90 results for "abb+verify+eyecare+partners"

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• Pediatric Preclinical Testing Consortium (PPTC)

  The Pediatric Preclinical Testing Consortium (PPTC) is addressing the unmet need of streamlining the development of new therapies for childhood cancers. The PPTC seeks to develop robust biomarkers of anticancer drug activity, and the majority of these are predicted to be genetic mutations that can be detected in tumor DNA and/or RNA. In order to design the most impactful experiments that can be rapidly translated to the clinic, PPTC investigators require a complete genomic characterization of the patient-derived xenograft tumor models that are utilized across the consortium. This will not only allow for the most robust experimental design, but also will increase the engagement of industry partners who seek collaborators poised to provide the proof-of-concept necessary for drugs in their development pipelines. All data and models will be made available to academically qualified investigators.

  Study phs001437

• Childhood Cancer Data Initiative (CCDI): Pediatric In Vivo Testing Program - Neuroblastoma

  The goal of NCI's Pediatric In Vivo Testing Consortium (PIVOT) is to advance the development of effective treatments for pediatric cancers through preclinical in vivo testing of novel therapeutic agents. To design impactful experiments that can be rapidly translated to the clinic, PIVOT investigators require comprehensive genomic characterization of the patient-derived xenograft (PDX) models used across the consortium. This robust experimental design enhances collaboration with industry partners by providing proof-of-concept data for drugs in development. As part of this effort, neuroblastoma PDX models are being molecularly characterized to identify promising therapeutic candidates. The molecular profiling includes whole exome sequencing (WES), RNA-seq, MethylEPIC array, CytoSNP array, and DNA fingerprinting for quality control. Additionally, demographic and clinical data (e.g., diagnosis, disease site, disease status) are shared. These characterized PDX models, matched with patient tumors, guide model selection for preclinical drug testing.

  Study phs003163

• Acquisition of additional mutations drives accelerated progression of NPM1 positive CMML to AML

  This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/ We performed exome sequencing on serial samples from a patient with CMML who progressed to AML. The exome sequencing suggests that NPM1, TET2 and DNMT3a mutations were present in the dominant clone in the CMML sample and that NRAS is a new subclonal mutation in the AML sample. Diagnostic data shows the presence of a FLT3-ITD mutation in the AML sample, which is likely to have driven progression. Here we are performing re-sequencing of the putative driver and some passenger mutations which appear to be in the same clone to validate these mutations and to verify the relative quantification of these abnormalities .

  Dataset EGAD00001002194

• Using NGS to Sequence Whole Genomes to Identify Genes Underlying ALS

  Our ALS Consortium - a partnership of clinicians, basic scientists, geneticists, and computational biologists from 48 institutions (4 of which are industry partners) across 5 countries - establishes a framework to apply whole genome sequencing (WGS) and functional genomics to the study of amyotrophic lateral sclerosis (ALS). Because ALS-causing mutations tend to be of moderate impact and are relatively rare in the population (reviewed in Al-Chalabi et al., 2017, PMID: 27982040), identification of new mutations require several thousand samples, which need to be obtained from multiple sites (even the busiest ALS clinics see only 200-400 patients per year). ALS Consortium is using genomics technologies to study the causes and mechanisms underlying neurodegenerative disease, and the contribution of various cell types within the brain and spinal cord. Much of this work is done and continues to be done in collaboration with the members of the NYGC ALS Consortium.

  Study phs003067

• Common origin and somatic mutation patterns of composite lymphomas and leukemias

  When two lymphomas occur concurrently or sequentially in a patient, it is a major question whether they derive from the same lymphocyte or hematopoietic precursor cell or developed independently. We studied four composite classic Hodgkin lymphomas (HL) and other mature B-cell lymphomas, and two composite mature B- and T-cell neoplasias by whole exome sequencing (WES) and analyzed shared somatic mutations in the lymphomas of these clonally related composite lymphomas, indicating their derivation from a common, pre-malignant precursor. Most identified mutations were restricted to one or the other of these lymphomas, likely explaining how distinct lymphomas developed from a common ancestral B cell. In the two B-cell/T-cell lymphoma cases, and a composite clonally unrelated HL/chronic lymphocytic leukemia, the lymphoma partners did not share any somatic mutations. In three cases, we identified potentially oncogenic variants also in cells serving as constitutional controls.

