Methylenetetrahydrofolate Reductase Polymorphism C677T Is a Protective Factor for Pediatric Acute Lymphoblastic Leukemia in the Chinese Population: A Meta-Analysis

Abstract Plenty of studies have investigated the effect of methionine synthase (MTR) A2756G polymorphism on risk of developing pediatric acute lymphoblastic leukemia (ALL), but the available results were inconsistent. Therefore, a meta-analysis was conducted to derive a more precise estimation of the association between MTR A2756G polymorphism and genetic susceptibility to pediatric ALL. The PubMed, Embase, Google Scholar, Web of Science, ScienceDirect, Wanfang Databases and China National Knowledge Infrastructure were systematically searched to identify all the previous published studies exploring the relationship between MTR A2756G polymorphism and pediatric ALL risk. Odds ratios (ORs) and 95% confidence intervals (CIs) were applied to evaluate the strength of association. Sensitivity analysis and publication bias were also systematically assessed. This meta-analysis finally included ten available studies with 3224 ALL cases and 4077 matched controls. The results showed that there was significant association between MTR A2756G polymorphism and risk of pediatric ALL in overall population (AG vs. AA: OR = 1.13, 95%CI = 1.02–1.26, P = 0.02; AG+GG vs. AA: OR = 1.13, 95%CI = 1.02–1.25, P = 0.01; G allele vs. A allele: OR = 1.10, 95%CI = 1.01–1.20, P = 0.03). In the stratification analyses by ethnicity, quality score and control source, significant association was found in Caucasians, population-based designed studies and studies assigned as high quality. In conclusion, this meta-analysis suggests that MTR A2756G polymorphism may influence the development risk of pediatric ALL in Caucasians. Future large scale and well-designed studies are required to validate our findings.

Download Full-text

Pharmacogenomic Markers of Methotrexate Response in the Consolidation Phase of Pediatric Acute Lymphoblastic Leukemia Treatment

Genes ◽

10.3390/genes11040468 ◽

2020 ◽

Vol 11 (4) ◽

pp. 468

Author(s):

Nikola Kotur ◽

Jelena Lazic ◽

Bojan Ristivojevic ◽

Biljana Stankovic ◽

Vladimir Gasic ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Allele Frequency ◽

Methylenetetrahydrofolate Reductase ◽

Lymphoblastic Leukemia ◽

Statistical Modelling ◽

Joint Effect ◽

Allele Frequency Distribution ◽

Pediatric Acute Lymphoblastic Leukemia ◽

Consolidation Phase ◽

Pediatric All

Methotrexate (MTX) is one of the staples of pediatric acute lymphoblastic leukemia (ALL) treatment. MTX targets the folate metabolic pathway (FMP). Abnormal function of the enzymes in FMP, due to genetic aberrations, leads to adverse drug reactions. The aim of this study was to investigate variants in pharmacogenes involved in FMP and their association with MTX pharmacokinetics (MTX elimination profile) and toxicity in the consolidation therapy phase of pediatric ALL patients. Eleven variants in the thymidylate synthetase (TYMS), methylenetetrahydrofolate reductase (MTHFR), dihydrofolate reductase (DHFR), SLC19A1 and SLCO1B genes were analyzed in 148 patients, using PCR- and sequencing-based methodology. For the Serbian and European control groups, data on allele frequency distribution were extracted from in-house and public databases. Our results show that the A allele of SLC19A1 c.80 variant contributes to slow MTX elimination. Additionally, the AA genotype of the same variant is a predictor of MTX-related hepatotoxicity. Patients homozygous for TYMS 6bp deletion were more likely to experience gastrointestinal toxicity. No allele frequency dissimilarity was found for the analyzed variants between Serbian and European populations. Statistical modelling did not show a joint effect of analyzed variants. Our results indicate that SLC19A1 c.80 variant and TYMS 6bp deletion are the most promising pharmacogenomic markers of MTX response in pediatric ALL patients.

Download Full-text

Assessment of the relationship between methylenetetrahydrofolate reductase polymorphism and acute lymphoblastic leukemia: Evidence from an updated meta-analysis

Journal of Oncology Pharmacy Practice ◽

10.1177/1078155219900914 ◽

2020 ◽

Vol 26 (7) ◽

pp. 1598-1610

Author(s):

Rim Frikha

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Methylenetetrahydrofolate Reductase ◽

Lymphoblastic Leukemia ◽

Meta Analysis ◽

Case Control ◽

C677t Polymorphism ◽

Case Control Studies ◽

Gene Environment ◽

Reductase Gene ◽

The Relationship

Objective The methylenetetrahydrofolate reductase gene C677T polymorphism is closely related to the acute lymphoblastic leukemia. Several case–control studies have investigated this association; however, no conclusions could be drawn. A comprehensive updated meta-analysis is established to explain these contradictions and clarify the overall impact of this variant on the susceptibility to acute lymphoblastic leukemia. Methods Electronic searches were conducted to select published studies prior to June 2018. Pooled odds ratios and stratification analysis were performed under different genetic comparison models, age, and ethnicity. Results Totally, 66 case–control studies including 9619 acute lymphoblastic leukemia cases and 17,396 controls were selected. Our analyses showed that methylenetetrahydrofolate reductase C677T polymorphism was protective mainly in Asian and European countries, under all genetic models and regardless of age, but leukemogenic in mixed population. Conclusion Thus, C677T polymorphism may be a promising acute lymphoblastic leukemia biomarker, but they should be interpreted with caution considering other factors such as folic acid intake, gene–gene and gene–environment interactions.

Download Full-text