Gene Summary

Gene:MTHFR; methylenetetrahydrofolate reductase (NAD(P)H)
Summary:The protein encoded by this gene catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, a co-substrate for homocysteine remethylation to methionine. Genetic variation in this gene influences susceptibility to occlusive vascular disease, neural tube defects, colon cancer and acute leukemia, and mutations in this gene are associated with methylenetetrahydrofolate reductase deficiency.[provided by RefSeq, Oct 2009]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:methylenetetrahydrofolate reductase
Source:NCBIAccessed: 28 February, 2015


What does this gene/protein do?
Show (13)
Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 28 February 2015 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Single-Stranded Conformational Polymorphism
  • Pregnancy Complications
  • Radiotherapy
  • Sigmoidoscopy
  • Case-Control Studies
  • Odds Ratio
  • Publication Bias
  • Polymerase Chain Reaction
  • Spine
  • Restriction Fragment Length Polymorphism
  • Survival Rate
  • Vitamin B Complex
  • Vitamins
  • Acute Lymphocytic Leukaemia
  • Smoking
  • Serbia
  • Polymorphism
  • Stomach Cancer
  • Tandem Mass Spectrometry
  • Vitamin D
  • Questionnaires
  • Small Cell Lung Cancer
  • Vitamin B 12
  • Genotype
  • Thyroid Cancer
  • Single Nucleotide Polymorphism
  • Transcobalamins
  • Ubiquitin-Protein Ligases
  • Genetic Predisposition
  • Methylenetetrahydrofolate Reductase (NADPH2)
  • Sex Factors
  • Promoter Regions
  • Tobacco
  • Spectrophotometry
  • Turkey
  • Taiwan
  • Colorectal Cancer
  • Skin Cancer
  • Chromosome 1
  • Sex Characteristics
  • Syria
Tag cloud generated 28 February, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (7)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: MTHFR (cancer-related)

Deng F, Gao Y, L V JH, Gao JM
Methylenetetrahydrofolate reductase gene polymorphisms and skin cancer risk: a meta-analysis.
Cancer Genet. 2014 Jul-Aug; 207(7-8):299-305 [PubMed] Related Publications
We sought to determine whether the methylenetetrahydrofolate reductase (MTHFR) A1298C and C677T polymorphisms are associated with increased skin cancer risk. We performed literature searches of the PubMed, BIOSIS Previews, and Web of Science databases to identify eligible articles published through September 15, 2013. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using fixed-effects or random-effects models. Publication bias and subgroup analyses were also performed. Eight articles, which consisted of 10,066 subjects (2,672 patients and 7,394 controls), were included in the meta-analysis. Homozygous MTHFR 1298C individuals were 1.29 times more likely to develop skin cancer (95% CI, 1.04-1.61) compared with A1298C allele (AA or AC) carriers. There was an increased risk for C allele homozygotes compared with the 1,298 AA+AC carriers (OR, 1.45; 95% CI, 1.08-1.96) when restricted to basal cell carcinomas (BCC). The 1298C homozygote carriers increased the odds of BCC by 1.47 times (95% CI, 1.07-2.01) compared with those who were 1298A homozygote carriers. ORs for all genetic models yielded a null association. The data obtained from this meta-analysis suggest that the MTHFR 1298C allele is associated with increased skin cancer risk, particularly BCC; however, no association was observed between the MTHFR C677T polymorphism and skin cancer.

Kanazawa K, Yokouchi H, Wang X, et al.
Phase II trial of carboplatin and pemetrexed as first-line chemotherapy for non-squamous non-small cell lung cancer, and correlation between the efficacy/toxicity and genetic polymorphisms associated with pemetrexed metabolism: Hokkaido Lung Cancer Clinical Study Group Trial (HOT) 0902.
Cancer Chemother Pharmacol. 2014; 74(6):1149-57 [PubMed] Related Publications
PURPOSE: This phase II study evaluated the response rate (RR) and safety of combination therapy with carboplatin (CBDCA) and pemetrexed (PEM) in Japanese patients with non-squamous non-small cell lung cancer (non-sq NSCLC). Further, the relationship between therapy efficacy/toxicity and genetic polymorphisms associated with PEM metabolism was analyzed.
METHODS: Forty-one patients received CBDCA at a dose targeting an area under the concentration-time curve of 5 mg/mL × min and PEM of 500 mg/m(2) on day 1 every 3 weeks. Single-nucleotide polymorphisms of the thymidylate synthase (TYMS) coding gene, the variable number of tandem repeat (VNTR) in the TYMS, and the methylenetetrahydrofolate reductase (MTHFR) coding gene were analyzed.
RESULTS: The overall RR was 36.6 %. Median progression-free survival and median survival time were 4.7 months [95 % confidence interval (CI) 3.9-5.6 months] and 16.2 months (95 % CI 6.1-26.2 months), respectively. Epidermal growth factor receptor gene mutations were detected in 6 patients (14.6 %). The VNTR in the TYMS significantly correlated with anemia (p = 0.047) and thrombocytopenia (p = 0.038).
CONCLUSIONS: This combination therapy was effective and tolerable in patients with advanced non-sq NSCLC. The VNTR in the TYMS appears to be a predictive factor for anemia and thrombocytopenia in patients treated with this regimen.

Krawczyk P, Kucharczyk T, Kowalski DM, et al.
Polymorphisms in TS, MTHFR and ERCC1 genes as predictive markers in first-line platinum and pemetrexed therapy in NSCLC patients.
J Cancer Res Clin Oncol. 2014; 140(12):2047-57 [PubMed] Free Access to Full Article Related Publications
PURPOSE: We presented retrospective analysis of up to five polymorphisms in TS, MTHFR and ERCC1 genes as molecular predictive markers for homogeneous Caucasian, non-squamous NSCLC patients treated with pemetrexed and platinum front-line chemotherapy.
METHODS: The following polymorphisms in DNA isolated from 115 patients were analyzed: various number of 28-bp tandem repeats in 5'-UTR region of TS gene, single nucleotide polymorphism (SNP) within the second tandem repeat of TS gene (G>C); 6-bp deletion in 3'-UTR region of the TS (1494del6); 677C>T SNP in MTHFR; 19007C>T SNP in ERCC1. Molecular examinations' results were correlated with disease control rate, progression-free survival (PFS) and overall survival.
RESULTS: Polymorphic tandem repeat sequence (2R, 3R) in the enhancer region of TS gene and G>C SNP within the second repeat of 3R allele seem to be important for the effectiveness of platinum and pemetrexed in first-line chemotherapy. The insignificant shortening of PFS in 3R/3R homozygotes as compared to 2R/2R and 2R/3R genotypes were observed, while it was significantly shorter in patients carrying synchronous 3R allele and G nucleotide. The combined analysis of TS VNTR and MTHFR 677C>T SNP revealed shortening of PFS in synchronous carriers of 3R allele in TS and two C alleles in MTHFR. The strongest factors increased the risk of progression were poor PS, weight loss, anemia and synchronous presence of 3R allele and G nucleotide in the second repeat of 3R allele in TS. Moreover, lack of application of second-line chemotherapy, weight loss and poor performance status and above-mentioned genotype of TS gene increased risk of early mortality.
CONCLUSION: The examined polymorphisms should be accounted as molecular predictor factors for pemetrexed- and platinum-based front-line chemotherapy in non-squamous NSCLC patients.

