Gene Summary

Gene:MTHFR; methylenetetrahydrofolate reductase
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, HGNC, Ensembl, GeneCard, Gene
Protein:methylenetetrahydrofolate reductase
Source:NCBIAccessed: 01 September, 2019


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

Research Indicators

Publications Per Year (1994-2019)
Graph generated 01 September 2019 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 01 September, 2019 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)

Zhong R, Chen Q, Zhang X, et al.
Association between methylenetetrahydrofolate reductase (MTHFR) polymorphisms and lung cancer risk in Chinese people: An updated meta-analysis.
Medicine (Baltimore). 2019; 98(24):e16037 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The association between Methylenetetrahydrofolate Reductase (MTHFR) polymorphisms and lung cancer risk in Chinese people has been widely explored; however, the results remain controversial. Thus, we conducted a meta-analysis to investigate the association between MTHFR gene polymorphisms and susceptibility to lung cancer in Chinese people.
OBJECTIVE: We performed an updated meta-analysis to investigate the association between MTHFR gene polymorphisms and susceptibility to lung cancer in Chinese people.
METHODS: PubMed, EMBASE, WANFANG database, and CNKI were searched to collect eligible articles. The associations of MTHFR gene polymorphism with lung cancer risk were evaluated by calculating the pooled odds ratios (ORs) and the 95% confidence interval (CI). The dominant, recessive, heterozygous, homozygous, and allelic genetic models were used to calculate the combined ORs.
RESULTS: A total of 16 eligible studies were identified in the present meta-analysis. Evidence from the pooled results indicated a significant association between the MTHFR C677T polymorphism and lung cancer susceptibility in Chinese people under the dominant, recessive, homozygous and allelic genetic models (T vs C: OR = 1.252, 95% CI, 1.090-1.437; TT vs CC: OR = 1.741, 95% CI, 1.252-2.420. (TT + CT) vs CC: OR = 1.227, 95% CI, 1.030-1.426. TT vs (CT + CC): OR = 1.606, 95% CI, 1.207-2.137).
CONCLUSION: The present updated meta-analysis demonstrated that the MTHFR C677T polymorphism was significantly associated with susceptibility to lung cancer in Chinese people. Additional case-control studies with large sample sizes are needed to validate our findings.

Bai J, Li L, Li Y, et al.
Methylation of the promoter region of the MTRR gene in childhood acute lymphoblastic leukemia.
Oncol Rep. 2019; 41(6):3488-3498 [PubMed] Related Publications
Epigenetic analysis of the association between the methylation status of the promoter region of the MTRR (5‑methyltetrahydrofolate‑homocysteine methyltransferase reductase) gene and the risk of acute lymphoblastic leukemia (ALL) in children plays an important role in the early diagnosis, assessment of the malignant degree, treatment and evaluation of the risk of relapse and prognosis of the disease. In the present study, RT‑qPCR was used to detect the mRNA levels of the MTRR and MTHFR (methylenetetrahydrofolate reductase) genes in the bone marrow of 20 ALL patients and 20 age‑ and sex‑matched controls with normal bone marrow. The methylation pattern of the MTRR promoter region in eligible DNA samples was quantitatively analyzed using MALDI‑TOF MS. The results indicated that the mRNA expression level of MTRR in the bone marrow from children with ALL was lower than that in the control samples (P<0.05), but no significant difference was detected in the MTHFR gene between the two groups (P>0.05). According to the risk classification of ALL in children with high, medium and low risk, the low‑risk group had a higher methylation rate of CpG_6 compared to the medium‑risk group. However, the medium‑risk group had a higher CpG_46.47 methylation rate compared to the low‑risk group. The methylation rates of CpG_26 and CpG_46.47 in the high‑risk group were higher than these rates in the low‑risk group, while the CpG_42.23.44 methylation rate was lower in the high‑risk group than in the low‑risk group (P<0.05). The methylation rates at CpG_1, CpG_10, CpG_48 sites, score and the average methylation rate in the ALL‑H (high) group (≥50x109/l) were lower than these in the ALL‑NH (not high) group (<50x109/l) and the control group (P<0.05). We conclude that abnormal MTRR mRNA expression and the methylation of the MTRR promoter can be used to classify the risk of ALL in children.

Wei L, Niu F, Wu J, et al.
Association study between genetic polymorphisms in folate metabolism and gastric cancer susceptibility in Chinese Han population: A case-control study.
Mol Genet Genomic Med. 2019; 7(5):e633 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Gastric cancer (GC), the second leading cause of cancer mortality behind lung cancer worldwide, is caused by both genetic and environmental factors. In this study, we evaluated the association between the genetic polymorphisms of methylenetetrahydrofolate reductase (MTHFR), methionine synthesis reductase (MTR), and methyltransferase reductase (MTRR) genes and ischemic stroke risk in Chinese population.
METHODS: A case-control study was conducted including 681 patients with GC and 756 healthy controls. Chi-squared test/Fisher's exact test and genetic model were used to evaluate associations. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using unconditional logistic regression.
RESULTS: In the allele model, using the chi-square test, we found that the rs1532268 in MTRR with a minor allele T was significantly associated with increased risk of GC (OR = 1.24, 95% CI, 1.00-1.53; p = 0.048). In the genetic model analysis, we identified that the single-nucleotide polymorphism of the rs1801133 in MTHFR could increase the GC risk in the recessive model (OR = 1.31, 95% CI, 1.01-1.70; p = 0.042) and log-additive model (OR = 1.19, 95% CI, 1.02-1.38; p = 0.025). In MTHFR, a strong linkage of rs2274976 and rs1801133 was detected. The haplotype "GC" in the MTHFR gene was found to prominently increase the risk of GC (OR = 1.26, 95% CI: 1.07-1.47; p = 0.005). Other haplotypes did not display the correlativity.
CONCLUSION: This study suggested that MTR and MTHFR polymorphisms may contribute to increase the risk of GC.

