EXCLUSION OF A P53 GERMLINE MUTATION IN A CLASSIC LI-FRAUMENI SYNDROME FAMILY

Li-Fraumeni syndrome (LFS) is characterized by a high risk of sarcomas , early onset of breast cancer, and a diversity of other cancers occur ring as multiple primary tumors in multiple family members. In many fa milies with LFS, germline mutations within the tumor-suppressor gene p 53 have been identified. However, mutations in p53 have not been detec ted in approximately 30% of LFS families. To address the possibility e ither that p53 mutations were being missed or that another predisposin g gene is altered in LFS, we used a variety of methods to accurately d etermine the p53 status in a large LFS kindred. A transcriptional acti vation assay on exons 4-10 of p53 excluded a mutation within the DNA-b inding domain of p53. Single-stranded conformational-polymorphism anal ysis, using intronic primers and sequencing of all the coding exons an d intorn/exon junctions, also yielded no mutations. Finally, linkage a nalysis excluded potential mutations in the noncoding regions of p53. Our findings exclude the presence of a p53 germline mutation in a clas sic LFS family.