4774 results for "*oma"

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• Longitudinal profiling of circulating tumour DNA for tracking tumour dynamics in pancreatic cancer

  The utility of circulating tumour DNA (ctDNA) for longitudinal tumour monitoring in pancreatic ductal adenocarcinoma (PDAC) has not been explored beyond mutations in the KRAS proto-oncogene. We aim to characterise and track patient-specific somatic ctDNA variants, to assess longitudinal changes in disease burden and explore the landscape of actionable alterations.

  Study EGAS00001005981

• A Protein Neddylation Inhibitor MLN4924 Suppresses Patient-Derived Glioblastoma Cells via Inhibition of ERK and AKT Signaling

  Glioblastoma is a highly aggressive and lethal brain tumor, with limited treatment options. Abnormal activation of the neddylation pathway is observed in glioblastoma, and the NEDD8-activating enzyme (NAE) inhibitor, MLN4924 was previously shown to be effective in glioblastoma cell line models. However, its effect has not been tested in patient-derived glioblastoma stem cells. Immunohistochemistry and public data were analyzed to determine whether NEDD8 pathway proteins are important in glioblastoma development and patient survival. The effects of MLN4924 were evaluated in 4 glioblastoma cell lines and 15 patient-derived glioblastoma stem cells using high content analysis. Immunoblot analysis assessed the NEDD8 pathway proteins and biomarkers. Whole transcriptome analysis identified pathways associated with MLN4924 sensitivity. NAE1 and UBA3 levels increased in glioblastoma patients; high NEDD8 levels were associated with poor clinical outcomes. Glioblastoma cell lines and patient-derived stem cells were highly susceptible to MLN4924, while normal human astrocytes were resistant. Genomic analyses indicated that MLN4924 sensitive cells exhibited enrichment of ERK and AKT signaling. We verified that MLN4924 inhibits ERK and AKT phosphorylation in MLN4924 sensitive cells. Our findings suggest that patient-derived glioblastoma stem cells in the context of ERK and AKT activation are sensitive and highly regulated by neddylation inhibition.

  Study EGAS00001004018

• Therapeutic vulnerabilities in the DNA damage response for the treatment of ATRX mutant neuroblastoma

  Whole genome sequencing of ATRX / TP53 knockdown clones of the neuroblastoma cell line SK-N-SH

  Study EGAS00001004550

• SS18-SSX-mediated hijacking of BAF complexes drives synovial sarcoma

  Synovial sarcoma (SS) is defined by a recurrent t(x;18) chromosomal translocation, which produces the hallmark SS18-SSX oncogenic fusion. Incorporation of SS18-SSX into BAF complexes renders BAF complexes aberrant in two distinct manners: the addition of 78aa of SSX onto SS18, and concomitant loss of BAF47 assembly. However, the importance and functional contributions of each of these perturbations on BAF complex targeting and gene expression regulation remain unclear. Here we use an integrative set of genomic approaches in human cancer cell lines and primary tumor samples to define the mechanistic consequences of the SS18-SSX fusion oncoprotein. We find that SS18-SSX hijacks BAF complexes to broad polycomb domains to activate bivalent genes, driving a unique gene expression program distinct from other loss-of-function BAF complex malignancies. Importantly, restoration of BAF47 rescues enhancer activation but is dispensable for proliferative arrest in cell lines. These results demonstrate that gain-of-function SS18-SSX-mediated BAF complex targeting and gene activation is the driving event in SS, and present a mechanism by which distinct functions of BAF complexes can be co-opted to drive oncogenesis.

  Study EGAS00001002920

• Leeds Melanoma Cohort (LMC) gene expression study

  Array-based profiling (whole genome DASL HT12.4, Illumina Inc) in over 700 FFPE tumour blocks from the population-based Leeds Melanoma cohort recruited in the North of England, with a long follow up. Data used in tumour immune micro-environment investigation (Nsengimana et al 2018, J Clin Invest doi: 10.1172/JCI95351).

  Study EGAS00001002922

• RNA-seq of Ewing sarcoma tumors (ICGC)

  Ewing sarcoma (ES) is a primary bone tumor initiated by an EWSR1-ETS gene fusion. To characterize the transcriptome of Ewing sarcoma, RNA-seq was performed.