Selmin OI, Donovan MG, Skovan B, et al.
Arsenic‑induced BRCA1 CpG promoter methylation is associated with the downregulation of ERα and resistance to tamoxifen in MCF7 breast cancer cells and mouse mammary tumor xenografts.
Int J Oncol. 2019; 54(3):869-878 [PubMed] Free Access to Full Article Related Publications
A significant percentage (~30%) of estrogen receptor‑α (ERα)‑positive tumors become refractory to endocrine therapies; however, the mechanisms responsible for this resistance remain largely unknown. Chronic exposure to arsenic through foods and contaminated water has been linked to an increased incidence of several tumors and long‑term health complications. Preclinical and population studies have indicated that arsenic exposure may interfere with endocrine regulation and increase the risk of breast tumorigenesis. In this study, we examined the effects of sodium arsenite (NaAsIII) exposure in ERα‑positive breast cancer cells in vitro and in mammary tumor xenografts. The results revealed that acute (within 4 days) and long‑term (10 days to 7 weeks) in vitro exposure to environmentally relevant doses reduced breast cancer 1 (BRCA1) and ERα expression associated with the gain of cyclin D1 (CCND1) and folate receptor 1 (FOLR1), and the loss of methylenetetrahydrofolate reductase (MTHFR) expression. Furthermore, long‑term exposure to NaAsIII induced the proliferation and compromised the response of MCF7 cells to tamoxifen (TAM). The in vitro exposure to NaAsIII induced BRCA1 CpG methylation associated with the increased recruitment of DNA methyltransferase 1 (DNMT1) and the loss of RNA polymerase II (PolII) at the BRCA1 gene. Xenografts of NaAsIII‑preconditioned MCF7 cells (MCF7NaAsIII) into the mammary fat pads of nude mice produced a larger tumor volume compared to tumors from control MCF7 cells and were more refractory to TAM in association with the reduced expression of BRCA1 and ERα, CpG hypermethylation of estrogen receptor 1 (ESR1) and BRCA1, and the increased expression of FOLR1. These cumulative data support the hypothesis that exposure to AsIII may contribute to reducing the efficacy of endocrine therapy against ERα‑positive breast tumors by hampering the expression of ERα and BRCA1 via CpG methylation, respectively of ESR1 and BRCA1.

Morishita T, Hishida A, Okugawa Y, et al.
Polymorphisms in folic acid metabolism genes do not associate with cancer cachexia in Japanese gastrointestinal patients.
Nagoya J Med Sci. 2018; 80(4):529-539 [PubMed] Free Access to Full Article Related Publications
We used clinical data from Iga General Hospital to examine the association between polymorphisms in

Kumawat R, Gowda SH, Debnath E, et al.
Association of Single Nucleotide Polymorphisms (SNPs) in Genes Encoding for Folate Metabolising Enzymes with Glioma and Meningioma in Indian Population
Asian Pac J Cancer Prev. 2018; 19(12):3415-3425 [PubMed] Free Access to Full Article Related Publications
Background: The association of primary brain tumors with Single Nucleotide polymorphisms (SNPs) in genes of folate metabolising enzymes have been reported to vary among different ethnic population. Here, we have studied the association of SNPs of folate metabolizing genes with the primary brain tumors (glioma and meningioma) in North Indian population. Methods: SNPs of genes coding for folate metabolizing enzymes was carried out in 288 study population from North India [Glioma (n=108), Meningioma (n=76) and healthy-control (n=104)]. The allele-specific polymerase chain reaction (ARMS-PCR) was used to analyse the SNP A1298C of the MTHFR (Methylenetetrahydrofolate-reductase) and the SNP A66G of the methionine synthase reductase (MTRR) genes. The PCR-RLFP (Restriction Fragment Length Polymorphism) was used to analyse the SNP C677T of the Methylene tetrahydrofolate-reductase and the SNP A2756G of the methionine-synthase (MTR) genes. Serum homocysteine, vitamin B12 and folate levels were evaluated in controls/ patients serum using Chemiluminescence immunoassay and the levels were correlated with SNPs genotype. Results: The CC genotype of MTHFR A1298C was observed to have reduced risk of having meningioma than AA genotype (odd ratio=0.62, 95%CI 0.32-0.97, p=0.03). Similarly, the AG genotype of MTRR A66G showed reduced risk of glioma than AA genotype (odd ratio=0.56, 95%CI 0.32-0.97, p=0.039). Furthermore, in patients with AA genotype of MTR A2756G and CT genotype of MTHFR C677T showed higher serum homocysteine level than GG genotype (8.6 μmol/L, p=0.048) and CC genotype (11.2μmol/L, p=0.039) respectively. Conclusion: Our findings provide an insight into the risk association of SNPs in MTHFR A1298C and MTRR A66G genes with glioma/meningioma patients. Further studies are needed to evaluate their clinical implications.

Frikha R, Rebai T, Lobna BM, et al.
Comprehensive analysis of Methylenetetrahydrofolate reductase C677T in younger acute lymphoblastic leukemia patients: A single-center experience.
J Oncol Pharm Pract. 2019; 25(5):1182-1186 [PubMed] Related Publications
CONTEXT: Methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms, mainly the C677T, have been implicated as risk factors for several cancers as the acute lymphoblastic leukemia (ALL). In addition, a potential effect of such variant on the efficacy of methotrexate (MTX) has been reported.
OBJECTIVE: In this study, we evaluated the impact of the C677T variant of MTHFR on MTX-related toxicity in ALL patients from Tunisia; to provide new insights for a personalized therapy based on the human genotype.
MATERIALS AND METHODS: Genotyping was carried out with restriction fragment length polymorphism (RFLP) on blood samples from a total of 35 younger patients; suffering from ALL.
RESULTS: In the ALL patients, the MTHFR 677CT genotype confers a greater risk of toxicity with 1.3 times as relative risk mainly the hepatic toxicity when compared with MTHFR 677CC.
CONCLUSION: Our findings suggest that C677T polymorphism of MTHFR seems to be a good marker for MTX-related toxicity in ALL.

