Methotrexate (MTX) during maintenance therapy is essential to cure acute lymphoblastic leukemia (ALL), but dosing strategies to achieve adequate treatment intensity are challenged by inter-individual 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 Paediatric Haematology and Oncology ALL2008 study, validating results in an independent set of 196 patients. The intergenic SNP rs1382539 located in a regulatory element of DHFR was associated with increased levels of short-chain MTX polyglutamates (P = 1.1 × 10-8) due to suppression of enhancer activity, while 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 = 0.044). These findings show a genetic basis for inter-patient variability in MTX response and could be used to improve future dosing algorithms.Copyright © 2020 American Society of Hematology.
About The Expert
Morten Tulstrup
Takaya Moriyama
Chuang Jiang
Marie Grosjean
Jacob Nersting
Jonas Abrahamsson
Kathrine Grell
Lisa Lyngsie Hjalgrim
Olafur G Jonsson
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 Gupta
Jun J Yang
Kjeld Schmiegelow
References
PubMed