3796 results for "*oma"

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• Recurrent somatic mutations in POLR2A define a distinct subset of meningiomas

  RNA polymerase II mediates the transcription of all protein-coding genes in eukaryotic cells, a process that is fundamental to life. Genomic mutations in this enzyme have not been previously linked to any pathology in humans, a testament to its indispensable role in cell biology. Based on a combination of next-generation genomic analyses of 775 meningiomas, we report that recurrent somatic p.Gln403Lys or p.Leu438_His439del mutations in POLR2A, which encodes the catalytic subunit of RNA polymerase II1, are sufficient to hijack this essential enzyme and drive neoplasia. POLR2A mutant tumors reveal dysregulation of key meningeal identity genes, including WNT6 and ZIC1/ZIC42,3. In addition to POLR2A, NF2, SMARCB1, TRAF7, KLF4, AKT1, PIK3CA and SMO4-8, we also report somatic mutations in AKT3, PIK3R1, PRKAR1A, and SUFU in meningiomas. Our results identify a role for essential transcriptional machinery in driving tumorigenesis and define mutually exclusive meningioma subgroups with distinct clinical and pathological features.

  Study EGAS00001001916

• Integrated genomic analysis identifies recurrent mutations and evolution patterns driving the initiation and progression of follicular lymphoma.

  follicular lymphoma (FL), the most common indolent non-Hodgkin’s lymphoma, remains incurable. A well-recognized complication of FL is its transformation to a diffuse large B-cell lymphoma (DLBCL)-morphology in a subset of patients, for which the clinical outcomes are poor. Recent genetic profiling and single case studies of donor-derived FL following stem cell transplantation had alluded to the putative existence of a ‘long lived’ tumor-initiating progenitor cell compartment from which successive disease events occurred. To chronicle the genetic changes associated with progression to transformation, we conducted whole-genome sequencing (WGS) of FL-tFL pairs and matched germline (GL) samples from six patients, a total of 20 genomes.

  Study EGAS00001000399

• Sequencing of an organoid biobank for childhood soft tissue sarcoma.

  Rhabdomyosarcomas are diverse tumors of mesenchymal origin and the most common childhood soft tissue sarcoma. Patients receive intense treatment with a nevertheless poor prognosis for high-risk patients. New therapy would benefit from additional preclinical models and their rapid establishment. Tumor organoid models (tumoroids) have so far only been established from epithelial cancers. Here, we describe generation and characterization of a collection of pediatric RMS tumoroids comprising all major subtypes.

  Study EGAS00001005912

• Whole genome sequencing and whole exome sequencing of mucosal melanoma

  We conducted whole genome sequencing of 5 mucosal melanomas and their matched DNA from blood. We conducted whole exome sequencing of a further 5 mucosal melanomas and their matched DNA from blood.

  Study EGAS00001000474

• Whole genome sequencing of acral melanomas

  We conducted whole genome sequencing of 5 acral melanoma genomes and their matched DNA from blood.

  Study EGAS00001000486

• Overexpression of the miR-17-92 cluster in colorectal adenoma organoids induces a carcinoma-like genotype

  Study EGAS00001005949

• Whole Exome Sequences from Iberian Roma samples

  Study of high-depth Roma whole exomes to analyse the impact of complex demography on the functional genomic variation. This study also includes genome-wide array data of Iberian Roma individuals

  Study EGAS00001004599

• Landscape of somatic mutations and clonal evolution in mantle cell lymphoma

  Mantle cell lymphoma (MCL) is an aggressive tumor, but a subset of patients may follow an indolent clinical course. To understand the mechanisms underlying this biological heterogeneity, we performed whole-genome and/or whole-exome sequencing on 29 MCL cases and their respective matched normal DNA, as well as 6 MCL cell lines. Recurrently mutated genes were investigated by targeted sequencing in an independent cohort of 172 MCL patients. We identified 25 significantly mutated genes, including known drivers such as ataxia-telangectasia mutated (ATM), cyclin D1 (CCND1), and the tumor suppressor TP53; mutated genes encoding the anti-apoptotic protein BIRC3 and Toll-like receptor 2 (TLR2); and the chromatin modifiers WHSC1, MLL2, and MEF2B. We also found NOTCH2 mutations as an alternative phenomenon to NOTCH1 mutations in aggressive tumors with a dismal prognosis. Analysis of two simultaneous or subsequent MCL samples by whole-genome/whole-exome (n = 8) or targeted (n = 19) sequencing revealed subclonal heterogeneity at diagnosis in samples from different topographic sites and modulation of the initial mutational profile at the progression of the disease. Some mutations were predominantly clonal or subclonal, indicating an early or late event in tumor evolution, respectively. Our study identifies molecular mechanisms contributing to MCL pathogenesis and offers potential targets for therapeutic intervention.

  Study EGAS00001000510

• Combination of ribociclib and gemcitabine for the treatment of medulloblastoma

  Group 3 (G3) medulloblastoma (MB) is one of the deadliest forms of the disease for which novel treatment is desperately needed. Here we evaluate ribociclib, a highly selective CDK4/6 inhibitor, with gemcitabine in mouse and human G3 MBs. Ribociclib CNS penetration was assessed by in vivo microdialysis and by immunohistochemistry and gene expression studies. Survival studies to determine the efficacy of ribociclib and gemcitabine combination were performed on mice orthotopically implanted with luciferase labelled mouse and human G3 MB. Pharmacokinetic-pharmacodynamic outcomes and univariable survival models were analyzed to estimate survival. Gene activity inference using NetBID and tumor differentiation analysis investigated the effects of the combination after short and long-term treatments. Tumors from mice treated with oral ribociclib displayed inhibited RB phosphorylation, downregulated E2F target genes, and decreased proliferation. Treatment of mice with the combination of ribociclib and gemcitabine was well tolerated, slowed tumor progression and metastatic spread, and increased survival. Molecular analysis of treated versus untreated tumors showed a significant decrease in the activity and expression of genes involved in cell cycle progression and DNA damage response, and an increase in activity and expression of genes implicated in neuronal identity and neuronal differentiation. Ribociclib is CNS-penetrant. When administered/combined with gemcitabine in orthotopic G3 MB models resulted in improved survival. Our findings, with both mouse and human patient-derived-orthotopic xenograft models, suggest that this combination therapy has promise for children with G3 MB and may represent an effective treatment strategy for other CNS malignancies.

  Study EGAS00001006001

• Whole exome sequencing of peripheral T-cell lymphoma (PTCL)

  Somatic mutations in 3 AITL and 3 PTCL, not otherwise specified (PTCL-NOS) specimens were explored using whole-exome sequencing.

  Study EGAS00001000557