  Study EGAS50000001017

• Spatial and Temporal Homogeneity of Driver Mutations in Diffuse Intrinsic Pointine Glioma

  Diffuse Intrinsic Pontine Gliomas (DIPG) are deadly pediatric brain tumors where needle biopsies help guide diagnosis and targeted therapies. To address spatial heterogeneity, we analyzed 134 specimens from various neuroanatomical structures of whole autopsy brains from nine DIPG patients. Evolutionary reconstruction indicates histone 3 (H3)K27M – including novel H3.2K27M - mutations potentially arise first and are invariably associated with specific, high-fidelity obligate partners throughout the tumor and its spread, from diagnosis to end-stage disease, suggesting mutual need for tumorigenesis. These H3K27M ubiquitously-associated mutations involve alterations in TP53 cell-cycle (TP53/PPM1D) or specific growth factor pathways (ACVR1/PIK3R1). Later oncogenic alterations arise in sub-clones and often affect the PI3K pathway. Our findings are consistent with early tumor spread outside the brainstem including the cerebrum. The spatial and temporal homogeneity of driver mutations in DIPG implies they will be captured by limited biopsies and emphasizes the need to develop therapies specifically targeting obligate oncohistone partnerships.

  Study EGAS00001001654

• 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

• INCLUDE: Genetic Underpinnings of the Multifactorial Phenotype of Trisomy 21 Patients Unveiled by Multi-Omics Approaches

  The INCLUDE (INvestigation of Co-occurring conditions across the Lifespan to Understand Down syndromE) Project is an NIH-wide collaboration that seeks to improve health and quality-of-life for people with Down syndrome. The INCLUDE Project Data Coordinating Center and partners created the INCLUDE Data Hub, a centralized data resource that allows access to large-scale clinical and multi-omics datasets specific to Down syndrome and supports collaborative, cloud-based analysis to accelerate scientific discoveries related to Down syndrome and its co-occurring conditions.Down syndrome (DS) is the most common chromosomal abnormality in livebirths with an incidence of 1 in 700 in the US. To better understand the pathophysiology of DS, this proposal will generate and analyze sequence data on 777 pediatric DS patients from the Children's Hospital of Philadelphia (CHOP), as well as 321 mothers and 148 fathers. We anticipate that the information derived from this deeply-phenotyped cohort will allow for improved understanding of the pathophysiology and molecular mechanisms underlying DS-associated comorbidities, which may inform on new practices for treatment or innovative future therapies.

  Study phs002983

• Altered enhancer-promoter interaction leads to MNX1 expression in pediatric acute myeloid leukemia with t(7;12)(q36;p13)

  Acute myeloid leukemia (AML) with the t(7;12)(q36;p13) translocation occurs only in very young children and has a poor clinical outcome. The expected oncofusion between breakpoint partners (MNX1 and ETV6) has only been reported in a subset of cases. However, a universal feature is the strong transcript and protein expression of MNX1, a homeobox transcription factor that is normally not expressed in hematopoietic cells. Here, we map the translocation breakpoints on chromosomes 7 and 12 in affected patients to a region proximal to MNX1 and either introns 1 or 2 of ETV6. The frequency of MNX1 overexpression in pediatric AML (n=1556, own and published data) is 2.4% and occurs predominantly in t(7;12)(q36;p13) AML. Chromatin interaction assays in a t(7;12)(q36;p13) iPSC cell line model unravel an enhancer-hijacking event that explains MNX1 overexpression in hematopoietic cells. Our data suggest that enhancer-hijacking is a more common and overlooked mechanism for structural rearrangement-mediated gene activation in AML.

  Study EGAS50000000130

• The brain neurovascular epigenome and its association with dementia

  Cerebral small vessel disease (SVD) is frequently comorbid with Alzheimer’s disease (AD) and vascular brain endothelial cells (BECs) are enriched for the expression of genes associated with AD genetic risk. However, the gene regulatory landscapes of neurovascular cells and their intersection with genetic risk for disease remains unexplored. Here we have generated gene regulomes for human BECs, mural cells and other brain cell types to show that AD heritability is primarily immune-related and that it shows modest enrichment in BECs. By contrast, genetic risk for SVD is enriched across cells of the neurovascular unit, including astrocytes. Enhancer-to-gene interactomes implicate amyloid processes in both AD and SVD, though the risk genes are mostly distinct for the two disorders. Motifs for putative partners of lineage transcription factors in microglia and BECs were enriched for AD and SVD variants at genes linked to disease pathways. Gene prioritization and enrichment analyses further identified potential repurposable drugs for AD. Our findings highlight novel regulatory mechanisms and therapeutic targets within the neurovascular system.

  Study EGAS50000001160