C677T and MTHFR A1298C demonstrated no association with risk of breast cancer. However, we found patients with low intake of vitamin $B_6$ and MTHFR 665TT genotype had a higher risk of breast cancer (OR=1.87, 95% CI=1.29-2.77), the association being less pronounced among subjects with a moderate intake of vitamin $B_6$ and MTHFR 665TT genotype (OR=1.58, 95% CI=1.03-2.49, P=0.03). Conclusion: Our study indicated that the MTHFR C665T polymorphism and vitamin $B_6$ are associated with risk of breast cancer, which indicated roles for nutrients in developing breast cancer.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.12
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• pp.5007-5011
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• 2015

Background: Breast cancer is a major cause of morbidity and mortality in Jordan and worldwide. Abnormality of DNA methylation is a possible mechanism for the development of cancer. Methylenetetrahydrofolate reductase (MTHFR) is involved in DNA methylation. Our aim was to study the association between genetic polymorphisms of MTHFR at two sites (C677T and A1298C) and their haplotypes and the risk of breast cancer among Jordanian females. Materials and Methods: A case-control study involving 150 breast cancer cases and 150 controls was conducted. Controls were age-matched to cases. Polymerase chain reaction/restriction fragment length polymorphism (PCR-RFLP) technique and sequencing were conducted to determine the genotypes. Results: There was a significant difference in genotype frequency of C677T in the 41-60 year age category [cases: CC (37.4%), CT (49.5%) and TT (13.2%); controls: CC (56.3%), CT (35.6%) and TT (8%), p= 0.04; $OR_{TT\;vs.\;CC}$: 2.5, 95% CI: (0.9-6.9); $OR_{at\;least\;on\;T$: 2.1, 95%CI: (1.2-3.9)]. There was no significant difference in genotype frequency of A1298C between cases and controls [cases: AA (46.6%), AC (41.8%) and CC (11.6%); controls: AA (43%), AC (47.4%) and CC (9.6%); p= 0.6]. There was a significant difference of MTHFR genetic polymorphism haplotypes among breast cancer cases and controls [cases/control: CA: 38.3/45.4%; CC: 28.9/25.2%; TA: 29.2/21; TC: 3.6/8.3; p value= 0.01; $OR_{TA\;vs.\;CA}=1.6$; 95% CI (1.1-2.5); p= 0.02]. Conclusions: Genetic polymorphism of MTHFR C677T may modulate the risk of breast cancer especially in the 41-60 year age group. Additionally, TA haplotype amends the risk of breast cancer. Future studies with a larger sample size are needed to validate the role of MTHFR genetic polymorphisms in breast cancer.

• Asian Pacific Journal of Cancer Prevention
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• v.14 no.8
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• pp.4559-4565
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• 2013

Background: Methylenetetrahydrofolate reductase (MTHFR) is involved in DNA synthesis and repair. We here aimed to investigate two common polymorphisms, C677T and A1298C, with genotype and haplotype frequencies in colorectal cancer (CRC) cases among Jordanian. Materials and Methods: 131 CRC cases were studied for MTHFR C677T and A1298C polymorphisms, compared to 117 controls taken from the general population, employing the PCR-RFLP technique. Results: We found the frequency of the three different genotypes of MTHFR C677T among Jordanians to be CC: 61.7%, CT: 35.2%, and TT 3.1% among CRC cases and 50.9%, 38.8% and 10.3% among controls. Carriers of the TT genotype were less likely to have CRC (OR=0.25; 95%CI: 0.076-0.811; p=0.021) as compared to those with the CC genotype. Genotype analysis of MTHFR A12987C revealed AA: 38.9%, AC: 45%, and CC 16% among CRC cases and 37.4%, 50.4% and 12.2% among controls. There was no significant association between genetic polymorphism at this site and CRC. Haplotype analysis of MTHFR polymorphism at the two loci showed differential distribution of the TA haplotype (677T-1298A) between cases and controls. The TA haplotype was associated with a decreased risk for colorectal cancer (OR=0.6; 95% CI: 0.4-0.9, p=0.03). Conclusions: The genetic polymorphism of MTHFR at 677 and the TA haplotype may modulate the risk for CRC development among the Jordanian population. Our findings may reflect an importance of genes involved in folate metabolism in cancer risk.

