Overexpression of the EGF Receptor and <i>p53</i> Mutations are Mutually Exclusive in the Evolution of Primary and Secondary Glioblastomas

TLDR

Glioblastoma multiforme can arise de novo as primary glioblastoma or evolve from low‑grade or anaplastic astrocytoma as secondary glioblastoma. The study examined 49 primary or secondary glioblastoma biopsies, assessing p53 mutations, p53 protein accumulation, and EGFR overexpression, with primary cases defined by a ≤3‑month history and initial glioblastoma histology, and secondary cases by at least two biopsies and documented progression. Primary glioblastomas showed rare p53 mutations (11%) and frequent EGFR overexpression (63%), whereas secondary glioblastomas had common p53 mutations (67%) and rare EGFR overexpression (10%); p53 protein accumulation mirrored these patterns, and only one tumor exhibited both alterations, indicating mutually exclusive genetic pathways.

Abstract

Glioblastoma multiforme, the most malignant human brain tumor, may develop de nova (primary glioblastoma) or through progression from low‐grade or anaplastic astrocytoma (secondary glioblastoma). We present further evidence that primary and secondary glioblastomas constitute distinct disease entities which develop through the acquisition of different genetic alterations. We analyzed p53 mutations, p53 protein accumulation and epidermal growth factor receptor (EGFR) overexpression in 49 biopsies classified as primary or secondary glioblastorna according to clinical and histopathologic criteria. Patients with primary glioblastoma were selected on the basis of a clinical history of less than 3 months and histopathologic features of glioblastoma at the first biopsy 119 cases; mean age, 55 years). The diagnosis of secondary glioblastomas required at least two biopsies and clinical as well as histologic evidence of progression from low grade or anaplastic astrocytoma (30 cases; mean age, 39 years). DNA sequence analysis showed that p53 mutations were rare in primary glioblastomas (11%) while secondary glioblastomas had a high incidence of p53 mutations (67%), of which 90% were already present in the first biopsy. The incidence of p53 protein accumulation (nuclear immunoreactivity to PAb 1801) was also lower in primary (37%) than in secondary glioblastornas (97%). In contrast, immunoreactivity for the EGF receptor prevailed in primary glioblastornas (63%) but was rare in secondary glioblastornas (10%). Only one out of 49 glioblastomas showed EGFR overexpression and a p53 mutation. These data indicate that overexpression of the EGF receptor and mutations of the p53 tumor suppressor gene are mutually exclusive events defining two different genetic pathways in the evolution of glioblastoma as the common phenotypic endpoint.