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WGSeq_PreMalignant_DATA_SET_xmas_MB_2013_07_10 - samples

ABSTRACT: Illumina HiSeq sequence data (with >30x coverage) were aligned to the hg19 human reference genome assembly using BWA (Li and Durbin, 2009); duplicate reads were removed from the final BAM file. No realignment or recalibration was performed. Sample derived from secondary myelodysplastic syndrome (MDS), arising after treatment for medulloblastoma in an 11-year old female Li-Fraumeni syndrome case (LFS-MB1; Rausch et al., 2012; matching WGS data available under EGAS00001000085).

PROVIDER: EGAD00001000665 | EGA |

REPOSITORIES: EGA

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Hypermutation of the inactive X chromosome is a frequent event in cancer.

Jäger Natalie N Schlesner Matthias M Jones David T W DT Raffel Simon S Mallm Jan-Philipp JP Junge Kristin M KM Weichenhan Dieter D Bauer Tobias T Ishaque Naveed N Kool Marcel M Northcott Paul A PA Korshunov Andrey A Drews Ruben M RM Koster Jan J Versteeg Rogier R Richter Julia J Hummel Michael M Mack Stephen C SC Taylor Michael D MD Witt Hendrik H Swartman Benedict B Schulte-Bockholt Dietrich D Sultan Marc M Yaspo Marie-Laure ML Lehrach Hans H Hutter Barbara B Brors Benedikt B Wolf Stephan S Plass Christoph C Siebert Reiner R Trumpp Andreas A Rippe Karsten K Lehmann Irina I Lichter Peter P Pfister Stefan M SM Eils Roland R

Cell 20131017 3

Mutation is a fundamental process in tumorigenesis. However, the degree to which the rate of somatic mutation varies across the human genome and the mechanistic basis underlying this variation remain to be fully elucidated. Here, we performed a cross-cancer comparison of 402 whole genomes comprising a diverse set of childhood and adult tumors, including both solid and hematopoietic malignancies. Surprisingly, we found that the inactive X chromosome of many female cancer genomes accumulates on av ...[more]

PMID: 24139898

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2013-11-19-17-24-36-breez-MB-2013-10-18-Whole_genome_DNAseq_Medulloblastoma_ICGC - samples

Project description:Illumina HiSeq sequence data (with >30x coverage) were aligned to the hg19 human reference genome assembly using BWA (Li and Durbin, 2009); duplicate reads were removed from the final BAM file. No realignment or recalibration was performed.

| EGAD00001000697 | EGA

2013-11-19-17-24-36-breez-MB-2013-10-18-Targeted_DNAseq_Medulloblastoma_ICGC - samples

| EGAD00001000699 | EGA

Rewired m6A epitranscriptomic networks link mutant p53 to neoplastic transformation

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.

2023-02-18 | GSE163088 | GEO

Genomic profiling of TP53 and non-TP53 Li-Fraumeni syndrome tumors reveals hits in the p53 and overlapping pathways

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

2008-07-16 | E-GEOD-8798 | biostudies-arrayexpress

TP53 c.1000G>C; p.G334R is an Ashkenazi Jewish predominant mutation associated with a low penetrance Li-Fraumeni Syndrome

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

2020-07-24 | GSE143741 | GEO

2013-11-19-17-24-36-breez-MB-2013-10-18-Whole_exome_DNAseq_Medulloblastoma - samples

Project description:Illumina HiSeq sequence data (with >80x coverage) were aligned to the hg19 human reference genome assembly using BWA (Li and Durbin, 2009); duplicate reads were removed from the final BAM file. No realignment or recalibration was performed. The whole exome sequencing data of 20 SHH medulloblastomas from phs000504.v1.p1 dataset has been used in our study on SHH medulloblastomas: http://www.ncbi.nlm.nih.gov/projects/gap/cgi- bin/study.cgi?study_id=phs000504.v1.p1

