4895 results for "*oma"

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• Integrated genomic analysis identifies driver genes and cisplatin-resistant progenitor phenotype in pediatric liver cancer

  Pediatric liver cancers (PLCs) comprise diverse diseases affecting infants, children and adolescents. Despite overall good prognosis, PLCs display heterogeneous response to chemotherapy. Integrated genomic analysis of 126 pediatric liver tumors showed a continuum of driver mechanisms associated with patient age, including new targetable oncogenes. In 10% of hepatoblastoma patients, all before 3 years old, we identified a mosaic premalignant clonal expansion of cells altered at the 11p15.5 locus. Analysis of spatial and longitudinal heterogeneity revealed an important plasticity between ‘Hepatocytic’, ‘Liver Progenitor’ and ‘Mesenchymal’ molecular subgroups of hepatoblastoma. We showed that during chemotherapy, ‘Liver Progenitor’ cells accumulated massive loads of cisplatin-induced mutations with a specific mutational signature, leading to the development of heavily mutated relapses and metastases. Drug screening in PLC cell lines identified promising targets for cisplatin-resistant progenitor cells, validated in mouse xenograft experiments. These data provide new insights into cisplatin resistance mechanisms in PLC and suggest alternative therapies.

  Study EGAS00001005108

• Whole-Genome Sequencing of Salivary Gland Adenoid Cystic Carcinoma

  Adenoid cystic carcinomas (ACCs) of the salivary glands are challenging to understand, treat, and cure. To better understand the genetic alterations underlying the pathogenesis of these tumors, we performed comprehensive genome analyses of 25 fresh-frozen tumors, including whole genome sequencing, expression and pathway analyses. In addition to the well-described MYB-NFIB fusion which was found in 11 tumors (44%), we observed five different rearrangements involving the NFIB transcription factor gene in seven tumors (28%). Taken together, NFIB translocations occurred in 15 of 25 samples (60%, 95%CI=41–77%). In addition, mRNA expression analysis of 17 tumors revealed overexpression of NFIB in ACC tumors compared with normal tissues (p=0.002). There was no difference in NFIB mRNA expression in tumors with NFIB fusions compared to those without. We also report somatic mutations of genes involved in the axonal guidance and Rho family signaling pathways. Finally, we confirm previously described alterations in genes related to chromatin regulation and Notch signaling. Our findings suggest a separate role for NFIB in ACC oncogenesis and highlight important signaling pathways for future functional characterization and potential therapeutic targeting.

  Study EGAS00001002812

• THE GENOMIC LANDSCAPE OF ACTINIC KERATOSIS

  Actinic keratoses (AK) are lesions of epidermal keratinocyte dysplasia and are pre-cursor lesions to invasive cutaneous squamous cell carcinoma (cSCC). Identifying the specific genomic alterations driving the progression of normal skin to AK and invasive cSCC is challenging due to the massive, ultraviolet radiation-induced mutational burden characteristic to these lesions. Here, we present the largest whole exome sequencing study to date on AK with matched cSCC and demonstrate that AK and cSCC are almost indistinguishable at the genomic level, in terms of mutational burden, patterns of driver gene mutations and copy number alterations. We identified 44 significantly mutated AK driver genes through our established bioinformatics pipeline and demonstrate these genes are similarly mutated in cSCC. We also identified mutational signature-32 exclusively in AK from patients exposed to azathioprine, providing further, compelling evidence for this drug’s role in keratinocyte carcinogenesis, likely through its blocking of transcription coupled repair. We demonstrated that cSCC had higher levels of intra-sample heterogeneity than AK and that several signaling pathways, including immune-related signaling and TGF-beta signaling were significantly more mutated in cSCC. Integrating our findings with independent gene expression data confirms that dysregulated TGF-beta signaling may represent the critical pathway in the progression from AK to cSCC.

