Association analysis of genetic polymorphisms of METTL3 with clinical outcomes in a Chinese pediatric population with primary brain tumors

Background: Methyltransferase-like 3 (METTL3) regulates numerous biological processes and diverse cancers.

Objective: To explore the frequency distribution of METTL3 rs1061026, rs1139130, and rs1263801 polymorphisms, and their potential impacts on clinical outcomes and chemotherapy-induced toxicities in a cohort of Chinese pediatric patients diagnosed with primary brain tumors (PBTs).

Methods: Genotyping for three investigated SNPs was performed in 107 pediatric patients with PBTs using the Sequenom MassARRAY iPLEX platform. Serum METTL3 levels were determined by Enzyme-Linked Immunosorbent Assay. Serum methotrexate (MTX) concentrations were quantified utilizing fluorescence polarization immunoassay.

Results: The three investigated SNPs were not significantly associated with the risks of relapse and metastasis after adjusting all confounders. Compared to individuals with the rs1139130 GG genotype, GA genotype carriers exhibited a significantly higher risk of oral mucositis (adjusted OR: 7.504; 95 % CI, 1.931-29.436; P = 0.004). The rs1139130 GA (adjusted OR: 5.091; 95 % CI, 1.351-19.176; P = 0.016) and AA (adjusted OR: 9.588; 95 % CI, 1.769-51.949; P = 0.009) genotype carriers exhibited a significantly lower risk of fever than GG genotype carriers. The median dose-normalized MTX concentrations at 42 h were lower with borderline significance in children with rs1061026 GT and GG genotypes (0.004 μmol/L per g/m²) than the TT genotype carriers (0.006 μmol/L per g/m², P = 0.048). Patients with the rs1139130 GA genotype had significantly higher median serum METTL3 protein levels (59.91 ng/mL) than GG genotype carriers (44.57 ng/mL, P = 0.015).

Conclusion: This study demonstrated the association of the rs1139130 polymorphism with the development of oral mucositis and fever and the rs1061026 polymorphism with MTX exposure.