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Clonal Expansion and Attenuated Apoptosis in Wilms' Tumors Are Associated with p53 Gene Mutations¹

Department of Biochemistry [N. B., J. P.] and McGill Cancer Center [J. P.], McGill University, 3655 Drummond Street, Montreal, Canada, H3G 1Y6, and Pathology Department, Division of Pediatric Pathology, Loma Linda University, Loma Linda, California 92350 [J. B. B.]

The p53 gene product is required for activation of an apoptotic pathway triggered by oncogenes and cytotoxic agents. Wilms' tumor, a pediatric renal malignancy, provides a paradigm for evaluating genetic events involved in tumor progression. This malignancy is generally not associated 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 gene mutations and shows poor prognosis. We analyzed seven Wilms' tumors for which we had paired samples from nonanaplastic and anaplastic regions. p53 mutations were detected in six of these tumors, five of which demonstrated mutations restricted to anaplastic regions. Nonanaplastic cells of the sixth sample were heterozygous for a p53 mutation, whereas the anaplastic area of this tumor showed reduction to homozygosity. 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 apoptosis, suggesting that such lesions may provide a selective advantage in vivo by decreasing cell death.

¹ N. B. is supported by a fellowship from the Medical Research Council of Canada. J. P. is a Medical Research Council of Canada Scholar. This work was supported by USPHS Grant CA42326 (J. B. B.) and a grant from the National Cancer Institute of Canada (J. P.).

² To whom requests for reprints should be addressed.

Received 10/ 3/94. Accepted 12/ 1/94.

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