CLONAL EXPANSION AND ATTENUATED APOPTOSIS IN WILMS-TUMORS ARE ASSOCIATED WITH P53 GENE-MUTATIONS

The p53 gene product is required for activation of an apoptotic pathwa y triggered by oncogenes and cytotoxic agents. Wilms' tumor, a pediatr ic renal malignancy, provides a paradigm for evaluating genetic events involved in tumor progression. This malignancy is generally not assoc iated with p53 mutations, and even in advanced disease states is quite responsive to current treatment regimens. The anaplastic histological variant of Wilms' tumor, however, is frequently associated with p53 g ene mutations and shows poor prognosis. We analyzed seven Wilms' tumor s for which we had paired samples from nonanaplastic and anaplastic re gions. p53 mutations were detected in six of these tumors, five of whi ch demonstrated mutations restricted to anaplastic regions. Nonanaplas tic cells of the sixth sample were heterozygous for a p53 mutation, wh ereas the anaplastic area of this tumor showed reduction to homozygosi ty. These results indicate that progression to anaplasia is associated with clonal expansion of cells which have acquired a p53 mutation. We demonstrated that tumor cells with p53 mutations show attenuated apop tosis, suggesting that such lesions mag provide a selective advantage in vivo by decreasing cell death.