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:Targeted panel sequencing of hereditary cancer syndrome-associated genes (TP53, BRCA1, BRCA2, PALB2, MLH1, MSH2, MSH6, PMS2, EPCAM, and APC) in plasma and buffy coat samples from patients with Li-Fraumeni syndrome.
Project description:We performed shallow whole genome sequencing (WGS) on circulating free (cf)DNA extracted from plasma or cerebrospinal fluid (CSF), and shallow WGS on the tissue DNA extracted from the biopsy in order to evaluate the correlation between the two biomaterials. After library construction and sequencing (Hiseq3000 or Ion Proton), copy number variations were called with WisecondorX.
Project description:Genomic rearrangements typically occur progressively during tumor development. Recent findings, however, suggest an alternative mechanism, involving chromosome shattering and reshuffling ('chromothripsis'), for which no genetic basis has yet been described. Whole-genome sequencing of a Sonic-Hedgehog medulloblastoma (SHH-MB) brain tumor from a patient with a germline TP53 mutation (Li-Fraumeni syndrome) revealed massive, complex rearrangements resulting from chromothripsis. Integrating TP53 status with genomic rearrangement data in additional medulloblastomas revealed a striking association between TP53 mutation and chromothripsis in SHH-MBs. Unexpectedly, five seemingly sporadic SHH-MB patients with chromothripsis harbored TP53 germline mutations – findings relevant for clinical management. Analysis of additional tumor entities substantiated a link between TP53 mutation and chromothripsis, beyond general genomic instability. Among these, we observed a strong association between somatic TP53 mutations and chromothripsis in acute myeloid leukemia. These findings implicate p53 in the initiation of, or cellular reaction to, chromothripsis – a novel role for the 'guardian of the genome'. The DNA copy-number profiles of 11 primary medulloblastoma samples were analyzed on the Affymetrix Mapping250K Nsp array, together with data from 70 primary samples taken from GSE21140. Data from diploid reference samples were taken from GSE9222. Additionally, DNA copy-number profiles for 19 additional medulloblastoma samples were generated on the Affymetrix SNP6 platform with matched blood samples.
Project description:Li-Fraumeni syndrome (LFS) is a rare, clinically and genetically heterogeneous inherited cancer syndrome. Most cases are due to mutations in TP53. CHK2 is a minor predisposing locus; we recently mapped a third locus to 1q23. In both TP53 and non-TP53 LFS, there is evidence for risk heterogeneity within and between kindreds, suggesting additional risk modifiers. Using BAC- and SNP-based microarrays, we performed genomic profiling of primary soft tissue sarcomas, osteosarcomas and matching constitutive samples of 10 LFS patients (6 with and 4 without TP53 mutations), to identify genome-wide patterns of copy number changes and loss-of-heterozygosity (LOH). Our complementing global approaches revealed several interesting patterns for TP53 and non-TP53 LFS tumors, including positive (1q/7, 3p/15, 4q/9q, 8q/19p, 9p/10q, 13/14 and 15q/18q) and negative (2q/9q, 3q/14q and 4q/6q) associations between chromosomal regions. The region containing the oncogene TWIST1 (7p21.1) was the most common gain independent of TP53 status and tumor type, while LOH of 8q11.2 with the tumor suppressor ST18 was the only region exclusively associated with non-TP53 soft tissue sarcomas. We resequenced known mutations in BRAF, KRAS and NRAS and identified somatic NRAS mutations in 2 of 10 tumors. TP53 and non-TP53 LFS tumors shared multiple hits in genes of the p53 and overlapping pathways. Although common dogma in cancer genetics holds that multiple hits in the same pathway are redundant and thus unlikely, we show that different combinations of genetic alterations in both TP53 and non-TP53 LFS tumors appear to act together in the p53 network in LFS tumorigenesis Keywords: Comparative genomic hybridization Using the Spectral Genomics dye-swap BAC arrays we studied 10 Li Fraumeni syndrome tumor cases
Project description:Genomic rearrangements typically occur progressively during tumor development. Recent findings, however, suggest an alternative mechanism, involving chromosome shattering and reshuffling ('chromothripsis'), for which no genetic basis has yet been described. Whole-genome sequencing of a Sonic-Hedgehog medulloblastoma (SHH-MB) brain tumor from a patient with a germline TP53 mutation (Li-Fraumeni syndrome) revealed massive, complex rearrangements resulting from chromothripsis. Integrating TP53 status with genomic rearrangement data in additional medulloblastomas revealed a striking association between TP53 mutation and chromothripsis in SHH-MBs. Unexpectedly, five seemingly sporadic SHH-MB patients with chromothripsis harbored TP53 germline mutations – findings relevant for clinical management. Analysis of additional tumor entities substantiated a link between TP53 mutation and chromothripsis, beyond general genomic instability. Among these, we observed a strong association between somatic TP53 mutations and chromothripsis in acute myeloid leukemia. These findings implicate p53 in the initiation of, or cellular reaction to, chromothripsis – a novel role for the 'guardian of the genome'.