Zgheib NK, Akra-Ismail M, Aridi C, et al.
Genetic polymorphisms in candidate genes predict increased toxicity with methotrexate therapy in Lebanese children with acute lymphoblastic leukemia.
Pharmacogenet Genomics. 2014; 24(8):387-96 [PubMed] Related Publications
BACKGROUND: The aim of this study is to analyze polymorphisms in genes involved in 6-mercaptopurine detoxification (TPMT); methotrexate (MTX) metabolism including ABCB1 (or MDR1), ABCC2, SLC19A1 (or RFC1), and SLCO1B1; and the MTX effect mainly MTHFR and TYMS, and to assess whether these polymorphisms are predictors of treatment toxicity and/or MTX clearance.
MATERIALS AND METHODS: This study included 127 Lebanese acute lymphoblastic leukemia patients, of whom 117 were treated following the St Jude's Children Research Hospital protocol. Genotyping was performed using real-time PCR or restriction fragment length polymorphism. MTX levels were measured using a polarization fluorescence assay from Roche. MTX clearance was estimated on the basis of all available MTX levels measured after high-dose MTX treatment during the consolidation phase.
RESULTS: Five variants in four genes (MTHFR, ABCB1, ABCC2, and TYMS) were shown to be associated with toxicity, but neither was associated with MTX pharmacokinetic parameters. For instance, during the consolidation phase, a statistically significant association was found between MTHFR rs1801133 variant allele carriers and a decrease in hemoglobin levels [odds ratio (OR)=3.057; 95% confidence interval (CI): 1.217; 7.680]. In addition, a statistically significant association was found among neutropenia (absolute neutrophil count<500) and variant allele carriers of ABCB1 rs1045642 (OR=5.174; 95% CI: 1.674; 15.989) and ABCB1 rs1128503 (OR=3.364; 95% CI: 1.257; 9.004), respectively. ABCC2 rs717620 variant allele carriers needed significantly more time to reach a MTX level below 0.1 µmol/l (β=5.122; 95% CI: 1.412; 8.831). During the continuation phase, a statistically significant association was found between ABCC2 rs717620 and TYMS 28-bp tandem repeats carriers with the need to decrease weekly MTX doses (β=-4.905; 95% CI: -9; -0.809 and β=-5.770; 95% CI: -10.138; -1.403), respectively.
CONCLUSION: Genotyping for MTHFR, ABCB1, ABCC2, and TYMS polymorphisms may be useful in identifying patients at risk of increased MTX toxicity and the need for dose optimization before treatment initiation.

Aly RM, Taalab MM, Ghazy HF
MTHFR A1298C and C677T gene polymorphisms and susceptibility to chronic myeloid leukemia in Egypt.
Int J Clin Exp Pathol. 2014; 7(5):2571-8 [PubMed] Free Access to Full Article Related Publications
Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme regulating the intracellular folate metabolism which plays an important role in carcinogenesis through DNA methylation. We aimed to evaluate the association between MTHFR A1298C and C677T polymorphisms and the risks of chronic myeloid leukemia (CML). Eighty-five patients with CML and a control group containing 100 healthy, age and sex matched individuals were examined for MTHFR C677T and A1298C polymorphisms using polymerase chain reaction-restriction fragment-length (PCR-RFLP) method. The frequency of 677TT genotype in patients with CML was significantly higher compared to controls (OR=2.513, 95% CI: 0.722-4.086, P=0.025). No such association was shown for heterozygous 677CT (OR=1.010, 95% CI: 0.460-2.218, P=0.981). Moreover, for A1298C genotype, a statistically significant higher frequency of 1298CC was also detected in CML patients compared to control group (OR=1.1816, 95% CI: 0.952-3.573, P=0.036), 0.036). No such statistical significance was demonstrable for heterozygote 1298AC (OR=1.046, 95% CI: 0.740-1.759, P=0.092). In addition, patients with joint 677CT/1298AC or 677TT/1298CC genotypes showed an association with increased risk of CML (OR=1.849, 95% CI: 0.935-2.540, P=0.024; OR=1.915, 95% CI: 1.202-3.845, P=0.020 respectively). .A statistically significant increased risk of resistant to therapy was observed with 677CT and 1298AC genotypes (P=0.001, P=0.002 respectively). We conclude that both MTHFR 677TT and 1298CC polymorphisms have been associated with risk of CML and both 677CT and 1298AC genotypes are associated with higher risk of resistant to therapy.

Naderi E, Mostafaei M, Pourshams A, Mohamadkhani A
Network of microRNAs-mRNAs interactions in pancreatic cancer.
Biomed Res Int. 2014; 2014:534821 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: MicroRNAs are small RNA molecules that regulate the expression of certain genes through interaction with mRNA targets and are mainly involved in human cancer. This study was conducted to make the network of miRNAs-mRNAs interactions in pancreatic cancer as the fourth leading cause of cancer death.
METHODS: 56 miRNAs that were exclusively expressed and 1176 genes that were downregulated or silenced in pancreas cancer were extracted from beforehand investigations. MiRNA-mRNA interactions data analysis and related networks were explored using MAGIA tool and Cytoscape 3 software. Functional annotations of candidate genes in pancreatic cancer were identified by DAVID annotation tool.
RESULTS: This network is made of 217 nodes for mRNA, 15 nodes for miRNA, and 241 edges that show 241 regulations between 15 miRNAs and 217 target genes. The miR-24 was the most significantly powerful miRNA that regulated series of important genes. ACVR2B, GFRA1, and MTHFR were significant target genes were that downregulated.
CONCLUSION: Although the collected previous data seems to be a treasure trove, there was no study simultaneous to analysis of miRNAs and mRNAs interaction. Network of miRNA-mRNA interactions will help to corroborate experimental remarks and could be used to refine miRNA target predictions for developing new therapeutic approaches.

