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Methylation-specific multiplex ligation-dependent probe amplification identifies promoter methylation events associated with survival in glioblastoma

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Abstract

DNA methylation plays an important role in cancer biology and methylation events are important prognostic and predictive markers in many tumor types. We have used methylation-specific multiplex ligation-dependent probe amplification to survey the methylation status of MGMT and 25 tumor suppressor genes in 73 glioblastoma cases. The data obtained was correlated with overall survival and response to treatment. The study revealed that methylation of promoter regions in TP73 (seven patients), THBS1 (eight patients) and PYCARD (nine patients) was associated with improved outcome, whereas GATA5 (21 patients) and WT1 (24 patients) promoter methylation were associated with poor outcome. In patients treated with temozolomide and radiation MGMT and PYCARD promoter methylation events remained associated with improved survival whereas GATA5 was associated with a poor outcome. The identification of GATA5 promoter methylation in glioblastoma has not previously been reported. Furthermore, a cumulative methylation score separated patients into survival groups better than any single methylation event. In conclusion, we have identified specific methylation events associated with patient outcome and treatment response in glioblastoma, and these may be of functional and predictive/prognostic significance. This study therefore provides novel candidates and approaches for future prospective validation.

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Acknowledgments

We would like to thank our colleagues within the Yorkshire Regional Genetics Service and Leeds Teaching Hospitals NHS Trust for their support in providing the diagnostic MGMT methylation service with special thanks to Ian Cook and Lampros Mavrogiannis. DAC is supported by a UK Medical Research Council Career Development Fellowship [G0802416]. SEL is supported by a grant from Brain Tumour Research and Support across Yorkshire and Candlelighters.

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical standards

The experiments described in this paper comply with the current laws of the United Kingdom regarding ethics.

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Author notes

  1. S. E. Lawler

    Present address: Department of Neurosurgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, 02115, USA

Authors and Affiliations

  1. Yorkshire Regional Cytogenetics Unit, St James’s University Hospital, Leeds, LS9 7TF, UK

    K. L. Rankeillor & P. Roberts

  2. Section of Oncology and Clinical Research, Leeds Institute of Molecular Medicine, St James’s University Hospital, Leeds, LS9 7TF, UK

    D. A. Cairns, S. C. Short & S. E. Lawler

  3. Department of Oncology, St James’s University Hospital, Leeds, LS9 7TF, UK

    C. Loughrey

  4. Department of Neurosurgery, Leeds General Infirmary, Leeds, LS1 3BR, UK

    P. Chumas

  5. Department of Histopathology, St James’s University Hospital, Leeds, LS9 7TF, UK

    A. Ismail & A. Chakrabarty

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  1. K. L. Rankeillor
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Correspondence to K. L. Rankeillor or S. E. Lawler.

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Rankeillor, K.L., Cairns, D.A., Loughrey, C. et al. Methylation-specific multiplex ligation-dependent probe amplification identifies promoter methylation events associated with survival in glioblastoma. J Neurooncol 117, 243–251 (2014). https://doi.org/10.1007/s11060-014-1372-y

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  • DOI: https://doi.org/10.1007/s11060-014-1372-y

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