Frequent aberrant expression of p53 protein in gliomas but not in capillary hemangioblastomas and pheochromocytomas

Abstract

Background. Glioma is the most common and deadly malignancy of the central ner vous system. Capillary hemangioblastoma (CHB) is a rare and usually benign tumour of brain, occurring as part von Hippel-Lindau (VHL) disease or as a sporadic entity. For an improved understanding of the molecular mechanisms of the pathogenesis of VHL-related tumours and gliomas, we analysed the expression of the tumour suppressor proteins p53 and p16, and promoter methylation of the tumour suppressor genes (TSGs) MGMT and RASSF1A.Materials and methods. Expression of p53 and p16 was analysed in 27 cases of glioma, 5 cases of breast cancer, and 17 cases with VHL-related tumours, including CHBs and pheochromocytomas (PCCs), by means of immunohistochemistry. For the gene promoter methylation and deletion assessment, methylation-specific PCR and differential polymerase chain reaction combined with on-chip electrophoresis were used, respectively.Results. Aberrant expression of the p53 protein was frequent (p < 0.01) in malignant tumours, including gliomas and breast carcinomas, but not in benign tumours (PCC and CHB). Protein p53 alterations were most frequent (65%) in glioblastomas, and a low number (20%) of patients with p53-positive gliomas survived more than one year after diagnosing the disease. Other biomarkers, including loss of p16 expression, promoter hypermethylation of the MGMT gene and promoter hypermethylation or deletion of the RASSF1A gene, were frequent in all groups of tumours.Conclusions. Alterations of the tumour suppressors p16, MGMT and RASSF1A are frequent in VHL-related tumours, while aberrant expression of p53 is only detectable in malignant tumours -gliomas and breast carcinomas.

Frequent aberrant DNA methylation of CDKN2A locus in capillary hemangioblastomas, pheochromocytomas and gliomas

“…ARF, encoded by p14, is a protein of the p53-regulated pathway. When the results of our previous study (8) were considered in combination with the present data, we noted an exclusive nature of the occurrence of p53 alterations and p14 hypermethylation. In PCC and CHB, where no aberrant expression of p53 was detected by means of immunohistochemistry, aberrant methylation of p14 was a frequent event that occurred in 44% of cases.…”

“…In gliomas, 14 out of 15 cases with the genetic or epigenetic inactivation of p16 had also reduced the expression of the p16 protein. Interestingly, all cases with CHB and PCC showed a reduced or no p16 staining in our previous study (8), despite DNA methylation or mutation status, showing the importance of additional regulators for the p16 expression in these tumours. Similarly, the study of Muscarella et al (6) showed a reduced p16 expression in all but one cases with PCC, while the genetic and epigenetic alterations occurred only in a set (68%) of the cases.…”

“…Previous studies (6,24), including our own data (8), revealed a frequent loss of p16 expression in gliomas and PCCs. Also, our recent study (8) for the first time showed a frequent loss of p16 expression in CHB. Both events, genetic deletion and promoter hypermethylation, are shown to be involved in the inactivation of p16 expression in gliomas and PCCs.…”

“…Moreover, the evidence obtained using a mouse model (7) strongly supports involvement of CDKN2A locus in the development of pheochromocytoma (PCC). Our previous study (8), conducted by means of immunohistochemistry, identified a frequent loss of the p16 protein expression in gliomas, PCC and capillary hemangioblastomas (CHB). We continued our studies on the pathogenesis of PCC and CHB (8,9) by analysing genetic losses and DNA hypermethylation in the promoter region of the p16 and p14 genes at the CDKN2A locus.…”

“…Our previous study (8), conducted by means of immunohistochemistry, identified a frequent loss of the p16 protein expression in gliomas, PCC and capillary hemangioblastomas (CHB). We continued our studies on the pathogenesis of PCC and CHB (8,9) by analysing genetic losses and DNA hypermethylation in the promoter region of the p16 and p14 genes at the CDKN2A locus. For comparison, cases with glioma -a highly malignant tumour of the central nervous system (CNS) -were included into the study.…”