Dong S, Liu Y, Chen J
MTHFR gene polymorphism and risk of myeloid leukemia: a meta-analysis.
Tumour Biol. 2014; 35(9):8913-9 [PubMed] Related Publications
An increasing body of evidence has shown that the amino acid changes at position 1298 might eliminate methylenetetrahydrofolate reductase (MTHFR) enzyme activity, leading to insufficient folic acid and subsequent human chromosome breakage. Epidemiological studies have linked MTHFR single-nucleotide polymorphism (SNP) rs1801131 to myeloid leukemia risk, with considerable discrepancy in their results. We therefore were prompted to clarify this issue by use of a meta-analysis. The search terms were used to cover the possible reports in the MEDLINE, Web of Knowledge, and China National Knowledge Infrastructure (CNKI) databases. Odds ratios were estimated to assess the association of SNP rs1801131 with myeloid leukemia risk. Statistical heterogeneity was detected using the Q-statistic and I (2) metric. Subgroup analysis was performed by ethnicity, histological subtype, and Hardy-Weinberg equilibrium (HWE). This meta-analysis of eight publications with a total of 1,114 cases and 3,227 controls revealed no global association. Nor did the subgroup analysis according to histological subtype and HWE show any significant associations. However, Asian individuals who harbored the CC genotype were found to have 1.66-fold higher risk of myeloid leukemia (odds ratio, 1.66; 95 % confidence interval, 1.10 to 2.49; P h = 0.342; I (2) = 0.114). Our meta-analysis has presented evidence supporting a possible association between the CC genotype of MTHFR SNP rs1801131 and myeloid leukemia in Asian populations.

Jiang N, Zhu X, Zhang H, et al.
The relationship between methylenetetrahydrofolate reductase polymorphism and hematological malignancy.
Clin Lab. 2014; 60(5):767-74 [PubMed] Related Publications
BACKGROUND: Methylenetetrahydrofolate reductase (MTHFR) is the key enzyme for folate metabolism. Previous studies suggest a relationship between its single nucleotide polymorphisms (SNP) of C677T and A1298C with a variety of tumor susceptibility including hematological malignancy. SNP frequency distribution in different ethnic populations might lead to differences in disease susceptibility. There has been little research in Chinese people on the MTHFR SNP with the susceptibility of the hematological malignancy. Therefore, this study investigated the relationship between MTHFR SNPs and hematological malignancy in Jiangsu province in China.
METHODS: Gene microarray was used to detect MTHFR C677T and A1298C single nucleotide polymorphism loci on 157 healthy controls and 127 patients from Jiangsu province with hematological malignancies (30 with multiple myeloma, 28 with non-Hodgkin's lymphoma, 22 with acute lymphoblastic leukemia, 40 with acute myeloid leukemia, and seven with chronic myeloid leukemia).
RESULTS: The allele frequency of 677T was 41.3% in patients and 33.1% in controls, showed significant difference (chi2 = 4.08, p = 0.043); 677TT genotype with a high susceptibility to hematological malignancy (OR 1.96, 95% CI 1.01 - 4.45, p = 0.041). In subgroup analyses, the genotypes 677TT and 1298CC were associated with significantly increased multiple myeloma risk (TT vs. CC: OR 8.92, 95% CI 1.06 - 75.24, p = 0.006; CC vs. AA: OR = 4.80, 95% CI 1.56 - 14.73, p = 0.044). No associations were found between polymorphisms and susceptibilities to acute lymphoblastic leukemia, acute myeloid leukemia, or non-Hodgkin's lymphoma.
CONCLUSIONS: MTHFRC677T polymorphisms influence the risk of hematological malignancy among the population in Jiangsu province. Both MTHFR 677TT and MTHFR 1298CC genotypes increase susceptibility to myeloid leukemia.

Casarini L, Simoni M
Gene polymorphisms in female reproduction.
Methods Mol Biol. 2014; 1154:75-90 [PubMed] Related Publications
This chapter presents an overview of the gene polymorphisms underlying the functions of ovarian receptors and their clinical implications in the female fecundity. A selection of genetic studies revealing significant associations between receptor polymorphisms, gene mutations, and some pathological conditions (i.e., female infertility, premature ovarian failure, polycystic ovary syndrome, endometriosis) are reviewed.

Tang M, Wang SQ, Liu BJ, et al.
The methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and tumor risk: evidence from 134 case-control studies.
Mol Biol Rep. 2014; 41(7):4659-73 [PubMed] Related Publications
Methylenetetrahydrofolate reductase (MTHFR) is an important enzyme involved in folate metabolism, which is essential for DNA synthesis and methylation. Genetic variations in the MTHFR gene seem to contribute to a decreased activity of MTHFR, ultimately confer increased susceptibility to cancer. As the most extensively studied polymorphism, MTHFR C677T polymorphism was shown to contribute to cancer susceptibility but the results were inconsistent. The authors performed a meta-analysis including 134 studies (46,207 cases and 69,160 controls) to address the issue. Odds ratios (ORs) with corresponding 95% confidence intervals (CIs) were used to assess the association. Overall, a significant elevated risk of cancer was associated with the MTHFR C677T polymorphism in T-allele versus C-allele comparison (OR = 1.06, 95% CI 1.02-1.11, P(heterogeneity) < 0.001), homozygote model (OR = 1.08, 95% CI 1.01-1.17, P(heterogeneity) < 0.001) and dominant model (OR = 1.05, 95% CI 1.00-1.10, P(heterogeneity) < 0.001). In the stratified analyses, significantly increased cancer risks were indicated among Asians in all genetic models except for heterozygote model. Further analysis revealed that C677T was significantly associated with an increased risk of esophageal and stomach cancer. This meta-analysis supports an association between the MTHFR C677T polymorphism and increased risk of esophageal and stomach cancer, especially among Asians. Additionally, more high-quality studies and that the covariates responsible for heterogeneity should be controlled to obtain a more conclusive response about the function of MTHFR C677T in cancer.

Lin J, Zeng RM, Li RN, Cao WH
Aberrant DNA methylation of the P16, MGMT, and hMLH1 genes in combination with the methylenetetrahydrofolate reductase C677T genetic polymorphism and folate intake in gastric cancer.
Genet Mol Res. 2014; 13(1):2060-8 [PubMed] Related Publications
Epidemiological studies have indicated that folate metabolism is correlated with increased risk of gastric cancer. Since methylenetetrahydrofolate reductase (MTHFR) is an important enzyme involved in folate metabolism, in this study, we examined whether polymorphisms and haplotypes of MTHFR are correlated with the risk of gastric cancer. The polymorphisms MTHFR C677T and MTHFR A1298C were genotyped by polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) analysis in 285 patients and 570 healthy controls. Association analyses based on binary logistic regression were conducted to determine the odds ratio (OR) and its 95% confidence interval (95%CI) for each genotype. The MTHFR 677TT genotype was significantly related with a reduced risk of gastric cancer (OR = 0.60, 95%CI = 0.39-0.92) compared to the CC genotype. Similarly, the MTHFR 1298CC genotype was significantly associated with a decreased risk of cancer (OR = 0.52, 95%CI = 0.32- 0.81). Haplotype analysis showed that the TC haplotype was associated with a reduced risk of gastric cancer compared to the most common haplotype, CA (OR = 0.28, 95%CI = 0.12-0.60). Our results suggest that the MTHFR C677T and MTHFR A1298C polymorphisms are related to gastric cancer susceptibility in the Chinese population.

