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Published on: June 13, 2018
MTHFR variant is associated with high-dose methotrexate-induced toxicity in the Chinese osteosarcoma patients
Leilei Xu1, Lujun Wang2, Bingchuan Xue1
1Department of Orthopedic Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Zhongshan Road 321, Nanjing 210008, China.
Background:
The role of Methylene tetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms in the efficacy and toxicity of MTX-based therapy remains uncertain. Our purpose was to clarify whether these two polymorphisms are associated with the outcome of chemotherapy in a cohort of Chinese osteosarcoma (OS) patients treated by high-dose MTX.
Methods:
109 OS patients who had sequentially received high-dose MTX therapy were included in this study. Plasma MTX level was measured routinely at 0, 24, 48 and 72 h after the administration of MTX. Two variants of MTHFR were genotyped using TaqMan SNP Genotyping Assay, including rs1801133 (C667T) and rs1801131 (A1298C). The extent of toxicity induced by MTX, including hematological toxicity, hepatic toxicity, renal toxicity and mucositis, was scored from grade 1 to 4. Severe toxicity was defined as a grade score of ≥3. Patients were dichotomized as follows: grade <3 or ≥3 for toxicity, and ≤0.2 µmol/L or >0.2 µmol/L for plasma MTX level at 72 h. The frequencies of genotypes and allele were compared between the dichotomized groups with the Chi-square test.
Results:
24.8% (27/109) of the patients were found to have significantly high plasma MTX level at the 72 h. Patients with high MTX level at 72 h were found to have significantly higher frequency of genotype TT of rs1801133 (p = 0.002). As for rs1801131, no significant association was found with plasma MTX level. Patients with severe hepatic toxicity or mucositis were found to have remarkably higher incidence of genotype TT of rs1801133 than those with mild toxicity (33.3% vs. 14.8%, p = 0.04 for hepatic toxicity; 34.8% vs. 19.8%, p = 0.05 for mucositis).
Conclusions:
Variant rs1801133 was confirmed to have remarkable influence on the MTX-induced toxicity. We recommend identification of the genotype of MTHFR variant prior to the application of high-dose MTX to OS patients, which could be an important predictor to screen severe toxicities and thus improve treatment outcomes.
Insights
Methylene tetrahydrofolate reductase (MTHFR) C677T variant TT genotype is linked to higher methotrexate (MTX) toxicity in Chinese osteosarcoma patients. Identifying this MTHFR genotype can help predict and mitigate severe MTX-induced toxicities.
Area of Science:
- Pharmacogenomics
- Oncology
- Genetics
Background:
- The role of Methylene tetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms in methotrexate (MTX) therapy efficacy and toxicity is unclear.
- High-dose MTX is used for osteosarcoma (OS) chemotherapy, but patient response and toxicity vary.
Purpose of the Study:
- To investigate the association between MTHFR C677T and A1298C polymorphisms and the outcome of high-dose MTX chemotherapy in Chinese OS patients.
- To determine if these MTHFR variants predict MTX efficacy and toxicity.
Main Methods:
- 109 Chinese osteosarcoma patients treated with high-dose MTX were studied.
- MTHFR C677T (rs1801133) and A1298C (rs1801131) genotypes were determined.
- Plasma MTX levels and MTX-induced toxicities (hematological, hepatic, renal, mucositis) were assessed and correlated with genotypes.
Main Results:
- A significantly higher frequency of the MTHFR rs1801133 TT genotype was observed in patients with high plasma MTX levels at 72 hours (p=0.002).
- Patients with severe hepatic toxicity (p=0.04) and mucositis (p=0.05) showed a higher incidence of the rs1801133 TT genotype.
- No significant association was found between the MTHFR rs1801131 polymorphism and plasma MTX levels or toxicity.
Conclusions:
- The MTHFR rs1801133 polymorphism, particularly the TT genotype, significantly influences MTX-induced toxicity in osteosarcoma patients.
- Genotyping MTHFR variants before high-dose MTX treatment could help predict severe toxicities and improve patient outcomes.
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