5,10-methylenetetrahydrofolate reductase (MTHFR) polymorphisms and the risk of acute lymphoblastic leukemia (ALL) in Filipino children

Abstract The central role of methylenetetrahydrofolate reductase (MTHFR) in the folate metabolism renders MTHFR gene polymorphisms (C677T and A1298C) potential modulators of a variety of disorders whose development depends on folate/homocysteine imbalance. Here, we provide additional evidence on the protective role of these polymorphisms in acute lymphoblastic leukemia (ALL), the most common pediatric cancer. A case-control study was conducted in 270 ALL patients and 300 healthy controls of French-Canadian origin. The TT677/AA1298 and CC677/CC1298 individuals were associated with reduced risk of ALL (crude odds ratio [OR] = 0.4; 95% confidence interval [CI], 0.2-0.9; and OR = 0.3; 95% CI, 0.1-0.6; respectively). Further stratification in patients born before and after January 1996 (approximate time of Health Canada recommendation for folic acid supplement in pregnancy) revealed that the protective effect of MTHFR variants is accentuated and present only in children born before 1996. Similar results were obtained when a transmission disequilibrium test was performed on a subset of children (n = 95) in a family-based study. This finding suggests gene-environment interaction and its role in the susceptibility to childhood ALL, which is consistent with previous findings associating either folate deficiency or MTHFR polymorphisms with risk of leukemia.

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MTHFR 677T-1298C haplotype in acute lymphoblastic leukemia: Impact on methotrexate therapy

Journal of Oncology Pharmacy Practice ◽

10.1177/10781552211017193 ◽

2021 ◽

pp. 107815522110171

Author(s):

Rim Frikha ◽

Moez Elloumi ◽

Tarek Rebai ◽

Hassen Kamoun

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Methylenetetrahydrofolate Reductase ◽

Fragment Length Polymorphism ◽

Lymphoblastic Leukemia ◽

Allelic Frequency ◽

Mthfr Gene ◽

Methotrexate Therapy ◽

Wild Type ◽

Functional Variants ◽

Toxicity Score

Introduction Functional variants of the Methylenetetrahydrofolate reductase ( MTHFR) gene, the C677T and A1298C, have largely investigated in pharmacogenomics of Methotrexate (MTX) in acute lymphoblastic leukemia (ALL), yet the conclusions are inconsistent. In addition; most of these studies do not analyze haplotypes. Here, we investigate the MTHFR 677/1298 genotypes and the 677-1298 haplotype and characterize the MTX response in Northern African ALL patients. Methods Genomic DNA was extracted from whole venous from a total of 28 patients with ALL. Genotyping were carried out with restriction fragment length polymorphism (RFLP). A toxicity score (TS) is calculated for each patient and correlate to the haplotype. Results The allelic frequency of MTHFR 677T-1298C haplotype was 10.7% in ALL patients. According to the toxicity’s score (TS) there was no significant differences between haplotype groups (p = 0.79): TS was higher with wild type of MTHFR (TS = 3.43; SEM ± 0.85) followed by combined genotype (677T-1298C) (TS = 2.67; SEM ± 0.88) and isolated variant (C677T or A1298C) (TS = 2.64; SEM ± 0.92). Conclusion Despite the limitation of this study; our results suggest that the MTHFR 677T-1298C haplotype is common in ALL and may be a promising HD-MTX chemotherapy-related adverse effects biomarker.

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Comprehensive analysis of Methylenetetrahydrofolate reductase C677T in younger acute lymphoblastic leukemia patients: A single-center experience

Journal of Oncology Pharmacy Practice ◽

10.1177/1078155218818244 ◽

2018 ◽

Vol 25 (5) ◽

pp. 1182-1186 ◽

Cited By ~ 2

Author(s):

Rim Frikha ◽

Tarek Rebai ◽

Ben Mahmoud Lobna ◽

Fakher Frikha ◽

Moez Mdhaffar ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Methylenetetrahydrofolate Reductase ◽

Lymphoblastic Leukemia ◽

Comprehensive Analysis ◽

Single Center ◽

Single Center Experience

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A systematic review and meta-analysis of MTHFR polymorphisms in methotrexate toxicity prediction in pediatric acute lymphoblastic leukemia

The Pharmacogenomics Journal ◽

10.1038/tpj.2012.44 ◽

2012 ◽

Vol 13 (6) ◽

pp. 498-506 ◽

Cited By ~ 41

Author(s):

E Lopez-Lopez ◽

I Martin-Guerrero ◽

J Ballesteros ◽

A Garcia-Orad

Keyword(s):

Systematic Review ◽

Acute Lymphoblastic Leukemia ◽

Lymphoblastic Leukemia ◽

Meta Analysis ◽

Toxicity Prediction ◽

Mthfr Polymorphisms ◽

Pediatric Acute Lymphoblastic Leukemia ◽

Methotrexate Toxicity

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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.

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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.

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