Pu D, Jiang SW, Wu J
Association between MTHFR gene polymorphism and the risk of ovarian cancer: a meta-analysis of the literature.
Curr Pharm Des. 2014; 20(11):1632-8 [PubMed] Related Publications
OBJECTIVES: Methylenetetrahydrofolate reductase (MTHFR) is an essential enzyme for DNA biosynthesis and the epigenetic process of DNA methylation. MTHFR gene polymorphisms have been implicated as risk factors for several types of cancers. However, reports on the association of MTHFR polymorphisms with ovarian cancers are inconclusive. The aim of this study is to summarize on the reported data and meta-analytically investigate the relationship between the MTHFR C677T and A1298C polymorphism and the risk of ovarian cancer.
METHODS: We searched for all published articles indexed in MEDLINE (1950-2012), EMBASE (1974-2012), and CNKI (1994-2012). Case-control or cohort studies that relating to MTHFR polymorphism and ovarian cancer women were included and data were extracted independently by two reviewers. The search yielded 21 articles, from which 7 studies met the inclusion criteria. We performed a metaanalysis involving 3493 patients with ovarian cancer and 3863 controls with Review Manager 5.1 software. Odds ratio (OR) and 95% confidence intervals (CIs) were used to evaluate the ovarian cancer risk.
RESULTS: All the available data considered together, no association between the MTHFR C677T polymorphism and ovarian cancer risk was found in any genetic variations. However, in the subgroup analysis by ethnicity of Asian and Caucasian, MTHFR 677T was associated with significantly increased ovarian cancer risk among Asian [T allele vs. C allele: OR=1.50, 95% CI: 1.25-1.81, P<0.0001; CT + TT vs. CC (dominant model): OR=1.49, 95% CI: 1.18-1.88, P=0.0009; TT vs. CT + CC (recessive model): OR=2.33, 95% CI: 1.57-3.45, P<0.00001], while, there was no significant increased risk in Caucasian. As for MTHFR A1298C polymorphism, no marked association was found in either group of Caucasian population, while no data was available to analyze in Asian population.
CONCLUSIONS: The C677T polymorphism of the MTHFR gene is associated with the susceptibility of ovarian cancer in Asian population, suggesting that TT genotype may serve as a risk factor of ovarian cancer among Asian but not Caucasians. In addition, there is no association between A1298C gene polymorphism and ovarian cancer, including Caucasian and Asian women.

Li P, Chen Q, Wang YD, Ha MW
Effects of MTHFR genetic polymorphisms on toxicity and clinical response of irinotecan-based chemotherapy in patients with colorectal cancer.
Genet Test Mol Biomarkers. 2014; 18(5):313-22 [PubMed] Related Publications
AIMS: This meta-analysis aims to evaluate the effects of common polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene on the toxicity and clinical responses of irinotecan-based chemotherapy in patients with colorectal cancer (CRC).
METHODS: The PubMed, CISCOM, CINAHL, Web of Science, Google Scholar, EBSCO, Cochrane Library, and CBM databases were searched from their inception through November 1st, 2013 without language restrictions. Meta-analysis was conducted with the use of the STATA 12.0 software. Crude odds ratios (ORs) and their 95% confidence intervals (95% CIs) were calculated. Seven clinical cohort studies with a total of 815 CRC patients met the inclusion criteria. Two common polymorphisms (677 C>T and 1298 A>C) in the MTHFR gene were assessed.
RESULTS: The results from our meta-analysis suggested that MTHFR genetic polymorphisms might significantly decrease the rate of grade 3/4 toxicity of irinotecan-based chemotherapy in CRC patients (OR=0.53, 95% CI: 0.32-0.89, p=0.015). Furthermore, we also demonstrated that MTHFR genetic polymorphisms strongly correlated with good clinical responses (complete response+partial response) to irinotecan-based chemotherapy in CRC patients (OR=1.47, 95% CI: 1.05-2.04, p=0.024).
CONCLUSIONS: Our findings provide empirical evidence that MTHFR genetic polymorphisms may decrease the toxicity of irinotecan-based chemotherapy and increase the clinical benefits for CRC patients. Thus, MTHFR genetic polymorphisms may be screened to predict the clinical responses to irinotecan-based chemotherapy in CRC patients.

Ayad MW, El Naggar AA, El Naggar M
MTHFR C677T polymorphism: association with lymphoid neoplasm and effect on methotrexate therapy.
Eur J Haematol. 2014; 93(1):63-9 [PubMed] Related Publications
The aim of this study was to detect the possible role of methylene tetrahydrofolate reductase gene polymorphism (MTHFR C677T) in the pathogenesis of lymphoid neoplasms and to investigate the influence of this polymorphism on methotrexate toxicity in adult ALL patients treated with methotrexate maintenance therapy. There was a statistically significant increase in the risk of non-Hodgkin lymphoma in patients with CT genotype (OR, 2.9; 95% CI, 1.3-6.3; P = 0.007) and combined CT + TT genotype (OR, 3.2; 95% CI, 1.5-6.6; P = 0.006). While no significant association was found between this polymorphism and ALL risk. The patients with ALL treated with methotrexate during maintenance therapy were observed for signs of toxicity. MTHFR 677C>T polymorphism (CT + TT) was significantly overrepresented among cases with hepatic toxicity (OR = 15.6; 95% CI, 2.6-81.3; P = 0.001). In addition, they were overrepresented among cases with mucositis, anemia, thrombocytopenia, and leukopenia. However, it did not reach statistical significance level. Further studies on larger number of subjects are necessary. Additional studies on the role of MTHFR gene polymorphism with environment (folate intake) interaction are needed to confirm the role of these genetic polymorphisms.

Rai PS, Pai GC, Alvares JF, et al.
Intraindividual somatic variations in MTHFR gene polymorphisms in relation to colon cancer.
Pharmacogenomics. 2014; 15(3):349-59 [PubMed] Related Publications
AIM: MTHFR mediates the one carbon metabolism pathway. Two common genetic variants, C677T and A1298C, of MTHFR are associated with number of human diseases, including cancer, as well as being involved in the modulation of therapy outcome to antifolate drugs. To understand the distribution pattern of SNPs among different tissues of an individual, we examined MTHFR polymorphisms in normal and colon cancer tissues and compared the genotype frequencies in peripheral blood samples.
MATERIALS & METHODS: DNA was isolated from tumor tissue and matched normal tissues from 155 colon cancer patients. These samples as well as DNA from blood samples of the control group (n = 294) were analyzed for MTHFR polymorphisms by PCR-RFLP and confirmed by a direct DNA sequencing method.
RESULTS: Our data suggest that the allele and genotype frequencies of C677T and A1298C were significantly different between tumor tissues and both types of normal tissues. We have established that MTHFR variants that exist in tumor and matched normal tissues of colon cancer patients differ suggesting somatic variation in MTHFR polymorphisms among different tissues of an individual. The MTHFR A1298C polymorphism was associated with risk of colon cancer.
CONCLUSION: Different MTHFR variants may exist in different tissues to maintain physiological functions and may have implications for disease susceptibility and pharmacogenomics based therapies. Original submitted 21 January 2013; Revision submitted 3 January 2014.

