title: Impact of genetic variants of RFC1, DHFR and MTHFR in osteosarcoma patients treated with high-dose methotrexate.
abstract: Osteosarcoma patients are commonly treated with high doses of methotrexate (MTX). MTX is an analog of folate, which is essential for DNA synthesis. Genetic polymorphism at single nucleotide can be indicative to the prognostic outcome in patients. Germ-line variants in candidate genes, coding for enzymes active in the metabolism of MTX, were studied in 62 osteosarcoma patients. Patients harboring the GG genotype in reduced folate carrier 1 (RFC1) rs1051266 had significantly better survival in comparison with patients having the AA genotype (P=0.046). These patients also had a lower frequency of metastasis (15%, P=0.029). Also patients homozygous for the G allele of rs1053129 in the dihydrofolate reductase (DHFR) gene were more likely to have a metastasis (45%, P= 0.005), and the methylenetetetrahydrofolate reductase (MTHFR) 677C allele was associated with higher degree of liver toxicity (88%, P=0.007). The study suggests that germ-line variants in the MTX metabolic pathway are associated with survival and side effects in patients treated with MTX.
authors.affiliation: Division of Medicine, Department for Clinical Molecular Biology and Lab Science (EpiGen), Akershus University Hospital, Lørenskog, Norway.|KG Jebsen Center for Breast Cancer Research, Department of Genetics, Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
authors.forename: S
authors.initials: S
authors.lastname: Jabeen
authors.affiliation: Department of Nuclear Medicine, Oslo University Hospital Ullevål, Oslo, Norway.
authors.forename: L
authors.initials: L
authors.lastname: Holmboe
authors.affiliation: KG Jebsen Center for Breast Cancer Research, Department of Genetics, Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.|Division of Cancer Surgery and Transplantation, Department of Genetics, Institute for Cancer Research, OUS HF, Radiumhospitalet, Oslo, Norway.
authors.forename: G I G
authors.initials: GI
authors.lastname: Alnæs
authors.affiliation: Department of Pharmacology, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
authors.forename: A M
authors.initials: AM
authors.lastname: Andersen
authors.affiliation: Department of Oncology, Oslo University Hospital, Radiumhospitalet, Oslo, Norway.
authors.forename: K S
authors.initials: KS
authors.lastname: Hall
authors.affiliation: Division of Medicine, Department for Clinical Molecular Biology and Lab Science (EpiGen), Akershus University Hospital, Lørenskog, Norway.|KG Jebsen Center for Breast Cancer Research, Department of Genetics, Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.|Division of Cancer Surgery and Transplantation, Department of Genetics, Institute for Cancer Research, OUS HF, Radiumhospitalet, Oslo, Norway.
authors.forename: V N
authors.initials: VN
authors.lastname: Kristensen
mesh_terms: D000483:Alleles; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage / Q000009:adverse effects; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics*; D012516:Osteosarcoma / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D020641:Polymorphism, Single Nucleotide; D051818:Replication Protein C / Q000235:genetics*; D013762:Tetrahydrofolate Dehydrogenase / Q000235:genetics*
chemical_list: C081632:RFC1 protein, human; C573423:MTHFR protein, human; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D013762:Tetrahydrofolate Dehydrogenase; D051818:Replication Protein C; D008727:Methotrexate