The impact of genetic variations in FPGS , MTHFR , and ATIC on methotrexate response among pediatric patients with acute lymphoblastic leukemia.

Objectives: Genetic polymorphisms in FPGS , MTHFR , and ATIC have emerged as important modulators of methotrexate (MTX) metabolism and toxicity. We investigated the distribution of FPGS rs10106, MTHFR rs1801131, and ATIC rs2372536 polymorphisms in children with acute lymphoblastic leukemia (ALL) and assessed their influence on MTX concentrations, toxicity profiles, and clinical outcomes.

Methods: Genotyping of FPGS rs10106 G > A, MTHFR rs1801131 A > C, and ATIC rs2372536 C > G polymorphisms was conducted using the Sequenom MassARRAY iPLEX platform in 145 pediatric ALL patients.

Results: Significant ethnic differences were observed in the allelic and genotypic distributions of the three single nucleotide polymorphisms (SNPs) investigated. None of these three SNPs had a significant effect on MTX levels or toxicities. The frequencies of the ATIC rs2372536 CC genotype and C allele in ALL patients (44.8% and 68.6%, respectively) were significantly lower than those in Han Chinese in Beijing, China (58.3% and 78.2%, respectively; P  = 0.036 and 0.019, respectively). Patients carrying the ATIC rs2372536 GG genotype (36.4%, 4/11) had a significantly higher relapse rate than the CC genotype carriers (6.2%, 4/65, P  = 0.013). There, however, were no significant effects on relapse-free survival in Kaplan-Meier and Cox regression analyses for all three candidate SNPs.

Conclusion: Our findings offer valuable insights into the intricate interplay between genetic polymorphisms, MTX exposure, toxicities, and clinical outcomes in patients with ALL and have the potential to inform precision medicine strategies.