16792 results for "sec+and+unspecified+malignant+neoplasm"

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• A super-enhancer associated with CD47 links pro-inflammatory signaling to CD47 upregulation in breast cancer

  CD47 is a cell surface molecule that inhibits phagocytosis of cells that express it by binding to its receptor, SIRPα, on macrophages and other immune cells. CD47 is expressed at different levels in normal cells, however, in cancer cells, CD47 transcript and protein expression is aberrantly increased. Here we sought to uncover the regulators of CD47 transcription, including active enhancers that increase its aberrant expression in cancer cells, in order to reveal mechanisms by which different neoplastic cells generate this dominant 'don't eat me' signal. Enhancers are genomic regions, often referred to as "switches", that can turn on or off the transcription of target genes. Recently the discovery of super-enhancers (SEs) has given more insight into the regulatory architecture of key genes that are highly expressed in a specific cell type, during a particular developmental stage or in disease. By analyzing the CD47 regulatory genomic landscape, we discovered: i) A distinct super-enhancer (SE) is associated with CD47 upregulation in breast cancer cells ii) Disruption of CD47 SEs by using the BRD4 inhibitor JQ1 robustly reduces CD47 gene expression; and iii) The TNF-NFKB1 signaling pathway is directly involved in the regulation of CD47 by interacting with a distal downstream constituent enhancer located within a CD47-associated SE specific to breast cancer. Our results describe a novel mechanism that cancer cells have evolved to drive CD47 overexpression to escape immune surveillance.

  Study phs001264

• HuBMAP: A Spatially Resolved Molecular Atlas of Human Endothelium

  The human circulatory system plays a vital role in the proper functioning of every organ in the human body. Because vascular related diseases, such as atherosclerosis, do not occur homogeneously throughout the vascular tree, differences in the endothelium of various organs must exist. There is even evidence of heterogeneity of adjacent endothelial cells. We are studying normal endothelium throughout the body and across individuals of different ages to characterize these differences. The first step will be to procure normal tissue samples from a wide range of organs. From disaggregated samples of these tissues, we will perform single cell combinatorial indexing (sci-) to generate chromatin accessibility (sci-ATAC-seq) and transcriptome (sci-RNA-seq) data from millions of single cells across hundreds of samples.  Molecular heterogeneity might correlate with multiple facets of the anatomical distribution of endothelium, including vascular vs. lymphatic, arteries vs. veins, capillaries vs. larger vessels, differences between organs, organ zonation, cell-to-cell differences, etc. Based on heterogeneous markers defined from deep profiling of disaggregated cells, we will employ seqFISH to spatially relate the distinct endothelial subpopulations arising from the single nuclei data to histologic preparations. For example, this will allow us to identify subpopulations with particular markers as arterial, capillary, venous, or lymphatic. The end product will include multiparameter images in which the complete gene expression and chromatin accessibility profile can be interactively visualized for every cell.

  Study phs002267

• Plasma-Seq of patients with metastatic prostate cancer

  Study 1 In this study we analysed patients with metastatic prostate cancer to scan their tumor genomes noninvasively in plasma DNA. We wanted to make whole-genome analysis from plasma DNA amenable to clinical routine applications and developed an approach based on a benchtop high-throughput platform, i.e. Illuminas MiSeq instrument. We performed whole-genome sequencing from plasma at a shallow sequencing depth to establish a genome-wide copy number profile of the tumor at low costs within 2 days. The genome-wide profiling in the plasma of our patients revealed multiple copy number aberrations including those previously reported in prostate tumors, such as losses in 8p and gains in 8q. High-level copy number gains in the AR locus were observed in patients with CRPC but not with CSPC disease. We identified the TMPRSS2-ERG rearrangement associated 3-Mbp deletion on chromosome 21 and found corresponding fusion plasma fragments in these cases. In an index case multiregional sequencing of the primary tumor identified different copy number changes in each sector, suggesting multifocal disease. Our plasma analyses of this index case, performed 13 years after resection of the primary tumor, revealed novel chromosomal rearrangements, which were stable in serial plasma analyses over a 9 months period, which is consistent with the presence of one metastatic clone. Our approach provides specific genomic signatures within 2 days which may therefore serve as “liquid biopsy”.

