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Results Found: 451

  • (Metabolome analysis data): Mutant ASXL1 induces age-related expansion of phenotypic hematopoietic stem cells through activation of Akt/mTOR pathway

    Authors
    Kitamura, Toshio
    Description

    Description from MassIVE: Somatic mutations of ASXL1 are frequently detected in age-related clonal hematopoiesis (CH). However, how ASXL1 mutations drive CH remains elusive. Using knockin (KI) mice expressing a C-terminally truncated form of ASXL1-mutant (ASXL1-MT), we examined the influence of ASXL1-MT on physiological aging in hematopoietic stem cells (HSCs). HSCs expressing ASXL1-MT display competitive disadvantage after transplantation. Nevertheless, in genetic mosaic mouse model, they acquire clonal advantage during aging, recapitulating CH in humans. Mechanistically, ASXL1-MT cooperates with BAP1 to deubiquitinate and activate AKT. Overactive Akt/mTOR signaling induced by ASXL1-MT results in aberrant proliferation and dysfunction of HSCs associated with age-related accumulation of DNA damage. Treatment with an mTOR inhibitor rapamycin ameliorates aberrant expansion of the HSC compartment as well as dysregulated hematopoiesis in aged ASXL1-MT KI mice. Our findings suggest that ASXL1-MT provokes dysfunction of HSCs, whereas it confers clonal advantage on HSCs over time, leading to the development of CH."

    Subject
    Clonal Hematopoiesis
    Hematopoietic Stem Cells
    Metabolome
    Myelodysplastic Syndromes
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  • 33 patients with Monoclonal Gammopathy of Undetermined Significance (MGUS)

    Description

    Dataset Description from EGA: " Monoclonal gammopathy of undetermined significance (MGUS) is a premalignant precursor of multiple myeloma (MM) with a 1% risk of progression per year. Although targeted analyses have shown the presence of specific genetic abnormalities such as IGH translocations, RB1 deletion, 1q gain, hyperdiploidy or RAS genes mutations, little is known about molecular mechanism of malignant transformation. We have performed whole exome sequencing together with SNP array analysis in 33 flow-cytometry separated abnormal PC samples of MGUS patients to describe somatic gene mutations and chromosome changes at the genome-wide level. Non-synonymous mutations (NS-SNVs) and copy number alterations (CNAs) were present in 97.0% and in 63.6% of cases, respectively. Importantly, the number of somatic mutations was significantly lower in MGUS compared to MM (p

    Subject
    Monoclonal Gammopathy of Undetermined Significance
    Multiple Myeloma
    Oncogene Proteins, Fusion
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  • A Molecular Taxonomy of Urothelial Carcinoma

    Authors
    Sjödahl, Gottfrid
    Lauss, Martin
    Lindgren, David
    Höglund, Mattias
    Description

    Summary from the GEO: " Even though urothelial cancer (UC) is the fourth common tumor type among males, progress in treatment development has been deficient. Pathological assessment provides the urologists with only a broad classification, complicated by frequent disagreement among pathologist and the co-existence of different grading systems. Consequently, there is a great need for an objective, reproducible and biologically relevant classification system to make treatment more efficient. In the present investigation we present a molecular taxonomy for UC stratification based on integrated genomics.
    We used gene expression profiles from 308 UC to define seven molecular subtypes using step-by-step partitions and a bootstrap approach. Results were validated in three independent and publically available data sets. The subtypes differ significantly with respect to expression of cell cycle genes, of receptor tyrosine kinases particularity FGFR3, ERBB2 (HER2), and EGFR, of an FGFR3 associated gene expression signature, of cytokaratins, and of cell adhesion genes. The subtypes also differ significantly with respect to FGFR3, PIK3CA, and TP53 mutations. The expression of key proteins was validated by IHC on TMA. A further inspection indicated that the subtypes could be reduced to four major types of UC; Urobasal/D-driven, Genomically unstable/E-driven, Evolved urobasal, and Basal/SCC like, with characteristic and highly divergent molecular phenotypes. We show that the molecular subtypes cut across pathological classification and that tumors classified as one subtype maintain their characteristic molecular phenotype irrespective of pathological stage and grade. Available data from the Drugbank database and the Cochrane central registry of controlled trials indicate that susceptibility to specific drugs is more likely to be associated with the molecular stratification than with pathological classification.
    The presented molecular taxonomy stratifies UC into subtypes with distinct molecular phenotypes and biological properties. We anticipate that the molecular taxonomy will be a useful tool in future clinical investigations.
    Overall Design: Total RNA from fresh-frozen resection samples of 308 urothelial carcinomas was hybridized to the Illumina HumanHT-12 V3.0 expression beadchip arrays (Illumina Inc) at the SCIBLU Genomics Centre at Lund University Sweden (http://www.lth.se/sciblu).