Salvador-Martín S, García-González X, García MI, et al.
Clinical utility of ABCB1 genotyping for preventing toxicity in treatment with irinotecan.
Pharmacol Res. 2018; 136:133-139 [PubMed] Related Publications
Preventing severe irinotecan-induced adverse reactions would allow us to offer better treatment and improve patients' quality of life. Transporters, metabolizing enzymes, and genes involved in the folate pathway have been associated with irinotecan-induced toxicity. We analyzed 12 polymorphisms in UGT1A1, ABCB1, ABCG2, ABCC4, ABCC5, and MTHFR in 158 patients with metastatic colorectal cancer treated with irinotecan and studied the association with grade >2 adverse reactions (CTCAE). Among the most frequent ADRs, the SNPs rs1128503, rs2032582, and rs1045642 in ABCB1 and rs1801133 in MTHFR were associated with hematological toxicity and overall toxicity. The SNP rs11568678 in ABCC4 was also associated with overall toxicity. After correction of P values using a false discovery rate, only ABCB1 variants remained statistically significant. Haplotype analysis in ABCB1 showed an 11.3-fold and 4.6-fold increased risk of hematological toxicity (95% CI, 1.459-88.622) and overall toxicity (95% CI, 2.283-9.386), respectively. Consequently, genotyping of the three SNPs in ABCB1 can predict overall toxicity and hematological toxicity with a diagnostic odds ratio of 4.40 and 9.94, respectively. Genotyping of ABCB1 variants can help to prevent severe adverse reactions to irinotecan-based treatments in colorectal cancer.

Zawiah M, Yousef AM, Kadi T, et al.
Early disease relapse in a patient with colorectal cancer who harbors genetic variants of DPYD, TYMS, MTHFR and DHFR after treatment with 5-fluorouracil-based chemotherapy.
Drug Metab Pers Ther. 2018; 33(4):201-205 [PubMed] Related Publications
Background Early relapse in colorectal cancer (CRC) after curative resection is mainly attributed to the key determinants such as tumor histology, stage, lymphovascular invasion, and the response to chemotherapy. Case presentation Interindividual variability in the efficacy of adjuvant chemotherapy between patients receiving the same treatment may be ascribed to the patients' genetic profile. In this report, we highlight a clinical case of a patient with stage II CRC who relapsed within a short period after starting adjuvant chemotherapy and was later found to have multiple genetic polymorphisms in the DPYD, TYMS, MTHFR, and DHFR genes. Conclusions Based on the clinical data of the patient and the key role of these genes in 5-fluorouracil pathway, we hypothesize that these variants may contribute to the drug response and early relapse in CRC.

Ge W, Jiao Y, Chang L
The association between MTHFR gene polymorphisms (C677T, A1298C) and oral squamous cell carcinoma: A systematic review and meta-analysis.
PLoS One. 2018; 13(8):e0202959 [PubMed] Free Access to Full Article Related Publications
A consensus has not been reached regarding the association of MTHFR gene polymorphism and susceptibility to oral squamous cell carcinoma (OSCC). We performed a meta-analysis to better evaluate the association between MTHFR C677T, A1298C polymorphism and OSCC risk. The studies regarding the association of MTHFR C677T, A1298C polymorphisms and OSCC were identified in PubMed and EMBASE and Google Scholar. The pooled odd rates (ORs) with 95%CIs were estimated using a fixed-effect or random-effect model. The associations between MTHFR polymorphisms and OSCC risk were assessed under the dominant, recessive and additive models. A collective total of 1539 OSCC patients and 2131 normal controls were included across 13 studies. The minor T allele of MTHFR C677T was significantly associated with the increased risk of OSCC development(OR = 1.35, 95%CI 1.04-1.76). Individuals carrying the ''T" allele (TT+CT) had a nearly 43% increased risk for OSCC development when compared with CC (OR = 1.43, 95%CI 1.02-1.99). Under additive model, the results also showed that individuals with CT or TT genotype were more susceptible to OSCC than CC (OR = 1.45, 95%CI 1.02-2.08; OR = 1.79, 95%CI 1.28-2.50; respectively). The subgroup analysis by ethnicity revealed that significant difference in C677T allele distribution could be observed in European (OR = 1.33, 95%CI 1.02-1.75) rather than Asian (OR = 1.59, 95%CI 0.91-2.78). No significant association of MTHFR A1298C polymorphism and OSCC risk could be observed. The present study revealed that T allele and TT genotype of MTHFR C677T polymorphism were significantly associated with the increased risk of OSCC development.

Pieroth R, Paver S, Day S, Lammersfeld C
Folate and Its Impact on Cancer Risk.
Curr Nutr Rep. 2018; 7(3):70-84 [PubMed] Free Access to Full Article Related Publications
PURPOSE OF REVIEW: Research has evaluated the potential impact of folate on cancer risk with conflicting findings. Studies have demonstrated increased risk, no effect, and decreased risk. This review summarizes findings of mixed results between folate intake, serum levels, gene polymorphisms, and cancer risk based on meta-analyses from the past five years.
RECENT FINDING: Low or deficient folate status is associated with increased risk of many cancers. Folic acid supplementation and higher serum levels are associated with increased risk of prostate cancer. Gene polymorphisms may impact risk in certain ethnic groups. Folate has been studied extensively due to its role in methylation and nucleotide synthesis. Further prospective studies are needed to clarify optimal levels for nutrient remediation and risk reduction in those at risk, as well as elucidate the association between high intake, high serum levels, and prostate cancer risk. Future considerations for cancer risk may include gene interactions with nutrients and environmental factors.