Panic N, Mastrostefano E, Leoncini E, et al.
Susceptibility to Helicobacter pylori infection: results of an epidemiological investigation among gastric cancer patients.
Mol Biol Rep. 2014; 41(6):3637-50 [PubMed] Related Publications
The aim of this study was to identify the clinical, demographic, lifestyle factors and selected genetic polymorphisms that affect the susceptibility towards Helicobacter pylori (H. pylori) infection in gastric cancer patients. Histological confirmed gastric adenocarcinoma cases that underwent curative gastrectomy between 2002 and 2012 were included. Gastric biopsy samples were obtained to determine the H. pylori status, and further cagA status and vacA m and s genotypes by polymerase chain reaction. Patients were interviewed with structured questionnaires, and blood samples were collected for EPHX1, GSTM1, GSTT1, IL1B, IL1-RN, MTHFR and p53 genotyping. Proportions were compared in univariate analysis, while the relation between putative risk factors and H. pylori status and genotype were measured using logistic regression analysis. One hundred forty-nine gastric cancer patients were included, of which 78.5% were H. pylori positive. Among positive patients 50% were cagA+, 72.5% vacA m1 and 80.7% vacA s1. The presence of cagA was less frequent among vacA m1 (p = 0.031) and vacA s1 (p = 0.052) subtypes. The presence of father history for any cancer was a significant risk factor for H. pylori infection [adjusted odds ratio (OR) = 8.18, 95% confidence interval (CI) 1.04-64.55]. EPHX1 exon 3 T > C (OR = 0.35, CI 95% 0.13-0.94), IL1B-511 T > C (OR = 0.38, CI 95% 0.15-0.97) and IL1-RN VNTR (OR = 0.19, CI 95% 0.06-0.58) polymorphisms were protective towards H. pylori infection in the univariate analysis. Wine consumption was associated with higher risk of carrying the H. pylori vacA m1 virulent subtype (p = 0.034). Lastly, cardiovascular diseases were less common among cagA positive subjects (p = 0.023). Father history of any cancer is a risk factor for H. pylori infection. Polymorphisms in IL1B-511, IL1-RN and EPHX1 exon 3 genes might be protective towards H. pylori infection.

Martino A, Campa D, Jurczyszyn A, et al.
Genetic variants and multiple myeloma risk: IMMEnSE validation of the best reported associations--an extensive replication of the associations from the candidate gene era.
Cancer Epidemiol Biomarkers Prev. 2014; 23(4):670-4 [PubMed] Related Publications
BACKGROUND: Genetic background plays a role in multiple myeloma susceptibility. Several single-nucleotide polymorphisms (SNP) associated with genetic susceptibility to multiple myeloma were identified in the last years, but only a few of them were validated in independent studies.
METHODS: With the aim to conclusively validate the strongest associations so far reported, we selected the polymorphisms rs2227667 (SERPINE1), rs17501108 (HGF), rs3136685 (CCR7), rs16944 (IL1B), rs12147254 (TRAF3), rs1805087 (MTR), rs1800629 (TNF-α), rs7516435 (CASP9), rs1042265 (BAX), rs2234922 (mEH), and rs1801133 (MTHFR). We genotyped them in 1,498 multiple myeloma cases and 1,934 controls ascertained in the context of the International Multiple Myeloma rESEarch (IMMEnSE) consortium, and meta-analyzed our results with previously published ones.
RESULTS: None of the selected SNPs were significantly associated with multiple myeloma risk (P value range, 0.055-0.981), possibly with the exception of the SNP rs2227667 (SERPINE1) in women.
CONCLUSIONS: We can exclude that the selected polymorphisms are major multiple myeloma risk factors.
IMPACT: Independent validation studies are crucial to identify true genetic risk factors. Our large-scale study clarifies the role of previously published polymorphisms in multiple myeloma risk.

Coppedè F, Migheli F, Lopomo A, et al.
Gene promoter methylation in colorectal cancer and healthy adjacent mucosa specimens: correlation with physiological and pathological characteristics, and with biomarkers of one-carbon metabolism.
Epigenetics. 2014; 9(4):621-33 [PubMed] Article available free on PMC after 01/04/2015 Related Publications
We evaluated the promoter methylation levels of the APC, MGMT, hMLH1, RASSF1A and CDKN2A genes in 107 colorectal cancer (CRC) samples and 80 healthy adjacent tissues. We searched for correlation with both physical and pathological features, polymorphisms of folate metabolism pathway genes (MTHFR, MTRR, MTR, RFC1, TYMS, and DNMT3B), and data on circulating folate, vitamin B12 and homocysteine, which were available in a subgroup of the CRC patients. An increased number of methylated samples were found in CRC respect to adjacent healthy tissues, with the exception of APC, which was also frequently methylated in healthy colonic mucosa. Statistically significant associations were found between RASSF1A promoter methylation and tumor stage, and between hMLH1 promoter methylation and tumor location. Increasing age positively correlated with both hMLH1 and MGMT methylation levels in CRC tissues, and with APC methylation levels in the adjacent healthy mucosa. Concerning gender, females showed higher hMLH1 promoter methylation levels with respect to males. In CRC samples, the MTR 2756AG genotype correlated with higher methylation levels of RASSF1A, and the TYMS 1494 6bp ins/del polymorphism correlated with the methylation levels of both APC and hMLH1. In adjacent healthy tissues, MTR 2756AG and TYMS 1494 6bp del/del genotypes correlated with APC and MGMT promoter methylation, respectively. Low folate levels were associated with hMLH1 hypermethylation. Present results support the hypothesis that DNA methylation in CRC depends from both physiological and environmental factors, with one-carbon metabolism largely involved in this process.