  Study EGAS00001003333

• Sequence Data from the phase 2 PrE0505 trial of Durvalumab with First Line Platinum-Pemetrexed for Unresectable Pleural Mesothelioma

  Mesothelioma is a rare and fatal cancer with limited therapeutic options until the recent approval of combination immune checkpoint blockade. We report the results of the phase 2 PrE0505 trial (NCT02899195) of the anti-PD-L1 antibody, durvalumab, plus platinum-based and pemetrexed chemotherapy for patients with previously untreated unresectable pleural mesothelioma. The primary endpoint was overall survival compared to historic control with cisplatin and pemetrexed chemotherapy. The combination of durvalumab with chemotherapy met the pre-specified primary endpoint reaching a median survival of 20.4 months vs. 12.1 months with historic control. Treatment emergent adverse events were consistent with known side effects of chemotherapy and all adverse events due to immunotherapy were grade ≤2. Integrated genomic and immune cell repertoire analyses revealed that a higher immunogenic mutation burden coupled with a more diverse T cell repertoire were linked with favorable clinical outcome. Structural genome-wide analyses demonstrated a higher degree of genomic instability in responding tumors of epithelioid histology. Patients with germline alterations in cancer predisposing genes, especially those involved in DNA repair, were more likely to attain long term survival. Our findings indicate that concurrent durvalumab with platinum-based chemotherapy has promising clinical activity and that responses are driven by the complex genomic background of malignant pleural mesothelioma.

  Study EGAS00001005426

• Whole exome sequencing CYLD cutaneous syndrome

  Patients with CYLD cutaneous syndrome (CCS; syn. Brooke-Spiegler syndrome) carry germline mutations in the tumor suppressor CYLD and develop multiple skin tumors with diverse histophenotypes. We comprehensively profiled the genomic landscape of 42 benign and malignant tumors across 13 individuals from four multigenerational families. Novel recurrent mutations were found in epigenetic modifiers DNMT3A and BCOR in 29% of benign tumors. Multi-level and microdissected sampling strikingly reveal that many clones with different DNMT3A mutations exist in these benign tumors, suggesting that intra-tumor heterogeneity is common. Integrated genomic, methylation and transcriptomic profiling in selected tumours suggest that isoform specific DNMT3A2 mutations are associated with dysregulated Wnt/ß-catenin pathway signaling. Phylogenetic and mutational signature analyses confirm cylindroma pulmonary metastases from primary skin tumours. These findings add novel dimensions to existing paradigms of cutaneous tumorigenesis and metastasis.

  Study EGAS00001003839

• Targeted sequencing CYLD cutaneous syndrome

  Patients with CYLD cutaneous syndrome (CCS; syn. Brooke-Spiegler syndrome) carry germline mutations in the tumor suppressor CYLD and develop multiple skin tumors with diverse histophenotypes. We comprehensively profiled the genomic landscape of 42 benign and malignant tumors across 13 individuals from four multigenerational families. Novel recurrent mutations were found in epigenetic modifiers DNMT3A and BCOR in 29% of benign tumors. Multi-level and microdissected sampling strikingly reveal that many clones with different DNMT3A mutations exist in these benign tumors, suggesting that intra-tumor heterogeneity is common. Integrated genomic, methylation and transcriptomic profiling in selected tumours suggest that isoform specific DNMT3A2 mutations are associated with dysregulated Wnt/ß-catenin pathway signaling. Phylogenetic and mutational signature analyses confirm cylindroma pulmonary metastases from primary skin tumours. These findings add novel dimensions to existing paradigms of cutaneous tumorigenesis and metastasis.

  Study EGAS00001003840

• Osteosarcoma mate-pair and RNA-sequencing

  DNA mate pair and RNA sequencing data of conventional osteosarcomas. Mate pair libraries, with average insert sizes of 2-4 kb, were prepared for sequencing using the Nextera Mate Pair Library Preparation Kit. Paired-end 76 base pair reads were generated using an Illumina NextSeq 500 sequencing instrument. Total RNA was enriched for polyadenylated RNA using magnetic oligo(dT) beads. Enriched RNA was prepared for sequencing using the TruSeq RNA Sample Preparation Kit v2 and paired-end 151 base pair reads were generated from the cDNA libraries using an Illumina NextSeq 500 instrument.

  Study EGAS00001003842