O6-methylguanine-DNA methyltransferase expression strongly correlates with outcome in childhood malignant gliomas: results from the CCG-945 Cohort.
OBJECTIVE
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.


CONCLUSIONS
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.
Pollack
Ian F
IF
Department of Neurosurgery, University of Pittsburgh Cancer Institute, University of Pittsburgh Medical Center and the Children's Hospital of Pittsburgh, Pittsburgh, PA 15213, USA. ian.pollack@chp.edu
Hamilton
Ronald L
RL
Sobol
Robert W
RW
Burnham
Judith
J
Yates
Allan J
AJ
Holmes
Emiko J
EJ
Zhou
Tianni
T
Finlay
Jonathan L
JL
D000293:Adolescent; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000201:enzymology*; D002648:Child; D002675:Child, Preschool; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D005910:Glioma / Q000188:drug therapy* / Q000201:enzymology*; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000378:metabolism*; D016032:Randomized Controlled Trials as Topic; D012189:Retrospective Studies; D016019:Survival Analysis; D016896:Treatment Outcome; D015854:Up-Regulation
D018906:Antineoplastic Agents, Alkylating; D014408:Biomarkers, Tumor; D019853:O(6)-Methylguanine-DNA Methyltransferase