Blank S, Rachakonda S, Keller G, et al.
A retrospective comparative exploratory study on two methylentetrahydrofolate reductase (MTHFR) polymorphisms in esophagogastric cancer: the A1298C MTHFR polymorphism is an independent prognostic factor only in neoadjuvantly treated gastric cancer patients.
BMC Cancer. 2014; 14:58 [PubMed] Article available free on PMC after 01/04/2015 Related Publications
BACKGROUND: Methylentetrahydrofolate reductase (MTHFR) plays a major role in folate metabolism and consequently could be an important factor for the efficacy of a treatment with 5-fluorouracil. Our aim was to evaluate the prognostic and predictive value of two well characterized constitutional MTHFR gene polymorphisms for primarily resected and neoadjuvantly treated esophagogastric adenocarcinomas.
METHODS: 569 patients from two centers were analyzed (gastric cancer: 218, carcinoma of the esophagogastric junction (AEG II, III): 208 and esophagus (AEG I): 143). 369 patients received neoadjuvant chemotherapy followed by surgery, 200 patients were resected without preoperative treatment. The MTHFR C677T and A1298C polymorphisms were determined in DNA from peripheral blood lymphozytes. Associations with prognosis, response and clinicopathological factors were analyzed retrospectively within a prospective database (chi-square, log-rank, cox regression).
RESULTS: Only the MTHFR A1298C polymorphisms had prognostic relevance in neoadjuvantly treated patients but it was not a predictor for response to neoadjuvant chemotherapy. The AC genotype of the MTHFR A1298C polymorphisms was significantly associated with worse outcome (p = 0.02, HR 1.47 (1.06-2.04). If neoadjuvantly treated patients were analyzed based on their tumor localization, the AC genotype of the MTHFR A1298C polymorphisms was a significant negative prognostic factor in patients with gastric cancer according to UICC 6th edition (gastric cancer including AEG type II, III: HR 2.0, 95% CI 1.3-2.0, p = 0.001) and 7th edition (gastric cancer without AEG II, III: HR 2.8, 95% CI 1.5-5.7, p = 0.003), not for AEG I. For both definitions of gastric cancer the AC genotype was confirmed as an independent negative prognostic factor in cox regression analysis. In primarily resected patients neither the MTHFR A1298C nor the MTHFR C677T polymorphisms had prognostic impact.
CONCLUSIONS: The MTHFR A1298C polymorphisms was an independent prognostic factor in patients with neoadjuvantly treated gastric adenocarcinomas (according to both UICC 6th or 7th definitions for gastric cancer) but not in AEG I nor in primarily resected patients, which confirms the impact of this enzyme on chemotherapy associated outcome.

Li X, Liao Q, Zhang S, Chen M
Association of methylenetetrahytrofolate reductase (MTHFR) C677T and A1298C polymorphisms with the susceptibility of childhood acute lymphoblastic leukaemia (ALL) in Chinese population.
Eur J Med Res. 2014; 19:5 [PubMed] Article available free on PMC after 01/04/2015 Related Publications
BACKGROUND: The aim of this study was to investigate the relationship between the polymorphisms of the methylenetetrahytrofolate reductase (MTHFR) gene and susceptibility to childhood acute lymphoblastic leukemia (ALL).
METHODS: A case-control study was conducted among 98 children with ALL and 93 age- and sex- matched non-ALL controls. Genotyping of MTHFR C677T and A1298C polymorphisms was performed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The odds ratios (ORs) of MTHFR genotypes were used to assess the associations of these polymorphisms with childhood ALL susceptibility.
RESULTS: No significant differences were observed for frequencies of the 677CC, 677CT and 677TT genotypes between patients and controls. Frequencies of the 1298AA, 1298 AC and 1298CC genotypes between the two groups were significantly different. The risk of ALL with the 1298C allele carriers (AC + CC) was elevated by 1.1 times compared with the AA genotype [OR = 2.100; 95% CI (1.149; 3.837); P = 0.015].
CONCLUSIONS: The MTHFR A1298C polymorphism is associated with susceptibility to childhood ALL in the Chinese population.

Wei ZH, Guo WH, Wu J, et al.
A nonsense mutation in the Xeroderma pigmentosum complementation group F (XPF) gene is associated with gastric carcinogenesis.
Gene. 2014; 537(2):238-44 [PubMed] Related Publications
XPF/ERCC1 endonuclease is required for DNA lesion repair. To assess effects of a C2169A nonsense mutation in XPF at position 2169 in gastric cancer tissues and cell lines, genomic DNA was extracted from blood samples of 488 cancer patients and 64 gastric tumors. The mutation was mapped using a TaqMan MGB probe. In addition, gastric cancer cell lines were transfected with mutated XPF to explore XPF/ERCC1 interaction, XPF degradation, and DNA repair by a comet assay. The C2169A mutation was not detected in 488 samples of blood genomic DNA, yet was found in 32 of 64 gastric cancer tissue samples (50.0%), resulting in a 194C-terminal amino acid loss in XPF protein and lower expression. Laser micro-dissection confirmed that this point mutation was not present in surrounding normal tissues from the same patients. The truncated form of XPF (tXPF) impaired interaction with ERCC1, was rapidly degraded via ubiquitination, and resulted in reduced DNA repair. In gastric cancers, the mutation was monoallelic, indicating that XPF is a haplo-insufficient DNA repair gene. As the C2169A mutation is closely associated with gastric carcinogenesis in the Chinese population, our findings shine light on it as a therapeutic target for early diagnosis and treatment of gastric cancer.

Qi X, Sun X, Xu J, et al.
Associations between methylenetetrahydrofolate reductase polymorphisms and hepatocellular carcinoma risk in Chinese population.
Tumour Biol. 2014; 35(3):1757-62 [PubMed] Related Publications
Genetic polymorphisms of methylenetetrahydrofolate reductase (MTHFR) gene are considered to have some influence on both folate metabolism and cancer risk. Previous studies on the associations of MTHFR genetic polymorphisms with hepatocellular carcinoma (HCC) risk in Chinese population reported inconsistent results. We performed this meta-analysis to comprehensively assess the associations. Finally, 12 individual case-control studies were included into the meta-analysis. There were seven studies (6,384 subjects) on the MTHFR C677T polymorphism and five studies (4,502 subjects) on the MTHFR A1298C polymorphism. Overall, MTHFR C677T polymorphism was significantly associated with susceptibility to HCC in Chinese population (T versus C, odds ratio (OR) = 1.09, 95 % confidence interval (95% CI) 1.01-1.17; TT versus CC, OR = 1.17, 95% CI 1.00-1.38; TT/CT versus CC, OR = 1.12, 95% CI 1.00-1.26). MTHFR A1298C polymorphism was conversely associated with HCC risk in Chinese population (CC versus AA, OR = 0.65, 95% CI 0.46-0.91; CC versus AA/AC, OR = 0.64, 95% CI 0.46-0.90). The sensitivity analysis confirmed the reliability and stability of the meta-analysis. Thus, the findings from our meta-analysis support the associations of MTHFR C677T and A1298C polymorphisms with HCC risk in Chinese population.