• Clinical and Experimental Reproductive Medicine
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• v.31 no.3
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• pp.183-190
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• 2004

Objectives: Methylenetetrahydrofolate reductase (MTHFR) mutation are commonly associated with hyperhomocysteinemia, and through their defects in homocysteine metabolism, they have been implicated as a risk factor for recurrent spontaneous abortion. Recent report describe that 28-bp tandem repeat polymorphism in thymidylate synthase enhancer region (TSER) that influence enzyme activity would affect plasma homocysteine level. We have investigated the relationship between TSER genotype and plasma homocysteine level in 54 patients with recurrent spontaneous abortion. Methods: Plasma homocysteine level was measured by fluorescent polarizing immunoassay. MTHFR mutation (C677T and A1298C) was identified by PCR-restriction fragment length polymorphism assay and TSER mutation was analyzed by PCR method. The data were analyzed using the program SAS 8.2 for Windows. Results: Total homocysteine level was significantly higher in MTHFR 677TT genotype ($9.80{\pm}3.87{\mu}mol/L$) than MTHFR 677CC genotype ($8.14{\pm}1.74{\mu}mol/L$) in Korean patients with unexplained recurrent spontaneous abortion (p=0.0143). However, the plasma homocysteine level was not significantly different in the MTHFR 1298AA ($8.42{\pm}2.65{\mu}mol/L$) and 1298CC ($6.09{\pm}0.32{\mu}mol/L$; p=0.2058) and, TSER 2R2R ($8.61{\pm}1.68{\mu}mol/L$) and 3R3R ($8.05{\pm}2.81{\mu}mol/L$; p=0.9319) mutant genotypes, respectively. In this study, we found the combination effects of TSER and MTHFR C677T genotypes. Plasma homocysteine levels were the highest ($11.47{\pm}4.66{\mu}mol/L$) in individuals with TSER 3R3R ($8.05{\pm}2.81{\mu}mol/L$) and MTHFR 677TT ($9.80{\pm}3.87{\mu}mol/L$) genotypes. Individuals with a combination of both TSER 2R2R/2R3R and MTHFR 677CC/CT genotypes ($7.69{\pm}1.77{\mu}mol/L$) had lower plasma homocysteine levels than TSER 2R2R ($8.61{\pm}1.68{\mu}mol/L$) and MTHR 677CC ($8.14{\pm}1.74{\mu}mol/L$) genotypes, respectively. The effect of MTHFR polymorphism in the homocysteine metabolism appears to be stronger than that of TSER polymorphism. Conclusion: Although statistically not significant, we found the elevated level of plasma homocysteine in combined genotypes with TSER and MTHFR (C677T and A1298C) in Korean patients with unexplained habitual abortion. In this study, we reported the possibility that TSER polymorphism is a genetic determinant of plasma homocysteine levels in the Korean patients as well as MTHFR C677T polymorphism. A large prospective study is needed to verify our findings.

• Asian Pacific Journal of Cancer Prevention
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• v.14 no.9
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• pp.5449-5454
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• 2013

Background: A large variety of familiar and non-familiar lung carcinomas (LC) are caused by long term exposure to chemical carcinogens that are present in tobacco smoke. We aimed to investigate the prevalence of 5 thrombophilic germ-line mutations in patients with lung carcinomas. Materials and Methods:A total of 52 LC patients and 212 healthy controls from same population were analyzed for FV Leiden, factor V H1299R (R2), PAI-1, MTHFR C677T, MTHFR A1298C, ACE I/D, and Apo E genes and compared. Results: Overall, heterozygous and/or homozygous point mutations in FV Leiden Apo E2, PAI-1 and MTHFR C677T genes were associated with LC in the current cohort. There was no meaningful association between LC and ACE I/D gene markers. Conclusions: The current results showed that LC is related to combined thrombophilic gene mutations and individuals with homozygosity of 4G in PAI-1 and MTHFR C677T genes and heterozygosity of FV Leiden, Apo E4 genes have a germ-line risk for LC tumorigenesis.

• Asian Pacific Journal of Cancer Prevention
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• v.13 no.8
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• pp.4017-4023
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• 2012

Background and Aim: Polymorphisms in methylenetetrahydrofolate reductase (MTHFR) are known to be associated with predisposition for certain cancers. This study aimed to evaluate the effects of lifestyle factors, family history and genetic polymorphisms in MTHFR C677T and A1298C on rectal cancer risk and possible interactions with lifestyle factors in Northeast Thailand. Methods: A hospital-based case-control study was conducted during 2002-2006 with recruitment of 112 rectal cancer cases and 242 non-rectal cancer patient controls. Information was collected using a structured-questionnaire. Blood samples were obtained for assay of MTHFR C677T and A1298C genotypes by polymerase chain reaction with restriction fragment length polymorphism (PCR-RFLP) techniques. Associations between lifestyle factors, family history and genetic polymorphisms v.s. rectal cancer risk were assessed using logistic regression analysis. Results: Subjects with frequent and occasional constipation had a higher risk ($OR_{adj.}$=14.64; 95%CI=4.28-50.04 and $OR_{adj.}$=2.15; 95%CI=1.14-4.06), along with those who reported ever having hemorrhoids ($OR_{adj.}$=2.82; 95%CI=1.36-5.84) or a family history of cancer ($OR_{adj.}$=1.90; 95%CI=1.06-3.39). Consumption of a high level of pork was also associated with risk ($OR_{adj.}$=1.82; 95%CI=1.05-3.15). Interactions were not observed between MTHFR and other risk factors. Conclusions: This study suggested that the risk factors for rectal cancer in the Thai population are bowel habits, having had hemorrhoids, a family history of cancer and pork consumption.