Project description:Whole Exome sequencing of two patients with Cardiac angiosarcoma in Li-Fraumeni-like families discovers that a mutation in the pot1 gene is responsible for cardiac angiosarcoma in tp53-negative li-fraumeni-like families
Project description:We report the application for high-throughput profiling of transcriptome, chromatin-associated proteins and histone-modifications on a genome-wide level in iPSC-derived family control astrocytes vs LFS (Li-Fraumeni Syndrome) patient astrocytes.
Project description:Multiple family members with cancer or individuals with multiple primary cancers are indicative of potential genetic etiology1. Germline mutations in TP53 cause a rare high penetrance cancer syndrome, Li Fraumeni Syndrome (LFS)2. We identified a TP53 tetramerization domain (TD) missense mutation c.1000G>C;p.G334R, in a family with LFS-associated cancers. Twenty-one additional probands were identified, and available tumors showed biallelic somatic inactivation of TP53. The majority of families were of Ashkenazi Jewish descent, and the TP53 c.1000G>C allele was found on a commonly inherited haplotype. While classical p53 target gene activation was maintained in p.G334R mutant cell lines treated with Nutlin-3a, a subset of p53 target genes, including PCLO, PLTP, PLXNB3 and LCN15, showed defective transactivation. Structural analysis demonstrated thermal instability of the mutant TD, and the G334R mutant protein showed increased preponderance of mutant conformation protein. TP53 c.1000G>C;p.G334R is a rare AJ-predominant mutation associated with low penetrance Li-Fraumeni Syndrome
