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Oxidative stress levels are correlated with P15 and P16 gene promoter methylation in myelodysplastic syndrome patients

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Abstract

Oxidative stress and abnormal DNA methylation have been implicated in some types of cancer, namely in myelodysplastic syndromes (MDS). Since both mechanisms are observed in MDS patients, we analyzed the correlation of intracellular levels of peroxides, superoxide anion, and glutathione (GSH), as well as ratios of peroxides/GSH and superoxide/GSH, with the methylation status of P15 and P16 gene promoters in bone marrow leukocytes from MDS patients. Compared to controls, these patients had lower GSH content, higher peroxide levels, peroxides/GSH and superoxide/GSH ratios, as well as higher methylation frequency of P15 and P16 gene promoters. Moreover, patients with methylated P15 gene had higher oxidative stress levels than patients without methylation (peroxides: 460 ± 42 MIF vs 229 ± 25 MIF, p = 0.001; superoxide: 383 ± 48 MIF vs 243 ± 17 MIF, p = 0.022; peroxides/GSH: 2.50 ± 0.08 vs 1.04 ± 0.34, p < 0.001; superoxide/GSH: 1.76 ± 0.21 vs 1.31 ± 0.10, p = 0.007). Patients with methylated P16 and at least one methylated gene had higher peroxide levels as well as peroxides/GSH ratio than patients without methylation. Interestingly, oxidative stress levels allow the discrimination of patients without methylation from ones with methylated P15, methylated P16, or at least one methylated (P15 or P16) promoter. Taken together, these findings support the hypothesis that oxidative stress is correlated with P15 and P16 hypermethylation.

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Acknowledgments

The present work was supported by CIMAGO—Center of Investigation on Environment, Genetics and Oncobiology, Faculty of Medicine, University of Coimbra, Portugal, and by center grant (to BioISI, Center Reference: UID/MULTI/04046/2013) from FCT/MCTES/PIDDAC, Portugal.

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Authors and Affiliations

  1. Applied Molecular Biology, University Clinic of Hematology, Center of Investigation in Environment, Genetics and Oncobiology (CIMAGO), Faculty of Medicine, University of Coimbra (FMUC), Azinhaga de Santa Comba - Celas, 3000-548, Coimbra, Portugal

    Ana Cristina Gonçalves, Emília Cortesão, Luís Rito & Ana Bela Sarmento-Ribeiro

  2. Center for Neuroscience and Cell Biology (CNC), Coimbra, Portugal

    Ana Cristina Gonçalves & Ana Bela Sarmento-Ribeiro

  3. Clinical Hematology Department, Centro Hospitalar e Universitário de Coimbra (CHUC), Coimbra, Portugal

    Emília Cortesão, Ana Isabel Espadana, Luís Rito, Emília Magalhães & Ana Bela Sarmento-Ribeiro

  4. Laboratory for Biostatistics and Medical Informatics, Faculty of Medicine, University of Coimbra (FMUC), Coimbra, Portugal

    Barbara Oliveiros

  5. Immunology, Faculty of Medicine, University of Coimbra (FMUC), Coimbra, Portugal

    Vera Alves

  6. Medicine Department, Hospital Distrital da Figueira da Foz, Figueira da Foz, Portugal

    Sónia Pereira & Amélia Pereira

  7. Oncology Department, Centro Hospital e Universitário de Coimbra (CHUC), Coimbra, Portugal

    José Manuel Nascimento Costa

  8. University Clinic of Oncology, Faculty of Medicine, University of Coimbra (FMUC), Coimbra, Portugal

    José Manuel Nascimento Costa

  9. Molecular Genetics and Pathology Unit, Hospital of Divino Espírito Santo of Ponta Delgada EPE, São Miguel Island, Azores, Portugal

    Luisa Mota-Vieira

  10. Azores Genetics Research Group, Instituto Gulbenkian de Ciência, Oeiras, Portugal

    Luisa Mota-Vieira

  11. Faculty of Sciences, Biosystems & Integrative Sciences Institute (BioISI), University of Lisboa, Lisbon, Portugal

    Luisa Mota-Vieira

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  1. Ana Cristina Gonçalves
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  2. Emília Cortesão
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  4. Vera Alves
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Correspondence to Ana Bela Sarmento-Ribeiro.

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Gonçalves, A.C., Cortesão, E., Oliveiros, B. et al. Oxidative stress levels are correlated with P15 and P16 gene promoter methylation in myelodysplastic syndrome patients. Clin Exp Med 16, 333–343 (2016). https://doi.org/10.1007/s10238-015-0357-2

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