MGMT methylation status: The advent of stratified therapy in glioblastoma?

Issue title: Epigenetic Markers

Article type: Research Article

Authors: Hau, Peter | Stupp, Roger | Hegi, Monika E.

Affiliations: Klinikum der Universität Regensburg, Klinik und Poliklinik für Neurologie am Bezirksklinikum, 93053 Regensburg, Germany. E-mail: [email protected] | Multidisciplinary Oncology Center, University Hospital Lausanne (CHUV), 1011 Lausanne, Switzerland. E-mail: [email protected] | Laboratory of Tumor Biology and Genetics Department of Neurosurgery, University Hospital Lausanne (CHUV), 1011 Lausanne, and National Center of Competence in Research (NCCR) Molecular Oncology, Swiss Institute for Cancer Research (ISREC), Switzerland. E-mail: [email protected]

Note: [] Corresponding author: Peter Hau, MD, Laboratory of NeuroOncology, Klinik und Poliklinik für Neurologie der Universität Regensburg am Bezirksklinikum, 93053 Regensburg, Germany. Tel.: +49 941 941 0; Fax: +49 941 9041 3005; E-mail: [email protected]

Abstract: Glioblastomas are the most malignant gliomas with median survival times of only 15 months despite modern therapies. All standard treatments are palliative. Pathogenetic factors are diverse, hence, stratified treatment plans are warranted considering the molecular heterogeneity among these tumors. However, most patients are treated with "one fits all" standard therapies, many of them with minor response and major toxicities. The integration of clinical and molecular information, now becoming available using new tools such as gene arrays, proteomics, and molecular imaging, will take us to an era where more targeted and effective treatments may be implemented. A first step towards the design of such therapies is the identification of relevant molecular mechanisms driving the aggressive biological behavior of glioblastoma. The accumulation of diverse aberrations in regulatory processes enables tumor cells to bypass the effects of most classical therapies available. Molecular alterations underlying such mechanisms comprise aberrations on the genetic level, such as point mutations of distinct genes, or amplifications and deletions, while others result from epigenetic modifications such as aberrant methylation of CpG islands in the regulatory sequence of genes. Epigenetic silencing of the MGMT gene encoding a DNA repair enzyme was recently found to be of predictive value in a randomized clinical trial for newly diagnosed glioblastoma testing the addition of the alkylating agent temozolomide to standard radiotherapy. Determination of the methylation status of the MGMT promoter may become the first molecular diagnostic tool to identify patients most likely to respond that will allow individually tailored therapy in glioblastoma. To date, the test for the MGMT-methylation status is the only tool available that may direct the choice for alkylating agents in glioblastoma patients, but many others may hopefully become part of an arsenal to stratify patients to respective targeted therapies within the next years.

Keywords: Glioblastoma, predictive factors, personalized therapy, targeted therapy, MGMT

Journal: Disease Markers, vol. 23, no. 1-2, pp. 97-104, 2007