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Complex Replication Error Causes p53 Mutation in a Li-Fraumeni Family¹

Division of Oncology, Department of Pediatrics, Children's Hospital of Philadelphia [E. A. S., M. R. H., C. A. F.], and Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine [K. S.], Philadelphia, Pennsylvania 19104, and Pediatric Hematology/Oncology, Cooperative Health Group of Puget Sound, Seattle, Washington 98112 [P. H., R. L.]

We demonstrated a germline p53 replication error in two generations of a Li-Fraumeni family affected with liposarcoma, adrenocortical carcinoma, and osteosarcoma. The trinucleotide repeat mutation changed 5'-AGT GTG GTG GTG-3' at codons 215–218 to 5'-AGT TGG TTG GTG GTG-3'. The predicted protein would be elongated by one amino acid (val²¹⁶trp leu) without a change in charge. Detection of p53 in the adrenal tumor by immunostaining suggested that the mutant protein was expressed. Persistence of the mutation in the germline may suggest a defect in DNA repair in the family member first affected. This is the first report where germline transmission of replication-damaged p53 trinucleotide repeats is associated with the Li-Fraumeni syndrome.

¹ Supported by American Cancer Society IRG 135-M and Leukemia Society of America Special Fellowship (both to C. A. F.) and by NIH Training Grant 5-T35-HD-07217 (to E. A. S.).

² Joint first authors.

³ To whom requests for reprints should be addressed, at Division of Oncology, Room 9093, Children's Hospital of Philadelphia, 324 South 34th Street, Philadelphia, PA 19104.

Received 3/30/95. Accepted 6/16/95.

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