Expression of retinoblastoma gene product and p21 (WAF1/Cip 1) protein in gliomas: correlations with proliferation markers, p53 expression and survival

Abstract

Using immunohistochemistry we evaluated the expression of two negative regulators of the cell cycle, the retinoblastoma gene product (pRb) and the WAF1/Cip1 gene product (p21), in consecutive paraffin sections from 54 gliomas (49 astrocytomas and 5 oligodendrogliomas) and related it to clinicopathological parameters, proliferative fraction, p53 expression and survival. Survival analysis was restricted to the group of diffuse astrocytomas (48 patients). pRb expression did not correlate with histological type, grade or p53 expression, while a moderately strong correlation existed between pRb expression and the percentages of proliferating cell nuclear antigen (PCNA) and MIB-1-positive cells. In 30% of cases we observed diminished pRb expression (i.e., a low pRb/Ki-67 ratio), irrespective of grade or histological type. p21 protein was elevated in 50% of cases, especially within the higher grades. The percentage of p21-positive cells was not related to histological type or grade but correlated loosely with PCNA and pRb expression. A p53-negative/p21-negative phenotype was characteristic of oligodendrogliomas and low-grade astrocytomas, whereas the p53-positive/p21-positive, p53-positive/p21-negative and p53-negative/p21-positive phenotypes were almost equally distributed among high-grade tumors. In survival analysis (either univariate or multivariate) diminished pRb expression was not a statistically significant prognostic indicator. In contrast, p21 expression emerged as an important indicator of shortened disease-free survival, in both univariate and multivariate analyses. Moreover, the double-positive p53/p21 phenotype tended to be associated with a shorter overall survival. Our results suggest that Rb gene deregulation does not significantly affect prognosis but p21 expression may play an important role in disease-free survival of astrocytoma patients.

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

“…A number of studies, besides our own, indicate inverse correlations among increased p53 expression and conventional factors indicating a favourable clinical course in astrocytomas (Chozick et al, 1994a;Iuzzolino et al, 1994;Korkolopoulou et al, 1998). Increased p53 protein was detected in a subset of low-grade vs high-grade astrocytomas (Chozick et al, 1994a).…”

“…Increased p53 protein was detected in a subset of low-grade vs high-grade astrocytomas (Chozick et al, 1994a). Increased p53 expression occurred in the recurrent vs the initial tumour pairs from the same patient, while tumours recurring within the same histologic grade category, failed to reveal this increase (Chozick et al, 1994a;Iuzzolino et al, 1994;Korkolopoulou et al, 1998;Sarkar et al, 2002). We excluded tumours of oligodendroglial or oligoastrocytic lineage from our analyses, because of the altered natural history as compared to 'pure' astrocytomas, thus increasing the likelihood of genetic mechanisms distinct from those of pure astrocytomas (Burger et al, 1987;Shaw et al, 1992).…”

Immunohistochemical expression of p53 and p21 in gliomas: a clinicopathological study

“…Like p53, p21 protein expression did not correlate with the tumor grade, a finding which is in agreement with that observed by Kamiya and Nazakato and Jung et al 20,21 who claimed that p21 overexpression appears to be an early event in the development of glial neoplasms. Faria et al, 5 reported a tendency of reducing p21 expression with histological grade in contrast to Korkolopoulou et al, 7 who observed a raised percentage of p21 positive cases in the higher grade tumors. The addition of p21 expression can help in interpretation of some of the data concerning p53 expression since the antibody used (Do-7) detects both the wild-type and mutated p53 in addition to the fact that p53 overexpression is not always associated with mutation which make it difficult to draw conclusions 13 .…”

“…In the present study, the positive index for p21 was 25%. Faria et al, reported 34% while Korkolopoulou et al, noted 50% p21 protein expressions 5,7 . Two of 9 cases of ependymomas were immunopositive for p21.…”

“…Investigating the differences in the immunohistochemically detectable expression of cell cycle proteins between different types and grades of gliomas is an attempt to understand the genetic alterations associated with the cell cycle deranged regulation 6 . It has been shown that evaluation of p53 nuclear expression alone may fail to provide significant clinical information but such evaluation if combined with other gene proteins like p21 phenotype could be more informative in spite of the fact that both are linked to the p53 status 7 . Loss or mutation of p53 is especially common in gliomas and is reported to be the earliest detectable event in their development 8 .…”