| EGAD00001000698 | EGA

Modeling Familial Cancer with iPSC Approaches

Project description:In vitro modeling of human disease has recently become feasible with the adoption of induced pluripotent stem cell (iPSC) technology. Here, we established patient-derived iPSCs from an Li-Fraumeni Syndrome (LFS) family and investigated the role of mutant p53 in the development of osteosarcoma (OS). Several members of this family carried a heterozygous p53(G245D) mutation and presented with a broad spectrum of tumors including OS. Osteoblasts (OBs) differentiated from iPSC-derived mesenchymal stem cells (MSCs) recapitulated OS features including defective osteoblastic differentiation (OB differentiation) as well as tumorigenic ability. Systematic analyses revealed that the expression of genes enriched in LFS-derived OBs strongly correlated with decreased time to tumor recurrence and poor patient survival. In silico cytogenetic region enrichment analysis (CREA) demonstrated that LFS-derived OBs do not have genomic rearrangements and hence are a particularly valuable tool for elucidating early oncogenic events prior to the accumulation of secondary alterations. LFS OBs exhibited impaired upregulation of the imprinted gene H19 during osteogenesis. Restoration of H19 expression in LFS OBs facilitated osteogenic differentiation and repressed tumorigenic potential. By integrating human imprinted gene network (IGN) and functional genomic analyses, we found that H19-mediates suppression of LFS-associated OS through the IGN component DECORIN (DCN). Downregulation of DCN impairs H19-mediated osteogenic differentiation and tumor suppression. In summary, these findings demonstrate the feasibility of studying inherited human cancer syndromes with iPSCs and also provide molecular insights into the role of the IGN in p53 mutation-mediated tumorigenesis. mRNAseq profiling during mesenchymal stem cell differentiation to osteoblasts.

2015-04-10 | E-GEOD-58123 | biostudies-arrayexpress

Project description:Li-Fraumeni syndrome in Tunisian patients

| PRJNA803730 | ENA

A molecular signature of normal breast epithelial and stromal cells from Li-Fraumeni syndrome mutation carriers

Project description:Specific changes in gene expression during cancer initiation should enable discovery of biomarkers for risk assessment, early detection and targets for chemoprevention. It has been previously demonstrated that altered mRNA and proteome signatures of morphologically normal cells bearing a single inherited âhitâ in a tumor suppressor gene parallel many changes observed in the corresponding sporadic cancer. Here, we report on the global gene expression profile of morphologically normal, cultured primary breast epithelial and stromal cells from Li-Fraumeni syndrome (LFS) TP53 mutation carriers. Our analyses identified multiple changes in gene expression in both morphologically normal breast epithelial and stromal cells associated with TP53 haploinsufficiency, as well as interlocking pathways. Notably, a dysregulated p53 signaling pathway was readily detectable. Pharmacological intervention with the p53 rescue compounds CP-31398 and PRIMA-1 provided further evidence in support of the central role of p53 in affecting these changes in LFS cells and treatment for this cancer. Because loss of signaling mediated by TP53 is associated with the development and survival of many human tumors, identification of gene expression profiles in morphologically normal cells that carry âone-hitâ p53 mutations may reveal novel biomarkers, enabling the discovery of potential targets for chemoprevention of sporadic tumors as well. compare gene expression from different cell types

2010-10-21 | E-GEOD-23994 | biostudies-arrayexpress

Functional precision medicine pipeline combines comparative transcriptomics and tumor organoid modeling to identify be-spoke treatment strategies for glioblastoma

Project description:Li-Fraumeni syndrome (LFS) is a hereditary cancer predisposition syndrome caused by germline mutations in TP53. TP53 is the most common mutated gene in human cancer occurring in 30-50% of glioblastomas (GBM). Here, we highlight a precision medicine platform to identify potential targets for a GBM patient with LFS. We used novel comparative transcriptomics analysis to identify genes that are uniquely overexpressed in a LFS GBM patient relative to a cancer compen-dium of 12,747 tumor RNA sequencing datasets including 200 GBMs. We then used ex vivo pa-tient derived organoid (PDO) viability assays with 4 patient derived cell lines to test efficacy of our identified target. Our comparative transcriptomics bioinformatics pipeline identified that STAT1 and STAT2 were significantly overexpressed in our patient indicating ruxolitinib, a Janus kinase 1 and 2 inhibitor, as a potential therapy. In our institutional high-grade glioma cohort of 45 patients, the LFS patient had the highest level of STAT1 and STAT2 expression. STAT1 and STAT2 expression levels in 4 cell lines derived from patients (including the LFS patient) corre-lated with levels identified in the respective parent tumors. Using 2D and 3D assays from pa-tient derived cells, our LFS patient of interest was among the most sensitive to ruxolitinib in comparison to patients with lower STAT1 and STAT2 expression levels. Additionally a sphe-roid-based drug screening assay (3D-PREDICT) was performed and used to identify further therapeutic targets. This manuscript supports the use of comparative transcriptomics to identify personalized therapeutic targets in a functional precision medicine platform for malignant brain tumors.

2021-12-02 | GSE188739 | GEO

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