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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@chp.edu
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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.
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