  Study EGAS00001000451

• Long-read trio sequencing of unsolved patients with intellectual disability

  Long-read sequencing (LRS) has the potential to comprehensively identify all medically-relevant genome variation, including variation commonly missed by short read sequencing (SRS) approaches. To determine this potential, we performed LRS up to 40x coverage using the Pacific Biosciences Sequel instrument for 5 patient-parent trios with intellectual disability, whose aetiology remained unresolved after SRS exomes and genomes. A first systematic assessment of LRS coverage showed that ~35Mb of the genome was only accessible by LRS and not SRS. Structural variant (SV) calling yielded on average 28,292 SV calls per individual, totalling 12.9 MB of sequence. Trio-based analyses showed concordance for up to 95% of these SV calls across the genome, and 80% of the LRS SV calls were not identified by SRS. De novo mutation analysis did not identify any de novo SVs, confirming these are rare events. Because of high sequence coverage, we were also able to call single nucleotide substitutions. On average, we identified 3 million substitutions per genome, with a Mendelian inheritance concordance of up to 97%. Of these, approximately 100,000 were located in the ~35Mb of the genome that was only captured by LRS. Moreover, these variants affected the coding sequence of 64 genes, including 32 known to cause Mendelian disorders. Although no clinical diagnoses were made in these 5 patients, our data show the potential added value of LRS compared to SRS for identifying medically relevant genome variation.

  Study EGAS00001004319

• Identification of the mutational consequences of precancerous liver disease (including alcohol abuse) on the genomes of human adult stem cells.

  Stem cells are believed to be the cells-of-origin cancer. Nevertheless, their genome remains remarkably stable during life. To increase insight into how these cells can drive tumorigenesis, we set out to determine the genomic integrity of human adult stem cells from patients with liver disease associated with increased cancer risk. To this end, we characterized genome-wide mutation profiles of single ASCs from livers of patients with alcoholic liver disease, non-alcoholic liver disease and primary sclerosing cholangitis. The patients included in our study received a liver transplant due to their liver disease. Strikingly, we found that ASCs in these livers maintain a stable genome and have comparable mutation rates as healthy human liver ASCs. We did observe more nonsense and nonsynonymous mutations in COSMIC cancer genes that are hit by dominant mutations in tumors in comparison to healthy ASCs (n.s.), including two ASCs in alcoholic liver disease patients with a nonsense mutation in PTPRK. Next, we sequenced 5 biopsies of an alcoholic tumour to identify the mutational patterns in the tumour-initiating ASC. We found that the mutational patterns are, again, similar to healthy liver, but the mutational load is slightly higher. This suggests that the increased cancer risk in the liver disease patients is not caused by an increased mutational load, but rather that the precancerous liver environment promotes outgrowth of cells that would normally be selected against.

  Study EGAS00001002983

• NHLBI TOPMed: The Vanderbilt Atrial Fibrillation Registry (VU_AF)

  The Vanderbilt Atrial Fibrillation (AF) Registry was founded in 2001. Patients with AF and family members are prospectively enrolled. At enrollment a detailed past medical history is obtained along with an AF symptom severity assessment. Blood samples are obtained for DNA extraction. Patients are followed longitudinally along with serial collection of AF symptom severity assessments.

  Study phs001032

• Multimodal Genomic Features Predict Outcome of Immune Checkpoint Blockade in Non-small Cell Lung Cancer

  This study evaluates integrated genomic models of response to immune checkpoint blockade for lung cancer patients. A computationally adjusted tumor mutation burden was combined with HLA class I genetic variation, mutational smoking signature and activating mutations in receptor tyrosine kinase genes to generate a prognostic classifier that outperforms tumor mutation burden.

