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Impact of genetic variants of RFC1, DHFR and MTHFR in osteosarcoma patients treated with high-dose methotrexate

The Pharmacogenomics Journal volume 15, pages 385–390 (2015)Cite this article

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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.

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Acknowledgements

SJ is a PhD scholar from the Norwegian Health Authority grant nr HSE 2014061. This study was financed by a grant from the Norwegian Research Council to VNK (PK01-2007-0356). We would like to thank David Quigley for the critical reading of the manuscript and to Silje Nord for the contribution to the statistical analysis and presentation.

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Authors and Affiliations

  1. Division of Medicine, Department for Clinical Molecular Biology and Lab Science (EpiGen), Akershus University Hospital, Lørenskog, Norway

    S Jabeen & V N Kristensen

  2. Department of Genetics, KG Jebsen Center for Breast Cancer Research, Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo,, Norway

    S Jabeen, G I G Alnæs & V N Kristensen

  3. Department of Nuclear Medicine, Oslo University Hospital Ullevål, Oslo,, Norway

    L Holmboe

  4. Division of Cancer Surgery and Transplantation, Department of Genetics, Institute for Cancer Research, OUS HF, Radiumhospitalet, Oslo, Norway

    G I G Alnæs & V N Kristensen

  5. Department of Pharmacology, Oslo University Hospital, Rikshospitalet, Oslo, Norway

    A M Andersen

  6. Department of Oncology, Oslo University Hospital, Radiumhospitalet, Oslo, Norway

    K S Hall

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  1. S Jabeen
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Correspondence to V N Kristensen.

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Jabeen, S., Holmboe, L., Alnæs, G. et al. Impact of genetic variants of RFC1, DHFR and MTHFR in osteosarcoma patients treated with high-dose methotrexate. Pharmacogenomics J 15, 385–390 (2015). https://doi.org/10.1038/tpj.2015.11

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