Li B, Zhang J, Wang L, et al.
MTHFR genetic polymorphisms may contribute to the risk of chronic myelogenous leukemia in adults: a meta-analysis of 12 genetic association studies.
Tumour Biol. 2014; 35(5):4233-45 [PubMed] Related Publications
Chronic myelogenous leukemia (CML) is a complex disease with a genetic basis. The genetic association studies (GASs) that have investigated the association between adult CML and 5,10-methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms have produced contradictory and inconclusive results. The aim of this meta-analysis is to provide a relatively comprehensive assessment of the association of these polymorphisms with adult CML risk. A literature search for eligible GAS published before September 15, 2013 was conducted in PubMed, Embase, Web of Science, Cochrane Library, and China National Knowledge Infrastructure (CNKI) databases. Pooled odds ratios (ORs) with their corresponding 95% confidence intervals (95% CIs) were used to evaluate the strength of the association under a fixed or random effect model according to heterogeneity test results. All analyses were performed using the Stata software, version 12.0. Twelve case-control studies were included in this meta-analysis with a total of 932 CML patients and 3,465 healthy controls. For MTHFR C677T (dbSNP: rs1801133, C>T), though the pooled ORs were not significant in the overall population, all the ORs greater than 1 suggested an increased risk of CML for carriers of the risk allele. However, stratified analysis based on genotyping method revealed a significant association in the PCR-restriction fragment length polymorphism (RFLP) subgroup, possibly as a result of heterogeneity. For MTHFR A1298C (dbSNP: rs1801131, A>C), the combined results showed that carriers of the C allele may be associated with a decreased risk of adult CML. Stratified analysis showed that the magnitude of this effect was especially significant among Asians, indicating ethnicity differences in adult CML susceptibility. This meta-analysis shows that the C allele of MTHFR A1298C may be associated with a decreased risk in adult CML, especially among Asians, while MTHFR C677T may not be associated with adult CML risk. However, the development of adult CML may be the result of gene-gene and gene-environment interactions, which should be considered in future individual GAS and subsequent meta-analyses.

Dixon SC, Ibiebele TI, Protani MM, et al.
Dietary folate and related micronutrients, folate-metabolising genes, and ovarian cancer survival.
Gynecol Oncol. 2014; 132(3):566-72 [PubMed] Related Publications
OBJECTIVE: Folate is essential for DNA synthesis and methylation and is implicated in tumour progression. Few studies have examined its role in ovarian cancer survival. Our objective was to determine relationships between intake of folate, related one-carbon nutrients, single nucleotide polymorphisms (SNPs) in folate-metabolising genes and survival following ovarian cancer diagnosis.
METHODS: This analysis included 1270 women with invasive epithelial ovarian cancer diagnosed in 2002-2006. Pre-diagnostic and some post-diagnostic lifestyle, dietary, and sociodemographic information was collected via self-administered questionnaires. DNA samples were genotyped for SNPs in methylenetetrahydrofolate reductase (MTHFR), methionine synthase (MTR) and methionine synthase reductase (MTRR) genes. Adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox regression.
RESULTS: Multivariate analyses did not identify associations between higher pre-diagnostic intake of folate, folic acid, vitamins B2, B6, and B12, methionine, betaine or choline and survival overall. In stratified analyses, higher folic acid and folate intake was associated with significantly worse survival among women with mucinous tumours (HRs per 100 μg 1.30 and 1.43, respectively) and smokers (HRs per 100 μg 1.23 and 1.16 respectively). There was also a suggestion that higher supplemental folic acid use post-diagnosis was associated with worse survival (HR per 100 μg 1.03, 95%CI 1.00-1.05). MTHFR SNP rs2066470 was significantly associated with survival (per allele HR 0.81, 95%CI 0.67-0.98).
CONCLUSIONS: Our data provide little evidence that folate intake affects ovarian cancer survival. However, combined effects with smoking, and findings within the mucinous subtype and for post-diagnosis folic acid, warrant further investigation.

Zhao J, Li W, Zhu D, et al.
Association of single nucleotide polymorphisms in MTHFR and ABCG2 with the different efficacy of first-line chemotherapy in metastatic colorectal cancer.
Med Oncol. 2014; 31(1):802 [PubMed] Article available free on PMC after 01/04/2015 Related Publications
Either oxaliplatin- or irinotecan-containing regimen could receive a good effectiveness in patients with metastatic colorectal cancer as the first-line chemotherapy, but not all patients would benefit from the treatment they have received. This study was to investigate the role of single nucleotide polymorphisms (SNPs) of methylenetetrahydrofolate reductase (MTHFR) and ATP-binding cassette sub-family G member 2 (ABCG2) in selecting the most appropriate treatment for individual patients. Ninety-two metastatic colorectal cancer patients treated with first-line 5-fluoropyrimidine (5-FU), leucovorin, and oxaliplatin (FOLFOX), capecitabine, and oxaliplatin (XELOX) and sixty-two patients receiving 5-FU, leucovorin, and irinotecan (FOLFIRI) were reviewed. The SNPs of MTHFR and ABCG2 were detected using gene sequencing method after DNA PCR amplification, which was extracted from peripheral blood karyocytes. Clinical characteristics and gene polymorphisms were evaluated in univariate and multivariate analysis as predictive factors for response rate (RR) and progression-free survival (PFS). In patients bearing 2-4 genotypes of MTHFR 677C/C, MTHFR 1298 A/C or C/C, ABCG2 34G/G, and ABCG2 421C/A or A/A, those who received oxaliplatin-based chemotherapy achieved a higher RR (41.7 vs. 18.8 %, P = 0.027) and longer median PFS (mPFS) than irinotecan-based therapy [8.9 vs. 7.1 m, FOLFIRI: hazard ratio (HR) = 1.722, 95 % confidence interval (CI) 1.026-2.892, P = 0.040, compared with FOLFOX/XELOX]; on the contrary, patients carrying 0 or 1 above genotype exhibited better outcomes after receiving FOLFIRI chemotherapy (mPFS: 9.3 vs. 6.4 m, FOLFIRI: HR = 0.422, 95 % CI 0.205-0.870, P = 0.019, compared with FOLFOX/XELOX). Combination of SNPs with MTHFR and ABCG2 may play a role in helping clinicians to select first-line chemotherapy for patients with metastatic colorectal cancer.

Khorshied MM, Shaheen IA, Abu Khalil RE, Sheir RE
Methylene tetrahydrofolate reductase (MTHFR) gene polymorphisms in chronic myeloid leukemia: an Egyptian study.
Med Oncol. 2014; 31(1):794 [PubMed] Related Publications
Methylenetetrahydrofolate reductase (MTHFR) gene plays a pivotal role in folate metabolism. Several genetic variations in MTHFR gene as MTHFR-C677T and MTHFR-A1298C result in decreased MTHFR activity, which could influence efficient DNA methylation and explain susceptibility to different cancers. The etiology of chronic myeloid leukemia (CML) is obscure and little is known about individual's susceptibility to CML. In order to assess the influence of these genetic polymorphisms on the susceptibility to CML and its effect on the course of the disease among Egyptians, we performed an age-gender-ethnic matched case-control study. The study included 97 CML patients and 130 healthy controls. Genotyping of MTHFR-C677T and -A1298C was performed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. The results showed no statistical difference in the distribution of MTHFR-C677T and -A1298C polymorphic genotypes between CML patients and controls. The frequency of MTHFR 677-TT homozygous variant was significantly higher in patients with accelerated/blastic transformation phase when compared to those in the chronic phase of the disease. In conclusion, our study revealed that MTHFR-C677T and -A1298C polymorphisms could not be considered as genetic risk factors for CML in Egyptians. However, MTHFR 677-TT homozygous variant might be considered as a molecular predictor for disease progression.

