Effects of germline DHFR and FPGS variants on methotrexate metabolism and relapse of leukemia

Morten Tulstrup*, Takaya Moriyama, Chuang Jiang, Marie Grosjean, Jacob Nersting, Jonas Abrahamsson, Kathrine Grell, Lisa Lyngsie Hjalgrim, Ólafur Gísli Jónsson, Jukka Kanerva, Bendik Lund, Stine Nygaard Nielsen, Rikke Linnemann Nielsen, Ulrik Overgaard, Petter Quist-Paulsen, Kaie Pruunsild, Goda Vaitkeviciene, Benjamin Ole Wolthers, Hui Zhang, Ramneek GuptaJun J. Yang, Kjeld Schmiegelow*

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

Abstract

Methotrexate (MTX) during maintenance therapy is essential for curing acute lymphoblastic leukemia (ALL), but dosing strategies aiming at adequate treatment intensity are challenged by interindividual differences in drug disposition. To evaluate genetic factors associated with MTX metabolism, we performed a genome-wide association study in 447 ALL cases from the Nordic Society for Pediatric Haematology and Oncology ALL2008 study, validating results in an independent set of 196 patients. The intergenic single-nucleotide polymorphism rs1382539, located in a regulatory element of DHFR, was associated with increased levels of short-chain MTX olyglutamates (P = 1.1 × 10-8) related to suppression of enhancer activity, whereas rs35789560 in FPGS (p.R466C, P= 5.6 × 10-9) was associated with decreased levels of long-chain MTX polyglutamates through reduced catalytic activity. Furthermore, the FPGS variant was linked with increased relapse risk (P = .044). These findings show a genetic basis for interpatient variability in MTX response and could be used to improve future dosing algorithms.

Original languageEnglish
JournalBlood
Volume136
Issue number10
Pages (from-to)1161-1168
ISSN0006-4971
DOIs
Publication statusPublished - 2020

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