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Rigshospitalet - en del af Københavns Universitetshospital
Udgivet

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

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Vis graf over relationer

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 polyglutamates (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.

OriginalsprogEngelsk
TidsskriftBlood
Vol/bind136
Udgave nummer10
Sider (fra-til)1161-1168
Antal sider8
ISSN0006-4971
DOI
StatusUdgivet - 3 sep. 2020

Bibliografisk note

© 2020 by The American Society of Hematology.

ID: 62071975