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Molecular Features of Adult Glioma Associated with Patient Race/Ethnicity, Age, and a Polymorphism in O⁶-Methylguanine-DNA-Methyltransferase

¹ Division of Neuroepidemiology, Department of Neurological Surgery, School of Medicine; ² Laboratory for Molecular Epidemiology, Department of Epidemiology and Biostatistics, University of California San Franciso; ³ Statistical Core, University of California San Francisco Comprehensive Cancer Center, San Francisco, California; ⁴ Department of Pathology and Brain Tumor Center, M.D. Anderson Cancer Center, Houston, Texas; and ⁵ Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, Massachusetts

Requests for reprints: John K. Wiencke, Division of Neuroepidemiology, Department of Neurological Surgery, School of Medicine, University of California San Francisco, Box 0441, San Francisco, CA 94143-0441. Phone: 415-502-2494; Fax: 415-502-1787. E-mail: Wiencke{at}itsa.ucsf.edu

Background: Risk factors for adult glioma in the San Francisco Bay Area include well-known demographic features such as age and race/ethnicity, and our previous studies indicated that these characteristics are associated with the TP53 mutation status of patients' tumors. We enlarged our study to assess the relationships of risk factors with TP53 as well as epidermal growth factor receptor (EGFR) and murine double minute-2 (MDM2) gene amplification and expression and the germ line Leu84Phe polymorphism in the DNA repair protein O⁶-methylguanine-DNA-methyltransferase (MGMT). MGMT expression may depend on the TP53 status of cells.

Methods: Molecular analyses were carried out on 556 incident astrocytic tumors. MGMT genotype data were collected on germ line DNA from 260 of these cases.

Results: The tumor data confirm the inverse relationships between TP53 mutation and MDM2 (P = 0.04) or EGFR (P = 0.004) amplification and that patients whose tumors contain TP53 mutations are younger than those without (P < 0.001). Although there was little difference in age of patient by EGFR amplification or expression among glioblastoma multiforme cases, EGFR gene amplification was associated with much older age of onset of anaplastic astrocytoma; for example, EGFR-amplified anaplastic astrocytoma cases were on average 63 years old compared with 48 years for nonamplified cases (P = 0.005). An increased prevalence of TP53 mutation positive glioblastoma multiforme was noted among nonwhites (African American and Asian) compared with whites (Latino and non-Latino; P = 0.004). Carriers of the MGMT variant 84Phe allele were significantly less likely to have tumors with TP53 overexpression (odds ratio, 0.30; 95% confidence interval, 0.13-0.71) and somewhat less likely to have tumors with any TP53 mutation (odds ratio, 0.47; 95% confidence interval, 0.13-1.69) after adjusting for age, gender, and ethnicity. Interestingly, EGFR gene amplification and EGFR protein overexpression were also inversely associated with the MGMT 84Phe allele.

Conclusions: Our results are consistent with ethnic variation in glioma pathogenesis. The data on MGMT show that an inherited factor involving the repair of methylation and other alkylation damage, specifically to the O⁶ position of guanine, may be associated with the development of tumors that proceed in their development without TP53 mutations or accumulation of TP53 protein and possibly also those that do not involve amplification of the EGFR locus.

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