Senghore T, Li YF, Sung FC, et al.
Associations Between
Anticancer Res. 2018; 38(7):4021-4026 [PubMed] Related Publications
AIM: The study aimed to investigate the role of two polymorphisms of methylenetetrahydrofolate reductase (MTHFR), C677T and A1298C, in the risk of potentially malignant oral disorders (PMODs).
MATERIALS AND METHODS: Genotypes of the MTHFR C677T and A1298C polymorphisms were determined using polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) for 224 PMOD cases and 485 age-matched controls.
RESULTS: The C677T T allele-carrying genotypes were significantly associated with a decreased risk of PMODs [odds ratio (OR)=0.62, 95% confidence interval (CI)=0.44-0.86]. Haplotype analysis also indicated that the 677T/1298A haplotype was associated with a decreased risk of PMODs (OR=0.56, 95%CI=0.40-0.80). No significant interaction was observed between MTHFR polymorphisms and lifestyle factors.
CONCLUSION: Our findings suggest that the T-allele-carrying MTHFR C677T genotype or haplotype may reduce the risk of PMODs. However, these observations require further confirmation using larger samples.

Shiao SPK, Grayson J, Lie A, Yu CH
Personalized Nutrition-Genes, Diet, and Related Interactive Parameters as Predictors of Cancer in Multiethnic Colorectal Cancer Families.
Nutrients. 2018; 10(6) [PubMed] Free Access to Full Article Related Publications
To personalize nutrition, the purpose of this study was to examine five key genes in the folate metabolism pathway, and dietary parameters and related interactive parameters as predictors of colorectal cancer (CRC) by measuring the healthy eating index (HEI) in multiethnic families. The five genes included

Yousef AM, Zawiah M, Al-Yacoub S, et al.
The association of polymorphisms in folate-metabolizing genes with response to adjuvant chemotherapy of colorectal cancer.
Cancer Chemother Pharmacol. 2018; 82(2):237-243 [PubMed] Related Publications
BACKGROUND: Colorectal cancer (CRC) is one of the major health issues worldwide. 5-Fluorouracil (5-FU) is a cornerstone of chemotherapy for CRC and the major targets of 5-FU are folate-metabolizing enzymes.
METHODS: A total of 103 CRC patients with complete clinical data were included in this prospective cohort study. Genotyping was performed using polymerase chain reaction (PCR) followed by sequencing. Using Kaplan-Meier curves, log-rank tests, and Cox proportional hazard models, we evaluated associations between functional polymorphisms in four genes MTHFR (1298A>C and 677C>T), DPYD (496A>G and 85T>C), DHFR 19 bp del, and MTR (2756 A>G) with disease-free survival (DFS).
RESULTS: The minor allele frequencies of MTHFR 1298A>C, MTHFR 677C>T, DPYD 496A>G, DPYD 85T>C, DHFR 19 bp del, and MTR 2756 A>G were 0.364, 0.214, 0.116, 0.209, 0.383, and 0.097, respectively. CRC patients carrying the homozygous GG genotype in DPYD 496A>G had 4.36 times shorter DFS than wild-type AA carriers, (DFS
CONCLUSION: Genetic polymorphism in DPYD seems to be associated with DFS in CRC patients receiving an adjuvant regimen of 5-FU/capecitabine-based chemotherapy. Further studies are needed to verify these findings.

Zhong L, Fu Q, Zhou S, et al.
Relevance of
BMJ Open. 2018; 8(5):e020767 [PubMed] Free Access to Full Article Related Publications
OBJECTIVE: To evaluate the association between methylenetetrahydrofolate reductase (
DESIGN: Meta-analysis.
METHODS: We searched PubMed, Embase and Web of Science databases from inception up to October 2017 for relevant studies. The statistical analysis was performed using STATA V.12.0 software. The pooled ORs and 95% CIs were used to assess the strength of the association under the allele, dominant and recessive models. We also conducted subgroup analysis stratified by cancer type, ethnicity and study design. Additionally, the sensitivity analysis was performed by sequential omission of individual studies, and the publication bias was detected using both Begg's test and Egger's test.
RESULTS: A total of 2020 patients from 12 studies were included in this meta-analysis. The results showed that there was no significant association between
CONCLUSIONS: This meta-analysis suggested that

Gajjar KK, Vora HH, Kobawala TP, et al.
Deciphering the potential value of 5-fluorouracil metabolic enzymes in predicting prognosis and treatment response of colorectal cancer patients.
Int J Biol Markers. 2018; 33(2):180-188 [PubMed] Related Publications
INTRODUCTION: 5-flourouracil (5-FU) is one of the standard chemotherapeutic drugs used today in the treatment of colorectal cancer patients. Disruption of 5-FU metabolic pathway may contribute to altered effectiveness towards 5-FU-based therapy. Hence, the study of 5-FU metabolizing enzymes might have the potential efficacy to predict survival and response to treatment in colorectal cancer patients.
MATERIALS AND METHODS: Immunohistochemical localization of 5-FU metabolic enzymes (TS, MTHFR, DPYD, and TP) was evaluated in 143 untreated patients with colorectal cancer; their prognostic and predictive values were also evaluated.
RESULTS: Immuno-positivity for TS, MTHFR, DPYD, and TP was observed in 77%, 75%, 88%, and 96% of colorectal cancer patients, respectively. Univariate survival analysis in total patients showed that low DPYD expression significantly predicted adverse overall survival ( P=0.042). Moreover, subgroup of colon cancer patients with low TS expression was associated with unfavorable prognosis. TP expression also emerged as a prognosticator in the subgroup of early and advanced stage patients. Additionally, when effect of co-expression of 5-FU metabolic enzymes was evaluated in total patients, low coexpression of all four proteins was predictive of poor overall survival than for individuals expressing high coexpression of these proteins ( P=0.045). In contrast, none of the 5-FU metabolic enzymes-either singly or on coexpression-emerged as a useful biomarker of potential therapeutic value when evaluated in the subgroup of patients treated with 5-FU alone or 5-FU plus oxaliplatin.
CONCLUSION: The above findings suggest that coexpression of 5-FU metabolic enzymes possess significant prognostic value and could be useful biomarkers in colorectal cancer patients.

