Abstract
BackgroundPrevious 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.MethodEligible 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).ResultsSeven 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.ConclusionThe 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.
Highlights
Occurring in adolescents, osteosarcoma has been the second malignancy among young teenagers [1] and the most prevalent primary osseous tumor with an annual incidence of 1~3 cases per million worldwide [2]
MTX-related high-level liver toxicity was significantly associated with methylene tetrahydrofolate reductase (MTHFR) rs1801133 polymorphism under allele contrast (T vs. C: odds ratios (ORs)=1.61, 95%confidence interval (CI)=1.07-2.42, P=0.024), homozygote comparison (TT vs. CC: OR=2.11, 95%CI=1.064.21, P=0.011), and dominant genetic model (TT/TC vs. CC: OR=3.15, 95%CI=1.30-7.60, P=0.035) in the Asian population but not in the overall population (Figure 2)
Close relations between MTX mediated high level mucositis and MTHFR rs1801133 polymorphism were identified in allele contrast (T vs. C: OR=2.28, 95%CI=1.49-3.50, P
Summary
Osteosarcoma has been the second malignancy among young teenagers [1] and the most prevalent primary osseous tumor with an annual incidence of 1~3 cases per million worldwide [2]. Previous studies have reported a high incidence of medication toxicity during high-dose MTX treatment for osteosarcoma patients [10, 11]. The presence of toxicity is influenced by multiple factors such as age, gender, ethnicity, and genetic background [9, 12]. In this setting, patients may benefit from individualized chemotherapy that is tailored according to their disease characteristics and 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. We performed a meta-analysis to determine their association more precisely
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