  Study EGAS00001004243

• Genomic landscape and PD-1 blockade in Natural-killer/T cell lymphoma

  Natural killer/T-cell lymphoma (NKTL) is an aggressive malignancy with a predilection for Asian, Mexican and South American populations. With the exception of Japan, it is the most common mature T-cell lymphoma in Asia. NKTL presents as extranodal disease and mostly affects the upper aerodigestive tract. Neoplastic cells are invariably infected by the Epstein-Barr virus (EBV) and characterized by a cytotoxic phenotype. The genetic landscape of NKTL has been recently unraveled by discoveries describing recurring mutations altering the JAK-STAT pathway, epigenetic modifiers, the DDX3X gene and genetic predisposition in the HLA-DPB1 gene.The genomic landscape of NKTL has been interrogated by whole-exome sequencing, targeted sequencing and single nucleotide polymorphism arrays, but has yet been studied with whole-genome sequencing (WGS). In this study, we will use a combination of WGS, targeted-capture sequencing (TCS) and RNA sequencing data to explore the genetic landscape and its relevance to immunotherapy in NKTL

  Study EGAS00001003828

• Pediatric tumor in a single child of three large nuclear families

  We identify three nuclear families in which a pediatric tumor had been diagnosed in a single child and neither parent had been diagnosed with cancer. These families had 4, 5, and 7 children, respectively. Diagnoses included Wilms tumor, low-grade astrocytoma, and Burkitt’s lymphoma, respectively. We used whole-genome sequencing to profile normal cells from each family member and a linked-read technology for genomic phasing, which enabled us to identify compound-heterozygous and de novo variants in addition to simple-heterozygous and homozygous-alternate variants.

  Study EGAS00001005321

• New Brain Tumor Entities Emerge from Molecular Classification of CNS-PNETs

  Primitive neuroectodermal tumors of the central nervous system (CNS-PNETs) are highly aggressive, poorly differentiated embryonal tumors occurring predominantly in young children but also affecting adolescents and adults. Herein we demonstrate that a significant proportion of institutionally diagnosed CNS-PNETs display molecular profiles indistinguishable from those of various other well defined CNS tumor entities, facilitating diagnosis and appropriate therapy for patients with these tumors. From the remaining fraction of CNS-PNETs we identify four new CNS tumor entities, each associated with a recurrent genetic alteration and distinct histopathological and clinical features. These new molecular entities, designated “CNS neuroblastoma with FOXR2 activation (CNS NB-FOXR2)”, “CNS Ewing sarcoma family tumor with CIC alteration (CNS EFT-CIC)”, “CNS high grade neuroepithelial tumor with MN1 alteration (CNS HGNET-MN1)”, and “CNS high grade neuroepithelial tumor with BCOR alteration (CNS HGNET-BCOR)”, will enable meaningful clinical trials and the development of therapeutic strategies for patients affected by poorly differentiated CNS tumors.

  Study EGAS00001001632

• Accurate detection and classification of pediatric sarcomas based on cell-free DNA fragmentation patterns

  Sequencing of cell-free DNA in the blood of cancer patients (“liquid biopsy”) provides attractive opportunities not only for early diagnosis, but also for minimally invasive monitoring of treatment response and disease courses. To unlock liquid biopsy analysis for pediatric tumors with few genetic aberrations, we developed an integrated genetic/epigenetic analysis method and applied it to 241 deep whole-genome sequencing profiles of 95 patients with Ewing sarcoma and 31 patients with other pediatric sarcomas. We achieved sensitive detection and classification of circulating tumor DNA in peripheral blood independent of any genetic alterations. We evaluated different metrics for cell-free DNA fragmentation analysis and developed LIQUORICE, a bioinformatic tool for detecting circulating tumor DNA based on tumor-specific chromatin structure. Using machine learning methods, we combined several fragmentation-based metrics into an integrated approach for liquid biopsy analysis tailored to cancers with low mutation rates but widespread epigenetic deregulation. Clinical associations highlighted the potential value of cfDNA fragmentation patterns as prognostic biomarkers in Ewing sarcoma. Additionally, we performed low coverage whole-genome-sequencing on 43 tumor biopsy samples from patients with Ewing sarcoma, in order to compare copy number aberrations detected in cell-free DNA and biopsy samples of the same patients. For validation of the epigenetic signatures inferred from cell-free DNA, we further performed reduced representation bisulfite sequencing (RRBS) on 38 matched biopsy samples from patients with Ewing sarcoma. In summary, our study provides a comprehensive analysis of circulating tumor DNA beyond recurrent somatic mutations, and it renders the benefits of liquid biopsy more readily accessible for childhood cancers.