Kaur RP, Shafi G, Benipal RPS, Munshi A
Frequency of pathogenic germline mutations in cancer susceptibility genes in breast cancer patients.
Med Oncol. 2018; 35(6):81 [PubMed] Related Publications
In this study, we evaluated the incidence of pathogenic germline mutations in 30 breast cancer susceptibility genes in breast cancer patients. Our aim was to understand the involvement of the inherited mutations in these genes in a breast cancer cohort. Two hundred ninety-six female breast cancer patients including 4.5% of familial breast cancer cases were included in the study. 200 ng of genomic DNA was used to evaluate the pathogenic mutations, detected using Global Screening Array (GSA) microchip (Illumina Inc.) according to the manufacturer's instructions. The pathogenic frameshift and nonsense mutations were observed in BRCA2 (10.9%), MLH1 (58.6%), MTHFR (50%), MSH2 (14.2%), and CYTB (52%) genes. Familial breast cancer patients (4.5%) had variations in BRCA2, MLH1, MSH2, and CYTB genes. 28% of patients with metastasis, recurrence, and death harbored mono/biallelic alterations in MSH2, MLH1, and BRCA2 genes. The results of this study can guide to develop a panel to test the breast cancer patients for pathogenic mutations, from Malwa region of Punjab. The screening of MSH2, MLH1, and BRCA2 should be carried in individuals with or without family history of breast cancer as these genes have been reported to increase the cancer risk by tenfold.

Fesenko DO, Avdonina MA, Gukasyan LG, et al.
[Multiplex Genotyping of Allelic Variants of Genes Involved in Metabolizing Antileukemic Drugs].
Mol Biol (Mosk). 2018 Mar-Apr; 52(2):238-245 [PubMed] Related Publications
A biochip, primer set, and genotyping protocol were developed to simultaneously address 16 single nucleotide polymorphisms in antileukemic drug metabolism genes, including TPMT, ITPA, MTHFR, SLCO1B1, SLC19A1, NR3C1, GRIA1, ASNS, MTRR, and ABCB1. The genotyping procedure included a one-round multiplex polymerase chain reaction (PCR) with simultaneous incorporation of a fluorescent label into the PCR product and subsequent hybridization on a biochip with immobilized probes. The method was used to test 65 DNA samples of leukemia patients. Fluorescence signal intensity ratios in pairs of wild-type and respective mutant sequence probes were analyzed for all polymorphic markers and demonstrated high accuracy of genotyping. The reliability of genotype determination using the biochip was confirmed by direct Sanger sequencing.

Eldem İ, Yavuz D, Cumaoğullari Ö, et al.
SLCO1B1 Polymorphisms are Associated With Drug Intolerance in Childhood Leukemia Maintenance Therapy.
J Pediatr Hematol Oncol. 2018; 40(5):e289-e294 [PubMed] Related Publications
BACKGROUND: Therapy discontinuations and toxicities occur because of significant interindividual variations in 6-mercaptopurine (6-MP) and methotrexate (MTX) response during maintenance therapy of childhood acute lymphoblastic leukemia (ALL). 6-MP/MTX intolerance in some of the patients cannot be explained by thiopurine S-methyl transferase (TPMT) gene variants. In this study, we aimed to investigate candidate pharmacogenetic determinants of 6-MP and MTX intolerance in Turkish ALL children.
METHODS: In total, 48 children with ALL who had completed or were receiving maintenance therapy according to Children's Oncology Group (COG) protocols were enrolled. Fifteen single-nucleotide polymorphisms in 8 candidate genes that were related to drug toxicity or had a role in the 6-MP/MTX metabolism (TPMT, ITPA, MTHFR, IMPDH2, PACSIN2, SLCO1B1, ABCC4, and PYGL) were genotyped by competitive allele-specific PCR (KASP). Drug doses during maintenance therapy were modified according to the protocol.
RESULTS: The median drug dose intensity was 50% (28% to 92%) for 6-MP and 58% (27% to 99%) for MTX in the first year of maintenance therapy, which were lower than that scheduled in all patients. Among the analyzed polymorphisms, variant alleles in SLCO1B1 rs4149056 and rs11045879 were found to be associated with lower 6-MP/MTX tolerance.
CONCLUSIONS: SLCO1B1 rs4149056 and rs11045879 polymorphisms may be important genetic markers to individualize 6-MP/MTX doses.