    Supplementary files:
    GSE32894_non-normalized_308UCsamples.txt file = Raw intensity values for 308 UC (urothelial tumor) samples subjected only to background correction.
    GSE32894_reps_normals_preprocess*.txt files = Descriptive details and non-normalized data for technical replicates and normal samples that were used only in the preprocessing of the data."

    Subject
    Gene Expression Profiling
    Urinary Bladder Neoplasms
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  • A Study to Evaluate Denosumab in Young Patients With Primary Breast Cancer (D-Beyond)

    Description

    Description from the EGA: " This is a prospective, single arm phase IIa trial in which patients with early breast cancer will receive pre-operatively two doses of denosumab 120mg subcutaneously one week apart (maximum 12 days) followed by surgery. Tumor, normal breast tissue and blood samples will be collected at baseline and at surgery. Post-operative treatment will be at the discretion of the investigator.Primary objective: to determine if a short course of RANKL inhibition with denosumab can induce a decrease in tumor proliferation rates as determined by Ki67 immunohistochemistry (IHC) in newly diagnosed, early stage breast cancer in pre-menopausal women. "

    Subject
    Breast Neoplasms
    Denosumab
    Immunohistochemistry
    Ki-67 Antigen
    RANK Ligand
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  • A collection of Whole-genome sequencing files from the Cancer Genome Atlas program on Adenocarcinoma, filtered from the GDC Data Portal

    Description

    The GDC Data Portal is a robust data-driven platform that allows cancer researchers and bioinformaticians to search and download cancer data for analysis. This dataset is a filtered search result in the GDC Data Portal for TCGA Project, Adenocarcinoma, Whole Genome Sequencing Reads. It consists of 196 BAM files and 99 cases.

    Subject
    Adenocarcinoma of Lung
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    Application Required

  • A genomic classifier improves prediction of metastatic disease within 5 years after surgery in node-negative high-risk prostate cancer patients managed by radical prostatectomy without adjuvant therapy

    Authors
    Klein, Eric A.
    Yousefi, Kasra
    Haddad, Zaid
    Choeurng, Voleak
    6 more author(s)...
    Description

    Summary from the GEO: "To determine whether adding Decipher to standard risk stratification tools (CAPRA-S and Stephenson nomogram) improves accuracy in prediction of metastatic disease within 5 years after surgery in men with adverse pathologic features after RP.
    The study population consisted of 182 patients selected from 2,641 men who underwent RP at the Cleveland Clinic between 1987-2008 who met the following criteria: 1) preoperative PSA>20 ng/mL, stage pT3 or margin positive, or Gleason score >/8; 2) pathologic node negative; 3) undetectable post-RP PSA; 4) no neoadjuvant or adjuvant therapy; and 5) minimum of 5 years follow-up for the controls."

    Subject
    Prostatectomy
    Prostatic Neoplasms
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  • A multivalent signal-transducing model for the DNMT1-mediated maintenance DNA methylation

    Authors
    Wang, Gang G.
    Grimm, Sara A.
    Description

    Summary from the GEO: "Heterochromatin-specific histone modifications frequently coexist with mammalian DNA methylation to orchestrate a repressive chromatin state. However, it remains elusive how these epigenetic modifications crosstalk. Here, we report that the first bromoadjacent homology (BAH1) domain and the replication foci targeting sequence (RFTS) of maintenance DNA methyltransferase DNMT1 function as readers for H4K20me3 and H3K9me3, respectively. Engagements of H4K20me3 by BAH1 and H3K9me3 by RFTS ensure localization of DNMT1 to heterochromatin in cells, and cooperate with the RFTS-ubiquitination readout to allosterically stimulate DNMT1 s methylation activity at both global and focal levels. Strikingly, there is intramolecular crosstalk between the RFTS and BAH1 domains, which profoundly impacts the maintenance of DNA methylation and genomic resistance to radiation damage. Together, our study reveals an all-in-one model for DNMT1 in which repressive histone modifications directly influence the cellular landscape of DNA methylation and genomic stability, a process implicative of the DNMT1-related pathogenesis."

    Overall design from the GEO:"To examine patterns of maintenance DNA methylation deposited by DNMT1 in cells, we stably transduced either WT or mutant DNMT1 into mouse ES cells with knockout (KO) of DNMT1 (1KO), followed by genome-wide methylation in cells by enhanced reduced representation bisulfite sequencing (eRRBS). eRRBS was carried out side-by-side in three biological replicates of the 1KO rescued lines to generate datasets for across-sample comparisons."

