Sporadic p53 mutations and absence of ras mutations in glioblastomas

As concerns human adult brain neoplasms, the biological behaviour of gliobl astoma, a high-grade neuro-ectodermal tumour, is among the most disadvantag eous. Glioblastoma may develop either as a primary tumour without clinical and histological evidence of a prior precursor lesion, or as the final stag e of malignant transformation of a low-grade or anaplastic astrocytoma. There are conflicting reports in connection with the association of the p53 tumour suppressor gene mutation with the clinical and histological progres sion of gliomas. Previous studies likewise led to contradictory results con cerning the significance of ras oncogenes in different histological maligna ncies, and especially in neuro-epithelial tumours. The possible roles of p53 and ras gene alterations in the development of "p rimary'' and "transformed" glioblastomas were studied in this work. Eightee n tumours were investigated by means of immunohistochemistry and polymerase chain reaction-assisted-single strand conformation polymorphism (PCR-SSCP) sequence analysis in a search for molecular genetic differences between pr imary and transformed glioblastomas. An increased incidence of p53-immunopositive cells was observed in both typ es of glioblastomas but there was no significant difference between the tra nsformed tumours and the primary form. All samples were screened for point mutation in codons 12 and 61 of the H-, K-, and N-ras oncogenes and exons 5 -8 of the p53 gene. No aberrant band or mutation was found in the H-, K- an d N-ras oncogenes. Aberrant bands were seen in only 2 (11%) of the 18 rumou rs in the SSCP analyses of exons 6 and 8. Sequence analysis of the 2 abnorm al cases revealed G --> C transmission in the second nucleotide of codon 28 0 on exon 8, which resulted in a change in the encoded amino acid from argi nine to threonine (case 15). A ttagtct --> ttggtct transmission on intron 5 (case 8) was also found. No genetic difference could be identified between the primary and the transformed glioblastoma forms as concerns their p53 a nd ras oncogenes. There are two possible explanations for these findings: ( a) The p53 and ras gene mutations were not primary events in the morphologi cal transformations. Alterations in these genes may therefore take place at an early stage in glioma progression. (b) The different genetic changes ma y accumulate during glioblastoma development. These specific genetic events may additionally play a role in multistep tumourigenesis.