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p53 Gene Mutations and Abnormal Retinoblastoma Protein in Radiation-induced Human Sarcomas¹

Department of Radiation and Cellular Oncology, University of Chicago, Chicago, Illinois 60637 [D. G. B., D. E. H., M. A. B., R. R. W.], and Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, and Harvard Medical School, Boston, Massachusetts 02114 [D. W. Y.]

The potentially carcinogenic effect of therapeutic irradiation has been recognized for many years. Second malignancies, usually sarcomas, are known to arise within or at the edge of radiation fields after a period of several years after the initial radiation exposure. We analyzed tumor cells derived from seven radiation-induced tumors for abnormalities in tumor suppressor genes p53 and retinoblastoma at the DNA sequence and/or protein level. p53 mutations were detected by exon-specific polymerase chain reaction amplification and single-strand conformation polymorphism analysis of exons 5–8 followed by direct genomic sequencing of those tumors exhibiting a variant pattern. The p53 gene was abnormal in three of six sarcomas studied. Retinoblastoma gene analysis was performed by Western immunoblot; retinoblastoma protein was under-phosphorylated in three of seven tumors and absent in one other. In all, six of seven radiation-induced human tumors have abnormalities of one or both suppressor genes. Inactivation of tumor suppressor genes by ionizing radiation may contribute to radiation carcinogenesis.

¹ This work was supported by NI Health Grant CA41068, the Chicago Tumor Institute, a gift from the Passis Family, and the Center for Radiation Therapy.

² To whom requests for reprints should be addressed, at Department of Radiation and Cellular Oncology, University of Chicago, 5841 S. Maryland Avenue, Box 442, Chicago, IL 60637.

Received 9/ 9/91. Accepted 10/11/91.