Effects of germline DHFR and FPGS variants on methotrexate metabolism and relapse of leukemia
| Autor: | Morten Tulstrup, Jonas Abrahamsson, Ramneek Gupta, Chuang Jiang, Hui Zhang, Lisa Lyngsie Hjalgrim, Kjeld Schmiegelow, Jacob Nersting, Bendik Lund, Jukka Kanerva, Marie Grosjean, Takaya Moriyama, Olafur G. Jonsson, Benjamin Ole Wolthers, Kathrine Grell, Goda Vaitkeviciene, Stine Nygaard Nielsen, Kaie Pruunsild, Ulrik Malthe Overgaard, Jun J. Yang, Rikke Linnemann Nielsen, Petter Quist-Paulsen |
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| Rok vydání: | 2020 |
| Předmět: |
Adult
Male medicine.medical_specialty Adolescent medicine.medical_treatment Immunology Genome-wide association study Polymorphism Single Nucleotide Biochemistry Young Adult Maintenance therapy Internal medicine Dihydrofolate reductase medicine Humans Dosing Peptide Synthases Child Chemotherapy Lymphoid Neoplasia Hematology biology business.industry Infant Newborn Infant Cell Biology Middle Aged Precursor Cell Lymphoblastic Leukemia-Lymphoma Prognosis medicine.disease Tetrahydrofolate Dehydrogenase Leukemia Methotrexate Polyglutamic Acid Child Preschool biology.protein Cancer research Female Neoplasm Recurrence Local business Genome-Wide Association Study medicine.drug |
| Zdroj: | Blood |
| ISSN: | 1528-0020 0006-4971 |
| DOI: | 10.1182/blood.2020005064 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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