  Study phs001940

• Genome Wide Association Studies in ECOG 2997 Trial

  The ECOG 2997 trial was a randomized controlled trial for patients with previously untreated CLL comparing fludarabine monotherapy to the combination of fludarabine and cyclophosphamide. The initial clinical findings of this study were published in the Journal of Clinical Oncology in 2007 (JCO 25:793-8). Additional laboratory studies have also published (JCO 25:799-804).

  Study phs000621

• Drop-BS: High-Throughput Single-Cell Bisulfite Sequencing on a Microfluidic Droplet Platform

  We present a high-throughput droplet-based bisulfite sequencing library preparation platform. Our protocol allows the production of a BS library of 2,000-10,000 single cells within 2 days. In addition to validation using mixed cell lines, we also used the technology to profile various cell types in mouse and human brain samples.

  Study phs002123

• Washington University Coronary Artery Disease Study

  The genetic basis of coronary artery disease in individuals of non-European ancestry is largely unknown. The Washington University Coronary Artery Disease Study (WUCADS) recruited participants of non-European ancestry with and without coronary artery disease to address this question. Whole genome sequencing in WUCADS was performed at the McDonnell Genome Institute at Washington University.

  Study phs001227

• The Genetic Landscape of Mutations in Burkitt Lymphoma

  Burkitt lymphoma (BL) is characterized by deregulation of MYC, but the contribution of other genetic mutations to the disease is largely unknown. We sequenced exomes of 59 BL tumors, 14 of which had paired normal tissue. Our work elucidates commonly occurring gene-coding mutations in Burkitt lymphoma and implicates ID3 as a novel tumor suppressor gene.

  Study phs000562

• CALGB 80303:Genome-Wide Association Study of Advanced Pancreatic Cancer Patients - A Randomized Phase III trial of Gemcitabine Plus Bevacizumab versus Gemcitabine Plus Placebo in Patients with Advanced Pancreatic Cancer

  CALGB 80303 was a randomized, phase III study in advanced pancreatic cancer patients treated with Gemcitabine plus either Bevacizumab or placebo. No difference in overall survival (OS) was observed between the two arms. We prospectively collected germline DNA and conducted a genome-wide association study (GWAS).

  Study phs000250

• Determinants of Asthma Following RSV Bronchiolitis in Early Life

  The goal of the RSV Bronchiolitis in Early Life (RBEL) study is to determine how specific genetic, biologic, and immunologic characteristics interact to predispose individuals to develop asthma. Participants were carefully recruited by selecting a prospective cohort of 206 infants with severe respiratory syncytial virus (RSV) bronchiolitis who were at substantial risk of developing asthma.

  Study phs001009

• Myelodysplastic Syndrome (MDS) in Humanized Mice

  This study was to develop a faithful pre-clinical MDS patient-derived xenotransplantation model in cytokine-humanized immunodeficient "MISTRG" mice. We performed targeted genome sequencing on bone marrow from patients with MDS or AML and from bone marrow of mice engrafted with the respective patient bone marrow. Cytokine-humanized immunodeficient mice faithfully replicate human MDS.

  Study phs001778

• Whole Exome Sequencing of Six Signet Ring/Plasmacytoid Variant Bladder Tumors

  In this study, six plasmacytoid bladder cancers were analyzed by whole exome sequencing. The results show loss of the CDH1 gene in every sample and correlate with E-cadherin loss of expression by immunohistochemistry. A separate validation cohort of plasmacytoid samples showed loss of E-cadherin expression by CDH1 mutation or promoter hypermethylation.

  Study phs001064

• Prevalence of rare pathogenic variants in cancer-predisposing genes among Japanese advanced prostate cancer patients.

  The prevalence of rare pathogenic variants in cancer-predisposing genes including those associated with DNA repair remains unknown among Japanese patients with advanced prostate cancer. This study was designed to elucidate the prevalence of pathogenic variants in 27 known cancer-predisposing genes and to explore the prognostic significance of the variants identified.

