AUTHOR=Choi Jung Yoon , Kwon Hoshik , Kim Hyery , Hong Kyung Taek , Ma Youngeun , Koh Kyung-Nam , Yun Sunmin , Yoo Keon Hee , Song Sang Hoon , Im Ho Joon , Kim Ju Han , Kang Hyoung Jin 

TITLE=Novel genomic variants influencing methotrexate delayed clearance in pediatric patients with acute lymphoblastic leukemia

JOURNAL=Frontiers in Pharmacology

VOLUME=15

YEAR=2024

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2024.1480657

DOI=10.3389/fphar.2024.1480657

ISSN=1663-9812

ABSTRACT=<sec><title>Background</title><p>Methotrexate (MTX) is the primary drug used in the treatment of pediatric acute lymphoblastic leukemia (ALL). However, some patients exhibit delayed clearance of high-dose (HD) MTX, which induces severe nephrotoxicity, mucositis, hepatotoxicity, and neurotoxicity. We sought to identify relevant variants associated with delayed clearance of HD-MTX in pediatric patients with ALL.</p></sec><sec><title>Methods</title><p>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. MTX levels and laboratory measurements reflecting toxicity outcomes were obtained. Correlations between peak serum MTX levels at 24 h and toxicity outcomes were assessed. Analyses were performed to identify variants affecting delayed MTX clearance.</p></sec><sec><title>Results</title><p>The 24 h MTX level strongly correlated with the subsequent creatinine (Cr) level. Moreover, rs2229866 in <italic>contactin 2</italic> (<italic>CNTN2</italic>), rs200687372 in <italic>myotubularin Related Protein 9</italic> (<italic>MTMR9</italic>), rs777260512 in <italic>polymerase iota</italic> (<italic>POLI</italic>), rs16954698 in <italic>polycystic kidney disease 1-like 2</italic> (<italic>PKD1L2</italic>), rs117765468 in <italic>NSE1 Homolog, SMC5-SMC6 Complex Component</italic> (<italic>NSMCE1</italic>)<italic>,</italic> and rs1800956 in <italic>endoglin</italic> (<italic>ENG</italic>) were identified as candidate variants associated with delayed MTX clearance. In particular, <italic>ENG</italic> rs1800956 was significantly associated with delayed MTX clearance in all analyses and <italic>PKD1L2</italic> rs16954698 was replicated in an external dataset (phs000637.v1.p1) from the Database of Genotypes and Phenotypes (dbGaP).</p></sec><sec><title>Conclusion</title><p>This is the first whole-exome sequencing-based analysis of delayed MTX clearance in pediatric patients with ALL. <italic>ENG</italic> rs1800956 and <italic>PKD1L2</italic> rs16954698 were found to be potentially influential variants associated with delayed MTX clearance. These findings provide insights into HD-MTX-induced nephrotoxicity and may contribute to reducing adverse reactions through treatment modification.</p></sec>