Dataset Information

Relevance of methylenetetrahydrofolate reductase gene variants C677T and A1298C with response to fluoropyrimidine-based chemotherapy in colorectal cancer: a systematic review and meta-analysis.

ABSTRACT: Methylenetetrahydrofolate reductase (MTHFR) is a critical enzyme influencing the metabolism of fluoropyrimidines. The relevance of MTHFR polymorphisms with the clinical response to fluoropyrimidine-based chemotherapy has been explored, but the results remain controversial. Thus, a meta-analysis was performed to provide a comprehensive estimate in this account. Relevant studies were identified through PubMed, Embase and Web of Science databases from inception up to May 2017. Odds ratios (ORs) with corresponding 95% confidence intervals (CIs) were applied to assess the strength of association. A total of 2118 colorectal cancer patients from 21 studies were included in the meta-analysis. Overall, there was no significant association between MTHFR C677T (rs1801133) or A1298C (rs1801131) polymorphisms and the clinical response to fluoropyrimidine-based chemotherapy under all of the three genetic models (allele model, dominant model, and recessive model) and stratification analysis, except for the retrospective study subgroup in the dominant model of MTHFR C677T and the "5-Fu + FA" treatment group in the allele contrast of MTHFR A1298C. No or moderate heterogeneity was observed in all genetic models. This meta-analysis suggested that MTHFR polymorphisms could not be considered as reliable factors for predicting the clinical response to fluoropyrimidine-based chemotherapy in colorectal cancer patients.

SUBMITTER: Zhong L

PROVIDER: S-EPMC6101282 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Relevance of methylenetetrahydrofolate reductase gene variants C677T and A1298C with response to fluoropyrimidine-based chemotherapy in colorectal cancer: a systematic review and meta-analysis.

Zhong Lei L He Xia X Zhang Yuan Y Chuan Jun-Lan JL Chen Min M Zhu Shao-Min SM Peng Qian Q

Oncotarget 20180727 58

Methylenetetrahydrofolate reductase (MTHFR) is a critical enzyme influencing the metabolism of fluoropyrimidines. The relevance of <i>MTHFR</i> polymorphisms with the clinical response to fluoropyrimidine-based chemotherapy has been explored, but the results remain controversial. Thus, a meta-analysis was performed to provide a comprehensive estimate in this account. Relevant studies were identified through PubMed, Embase and Web of Science databases from inception up to May 2017. Odds ratios (O ...[more]

PMID: 30131855

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Project description:Background18 previous meta-analyses have been published on the methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms with male infertility risk. However, results of the previous meta-analyses were still inconsistent. Moreover, their meta-analyses did not assess false-positive report probabilities except one study. Furthermore, many new studies have been published, and therefore an updated meta-analysis and re-analysis of systematic previous meta-analyses were performed to further explore these issues.ObjectivesTo determine the association between MTHFR C677T and A1298C polymorphisms and male infertility risk.MethodsCrude odds ratios and their 95% confidence intervals were used to assess the association between MTHFR C677T and A1298C polymorphisms and male infertility risk. We used the Bayesian false discovery probability (BFDP) to assess the credibility of statistically significant associations.ResultsFifty-nine studies were included concerning the MTHFR C677T and 28 studies were found on the MTHFR A1298C with male infertility risk. Overall, the MTHFR C677T was associated with increased male infertility risk in overall populations, Africans, East Asians, West Asians, South Asians, azoospermia, and Oligoasthenoteratozoospermia (OAT). In further sensitivity analysis and BFDP test, the positive results were only considered as "noteworthy" in the overall population (TT vs CC: BFDP = 0.294, CT + TT vs CC: BFDP = 0.300, T vs C: BFDP = 0.336), East Asians (TT vs CC: BFDP = 0.089, TT vs CT + CC: BFDP = 0.020, T vs C: BFDP < 0.001), West Asians (TT vs CC: BFDP = 0.584), hospital-based studies (TT vs CC: BFDP = 0.726, TT vs CT + CC: BFDP = 0.126), and OAT (TT vs CT + CC: BFDP = 0.494) for MTHFR C677T. In addition, a significantly increased male infertility risk was found in East Asians and population-based studies for MTHFR A1298C. However, we did not find that the positive results were considered as "noteworthy" in the overall and all subgroup analyses for MTHFR A1298C.ConclusionsIn summary, this study indicates that the MTHFR C677T is associated with increased male infertility risk in East Asians, West Asians, and OAT. No significant association was observed on the MTHFR A1298C with male infertility risk.

