Effects of germline DHFR and FPGS variants on methotrexate metabolism and relapse of leukemia.
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Hjalgrim, Lisa Lyngsie
Jónsson, Ólafur Gísli
Nielsen, Stine Nygaard
Nielsen, Rikke Linnemann
Wolthers, Benjamin Ole
Yang, Jun J
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CitationTulstrup M, Moriyama T, Jiang C, Grosjean M, Nersting J, Abrahamsson J, et al. Effects of germline DHFR and FPGS variants on methotrexate metabolism and relapse of leukemia. Blood. 2020 Sep 3;136(10):1161-1168. doi: 10.1182/blood.2020005064
AbstractMethotrexate (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.
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Rights© 2020 by The American Society of Hematology.
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- Issue date: 2017 Apr
- Association of <i>NUDT15</i>*3 and <i>FPGS</i> 2572C>T Variants with the Risk of Early Hematologic Toxicity During 6-MP and Low-Dose Methotrexate-Based Maintenance Therapy in Indian Patients with Acute Lymphoblastic Leukemia.
- Authors: Kodidela S, Dorababu P, Thakkar DN, Dubashi B, Sundaram R, Muralidharan N, Nidanapu RP, Aribandi A, Pradhan SC, Uppugunduri CRS
- Issue date: 2020 May 28
- Risk of relapse in childhood acute lymphoblastic leukemia is related to RBC methotrexate and mercaptopurine metabolites during maintenance chemotherapy. Nordic Society for Pediatric Hematology and Oncology.
- Authors: Schmiegelow K, Schrøder H, Gustafsson G, Kristinsson J, Glomstein A, Salmi T, Wranne L
- Issue date: 1995 Feb
- Differences in folylpolyglutamate synthetase and dihydrofolate reductase expression in human B-lineage versus T-lineage leukemic lymphoblasts: mechanisms for lineage differences in methotrexate polyglutamylation and cytotoxicity.
- Authors: Galpin AJ, Schuetz JD, Masson E, Yanishevski Y, Synold TW, Barredo JC, Pui CH, Relling MV, Evans WE
- Issue date: 1997 Jul