  Study EGAS00001005127

• Neuroblastoma tumor heterogeneity and cell plasticity (from patients)

  Two cell identities, noradrenergic and mesenchymal, have been characterized in neuroblastoma cell lines according to their epigenetic landscapes relying on specific core regulatory circuitries of transcription factors. Yet, their relationship and relative contribution in patient tumors remain to be defined. Here, we document a spontaneous plasticity between the noradrenergic and mesenchymal identities in a subset of cell lines. Strikingly, mesenchymal neuroblastoma cells revert to a noradrenergic phenotype in vivo. Consistently, tumor cells with a mesenchymal identity are detected in single-cell transcriptomic analyses of neuroblastoma tumors and PDX models. Our data also highlight neuroblastoma intra-tumor heterogeneity with the co-existence of distinct tumor populations, including sympathoblast-like and chromaffin-like cells suggesting that neuroblastoma cells arise from a common sympatho-adrenal progenitor.

  Study EGAS00001005322

• Robust detection of translocations in lymphoma FFPE samples using Targeted Locus Capture-based sequencing - NGS targeted capture control cohort

  In routine diagnostic pathology, cancer biopsies are preserved by Formalin-Fixed, Paraffin-Embedding (FFPE) procedures for examination of (intra-) cellular morphology. Such procedures inadvertently induce DNA fragmentation, which compromises sequencing-based analyses of chromosomal rearrangements. Yet, rearrangements drive many types of hematolymphoid malignancies and solid tumors, and their manifestation is instructive for diagnosis, prognosis and treatment. Here, we present FFPE-Targeted Locus Capture (FFPE-TLC) for targeted sequencing of proximity-ligation products formed in FFPE tissue blocks, and PLIER, a computational framework that allows automated identification and characterization of rearrangements involving selected, clinically-relevant, loci. FFPE-TLC, blindly applied to 149 lymphoma and control FFPE samples, identifies the known and novel rearrangement partners. It outperforms fluorescence in situ hybridization (FISH) in sensitivity and specificity, and shows clear advantages over standard capture-NGS methods, finding rearrangements involving repetitive sequences which they typically miss. FFPE-TLC is therefore a powerful clinical diagnostics tool for accurate targeted rearrangement detection in FFPE specimens.

  Study EGAS00001005325

• Germline SDHB-inactivating mutation in gastric spindle cell sarcoma (HIPO-021)

  Gastrointestinal stromal tumors (GISTs) are the most frequent mesenchymal tumors of the gastrointestinal tract. Inactivating mutations or epigenetic deregulation of succinate dehydrogenase complex (SDH) genes are considered defining features of a subset of GIST occurring in the stomach. Based on comprehensive molecular profiling and biochemical analysis within a precision oncology program, we identified hallmarks of SDH deficiency (germline SDHB-inactivating mutation accompanied by somatic loss of heterozygosity, lack of SDHB expression, global DNA hypermethylation, and elevated succinate/fumarate ratio) in a 40-year-old woman with undifferentiated gastric spindle cell sarcoma that did not meet the diagnostic criteria for other mesenchymal tumors of the stomach, including GIST. These data reveal that the loss of SDH function can be involved in the pathogenesis of non-GIST sarcoma of the gastrointestinal tract.

  Study EGAS00001004277