Pérez-Ramírez C, Cañadas-Garre M, Alnatsha A, et al.
Pharmacogenetics of platinum-based chemotherapy: impact of DNA repair and folate metabolism gene polymorphisms on prognosis of non-small cell lung cancer patients.
Pharmacogenomics J. 2019; 19(2):164-177 [PubMed] Related Publications
Chemotherapy based on platinum compounds is the standard treatment for NSCLC patients with EGFR wild type, and is also used as second line in mutated EGFR patients. Nevertheless, this therapy presents poor clinical outcomes. ERCC1, ERCC2, XRCC1, MDM2, MTHFR, MTR, and SLC19A1 gene polymorphisms may contribute to individual variation in response and survival to platinum-based chemotherapy. The aim of this study was to investigate the influence of these polymorphisms on response and survival of NSCLC patients treated with platinum-based chemotherapy. A retrospective-prospective cohorts study was conducted, including 141 NSCLC patients. Polymorphisms were analyzed by PCR real-time with Taqman® probes. Patients with ERCC1 rs3212986-GG (p = 0.0268; OR = 2.50; CI

Lu D, Zhuo J, Yang M, et al.
The association between donor genetic variations in one-carbon metabolism pathway genes and hepatitis B recurrence after liver transplantation.
Gene. 2018; 663:121-125 [PubMed] Related Publications
BACKGROUNDS AND AIM: Hepatitis B recurrence adversely affects patients' survival after liver transplantation. This study aims to find association between donor gene variations of one carbon metabolism and post-transplant hepatitis B recurrence.
METHODS: This study enrolled 196 patients undergoing liver transplantation for HBV related end-stage liver diseases. We detected 11 single nucleotide polymorphisms (SNP) of 7 one-carbon metabolism pathway genes (including MTHFR, MTR, MTRR, ALDH1L1, GART, SHMT1 and CBS) in donor livers and analyzed their association with HBV reinfection after liver transplantation.
RESULTS: Hepatitis B recurrence was observed in 19 of the 196 patients (9.7%) undergoing liver transplantation. Hepatitis B recurrence significantly affected post-transplant survival in the 196 patients (p = 0.018), and correlate with tumor recurrence in the subgroup of HCC patients (n = 99, p = 0.006). Among the 11 SNPs, donor liver mutation in rs1979277 (G > A) was adversely associated with post-transplant hepatitis B recurrence (p = 0.042). In the subgroup of HCC patients, survival analysis showed donor liver mutations in rs1801133 (G > A) and rs1979277 (G > A) were risk factors for hepatitis B recurrence (p < 0.05). None of the 11 SNPs was related to hepatitis B recurrence in non-HCC patients (n = 97, p > 0.05).
CONCLUSION: Hepatitis B recurrence impaired post-transplant survival. Donor liver genetic variations in one-carbon metabolism pathway genes were significantly associated with post-transplant hepatitis B recurrence.

Lin KM, Yang MD, Tsai CW, et al.
The Role of
Anticancer Res. 2018; 38(4):2001-2006 [PubMed] Related Publications
AIM: To evaluate the contribution of methylenetetrahydrofolate reductase (MTHFR) genotype to the risk of colorectal cancer (CRC) in Taiwan.
MATERIALS AND METHODS: In this hospital-based case-control study, the role of MTHFR C677T (rs1801133) and A1298C (rs1801131) genotypes in determining CRC risk were investigated among 362 patients with CRC and an equal number of age- and gender-matched healthy individuals.
RESULTS: The percentages of CC, CT and TT genotypes for MTHFR rs1801133 were 64.1%, 29.8% and 6.1% in the CRC group and 51.1%, 37.0% and 11.9% in the control group, respectively (p for trend=0.0006). Analysis of the allelic frequency distribution showed that the variant T allele of MTHFR rs1801133 conferred a lower CRC susceptibility than did the wild-type C allele (odds ratio(OR)=0.66, 95% confidence interval(CI)=0.52-0.84, p=4.32×10
CONCLUSION: MTHFR rs1801133 T allele serves as a predictive marker for CRC risk and future studies with larger samples and functional evaluation are warranted to validate the current findings.

Gutierrez-Camino A, Umerez M, Santos B, et al.
Pharmacoepigenetics in childhood acute lymphoblastic leukemia: involvement of miRNA polymorphisms in hepatotoxicity.
Epigenomics. 2018; 10(4):409-417 [PubMed] Related Publications
AIM: Hepatotoxicity is one of the most common drug-related toxicities during the treatment of childhood acute lymphoblastic leukemia (ALL). Many genes involved in liver-specific signaling pathways are tightly controlled by miRNAs, and miRNA function could be modulated by SNPs. As a consequence, we hypothesized that variants in miRNAs could be associated with drug-induced hepatotoxicity.
METHODS: We analyzed 213 SNPs in 206 miRNAs in a cohort of 179 children with ALL homogeneously treated.
RESULTS: rs2648841 in miR-1208 was the most significant SNP during consolidation phase after false discovery rate correction, probably through an effect on its target genes DHFR, MTR and MTHFR.
CONCLUSION: These results point out the possible involvement of SNPs in miRNAs in toxicity to chemotherapy in children with ALL.

Chittiboyina S, Chen Z, Chiorean EG, et al.
The role of the folate pathway in pancreatic cancer risk.
PLoS One. 2018; 13(2):e0193298 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Pancreatic cancer is the third leading cause of cancer related deaths in the United States. Several dietary factors have been identified that modify pancreatic cancer risk, including low folate levels. In addition to nutrition and lifestyle determinants, folate status may be influenced by genetic factors such as single nucleotide polymorphisms (SNPs). In the present study, we investigated the association between folate levels, genetic polymorphisms in genes of the folate pathway, and pancreatic cancer.
METHODS: Serum and red blood cell (RBC) folate levels were measured in pancreatic cancer and control subjects. Genotypes were determined utilizing Taqman probes and SNP frequencies between cases and controls were assessed using Fisher's exact test. Logistic regression was used to estimate the odds ratio (OR) and corresponding 95% confidence intervals (CIs) to measure the association between genotypes and pancreatic cancer risk. The association between folate levels and SNP expression was calculated using one-way ANOVA.
RESULTS: Mean RBC folate levels were significantly lower in pancreatic cancer cases compared to unrelated controls (508.4 ± 215.9 ng/mL vs 588.3 ± 229.2 ng/mL, respectively) whereas serum folate levels were similar. Irrespective of cancer status, several SNPs were found to be associated with altered serum folate concentrations, including the D919G SNP in methionine synthase (MTR), the L474F SNP in serine hydroxymethyl transferase 1 (SHMT1) and the V175M SNP in phosphatidyl ethanolamine methyltransferase (PEMT). Further, the V allele of the A222V SNP and the E allele of the E429A SNP in methylene tetrahydrofolate reductase (MTHFR) were associated with low RBC folate levels. Pancreatic cancer risk was found to be significantly lower for the LL allele of the L78R SNP in choline dehydrogenase (CHDH; OR = 0.29; 95% CI 0.12-0.76); however, it was not associated with altered serum or RBC folate levels.

