Effects of germ line DHFR and FPGS variants on methotrexate metabolism and relapse of leukemia

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 per...

Full description

Saved in:
Bibliographic Details
Published in:Blood 2020, Vol.136 (10), p.1161
Main Authors: Tulstrup, M., Moriyama, T., Jiang, C., Grosjean, M., Nersting, J., Abrahamsson, Jonas, Grell, K., Hjalgrim, L. L., Jonsson, O. G., Kanerva, J., Lund, B., Nielsen, S. N., Nielsen, R. L., Quist-Paulsen, P., Pruunsild, K., Wolthers, B. O., Zhang, H., Gupta, R., Yang, J. J., Schmiegelow, K.
Format: Article
Language:English
Subjects:
acute lymphoblastic-leukemia
cell
chemotherapy
children
Clinical Medicine
free survival
Hematology
high-dose methotrexate
Klinisk medicin
maintenance
nopho all2008
nudt15 polymorphisms
polyglutamates
therapy
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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 x 10(-8)) related to suppression of enhancer activity, whereas rs35789560 in FPGS (p.R466C, P = 5.6 x 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.
ISSN:0006-4971
DOI:10.1182/blood.2020005064