Mutant, wild type, or overall p53 expression: freedom from clinical progression in tumours of astrocytic lineage

Abstract

Abnormalities of the p53 tumor-suppressor gene are found in a significant proportion of astrocytic brain tumours. We studied tumour specimens from 74 patients evaluated over 20 years at the Massachusetts General Hospital, where clinical outcome could be determined and sufficient pathologic material was available for immunostaining. p53 expression studies employed an affinity-purified p53 monoclonal antibody, whose specificity was verified in absorption studies and, in a minority of cases, a second antibody recognising a different epitope of p53. Significant overexpression of p53 protein was found in 48% of the 74 tumours included in this series and high levels of expression were associated with higher mortality from astrocytic tumours (Po0.001, log rank). Multivariate analyses revealed that immunohistochemically detected p53 was an independent marker of shortened progression-free and overall actuarial survival in patients with astrocytic tumours, suggesting that increased expression of p53 plays an important role in the pathobiology of these tumours. In a subset of 36 cases, coding regions of the p53 gene were completely sequenced via SSCP and direct DNA sequencing, revealing that overexpression of p53 protein is not always associated with point mutations in conserved exons of the p53 gene. Finally, we confirmed p53 protein expression in early-passage human glioma cell lines of known p53 mutational status and immunostaining scores. Although grade continues to be the strongest prognostic variable, the use of p53 staining as a prognostic indicator, in contrast to mutational DNA analyses, may be a useful adjunct in identifying patients at higher risk of treatment failure.

HDJ-2 as a Target for Radiosensitization of Glioblastoma Multiforme Cells by the Farnesyltransferase Inhibitor R115777 and the Role of the p53/p21 Pathway

“…With the exception of SF188, cell lines with p53 mutation (T98, SF188, U251, and SF763) had high protein levels of p53. Two cell lines (U343 and SF767) with wild-type p53 also had high p53 expression, as has been reported in several types of cancers, including gliomas (24). Interestingly, the two cell lines with wild-type p16 (SF188 and SF767) also had very high levels of CDK4 expression, indicating genetic alterations in the p16/cyclin D/CDK4 pathway.…”

Immunoexpression of tumor suppressor genes p53, p21WAF1/CIP1 and p27KIP1 in humam astrocystic tumors

“…Many researches also report the detection of the p53 protein in astrocytic tumors as a prognostic factor. Jaros et al 15 and Pardo et al 20 refer to p53 protein as an indicator of the malignant progression, low disease-free time after surgery and low general survival. On the other hand, Birner et al 30 associated the p53 protein detection to a greater sensibility of grade IV tumors to radiotherapy and adjuvant chemotherapy.…”

“…Actually, we suggest that this confl ict may be explained by the expression of the wild-type p53 protein in a portion of glioblastomas (grade IV). This expression would occur through the activation of this tumor suppressor caused by other genetic alterations present in grade IV tumors, leading to the accumulation of a notable quantity of functional p53 protein, which is able to persist in detectable amount in tissues 20 . This fraction would probably be represented by grade IV tumors found in group D, where the evidence of wild-type p53 detection is reinforced by the positivity for p21.…”

Oncolytic adenoviral vectors which employ the survivin promoter induce glioma oncolysis via a process of beclin-dependent autophagy

“…This interaction between survivin and p53 has particular implication in neurooncology, where the majority of tumors, including the No. 10 glioma tested in this study, have been shown to exhibit p53 mutations (55)(56)(57)(58).…”