Using a panel of five antibodies to p53 and a standard immunocytochemical method, we found detectable quantities of p53 in the cells of 3/16 diffuse astrocytomas, 8/14 anaplastic astrocytomas, and 24/34 glioblastoma multiforme.
LOH on chromosome 10 and p53 mutation were found together only in patients with glioblastoma multiforme (22%), suggesting that these genetic changes may accumulate during astrocytoma progression.
Since the loss of heterozygosity on 17p was detected in low-grade as well as in high-grade astrocytomas, it is possible that p53 suppressor gene loss may be an early genetic event in the multistep process of astrocytoma formation.
We present two cases of DCAI, with histopathologic, immunohistochemical, ultrastructural, and molecular genetic data, and draw the following conclusions: (1) the diagnosis of DCAI requires a high index of suspicion and immunohistochemical or ultrastructural proof of astrocytic differentiation; (2) the data argue against nosologically equating these tumors with the desmoplastic infantile ganglioglioma, pleomorphic xanthoastrocytoma, or gliofibroma; (3) the components of the extensive tumor basal lamina may be elaborated by the tumor cells themselves and may contribute in an autocrine fashion to the slow growth of these lesions; and (4) if the lack of allelic loss on chromosomes 17p (including the p53 tumor suppressor gene locus) and 10 seen in our cases is found in other cases of DCAI, this may further distinguish the DCAI from other astrocytomas.
The wild-type p53 protein, which is a transcriptional activator, may serve as a barrier to the progression of neoplastic processes, and alterations of p53 are involved in genesis of various cancers including astrocytomas.
The earliest genetic alteration in human astrocytoma progression is mutation of the p53 tumour suppressor gene, while one of the earliest phenotypic changes is the stimulation of neovascularization.
These results suggest that a gene or genes in addition to TP53 on 17p may be involved in the etiology or progression of high-grade astrocytomas and aggressive JPAs in children.(ABSTRACT TRUNCATED AT 250 WORDS)
The observation that somatic p53 mutations in sporadic brain tumours are largely restricted to those of astrocytic origin and that astrocytomas also prevail among CNS neoplasms associated with p53 germline mutation strongly suggests, that p53 mutations are capable of initiating neoplastic transformation in astrocytes of the human nervous system.
Mutations in p53 has been implicated as an early pathogenic event leading to sporadic low grade astrocytomas, and is the third most common tumour type in patients with Li-Fraumeni syndrome, where they are predisposed due to a germline mutation in the p53 tumour suppressor gene.
We conclude that, whilst p53 undoubtedly plays an important role in the molecular 'chain' leading to malignancy in some astrocytomas, within tumours of comparable grade it does not appear to influence survival.
These results indicate that p53 plays a tumour suppressor role in low grade and high grade human astrocytomas and raise the possibility of the involvement of p53 in glioma cell differentiation in vitro.
To test this hypothesis, we retrospectively studied the association of p53 overexpression with survival in 149 patients with astrocytomas, using univariate and multivariate analysis to determine its value in predicting survival.
Mutations of the p53 tumor suppressor gene are common in astrocytomas that occur in adults but are rarely found in astrocytomas or medulloblastomas of children.
Using a monoclonal antibody that reacts with both mutant and wild-type p53 protein (PAb 1801), reactivity was assessed immunohistochemically in specimens from the first diagnosis of astrocytic neoplasm in 95 patients: 26 astrocytomas (A), 19 anaplastic astrocytomas (AA), and 50 glioblastomas multiforme (GBM).
We conclude from these findings that p53 gene mutations in brain neoplasms are primarily limited to tumors of astrocytic origin and that the p53 gene mutations in sporadic astrocytomas are somatic in origin (i.e., nonprenatally determined).
Moreover, 4 of the 11 patients with LOH of the p53 gene developed a second neoplasm in addition to an astrocytoma, possibly indicating genetic instability in these patients.
Analysis of p53 gene mutations in low- and high-grade astrocytomas by polymerase chain reaction-assisted single-strand conformation polymorphism and immunohistochemistry.