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O⁶-Methylguanine-DNA Methyltransferase Expression Strongly Correlates With Outcome in Childhood Malignant Gliomas: Results From the CCG-945 Cohort

Ian F. Pollack, Ronald L. Hamilton, Robert W. Sobol, Judith Burnham, Allan J. Yates, Emiko J. Holmes, Tianni Zhou, Jonathan L. Finlay

From the Departments of Neurosurgery, Pathology, and Pharmacology, University of Pittsburgh Cancer Institute, University of Pittsburgh Medical Center and the Children's Hospital of Pittsburgh, Pittsburgh, PA; Department of Pathology, Ohio State University, Columbus, OH; Department of Pediatrics, Children's Hospital Los Angeles; Department of Preventive Medicine, University of Southern California, Los Angeles; and the Children's Oncology Group, Arcadia, CA

Address reprint requests to Ian F. Pollack, MD, Department of Neurosurgery, Children's Hospital of Pittsburgh, 3705 Fifth Avenue, Pittsburgh, PA 15213; e-mail: ian.pollack{at}chp.edu

PURPOSE: O⁶-Methylguanine-DNA methyltransferase (MGMT) functions to counteract the cytotoxic effects of alkylating agents, such as nitrosoureas, which play a central role in the treatment of childhood malignant gliomas. Epigenetic silencing of MGMT has been associated with prolonged survival in adults with malignant gliomas, although the association between MGMT expression status and outcome in pediatric malignant gliomas has not been defined.

METHODS: We examined the association between MGMT expression and survival duration using tumor samples from the Children's Cancer Group 945 study, the largest randomized trial for childhood malignant gliomas completed to date. All patients received alkylator-based chemotherapy as a component of adjuvant therapy. Archival histopathologic material yielded tissue of sufficient quality for immunohistochemical assessment of MGMT expression status in 109 specimens.

RESULTS: Twelve of the 109 samples demonstrated overexpression of MGMT compared with normal brain. Five-year progression-free survival was 42.1% ± 5% in the 97 patients whose tumors had low levels of MGMT expression versus 8.3% ± 8% in the 12 patients whose tumors overexpressed MGMT (P = .017, exact log-rank test). The association between MGMT overexpression and adverse outcome remained significant after stratifying for institutional histologic diagnosis (eg, anaplastic astrocytoma or glioblastoma multiforme), as well as age, amount of residual tumor, and tumor location.

CONCLUSION: Overexpression of MGMT in childhood malignant gliomas is strongly associated with an adverse outcome in children treated with alkylator-based chemotherapy, independently of a variety of clinical prognostic factors.

Supported in part by National Institute of Health Grants No. NS37704 (I.F.P.) and CA13539 to the Children's Cancer Group. A complete listing of grant support for research conducted by Children’s Oncology Group (COG) and Pediatric Oncology Group before initiation of the COG grant in 2003 is available online at http://www.childrensoncologygroup.org/admin/grantinfo.htm.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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