O6-Methylguanine-DNA Methyltransferase in Pediatric Primary Brain Tumors

O⁶-Methylguanine-DNA Methyltransferase in Pediatric Primary Brain Tumors

Relation to Patient and Tumor Characteristics1

Division of Neurosurgery, Department of Surgery [M. S. Bo., R. G. E., T. S. R.], and Division of Hematology/Oncology, Department of Pediatrics [J. R. G.], Children’s Hospital and Regional Medical Center, Seattle, Washington 98105; Department of Neurological Surgery, University of Washington, Seattle, Washington 98195-6470 [M. S. Bo., R. G. E., T. S. R., J. R. S.]; and Department of Neurological Surgery, University of California, San Francisco, California 94143-0112 [M. S. Be.]

Abstract

The DNA repair protein O⁶-methylguanine-DNA methyltransferase (MGMT) confers resistance to methylating and chloroethylating agents in pediatric medulloblastoma- and glioma-derived cell lines and xenografts. Here, we assayed MGMT activity in 110 pediatric brain tumors to establish correlates with patient and tumor characteristics. We also assayed MGMT in histologically normal brain adjacent to 22 tumors to characterize changes in activity accompanying neurocarcinogenesis. MGMT activity was detected in 94% of tumors, ranging ca. 1,500-fold from 0.34 to 498 fmol/10⁶ cells (∼205–300,000 molecules/cell). Mean activity was 25 ± 66 fmol/10⁶ cells, including six specimens with undetectable activity (Mer⁻ phenotype; <0.25 fmol/10⁶ cells or 151 molecules/cell). MGMT content varied 10-fold among diagnostic groups and was associated with degree of malignancy, as evidenced by a 4-fold difference in activity between high- and low-grade tumors (P = 0.03). Tumor MGMT content was age dependent, being 5-fold higher in children 3–12 years old than in infants (P = 0.015) and adolescents (P = 0.015). Mean activity in tumors was 9-fold higher than in adjacent histologically normal brain (21 ± 44 versus 2.4 ± 4.0 fmol/10⁶ cells; P = 0.05). By comparing tumor and adjacent normal tissue from the same patient, we found that 68% of cases exhibited an elevation of tumor activity that ranged from 2- to >590-fold. Moreover, 67% of Mer⁻ normal tissue was accompanied by Mer⁺ tumor. These observations indicate that MGMT activity is frequently elevated during pediatric neurocarcinogenesis. Significantly, enhanced MGMT activity may heighten resistance to alkylating agents, suggesting a potential role for MGMT inhibitors in therapy.

Footnotes

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
↵1 Supported by grants from the American Cancer Society (RPG-97-019 to J. R. S.) and the NIH (CA 719397 to M. S. Bo., CA 10382 and CA 81454 to J. R. G., and CA 707090 to J. R. S.). Additional support was from the Neurooncology Gift Fund and Jessie’s Perfect Peach Fund of Children’s Hospital and Regional Medical Center.
↵2 To whom requests for reprints should be addressed, at Division of Neurosurgery, Department of Surgery, Children’s Hospital and Regional Medical Center, Seattle, Washington 98105. Phone: (206) 526-2046; Fax: (206) 527-3925; E-mail: mbobol{at}chmc.org
↵3 The abbreviations used are: CNS, central nervous system; DNT, dysembryoplastic neuroepithelial tumor; Mer, methyl repair; MGMT, O⁶-methylguanine-DNA methyltransferase; PNET, primitive neuroectodermal tumor.
- Accepted December 15, 1900.
- Received August 16, 1900.
- Revision received December 14, 1900.