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dc.contributor.authorTulstrup, Morten
dc.contributor.authorMoriyama, Takaya
dc.contributor.authorJiang, Chuang
dc.contributor.authorGrosjean, Marie
dc.contributor.authorNersting, Jacob
dc.contributor.authorAbrahamsson, Jonas
dc.contributor.authorGrell, Kathrine
dc.contributor.authorHjalgrim, Lisa Lyngsie
dc.contributor.authorJónsson, Ólafur Gísli
dc.contributor.authorKanerva, Jukka
dc.contributor.authorLund, Bendik
dc.contributor.authorNielsen, Stine Nygaard
dc.contributor.authorNielsen, Rikke Linnemann
dc.contributor.authorOvergaard, Ulrik
dc.contributor.authorQuist-Paulsen, Petter
dc.contributor.authorPruunsild, Kaie
dc.contributor.authorVaitkeviciene, Goda
dc.contributor.authorWolthers, Benjamin Ole
dc.contributor.authorZhang, Hui
dc.contributor.authorGupta, Ramneek
dc.contributor.authorYang, Jun J
dc.contributor.authorSchmiegelow, Kjeld
dc.date.accessioned2020-11-19T10:58:45Z
dc.date.available2020-11-19T10:58:45Z
dc.date.issued2020-09-03
dc.date.submitted2020-11
dc.identifier.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.2020005064en_US
dc.identifier.pmid32391884
dc.identifier.doi10.1182/blood.2020005064
dc.identifier.urihttp://hdl.handle.net/2336/621563
dc.descriptionTo access publisher's full text version of this article click on the hyperlink belowen_US
dc.description.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.en_US
dc.description.sponsorshipDanish Cancer Society Danish Childhood Cancer Foundation Swedish Childhood Cancer Foundation Nordic Cancer Union Otto Christensen Foundation University Hospital Rigshospitalet Novo Nordisk Foundation United States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Institute of General Medical Sciences (NIGMS) Alex's Lemonade Stand Foundationen_US
dc.language.isoenen_US
dc.publisherAmerican Society of Hematologyen_US
dc.relation.urlhttps://ashpublications.org/blood/article-abstract/136/10/1161/455060/Effects-of-germline-DHFR-and-FPGS-variants-on?redirectedFrom=fulltexten_US
dc.rights© 2020 by The American Society of Hematology.
dc.subjectLeukemia, Acute Lymphoblasticen_US
dc.subjectAcute lymphoblastic leukemiaen_US
dc.subjectChemotherapyen_US
dc.subjectBráðahvítblæðien_US
dc.subjectLyfjameðferðen_US
dc.subject.meshMethotrexateen_US
dc.subject.meshPrecursor Cell Lymphoblastic Leukemia-Lymphomaen_US
dc.titleEffects of germline DHFR and FPGS variants on methotrexate metabolism and relapse of leukemia.en_US
dc.typeArticleen_US
dc.identifier.eissn1528-0020
dc.contributor.department1Department of Pediatrics and Adolescent Medicine and. 2Department of Hematology, University Hospital Rigshospitalet, Copenhagen, Denmark. 3Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, TN. 4Department of Hematology/Oncology, Shanghai Children's Medical Center, Shanghai Jiao Tong University, Shanghai, China. 5Department of Bio and Health Informatics, Technical University of Denmark, Lyngby, Denmark. 6Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. 7Section of Biostatistics, Department of Public Health, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. 8Pediatric Hematology-Oncology, Barnaspitali Hringsins, Landspitali University Hospital, Reykjavik, Iceland. 9Children's Hospital, Helsinki University Central Hospital, Helsinki, Finland. 10Department of Pediatrics, St Olavs University Hospital, Trondheim, Norway. 11Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway. 12Department of Health Technology, Technical University of Denmark, Kongens Lyngby, Denmark. 13Sino-Danish Center for Education and Research, University of Chinese Academy of Sciences, Beijing, China. 14Department of Hematology, St Olavs University Hospital, Trondheim, Norway. 15Department of Oncology and Haematology, Tallinn Children's Hospital, Tallinn, Estonia. 16Centre for Paediatric Oncology and Haematology, Vilnius University Hospital Santaros Klinikos and Vilnius University, Vilnius, Lithuania. 17Department of Pediatric Hematology/Oncology, Guangzhou Women and Children's Medical Center, Guangzhou, China; and. 18Institute of Clinical Medicine, Faculty of Medicine, University of Copenhagen, Copenhagen, Denmark.en_US
dc.identifier.journalBlooden_US
dc.rights.accessLandspitali Access - LSH-aðganguren_US
dc.departmentcodePED12
dc.source.journaltitleBlood
dc.source.volume136
dc.source.issue10
dc.source.beginpage1161
dc.source.endpage1168
dc.source.countryUnited States
dc.source.countryUnited States
dc.source.countryUnited States


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