Kotova N, Maichuk V, Fedorenko O
Georgian Med News. 2018; (274):52-59 [PubMed] Related Publications
Neural tube defects occupy second place in frequency after the defects of the cardiovascular system. The folate metabolism violation and hyperhomocysteinemia in women are proved to be the leading risk factors for the NTD of the fetus. Polymorphism of the 5,10-methylenetetrahydrofolate reductase gene (MTHFR) is a genetic determinant of folate metabolism violation. Admission of folic acid in a standard dose of 0.4 mg and / or the use of fortified foods does not allow reaching the protective level of folic acid if there is a mutation of the MTHFR gene or when several risk factors combine, which requires a higher dose of folic acid. The aim of the study is to develop an algorithm for the identification of women of reproductive age with the risk of having a child with NTD and to apply differentiated approach to the choice of a preventive dose of folic acid. A retrospective analysis of NTD cases in the Odessa region (Ukraine) for 2000-2013 was carried out. The frequency of the birth of children with CNS defects and NTD, risk factors of NTD in children were studied. Mothers and their children with NTD were evaluated for the level of folic acid, homocysteine and the presence of C677T and A1298C MTHFR polymorphisms. The incidence of spina bifida aperta is 4.9 per 10,000 newborns. Two groups of significant risk factors for the NTD in children were identified: 1) risk factors that can be eliminated - the absence of preconceptional prevention of NTD with folic acid (AR 0.4), second-hand tobacсo smoking (AR 0.33), fever/hot baths in the first trimester of pregnancy (AR 0.64), use of well water for cooking (AP 0.44); 2) risk factors that can not be eliminated, and which indicate a genetic risk of NTD - a family history of a stroke, heart attack, thrombosis, congenital malformations, malignant tumors (AR 0.54-0.7), an obstetrical history of miscarriage (AR 0.56 ), mother's diseases (varicose disease, obesity), NTD in other children in this family (AR 0.74). The mothers of children with NTD showed a decreased level of folic acid and an increased level of homocysteine in addition to the correlation of hyperhomocysteinemia with the mutations of the MTHFR gene. The algorithm for assessing the individual risk of having a child with NTD includes the evaluation of risk factors. If a genetic factor of folate metabolism violation or environmental risk factors that can not be eliminated are found, we recommend an additional examination. It includes determining the level of homocysteine and the MTHFR polymorphisms (in the case of hyperhomocysteinemia), which will identify the required dose of folic acid.

Nojima M, Iwasaki M, Kasuga Y, et al.
Correlation between global methylation level of peripheral blood leukocytes and serum C reactive protein level modified by MTHFR polymorphism: a cross-sectional study.
BMC Cancer. 2018; 18(1):184 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Chronic inflammatory conditions are associated with higher tumor incidence through epigenetic and genetic alterations. Here, we focused on an association between an inflammation marker, C-reactive-protein (CRP), and global DNA methylation levels of peripheral blood leukocytes.
METHODS: The subjects were 384 healthy Japanese women enrolled as the control group of a case-control study for breast cancer conducted from 2001 to 2005. Global DNA methylation was quantified by Luminometric Methylation Assay (LUMA).
RESULTS: With adjustment for lifestyle-related factors, including folate intake, the global DNA methylation level of peripheral blood leukocytes was significantly but weakly increased by 0.43% per quartile category for CRP (P for trend = 0.010). Estimated methylation levels stratified by CRP quartile were 70.0%, 70.8%, 71.4%, and 71.3%, respectively. In addition, interaction between polymorphism of MTHFR (rs1801133, known as C677T) and CRP was significant (P for interaction = 0.046); the global methylation level was significantly increased by 0.61% per quartile category for CRP in the CT/TT group (those with the minor allele T, P for trend = 0.001), whereas no association was observed in the CC group (wild type).
CONCLUSIONS: Our study suggests that CRP concentration is weakly associated with global DNA methylation level. However, this association was observed more clearly in individuals with the minor allele of the MTHFR missense SNP rs1801133. By elucidating the complex mechanism of the regulation of DNA methylation by both acquired and genetic factors, our results may be important for cancer prevention.

