Research
Print page Print page
Switch language
The Capital Region of Denmark - a part of Copenhagen University Hospital
Published

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

Research output: Contribution to journalJournal articleResearchpeer-review

DOI

  1. Relapse risk following truncation of pegylated asparaginase in childhood acute lymphoblastic leukemia

    Research output: Contribution to journalJournal articleResearchpeer-review

  2. Higher-order connections between stereotyped subsets: implications for improved patient classification in CLL

    Research output: Contribution to journalJournal articleResearchpeer-review

  3. Cost-effectiveness targeting CLL

    Research output: Contribution to journalJournal articleResearchpeer-review

  4. Novel manifestations of immune dysregulation and granule defects in gray platelet syndrome

    Research output: Contribution to journalJournal articleResearchpeer-review

  1. Increments in DNA-thioguanine level during thiopurine enhanced maintenance therapy of acute lymphoblastic leukemia

    Research output: Contribution to journalJournal articleResearchpeer-review

  2. Selection criteria for assembling a pediatric cancer predisposition syndrome gene panel

    Research output: Contribution to journalJournal articleResearchpeer-review

View graph of relations

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.

Original languageEnglish
JournalBlood
Volume136
Issue number10
Pages (from-to)1161-1168
Number of pages8
ISSN0006-4971
DOIs
Publication statusPublished - 3 Sep 2020

ID: 62071975