p53 gene mutations in medulloblastoma. Immunohistochemistry, gel shift analysis, and sequencing.

Medulloblastoma (MB), the most common malignant tumor of the CNS in children, bears a loss of the short arm of chromosome 17 in almost half of the cases. The tumor suppressor gene p53 is located on this chromosome and its role in the pathogenesis of this primitive tumor is controversial. Twenty-two MBs were analyzed by single-strand conformation polymorphism (SSCP) of polymerase chain reaction-amplified conserved exons. Fragments displaying a gel mobility shift were subsequently analyzed by direct sequencing. Immunohistochemistry for p53 was performed in all cases; three had cytogenetic analysis. Two cases (9%) were found to harbor a mutation: one homozygous and one heterozygous. The latter showed focal p53 immunostaining. None of the cases with chromosome 17p abnormality by cytogenetic analysis were found to have a mutation in the remaining allele. Loss of heterozygosity (LOH) of 17p, however, was found in four cases (one by SSCP and three by cytogenetic analysis). Together with the homozygous deletion in one case, the overall incidence of p53 allelic involvement in MB is 23%. Although LOH for the p53 gene may confer a selective advantage to tumor cells harboring mutations with dominant negative oncogenic effect, the infrequent occurrence of p53 mutations in face of frequent LOH for this gene supports the previously formulated hypothesis of a novel tumor-related locus distal to p53 on chromosome 17p.