Qi YH, Yao LP, Cui GB, et al.
Meta-analysis of MTHFR C677T and A1298C gene polymorphisms: association with the risk of hepatocellular carcinoma.
Clin Res Hepatol Gastroenterol. 2014; 38(2):172-80 [PubMed] Related Publications
OBJECTIVE: Several studies have indicated an association between methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms and the risk of hepatocellular carcinoma (HCC). However, the conclusions are inconsistent. Therefore, a meta-analysis was performed.
METHODS: Databases like Pubmed, EMBASE, and EBSCO (up to September 2012) were searched to retrieve case-control trials about MTHFR (C677T or A1298C) polymorphisms and HCC. Literatures were independently screened by two researchers according to the inclusion and exclusion criteria. Data were extracted and analyzed by software STATA 11.0.
RESULTS: Nine studies were included with 10 datasets and 5132 cases. C677T polymorphism was associated with HCC risk in a heterozygous model (TT vs. CT: OR=1.20, 95% CI: 1.02-1.40). For the A1298C polymorphism, a significantly decreased HCC risk was found in the dominant, heterozygous and homozygous models (CC vs. AA+AC: OR=0.52, 95% CI: 0.33-0.80; CC vs. AC: OR=0.50, 95% CI: 0.32-0.79; CC vs. AA: OR=0.52, 95% CI: 0.33-0.81). Subgroup analysis stratified by ethnicity and type of control further indicated decreased HCC risks in Asians (CC vs. AA+AC: OR=0.47, 95% CI: 0.26-0.84; CC vs. AC: OR=0.41, 95% CI: 0.24-0.71; CC vs. AA: OR=0.46, 95% CI: 0.27-0.78), studies with controls of healthy people (CC vs. AA: OR=0.54, 95% CI: 0.31-0.93; CC vs. AC: OR=0.54, 95% CI: 0.31-0.94; CC vs. AA+AC: OR=0.55, 95% CI: 0.32-0.94), and controls of non-HCC patients (CC vs. AC: OR=0.43, 95% CI: 0.19-0.96).
CONCLUSIONS: Homozygous carriers of MTHFR C677T mutation are more susceptible to HCC, but homozygous mutations of MTHFR A1298C may play a protective role for developing HCC.

Liu N, Jiang J, Song YJ, et al.
Impact of MTHFR polymorphisms on methylation of MGMT in glioma patients from Northeast China with different folate levels.
Genet Mol Res. 2013; 12(4):5160-71 [PubMed] Related Publications
Hypomethylation of the O6-methylguanine-DNA-methyltransferase (MGMT) promoter in glioma cells has been associated with temozolomide resistance. S-adenosylmethionine (SAM), which is produced during folate metabolism, is the main source of methyl groups during DNA methylation. As a key enzyme during folate metabolism, polymorphisms of 5,10-methylenetetrahydrofolate reductase (MTHFR) may regulate folate end-products. We investigated the effect of typical polymorphisms of MTHFR (C677T and A1298C) on MGMT methylation based on different serum folate levels in patients with glioma from Northeast China. A total of 275 patients with glioma and 329 without malignant tumors were tested. Serum folate concentration was assayed by using the electrochemiluminescence immunoassay. MTHFR polymorphisms were detected by Taqman-Fluorescence quantitative polymerase chain reaction (PCR). Methylation-specific PCR was used to assess MGMT methylation. The constituent ratio of glioma patients below the serum folate biological reference value was significantly higher than that of the control population (P < 0.001). In patients with oligodendroglioma and glioblastoma, heterozygotes for the A1298C mutation were found in higher frequency than homozygotes or wild types (oligodendroglioma, P < 0.001; glioblastoma, P < 0.01). When grouped by the median or biological reference value of serum folate, only homozygotes for C677T with low levels of folate were significantly associated with decreased methylation of MGMT (median, P < 0.001; biological reference value, P = 0.036). These data suggest that, in combination with a negative folate balance in glioma patients, T/T genotypes in MTHFR C677T may be associated with MGMT demethylation.

Nassiri M, Kooshyar MM, Roudbar Z, et al.
Genes and SNPs associated with non-hereditary and hereditary colorectal cancer.
Asian Pac J Cancer Prev. 2013; 14(10):5609-14 [PubMed] Related Publications
BACKGROUND: Colorectal cancer is the third most common cancer in both men and women in the world and the second leading cause of cancer-related deaths. The incidence of colorectal cancer has increased in Iran in the past three decades and is now considered as a serious problem for our society. This cancer has two types hereditary and non-hereditary, 80% of cases being the latter. Considering that the relationship between SNPs with diseases is a concern, many researchers believed that they offer valuable markers for identifying genes responsible for susceptibility to common diseases. In some cases, they are direct causes of human disease. One SNP can increase risk of cancer, but when considering the rate of overlap and frequency of DNA repair pathways, it might be expected that SNP alone cannot affect the final result of cancer, although several SNPs together can exert a significant influence. Therefore identification of these SNPs is very important. The most important loci which include mutations are: MLH1, MSH2, PMS2, APC, MUTYH, SMAD7, STK11, XRCC3, DNMT1, MTHFR, Exo1, XRCC1 and VDR. Presence of SNPs in these genes decreases or increases risk of colorectal cancer.
MATERIALS AND METHODS: In this article we reviewed the Genes and SNPs associated with non-hereditary and hereditary of colorectal cancer that recently were reported from candidate gene y, meta-analysis and GWAS studies.
RESULTS: As with other cancers, colorectal cancer is associated with SNPs in gene loci. Generally, by exploring SNPs, it is feasible to predict the risk of developing colorectal cancer and thus establishing proper preventive measures.
CONCLUSIONS: SNPs of genes associated with colorectal cancer can be used as a marker SNP panel as a potential tool for improving cancer diagnosis and treatment planning.

Skoric D, Ivana J, Tanja R, et al.
Methylenetetrahydrofolate reductase and glutathione S-tranferase gene polymorphisms in secondary mixed phenotype acute leukemia: a case report.
J Pediatr Hematol Oncol. 2014; 36(3):e152-4 [PubMed] Related Publications
BACKGROUND: Therapy-induced leukemia is a well-known clinical syndrome occurring as a late complication in patients treated with cytotoxic therapy.
OBSERVATION: We herein present results of analysis of common gene polymorphisms in methylenetetrahydrofolate reductase (MTHFR) and glutathione S-transferase (GST) genes in a 10-year-old boy who developed very rare type of cancer, mixed phenotype acute leukemia, 6 years after treatment of acute lymphoblastic leukemia.
CONCLUSIONS: Impairment in function of GST and MTHFR enzymes found in our patient may have contributed to the development of secondary mixed phenotype acute leukemia, although precise mechanism remains elusive.

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