MTHFR Polymorphism Is Associated With Severe Methotrexate-Induced Toxicity in Osteosarcoma Treatment

Wenchao Zhang; Zhongyue Liu; Zhimin Yang; Chengyao Feng; Xiaowen Zhou; Chao Tu; Zhihong Li

doi:10.3389/fonc.2021.781386

MTHFR Polymorphism Is Associated With Severe Methotrexate-Induced Toxicity in Osteosarcoma Treatment

Front Oncol. 2021 Dec 15:11:781386. doi: 10.3389/fonc.2021.781386. eCollection 2021.

Authors

Wenchao Zhang^{1

2}, Zhongyue Liu^{1

2}, Zhimin Yang^{1

2}, Chengyao Feng¹, Xiaowen Zhou³, Chao Tu^{1

2}, Zhihong Li^{1

2}

Affiliations

¹ Department of Orthopaedics, The Second Xiangya Hospital, Central South University, Changsha, China.
² Hunan Key Laboratory of Tumor Models and Individualized Medicine, The Second Xiangya Hospital, Central South University, Changsha, China.
³ Xiangya School of Medicine, Central South University, Changsha, China.

Abstract

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.

Keywords: MTHFR; methotrexate; osteosarcoma; polymorphism; toxicity.

Publication types

Systematic Review