Expression of p53, EGFR, pRb and bcl-2 Proteins in Pediatric Glioblastoma Multiforme: A Study of 54 Patients

Abstract

Pediatric glioblastoma multiforme (GBM) tumors, which have been established as ‘de novo’ neoplasms, are known to differ from their adult counterparts in terms of biology, genetics and ultimately survival of patients. In order to evaluate the utility of markers of tumor biology for refining prognostic assessment, we retrospectively analyzed 54 pediatric GBMs (age range 9 months to 15 years) occurring at different anatomical sites in the brain, operated at our institute between 1995 and 2001. The expression of p53, epidermal growth factor receptor (EGFR), bcl-2 and retinoblastoma proteins (pRb) was analyzed by immunohistochemistry and the results were compared with the clinical profile, MIB-1 labeling index (LI) and patient survival. p53 immunoreactivity was noted in 53.7% of cases, predominantly in thalamic (75%) and cerebral lobar (62.2%), followed by brainstem tumors (30%). It was absent in cerebellar tumors. p53-positive tumors had a higher MIB-1 LI, compared to p53-negative tumors (p = 0.003). EGFR and bcl-2 overex pression was observed in 25.9% and 33.3% of cases, respectively, and loss of pRb expression was evident in only 7.4% of cases, indicating that loss of this gene function is not significantly involved in pediatric GBMs. p53 and bcl-2 expression were maximally noted in patients with poorer outcome. Our results indicate that p53 expression status is noted in a significant number of pediatric supratentorial neoplasms. p53 with bcl-2 overexpression is more often associated with ominous prognosis. Further molecular characterization would provide newer insights into the biology of these neoplasms and form a basis for future therapeutic decision making.

Molecular predictors of human nervous system cancer responsiveness to enediyne chemotherapy

“…[24,25] Similarly, medulloblastomas and glioblastomas have all been shown to overexpress the bcl-2 and or bcl-X L gene, contributing to resistance to chemotherapeutic agent-induced apoptosis. [24,[26][27][28][29][30][31][32][33][34] The discovery and development of strategies that overcome such drug resistance and that enhance the ability to predict responsiveness of particular tumors to particular chemotherapeutic agents would contribute greatly to the conquest of these common and deadly diseases. Studies in our laboratory and those of others demonstrate that Bcl-2 exerts its effects at least in part by a mechanism that includes a shift in the cellular capacity for glutathione turnover.…”

“…[24,25] Similarly, medulloblastomas and glioblastomas have all been shown to overexpress the bcl-2 and or bcl-X L gene, contributing to resistance to chemotherapeutic agent-induced apoptosis. [24,[26][27][28][29][30][31][32][33][34] The discovery and development of strategies that overcome such drug resistance and that enhance the ability to predict responsiveness of particular tumors to particular chemotherapeutic agents would contribute greatly to the conquest of these common and deadly diseases.Studies in our laboratory and those of others demonstrate that Bcl-2 exerts its effects at least in part by a mechanism that includes a shift in the cellular capacity for glutathione turnover. [9,[11][12][13][35][36][37][38][39] Not surprisingly, other studies link both the initiating and subsequent steps involved in the apoptotic process to exposure of the cell to reactive oxygen species [39,40] and demonstrate release of cytochrome c from the mitochondrion with a resultant breakdown in electron transport and increased formation of endogenous reactive oxygen species.…”

Glioblastoma pediátrico: estudo clínico patológico de 12 casos com imunoistoquímica para proteína p53

“…A revisão da literatura demonstrou que as grandes séries de glioblastomas pediátricos variam de 2 a 13 casos 3 , a maior casuística encontrada foi a de Ganigi et al 13 , que estudaram 54 casos, entre 0 e 15 anos; a faixa etária na presente casuística foi 0 a 12 (OMS).…”

“…Pollack e colaboradores 12 estudaram a mutação e superexpressão do p53 em 29 crianças com gliomas malignos em relação ao prognóstico e observaram que 38% dos pacientes apresentaram a mutação e que os pacientes sem a mutação apresentaram uma sobrevida maior, em comparação com as que demonstraram a alteração; Pollack , em outro estudo, verifi cou a associação entre a idade e a freqüência de mutações no gene p53 11 . Ganigi et al 13 , também relacionaram a superexpressão do p53 e do bcl-2 a um pior prognós-tico. No presente estudo, nove das crianças tiveram a imunomarcação positiva para o p53 e a sobrevida foi pequena, com uma média de 6,7 meses, menor que a sobrevida global.…”

“…Ganigi et al 13 , estudaram 54 casos de glioblastomas em pacientes de 0 a 15 anos e suas expressões imunoistoquímicas para proteína p53, relacionando com a sobrevida e topografi a dos tumores. A imunorreatividade foi 53,7%, predominando nos talâmicos (75%), e hemisférios cerebrais (62,2%), seguido do tronco encefálico com positividade em 30% dos casos.…”