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The Relationship between TP53 Mutations and Overexpression of p53 and Prognosis in Malignant Gliomas of Childhood¹

Departments of Neurosurgery [I. F. P., J. W. C.], Pathology [R. L. H., S. D. F., A. J. M.], Neuropathology [R. L. H., A. J. M.], and Neurology (Division of Neuro-oncology) [M. E. B.], University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213; Department of Human Genetics, University of Pittsburgh Graduate School of Public Health [S. M. G.], University of Pittsburgh Cancer Institute Brain Tumor Center [I. F. P., R. L. H., A. J. M., M. E. B.]; Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania 15213 [I. F. P., R. L. H.]; and Emory and Henry College, Emory, Virginia 24327 [R. N. S.]

The prognosis for children with high-grade gliomas remains somewhat unpredictable. Although prolonged disease control is sometimes achieved after surgery, radiotherapy, and chemotherapy, most patients exhibit rapid disease progression. Because p53-dependent apoptosis mechanisms are involved in the cytotoxic effects of irradiation and chemotherapy, we questioned whether p53 status might be associated with outcome in childhood malignant gliomas. Therefore, we examined p53 status, both immunohistochemically and by direct sequencing of exons 5–8, in a series of 29 archival pediatric malignant non-brainstem gliomas treated consecutively at our institution between 1975 and 1992. Eighteen tumors had dense p53 staining in the majority of cells, although only 11 had mutations of the p53 gene (TP53). On univariate analysis, there was a significant association between p53 overexpression and a shorter progression-free survival (PFS) and overall survival (OS; P = 0.019 and 0.013, respectively; rank sum test). In addition, there was a significant association between TP53 mutations and a poorer PFS (P = 0.04), and a strong trend toward a shorter OS among patients with TP53 mutations (P = 0.06). Median PFS and OS for patients with TP53-mutated tumors were 6 months and 16 months, respectively, and for those with p53 overexpression 5.5 months and 14 months, respectively, versus 16 months and 25 months, respectively, for those without TP53 mutations and 25 months and >4 years, respectively, for those without p53 overexpression. The percentage of patients in this series with TP53 mutations (37.9%) was substantially higher than in previous studies of childhood gliomas and comparable to the frequency of mutations noted in adult gliomas. However, both TP53 mutation and p53 overexpression were significantly less frequent in tumors from children younger than 4 than from older children (P = 0.02 and 0.01, respectively). These results indicate that p53 mutation and expression status may be associated with prognosis in childhood malignant gliomas, and thus may provide a basis for stratifying patients biologically in future malignant glioma studies.

¹ This work was supported in part by a grant from the Copeland Foundation (to I. F. P.), NIH Grant 1KO8-NS01810 (to I. F. P.), the Andrew W. Mellon Trust (to R. S.), the Burroughs Wellcome Fund (to R. S.), the Appalachian College Association (to R. S.), and an American Cancer Society Career Development Award (to M. E. B.).

² To whom requests for reprints should be addressed, at Department of Neurosurgery, Children's Hospital of Pittsburgh, 3705 Fifth Avenue, Pittsburgh, PA 15213. Phone: (412) 692-5881; Fax: (412) 692-5921; E-mail: Ian_Pollack@poplar.chp.edu.

Received 7/23/96. Accepted 12/ 3/96.

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