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• Nascent transcriptome in T-ALL bone marrow

  Nascent RNA expression profiles were generated with Global Run-On sequencing (GRO-seq) from T-ALL patient samples to measure primary transcription genome-wide and to summarize the transcriptional activity at gene loci and enhancers.

  Study EGAS00001005864

• Longitudinal Single-Cell Profiling Reveals Molecular Heterogeneity and Tumor-Immune Evolution in Refractory Mantle Cell Lymphoma

  The mechanisms driving therapeutic resistance and poor outcomes of mantle cell lymphoma (MCL) are incompletely understood. We characterize the cellular and molecular heterogeneity within and across patients and delineate the dynamic evolution of tumor and immune cell compartments at single cell resolution in longitudinal specimens from ibrutinib-sensitive patients and non-responders. Temporal activation of multiple cancer hallmark pathways and acquisition of 17q are observed in a refractory MCL. Multi-platform validation is performed at genomic and cellular levels in PDX models and larger patient cohorts. We demonstrate that the molecular targeting of BIRC5/survivin, locates at 17q and upregulates in resistant MCL tumor cells, results in marked tumor inhibition in preclinical models. In addition, we discovere notable differences in the tumor microenvironment including progressive dampening of CD8+ T cells and aberrant cell-to-cell communication networks in refractory MCLs. This study reveales diverse and dynamic tumor and immune programs underlying therapy resistance in MCL.

  Study EGAS00001005019

• Molecular profiling of metastatic uveal melanoma

  Metastatic uveal melanoma is less well understood than its primary counterpart, has a distinct biology compared to skin melanoma and lacks effective treatments. Here we genomically profile metastatic tumors and infiltrating lymphocytes. BAP1 alterations were overrepresented and occurred in 29/32 of cases. An outlier tumor had high mutational burden associated with UV-damage. CDKN2A deletions also occurred, which are rarely present in primaries. We profiled recurrent copy number alterations associated with metastasis and performed a focused knockdown screen on overexpressed targets. We investigated the role of BAP1 by reintroducing a functional allele into a deficient patient-derived cell line, revealing a broad shift towards a transcriptomic subtype associated with better prognosis. Tumor-infiltrating lymphocytes were in several cases tumor-reactive, but expression of the immune checkpoint receptors TIM-3, TIGIT and LAG3 was abundant. This study represents the largest whole-genome analysis of uveal melanoma to date and presents an updated view of the metastatic disease.

  Study EGAS00001004296

• RNA-seq of Liver Cancer

  The present series corresponds to 161 RNA-seq samples from tumors with matched WES or WGS. Hepatocellular carcinoma (HCC) accounts for more than 90% of liver cancers, and is a major health problem. It is the 3rd cause of cancer-related mortality. Advances in genomic analyses have formed a comprehensive understanding of different underlying pathobiological layers resulting in hepatocarcinogenesis. Thus, the development of next-generation sequencing technologies has made it possible to generate more comprehensive catalogues of somatic alteration events (single nucleotide substitutions, structural variations, and epigenetic changes) in liver cancer genome than ever before.

  Dataset EGAD00001003993

• Integrated clinical, whole genome, and transcriptome analysis of multisampled lethal metastatic prostate cancer

  We report the first combined analysis of whole genome sequence, detailed clinical history, and transcriptome sequence of multiple prostate cancer metastases in a single patient (A21). Whole genome and transcriptome sequence was obtained from 9 anatomically separate metastases, and targeted DNA sequencing was performed in cancerous and noncancerous foci within the primary tumor specimen removed 5 years prior to death. Transcriptome analysis revealed increased expression of AR-regulated genes in liver metastases that harbored an AR p.L702H mutation, suggesting a dominant effect by the mutation despite being present in only 1 of an estimated 16 copies per cell. The metastases harbored several alterations to the PI3K/AKT pathway, including a clonal truncal mutation in PIK3CG and present in all metastatic sites studied. The list of truncal genomic alterations shared by all metastases included homozygous deletion of TP53, hemizygous deletion of RB1 and CHD1, and amplification of FGFR1. If the patient were treated today given this knowledge, use of second-generation androgen-directed therapies, cessation of glucocorticoid administration, and therapeutic inhibition of the PI3K/AKT pathway or FGFR1 receptor could provide personalized benefit. Three previously unreported truncal clonal missense mutations (ABCC4 p.R891L, ALDH9A1 p.W89R, and ASNA1 p.P75R) were expressed at the RNA level and assessed as druggable. The truncal status of mutations is critical for actionability, and can only be determined through analysis of multiple sites of metastasis. Our findings suggest that a large set of deeply analyzed cases could serve as powerful guide to more effective prostate cancer basic science and personalized cancer medicine clinical trials.

