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

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

doi:10.3389/fphar.2024.1480657

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

Front Pharmacol. 2024 Nov 14:15:1480657. doi: 10.3389/fphar.2024.1480657. eCollection 2024.

Authors

Jung Yoon Choi^#^{1

2}, Hoshik Kwon^#³, Hyery Kim⁴, Kyung Taek Hong^{1

2}, Youngeun Ma⁵, Kyung-Nam Koh⁴, Sunmin Yun³, Keon Hee Yoo⁶, Sang Hoon Song⁷, Ho Joon Im⁴, Ju Han Kim³, Hyoung Jin Kang^{1

2}

Affiliations

¹ Department of Pediatrics, Seoul National University Children's Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea.
² Seoul National University Cancer Research Institute, Seoul, Republic of Korea.
³ Seoul National University Biomedical Informatics (SNUBI), Division of Biomedical Informatics, Seoul National University College of Medicine, Seoul, Republic of Korea.
⁴ Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Republic of Korea.
⁵ Department of Pediatrics, Seoul Metropolitan Children's Hospital, Seoul, Republic of Korea.
⁶ Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
⁷ Department of Laboratory Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea.

^# Contributed equally.

Abstract

Background: 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.

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. 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.

Results: The 24 h MTX level strongly correlated with the subsequent creatinine (Cr) level. Moreover, rs2229866 in contactin 2 (CNTN2), rs200687372 in myotubularin Related Protein 9 (MTMR9), rs777260512 in polymerase iota (POLI), rs16954698 in polycystic kidney disease 1-like 2 (PKD1L2), rs117765468 in NSE1 Homolog, SMC5-SMC6 Complex Component (NSMCE1), and rs1800956 in endoglin (ENG) were identified as candidate variants associated with delayed MTX clearance. In particular, ENG rs1800956 was significantly associated with delayed MTX clearance in all analyses and PKD1L2 rs16954698 was replicated in an external dataset (phs000637.v1.p1) from the Database of Genotypes and Phenotypes (dbGaP).

Conclusion: This is the first whole-exome sequencing-based analysis of delayed MTX clearance in pediatric patients with ALL. ENG rs1800956 and PKD1L2 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.

Keywords: acute lymphoblastic leukemia; adverse reactions; children; delayed clearance; methotrexate; pediatric; pharmacogenomics.

Grants and funding

The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. This study was supported by a grant (16183MFDS541) from the Ministry of Food and Drug Safety in 2019.