p53 protein overexpression identifies a group of central primitive neuroectodermal tumours with poor prognosis

Abstract

Summary Primitive neuroectodermal tumours (PNET's) or medulloblastomas are common primary brain tumours of childhood. Current treatment protocols achieve 50-60% cures. However, it has proved difficult to develop better treatment for the remaining patients because prognostic factors are not established. We have investigated the prognostic value of p53 protein expression in 87 PNET's using immunohistochemistry with DO-7 and CM-1 antibodies on biopsy paraffin sections. Eight patients (9%) had intensely reactive tumour cell nuclei, and a significantly reduced survival (P = 0.002); only one survives and this with a recurrent tumour 50 months following diagnosis. Sixty eight per cent of patients had faintly reactive tumour cell nuclei, a reduced survival up to 4 years but a long term survival not significantly different (P = 0.41) from 23% of patients with p53 negative PNET's; the 10 year survival rates were 37% and 40%, respectively. Males had a reduced survival (P = 0.04) with a 2-fold relative risk of death compared to females. Multivariate analysis showed that intense overexpression of p53 protein identifies a group of PNET patients with a 7-fold relative risk of death compared to all other cases, irrespective of sex. This marked difference suggests the involvement of p53 in the pathogenesis of PNET's which have a particularly poor response to treatment, and should help to develop new therapies for this group of patients.

Comparative genomic hybridization and histological variation in primitive neuroectodermal tumours

“…The relative importance of 17p loss and 17q gain remains unclear. In the search for potential tumour suppressor genes, reports of the potential role for TP53 have been inconsistent (Jaros et al, 1993;Batra et al, 1995;Phelan et al, 1995), but evidence for a medulloblastoma-related locus at 17p13.3, distal to TP53, has been presented (McDonald et al, 1994). In PNETs, where isochromosome formation may occur in the absence of other imbalances, as shown in cytogenetic studies (Biegel et al, 1989) and in two of our cases, it is possible that development of i(17q) is an early event.…”

The molecular pathology of p53 in primitive neuroectodermal tumours of the central nervous system

“…The control tissue used for p53 was obtained from a glioblastoma multiforme (GBM) paraffinembedded tumour block. Sections from this block had previously been found to stain positive for DO-7 (Jaros et al, 1993). The control tissue used for Waf-1 staining was breast tumour tissue, and that for both Bax and Bcl-2 was tonsil tissue.…”

“…One hundred and one patients presenting with cPNETs (including 80 medulloblastomas) in the Northern region between 1963 and 1997 were studied, including 85 from the previous study mentioned above (Jaros et al, 1993) and 16 new cases. Patient samples were obtained from surgery, formalin-fixed and embedded in paraffin blocks.…”

“…A standard immunohistochemical staining method, described previously (Jaros et al, 1993), was performed in conjunction with an antigen retrieval technique. Prior to incubation with the primary antibody, sections were placed in citrate buffer and microwaved at high power for 10 min.…”

“…Our group has previously reported the prognostic value of the immunohistochemical staining intensity of p53 protein in a series of 88 cPNETs (Jaros et al, 1993). In the previous study, immunohistochemistry for p53 was performed without any form of antigen retrieval and high intensity of immunohistochemical staining was significantly associated with poor patient survival.…”