  Study JGAS000509

• Whole genome sequence: cardiomyopathy, 1 myotonic dystrophy patient

  In this study, we analyzed the genomic information by whole genome sequencing using peripheral blood samples from patients with various cardiovascular diseases including severe heart failure to identify genetic variants related to the pathology of cardiovascular diseases. The purpose is to elucidate the underlying mechanism and develop new therapeutic interventions for cardiovascular disease.

  Study JGAS000706

• Immune Landscape of Cervical Lymph Nodes in Multiple Sclerosis

  This study aimed to investigate the cellular compartment of deep cervical lymph nodes (dcLNs) during early MS before the influence of immunosuppressive treatments. We used ultrasound-guided FNAs followed by scRNA-seq,CITE-seq, TCR and BCR seq to characterize the immune landscape in MS patients compared to controls within the dcLNs.

  Study EGAS50000000843

• Paraganglioma Smart-Seq2 Single Nuclei Sequencing Data

  Paraganglioma is a rare neuroendocrine tumor that originates from chromaffin cells of the adrenal medulla or extra-adrenal paraganglia. This study aims to investigate the heterogeneity of this tumor and to identify potential biomarkers associated with its malignancy. To achieve this, we performed single-nucleus RNA sequencing of human paraganglioma samples using the SMART-Seq2 protocol.

  Study EGAS50000001184

• Immunoreactive_p53_areas_in_human_skin_2

  Previous work has suggested that in mice there may be a difference in mutational burden between areas expressing stabilised p53 protein and others. We wish to see if this observation holds true in human sun-exposed epidermis. We will take 0.25mm punch biopsies from peeled human skin epidermis which will be submitted to the low input pipeline prior to sequencing.

  Study EGAS00001004463

• Single-cell RNA-seq profiling of patient derived organoids

  The aim of this study was to profile developement of resistance to cancer treatments using organoids. Two patient derived colorectal cancer organoids were profiled using single cell RNAseq after treatment with a combination of different anticancer drugs. The organoids were profiled both after 4 weeks of treatment and after a drug holiday of 2 weeks.

  Study EGAS50000001025

• Clonal Evolution of PPM1D Mutations in the Spectrum of Myeloid Disorders

  PPM1D, a central regulator of the DNA damage response, is commonly mutated in therapy-related clonal hematopoiesis (CH), acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). PPM1D mutations have been shown to expand under selective pressure of DNA-damaging chemotherapy. However, whether PPM1D mutations promote the development of hematologic malignancies remains unclear.

  Study EGAS50000000840

• Evaluating potential drug candidates for the treament of Henamgiopericytoma on patient derived cell line models

  Solitary fibrous tumor/Hemangiopericytoma (SFT/HPC) is a rare subtype of soft tissue sarcoma associated with NAB2-STAT6 gene fusions. This study established and characterized a novel SFT/HPC patient-derived cell line called SFT-S1. Potential drug candidates that could be repurposed for the treatment of SFT/HPC were screened.

  Study EGAS50000000027

• PD1-targeted delivery of an IL-2 variant induces a multifaceted anti-tumoral T cell response in human lung cancer

  To explore PD1-IL2v-specific effects on CD8 and CD4 T cells at a transcriptomic level, we performed single-cell RNA sequencing of patient-derived tumor fragments (PDTFs) which were treated with either Isotype (DP47), Isotype-IL2v (DP47-IL2v), anti-PD1 (PembroPGLALA) or PD1-IL2v (PembroPGLALA-IL2v) for 48 hours.

  Study EGAS50000000396

• Single cell transcriptomic profiles of advanced melanoma patients treated with checkpoint inhibitor immunotherapy

  Little is known about the resistant clones within the tumour ecosystem treated with immunotherapy. This work provides a comprehensive and integrative analysis of each individual non-responding melanoma patients, including clinical features integrated with single cell analysis, which is critical to understand features of resistance in order to improve cancer patients’ outcomes.

  Study EGAS50000000339