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O⁶-Methylguanine-DNA Methyltransferase Activity in Adult Gliomas: Relation to Patient and Tumor Characteristics¹

Departments of Neurological Surgery [J. R. S., M. S. Bo., S. G., D. D. K., M. S. Be.] and Pathology [A. B.], University of Washington, Seattle, Washington 98195-6470, and Division of Neurosurgery, Children's Hospital and Medical Center, Seattle, Washington 98105 [M. S. Bo.]

The DNA repair protein O⁶-methylguanine-DNA methyltransferase (MGMT) confers resistance to therapeutic methylating and chloroethylating agents in human brain tumor-derived cell lines. In this work, we assayed MGMT activity in 152 adult gliomas to establish correlates with patient and tumor characteristics. We also assayed MGMT in histologically normal brain adjacent to 87 tumors to characterize changes in activity accompanying neurocarcinogenesis. MGMT activity was detectable in 76% (115 of 152) of tumors, ranging 300-fold from 0.30 to 89 fmol/10⁶ cells (180–57,000 molecules/cell). Mean activity was 6.6 ± 13 fmol/10⁶ cells and varied 4-fold among diagnostic groups. The mean for oligodendrogliomas was 2-fold lower (P < 0.03), and for mixed oligodendroglioma-astrocytomas, the mean was 4-fold lower (P < 0.006) than for astroglial tumors. Twenty-five % of gliomas had no detectable MGMT activity (Mer^- phenotype; < 0.25 fmol/10⁶ cells or 150 molecules/cell). Glioma MGMT was inversely correlated with age (P < 0.01), consistent with the observed age dependence in the progenitor tissue of brain tumors (J. R. Silber et al., Proc. Natl. Acad. Sci. USA, 93: 6941–6946, 1996). Neither MGMT activity nor proportion of Mer^- tumors differed by sex. Glioma MGMT was correlated with degree of aneuploidy (P < 0.006) but not with fraction of S-phase cells. Mean activity in tumors was 5-fold higher than in adjacent histologically normal brain (5.0 ± 7.6 versus 1.1 ± 1.9 fmol/10⁶ cells; P < 0.001). Notably, elevation of tumor activity was observed in 62% of tissue pairs, ranging from 2-fold to >105-fold. Moreover, 64% of Mer^- normal tissue was accompanied by Mer⁺ tumor. These observations indicate that expression of MGMT activity is frequently activated and/or increased during human neurocarcinogenesis, and that the enhancement is not related to proliferation per se. Significantly, enhanced MGMT activity may heighten the resistance of brain tumors to therapeutic alkylating agents.

¹ This work was supported by Grants CA 707090 and OIG R35-CA39903 from the NIH, Grants EDT-53 and CN84214 from the American Cancer Society, and a grant from the American Federation for Aging Research. Additional support was from the John Gallagher Fund, the Doris Schiffman Fund, and the Brain Tumor Research Fund of the Department of Neurological Surgery, University of Washington, and the Neurooncology Gift Fund and Jessie's Perfect Peach Fund of Children's Hospital and Medical Center.

² To whom requests for reprints should be addressed, at Department of Neurological Surgery, Box 356470, University of Washington School of Medicine, Seattle, WA 98195-6470. Phone: (206) 685-8642; Fax: (206) 543-8315; E-mail: jrsilber@u.washington.edu.

³ Present address: Department of Neurosurgery, University of California San Francisco, San Francisco, CA 94143-0112.

Received 9/11/97. Accepted 1/13/98.

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