  Dataset EGAD00001001869

• Gene Expression and Biomarker Utility in Post-Mortem Samples

  The FAA Functional Genomics Team examined the feasibility of analyzing gene expression profiles using post-mortem brain, lung, muscle, and blood samples collected from aviation accident fatalities, with the goal of validating post-mortem extracted RNA for use in RNA sequencing. We compared the RNA sequencing results obtained from THC-positive and THC-negative samples to determine whether RNA sequencing on samples collected from aviation accident fatalities was possible and if any differences in gene expression associated with THC consumption were detectable post-mortem. The study population included 57 males of indeterminant age who perished in general aviation accidents and for whom post-mortem toxicological testing identified delta-9-THC or its primary or secondary metabolites, as well as negative controls. We determined that RNA sequencing on post-mortem aviation accident fatality samples is possible, and further identified genes showing differential expression in lung and muscle between THC-positive and THC-negative samples. We conclude that post-mortem tissue samples collected from aviation accident fatalities are suitable for gene expression profiling, but caution researchers that such samples have low RNA integrity numbers and some degree of microbial contamination is both probable and to be expected. Raw sequencing files (.fastq) from this study are available in dbGaP.

  Study phs003546

• T cell landscape definition by multi-omics identifies galectin-9 as novel immunotherapy target in chronic lymphocytic leukemia (CLL)

  Failure of immunotherapy after applying checkpoint inhibitors or CAR-T cells is linked to T cell exhaustion. Here, we explored the T cell landscape in chronic lymphocytic leukemia (CLL) by single-cell omics analyses of blood, bone marrow and lymph node samples of patients and spleen samples of a CLL mouse model. By single-cell RNA- sequencing, mass cytometry (CyTOF), and multiplex image analysis of tissue microarrays, we defined the spectrum of phenotypes and transcriptional programs of T cells and and their differentiation state trajectories. We identified disease-specific accumulation of distinct regulatory T cell subsets and T cells harboring an exhausted phenotype exclusively in the CLL lymph node tissue. Integration of TCR data revealed a clonal expansion of CD8+ precursor exhausted T cells, suggesting their reactivity for CLL cells. Interactome analyses identified the TIM3 ligand Galectin-9 as novel immunoregulatory molecule in CLL. Blocking of Galectin-9 in CLL-bearing mice slowed down disease development and reduced the number of TIM3 expressing T cells. Galectin-9 expression correlated with shorter survival of CLL patients. Thus, Galectin-9 contributes to immune escape in CLL and represents a novel target for immunotherapy.

  Study EGAS00001006864

• A New High-Throughput Sequencing-Based Technology to Study Heterochromatin Structure

  In this study we report epigenomic and transcriptomics datasets for normal control fibroblasts. The following cell lines were obtained from the NIGMS Human Genetic Cell Repository at the Coriell Institute for Medical Research: AG08498, AG07095, originally collected as part of the NIA Aging Cell Repository study. We applied a high-throughput sequencing-based technique, named Sequential Analysis of MacroMolecules accessibilitY (SAMMY-seq), for the genome-wide mapping of chromatin regions separated by differential accessibility. The method is based on the sequential extraction of multiple chromatin fractions, corresponding to increasingly compacted and less accessible chromatin regions, which are mapped along the genome using high-throughput sequencing. Additionally we carried out ChIP-seq for the H3K9me3 and H3K27me3 histone modifications and RNA-seq for the characterization of transcriptome in control fibroblasts.

  Study phs002202

• Luminal progenitor cell line iHBEC(CD117)

  Basal-like breast cancer originates in luminal progenitors, frequently with an altered PI3K pathway, and focally in close association with genetically altered myoepithelial cells at the site of tumor initiation. The exact trajectory behind this bi-lineage phenomenon remains poorly understood. Here we used a breast cancer relevant transduction protocol including hTERT, shp16, shp53, and PIK3CA(H1047R) to immortalize FACS isolated luminal cells, and we identified a candidate multipotent progenitor. We found that the apparent luminal phenotype of these oncogene transduced progenitors was metastable giving rise to basal-like cells dependent on culture conditions. After culturing the cells for more than 60 passages, cells were subjected to scRNA-seq as well as bulk RNA sequencing of two subpopulations (CD271+ and CD271-).

  Dataset EGAD50000000723

• Truncated FOS impairs osteogenic differentiation and induces prostaglandin and NFkB signalling in an in vitro cell-of-origin model for osteoid osteoma and osteoblastoma

  The effect of FOS truncation on osteogenic differentiation and proliferation was investigated in an in vitro model for osteoid osteoma and osteoblastoma. In this model, truncated FOS (FOSΔ) was overexpressed in human foetal mesenchymal stem cells through a lentiviral vector. Osteogenic differentiation - assessed by measuring mineralization, ALPL expression and ALP activity - and proliferation rate were reduced in cells overexpressing FOSΔ compared to mesenchymal stem cells with an empty lentiviral vector (pLV). Transcriptome-sequencing and differential gene expression analysis revealed decreased gene expression of genes in pathways involving cell cycling and mitosis, and osteogenic differentiation, including WNT signalling, extracellular matrix (ECM) organization and matrix metalloproteinases (MMPs), in FOSΔ as compared to empty vector cells, indicating decreased proliferation and osteogenesis.

  Study EGAS50000001291