Key result
The MTHFR rs1801133 T allele was significantly associated with an increased risk of severe methotrexate-induced mucositis (OR 2.28) and liver toxicity in patients with osteosarcoma.
Why the study?
Does MTHFR rs1801133 polymorphism increase the risk of severe methotrexate-induced toxicity in osteosarcoma patients?
Meta-Analysis (n=585)
Does MTHFR rs1801133 polymorphism increase the risk of severe methotrexate-induced toxicity in osteosarcoma patients?
Odds Ratio: 2.28 (95% CI 1.49–3.5)
p-value: p=<0.001
The MTHFR rs1801133 polymorphism is significantly associated with severe liver toxicity and mucositis induced by high-dose methotrexate in osteosarcoma patients.
May support MTHFR rs1801133 testing to stratify methotrexate toxicity risk in osteosarcoma; leaves open whether genotype-guided dosing improves outcomes.
Background Previous studies have revealed the critical role of methylene tetrahydrofolate reductase (MTHFR) polymorphisms in response to high-dose methotrexate (MTX)-induced toxicity in osteosarcoma patients. However, the conclusions remain controversial. In this setting, we performed a meta-analysis to determine their association more precisely. Method Eligible studies were searched and screened in PubMed, Web of Science, Cochrane Library, Clinical-Trials.gov, Embase, and China National Knowledge Infrastructure (CNKI) following specific inclusion and exclusion criteria. The required information was retrieved and collected for subsequent meta-analysis. Association between MTHFR polymorphism and MTX toxicity was evaluated by odds ratios (ORs). Results Seven studies containing 585 patients were enrolled and analyzed in this meta-analysis. Overall, the MTX related grade 3-4 liver toxicity was significantly associated with MTHFR rs1801133 allele (T vs. C: OR=1.61, 95%CI=1.07-2.42, P=0.024), homozygote (TT vs. CC: OR=2.11, 95%CI=1.06-4.21, P=0.011), and dominant genetic model (TT/TC vs. CC: OR=3.15, 95%CI=1.30-7.60, P=0.035) in Asian population. Meanwhile, close associations between MTX mediated grade 3-4 mucositis and MTHFR rs1801133 polymorphism were identified in allele contrast (T vs. C: OR=2.28, 95%CI=1.49-3.50, P<0.001), homozygote comparison (TT vs. CC: OR=4.07, 95%CI=1.76-9.38, P=0.001), heterozygote comparison (TC vs. CC: OR=2.55, 95%CI=1.20-5.42, P=0.015), recessive genetic model (TT vs. TC/CC: OR=2.09, 95%CI=1.19-3.67, P=0.010), and dominant genetic model (TT/TC vs. CC: OR=2.97, 95%CI=1.48-5.96, P=0.002). Additionally, kidney toxicity was corelated with the heterozygote comparison (TC vs. CC: OR=2.63, 95%CI=1.31-5.29, P=0.007) of rs1801133 polymorphism. Conclusion The MTHFR rs1801133 polymorphism was significantly associated with severer liver toxicity induced by high-dose MTX treatment in the Asian population. In the meantime, patients with MTHFR rs1801133 polymorphism were predisposed to MTX- related mucositis.
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Zhang et al. (2021) conducted a meta-analysis in Osteosarcoma (n=585). MTHFR rs1801133 polymorphism (T allele) vs. MTHFR rs1801133 C allele was evaluated on Methotrexate-mediated grade 3-4 mucositis (OR 2.28, 95% CI 1.49-3.50, p=<0.001). The MTHFR rs1801133 T allele was significantly associated with an increased risk of severe methotrexate-induced mucositis (OR 2.28) and liver toxicity in patients with osteosarcoma.
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