MDM2 and p53 expression in gliomas: a multivariate survival analysis including proliferation markers and epidermal growth factor receptor

Abstract

Summary p53 and the murine double minute 2 (MDM2) oncoprotein expression was evaluated in paraffin-embedded tissue from 61 patients with central nervous system gliomas (53 astrocytomas and eight oligodendrogliomas) and related to proliferation-associated markers [i.e. proliferating cell nuclear antigen (PCNA), Ki-67 and nuclear organizer regions (NORs)] and epidermal growth factor receptor (EGFR). We used the monoclonal antibodies PC-1 0, MIB-1, DO-1, 1 Bi 0 and EGFR 113 and the colloid silver nitrate (AgNOR) technique. MDM2 and p53were co-expressed in 28% of cases. A p53-positive/MDM2-negative phenotype was observed in 15% and a p53-negative/MDM2-positive phenotype in 20% of cases. There was a positive correlation of p53 and MDM2 expression with grade and proliferation indices. Univariate analysis in the group of diffuse astrocytomas showed that older age, high histological grade, high PCNA labelling index (LI) and high AgNOR score were associated with reduced overall survival (P < 0.05). p53 LI, Ki-67 LI, AgNOR score, tumour location and grade influenced diseasefree survival (P < 0.05), whereas the only parameters affecting post-relapse survival were histological grade and Ki-67 LI (P < 0.1). Multivariate analysis revealed that age, radiotherapy, PCNA LI and p53 LI were the independent predictors of overall survival. p53 LI, Ki-67 LI, MDM2 LI, EGFR LI, grade and type of therapy were independent predictors of disease-free survival, and grade was the only independent predictor of post-relapse survival. Our results indicate that p53 LI and MDM2 LI, EGFR expression as well as proliferation markers (PCNA and Ki-67) are useful indicators of overall and disease-free survival in diffuse astrocytoma patients.Keywords: proliferating cell nuclear antigen; Ki-67; MIB-1; AgNORs; p53; MDM2; epidermal growth factor receptor; gliomas Central nervous system (CNS) gliomas range in clinical behaviour and histological appearance from indolent well-differentiated lesions to highly anaplastic, rapidly growing neoplasms. A cardinal property of almost all types of gliomas is a propensity to recur and undergo anaplastic change (Russel and Rubinstein, 1989). A major stimulus to the study of cell proliferation in gliomas has been the widely held belief that quantification of this fundamental process will be of value in the objective categorization of these tumours. However, while cell kinetic information is an important aspect of the biology of gliomas, it has become clear that neoplastic evolution towards glioblastoma is a multistep process that involves deregulation of several genes related to both cellular proliferation and differentiation. The molecular determinants of glioma progression are still under investigation, with considerable attention directed towards the tumour-suppressor gene p53. On the basis of findings from molecular genetic analysis, Bigner and Vogelstein (1990)

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

“…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). Interestingly, with respect to tumours of mixed or pure oligodendrocytic lineage, alterations in p53 expression may also portend a less favourable prognosis in the clinical setting (Soini et al, 1994;Korkolopoulou et al, 1997;Miettinen et al, 2001). Finally, pediatric tumours overexpressing p53 protein, revealed a worse prognosis with increasing age (Pollack et al, 2002).…”

Proliferation and aneusomy predict survival of young patients with astrocytoma grade II

“…In our study, immunostaining for the proliferation marker Ki-67 in over 1% of tumour cells showed the strongest association with survival of patients with A II. The proliferation (Ki-67) index has been described to increase with the grade of astrocytomas, although overlap between grades exists (Sallinen et al, 1994;Korkolopoulou et al, 1997). The additional value of the Ki-67 labelling protocol in A II was also demonstrated in two recent studies, although in these studies, no stratification for patient age was performed (McKeever et al, 1998;Heesters et al, 1999).…”

“…Proliferation and cytogenetic markers may therefore identify rapid progressive A II. Increased proliferation activity correlates with shorter survival in most series of astrocytomas, although the number of A II was often too small for separate analyses (Sallinen et al, 1994;Korkolopoulou et al, 1997). Numerical chromosomal aberrations have been reported in astrocytomas, such as aneusomy 1, trisomy 7 and monosomy 10.…”

Astrocytomas and Prognosis-From Morphology to Tumor Biology

“…They include flow cytometry [9], molecular genetic markers like p53, MDM2 and EGFR [13,17] and proliferation markers. Proliferation studies in astrocytomas gained momentum with the pioneering work of Hoshino and Wilson [18] …”

“…It serves to improve prognostic accuracy and understanding of tumor biological behaviour being a predictor of increased aggressiveness, recurrence and reduced survival. Recent works on a large series of cases (17,30] have established convincingly the need to look beyond classifications and grading towards molecular markers of cell biology to make pathology reports on such tumors prognostic ally viable in the next millennium.…”