    Subject
    DNA (Cytosine-5-)-Methyltransferase 1
    DNA Methylation
    Heterochromatin
    Histone Code
    Histones
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  • AICDA-induced epigenetic plasticity accelerates germinal center-derived lymphomagenesis

    Authors
    Teater, Matt
    Elemento, Olivier
    Melnick, Ari M.
    Description

    Summary from the GEO: "Epigenetic heterogeneity is emerging as a significant phenotypic feature of tumors. In diffuse large B-cell lymphomas (DLBCLs), increased cytosine methylation heterogeneity is associated with poor clinical outcome, yet the biological mechanisms driving epigenetic heterogeneity remain unclear. Activation-induced cytidine deaminase (AICDA), an enzyme that deaminates and facilitates demethylation of DNA methyl-cytosines in germinal center (GC) B-cells, is required for DLBCL pathogenesis and linked to inferior clinical outcomes. Here, we show that overexpression of AICDA causes more aggressive disease and worse outcome in BCL2-driven murine lymphomas. This phenotype was associated with significantly increased focal inter-tumor and intra-tumor cytosine methylation heterogeneity as compared to control lymphomas, but not with increased mutational burden. AICDA-mediated epigenetic heterogeneity was accompanied by DNA hypomethylation. Reciprocally, we observed that the focal inter-individual and intra-individual cytosine methylation heterogeneity characteristic of normal GC B-cells was lost upon depletion of AICDA. There was significant overlap of AICDA-induced methylation heterogeneity foci in GC B-cells and murine lymphomas. These observations are relevant to human patients, since DLBCLs with high AICDA expression likewise manifest extensive increases in focal inter-patient and intra-patient heterogeneity as compared to DLBCLs with low AICDA expression. Affected regions significantly overlapped with those found in murine AICDA-overexpressing lymphomas. Our results identify AICDA as a novel source of epigenetic plasticity and heterogeneity in B-cell lymphomas with potential significance for other tumors that express cytosine deaminases."

    Overall design from the GEO: "Enhanced reduced representation bisulfite sequencing (ERRBS), RNA-seq, and exome sequencing on murine VavP-Bcl2 and VavP-Bcl2+Aicda tumors. Enhanced reduced representation bisulfite sequencing (ERRBS), RNA-seq and exome sequencing on murine VavP-Bcl2 and VavP-Bcl2+Aicda tumors. Paired ERRBS and RNA-seq on low AICDA-expressing and high AICDA-expression DLBCL."

    Subject
    Cytidine Deaminase
    Germinal Center
    Lymphoma, Large B-Cell, Diffuse
    Access Rights
    Free to All

  • ATAC-seq on parental and acquired resistant cells (AqR)

    Authors
    Weirauch, Matthew T.
    Parameswaran, Sreeja
    Description

    Summary from GEO: "Parental and AqR cells were obtained. DNA was purified and submited for sequencing. Differential chromatin accessiblity was observed. AqR cells were derived from parental cells by adding inhibitor (CAY10566) every 3 days until cells became resistant (at about 3 weeks)."

    Overall design: from GEO: "1 parental cell in duplicate and 1 AqR cell in duplicate was submitted and analyzed."

    This dataset contains the ATAC sequencing from glioblastoma patient tumor samples for which there was a low median expression of the lipogenic enzyme stearoyl CoA desaturase (SCD). Cell lines from this subset of patients expressed undetectable SCD, yet retained residual SCD enzymatic activity. These lines evolved to survive independent of SCD through unknown mechanisms. Cell lines that escaped such genetic and epigenetic alterations expressed higher levels of SCD and were highly dependent on SCD for survival.

    Subject
    Brain Neoplasms
    Glioblastoma
    Stearoyl-CoA Desaturase
    Access Rights
    Free to All

  • Acral Melanoma (TGEN, Genome Res 2017): Whole exome sequencing and transcriptome analysis of 34 Acral Melanoma patients (33 with matched normals)

    Authors
    Liang, Winnie S.
    Hendricks, William
    Kiefer, Jeffrey
    Schmidt, Jessica
    22 more author(s)...
    Description

    This dataset contains summary data visualizations and clinical data from a comprehensive genomic and transcriptomic analysis of 38 acral lentiginous melanomas (ALM) from 34 patients. The study was conducted to analyze ALM, a rare sun-shielded melanoma subtype of cutaneous melanoma (CM) which is associated with worse survival than other CM in an effort to delineate non-UV oncogenic mechanisms. The clinical data includes mutation count, information about mutated genes, patient demographics, disease status, therapeutic details and copy number alterations among other relevant data points.

    Subject
    Chromosome Aberrations
    DNA Mutational Analysis
    Melanoma/genetics
    Melanoma/pathology
    Transcriptome
    Access Rights
    Free to All

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