Kałużna EM, Strauss E, Świątek-Kościelna B, et al.
The methylenetetrahydrofolate reductase 677T-1298C haplotype is a risk factor for acute lymphoblastic leukemia in children.
Medicine (Baltimore). 2017; 96(51):e9290 [PubMed] Free Access to Full Article Related Publications
The etiology of acute lymphoblastic leukemia (ALL) is complex, linked with both environmental exposures and genetic factors. Functional variants of the methylenetetrahydrofolate reductase (MTHFR) gene result in disturbance in folate metabolism and may affect susceptibility to cancer. The study was performed to evaluate whether MTHFR C677T and A1298C polymorphisms, analyzed separately and together, are associated with the development of ALL in a population under 18 years of age of Caucasian ancestry.The study included 117 pediatric patients (59% males, mean age at diagnosis 7.4 ± 5.2 years) with ALL, confirmed by conventional immunophenotyping surface-marker analysis and 404 healthy control subjects (48.5% men, mean age 37.7 ± 11.3 years). The MTHFR C677T and A1298C genotypes were analyzed using allele discrimination tests with Taq-Man fluorescent probes.The MTHFR 677TT genotype was related to a 2-fold increase in risk of ALL (P = .014). The 677T-1298C haplotype was found in ALL patients but not in controls (frequency 0.598%; P <.0001). The observed frequency of carriers of this rare haplotype was 12%, including 677CT/1298CC (1.7%), 677TT/1298AC (6.0%), and 677CT/1298AC (4.3%) genotypes.The MTHFR 677T allele alone or in combination with the MTHFR 1298C allele significantly increases the risk of development of ALL in Polish population under 18 years of age. Further studies of haplotype composition in subjects with the 677CT/1298AC genotype are necessary to assess the risk of childhood ALL.

Naghibalhossaini F, Shefaghat M, Mansouri A, et al.
The Impact of Thymidylate Synthase and Methylenetetrahydrofolate Reductase Genotypes on Sensitivity to 5-Fluorouracil Treatment in Colorectal Cancer Cells.
Acta Med Iran. 2017; 55(12):751-758 [PubMed] Related Publications
5-fluorouracil (5-FU) is one of the major components of many standard regimens for chemotherapy of colorectal cancer (CRC) and some other malignancies. Given the known relationship between thymidylate synthase (TS) and methylenetetrahydrofolate reductase (MTHFR) activity and 5-FU metabolism, this study investigated the impact of selected functional polymorphisms of the TS and MTHFR genes on chemotherapy resistance in 5 human CRC cell lines. HCT116, SW1116, HT29/219, LS180, and Caco-2 CRC cells were cultured as monolayer and their chemosensitivity to 5-FU, oxaliplatin, and irinotecan was determined by MTT assay. Genomic DNA was extracted from the cultured cells, and a 6-bp insertion or deletion (6-bp ins/del) polymorphism in 3´-UTR of the TS gene was determined by the PCR-RFLP method. Genotyping of MTHFR 677 C/T and 1298A/C single nucleotide polymorphism (SNP) was also performed by MS-PCR and PCR-RFLP, respectively. Caco-2 with the homozygous TS 6-bp ins/ins and MTHFR 677 T/T and 1298 C/C genotype, was the most 5-FU resistant cell line. HCT116 with the homozygous TS 6-bp del/del and MTHFR 1298 A/A and heterozygous MTHFR 677 C/T genotype was the least 5-FU resistant cell. LS180, the second most 5-FU resistant cell line, was heterozygous for all three polymorphic sits. HT29/219 and SW1116 cells with homozygous TS 6-bp ins/ins and heterozygous MTHFR 677 C/T and 1298 A/C genotypes had intermediate 5-FU sensitivity. The results indicate that TS 3´-UTR 6-bp insertion and MTHFR 677T and 1298C alleles increase 5-FU resistance in CRC cells. No relationship was observed between TS and MTHFR genotypes and oxaliplatin or irinotecan sensitivity in these cells.

Pérez-Ramírez C, Cañadas-Garre M, Alnatsha A, et al.
Impact of DNA repair, folate and glutathione gene polymorphisms on risk of non small cell lung cancer.
Pathol Res Pract. 2018; 214(1):44-52 [PubMed] Related Publications
Lung cancer, particularly non-small cell lung cancer (NSCLC) subtype, is the leading cause of cancer-related death related worldwide. Numerous gene polymorphisms in DNA repair, folate and glutathione pathways have been associated with susceptibility of NSCLC. We conducted this study to evaluate the effects of ERCC1, ERCC2, ERCC5, XRCC1, XRCC3, MTHFR, MTR, MTHFD1, SLC19A1 and GSTP1 gene polymorphisms on risk of NSCLC. No association between these gene polymorphisms and susceptibility of NSCLC were found in our patients, suggesting that genetic variations in genes involved in DNA repair, folate and glutathione metabolism pathways may not influence the risk of NSCLC.

Calderón-Garcidueñas AL, Cerda-Flores RM, Castruita-Ávila AL, et al.
[C677T-SNP of methylenetetrahydrofolate reductase gene and breast cancer in Mexican women].
Rev Med Inst Mex Seguro Soc. 2017 Nov-Dec; 55(6):720-724 [PubMed] Related Publications
BACKGROUND: Low-penetrance susceptibility genes such as 5,10-methylenetetrahydrofolate reductase gene (MTHFR) have been considered in the progression of breast cancer (BC). Cancer is a result of genetic, environmental and epigenetic interactions; therefore, these genes should be studied in environmental context, because the results can vary between populations and even within the same country. The objective was to analyze the allelic and genotypic frequencies of the MTHFR C667T SNP in Mexican Mestizo patients with BC and controls from Northeastern Mexico.
METHODS: 243 patients and 118 healthy women were studied. The analysis of the polymorphism was performed with a DNA microarray. Once the frequency of the polymorphism was obtained, Hardy-Weinberg equilibrium test was carried out for the genotypes. Chi square test was used to compare the distribution of frequencies.
RESULTS: The allele frequency in patients was: C = 0.5406; T = 0.4594 and in controls C = 0.5678, T = 0.4322. Genotype in BC patients was: C / C = 29.9%, C / T = 48.3% and T / T = 21.8. The distribution in controls was: C / C = 31.4%, C / T = 50.8%, T / T = 17.8% (chi squared 0.77, p = 0.6801).
CONCLUSIONS: Northeastern Mexican women in this study showed no association between MTFHR C667T SNP and the risk of BC. It seems that the contribution of this polymorphism to BC in Mexico varies depending on various factors, both genetic and environmental.

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