Project description:BackgroundMethylenetetrahydrofolate reductase, the encoded by the MTHFR gene, plays a crucial role in converting the amino acid homocysteine to methionine. Two polymorphisms of the MTHFR gene, C677T and A1298C, reportedly reduce enzyme activity, resulting in hyperhomocysteinemia. Patients with C677T and A1298C polymorphisms may be at higher risk for developing abnormal hyperhomocysteinemia, which has been linked to catastrophic neurological including fatal outcomes.ObjectiveDetermine the prevalence of the MTHFR gene variants C677T and A1298C among pediatric dental patients treated at King Abdulaziz University Hospital.DesignCross-sectional.SettingClinics of pediatric dentistry department.Subjects and methodsHealthy Saudi children 6-12 years old with no known allergies were screened for eligibility between May and December 2019. A single investigator collected saliva samples. The MTHFR C677T and A1298C polymorphisms were analyzed using polymerase chain reaction and restriction fragment length polymorphism.Main outcome measureThe prevalence of MTHFR gene variants (C677T and A1298C) among the subjects.Sample size138.ResultsMTHFR C677T polymorphism was present in 36.2% of the sample and 90.0% of children carrying this allele were heterozygotes. MTHFR A1298C polymorphism was present in 91.3% of the sample and 77.0% of the children carrying this allele were heterozygotes. No linkage disequilibrium between MTHFR C677T and MTHFR A1298C was observed within this sample.ConclusionsOur study found a high frequency of the MTHFR A1298C genotype, which was substantially more abundant than expected based on a Hardy-Weinberg distribution. Therefore, caution is advised in using N2O in Saudi children as the increased prevalence of this MTHFR allele may increase the incidence of serious adverse effects among these children.LimitationsFurther studies are recommended with a larger sample size from randomly selected hospitals from different regions of Saudi Arabia.Conflict of interestNone.

Project description:Background: Methylenetetrahydrofolate reductase (MTHFR) single nucleotide polymorphisms (SNPs) have been suggested as risk, prognostic, and predictive factors for colorectal cancer in various populations, but have not been validated so far. The aim of this study was to examine the association of MTHFR C677T (rs1801133) and A1298C (rs1801131) single nucleotide polymorphisms with the risk of rectal cancer as well as the response to neoadjuvant chemoradiotherapy (nCRT) based on 5-Fluorouracil (5-FU)/leucovorin (LV) in the locally advanced setting. Patients and methods: This case-control study included 119 healthy controls and 97 patients with locally advanced rectal cancer (LARC). For MTHFR genotyping, restriction fragment length polymorphism analysis (PCR-RFLP) was employed. Results: In silico analysis highlighted that SNPs C677T and A1298T correlate with MTHFR gene expression, and that gene expression profile correlates with cancer risk and stage. Using dominant and recessive models, it was found that the MTHFR 677CC vs. 677CT+677TT have increased risk of cancer development (odds ratio (OR): 2.27; 95% confidence interval (CI): 1.30-3.95, p = 0.002) as well as 677CC+677CT compared to 677TT (OR: 4.18, 95% CI: 1.16-14.99, p = 0.014). MTHFR 1298AA also shown increased risk for cancer development compared to 1298AC+1298CC (OR:2.0, 95% CI: 1.20-3.59, p = 0.035) Statistical analysis of combined genotypes highlighted the protective role of CT/AC combined genotype (OR: 3.15 95% CI: 1.576-6.279, p = 0.002) while the CC/AA genotype showed an increased risk for rectal cancer development (OR: 2.499, 95% CI: 1.246-5.081, p = 0.016) The carriers of the 677C/1298A haplotype had the highest risk for developing rectal cancer (OR: 1.74; 95% CI: 1.198-2.530, p = 0.002) while the 677T/1298C haplotype seems to provide a protective effect. (OR: 0.44; 95%CI 0.248-0.795, p = 0.003). No significant association with response to chemoradiotherapy was found. Conclusion: Our data point to MTHFR 667C allele and 1298A alleles as low-penetrance risk factors for rectal cancer in our population. To the best of our knowledge, this is the first study of this type performed on the Slavic population in the Western Balkan, as various population-based factors might also be significant our findings can be used for future meta-analyses and the construction of genetic cancer risk prediction panels.

Dataset Information

Relevance of methylenetetrahydrofolate reductase gene variants C677T and A1298C with response to fluoropyrimidine-based chemotherapy in colorectal cancer: a systematic review and meta-analysis.

Publications

Relevance of methylenetetrahydrofolate reductase gene variants C677T and A1298C with response to fluoropyrimidine-based chemotherapy in colorectal cancer: a systematic review and meta-analysis.

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