Novel genomic variants influencing methotrexate delayed excretion in pediatric patients with acute lymphoblastic leukemia

Abstract Background Methotrexate (MTX) is the primary drug used in the treatment of pediatric acute lymphoblastic leukemia (ALL). However, some patients exhibit delayed excretion of high-dose (HD) MTX, which induces severe nephrotoxicity. We sought to identify relevant mutations associated with delayed excretion of HD-MTX in pediatric patients with ALL. Methods Whole-exome sequencing of germline DNA was performed in 51 Korean pediatric patients with ALL. A total of 341 HD-MTX infusion data points from 51 patients were analyzed. Correlations between peak serum MTX levels at 24 h and toxicity markers were assessed. Analyses were performed to identify variants affecting delayed MTX excretion. Results The 24 h MTX level strongly correlated with the subsequent Cr level. Moreover, rs2229866 in CNTN2, rs200687372 in MTMR9, rs777260512 in POLI, rs16954698 in PKD1L2, rs117765468 in NSMCE1, and rs1800956 in ENG were identified as candidate variants associated with delayed MTX excretion. In particular, ENG rs1800956 was significantly associated with delayed MTX excretion in all analyses. Conclusions This is the first whole-exome sequencing-based analysis of delayed MTX excretion in pediatric patients with ALL. Six candidate variants were identified, and ENG rs1800956 was identified as a novel and promising variant affecting delayed MTX excretion. Therefore, further analyses and validation are required.