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• ENU-NCI-H508 cetuximab fixed concentration project

  Cetuximab is a targeted monoclonal antibody against the epidermal growth factor receptor (EGFR) which is used therapeutically for the treatment of KRAS wild-type colorectal cancer (CRC). The Cetuximab sensitive KRAS wild-type CRC cell line NCI-H508 has been treated with a fixed concentration of ENU for 24 hours and then selected with Cetuximab until drug resistant clones were ready to be picked and grown up as sub-clones of the parental cell line. These will have genes causally implicated in cancer sequenced to identify common point mutations in multiple independently derived drug resistant clones as a forward genetic screen for mechanisms of resistance to Cetuximab in CRC

  Dataset EGAD00001001948

• 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

• Variant analysis on FFPE specimen from NSCLC patients (FoundationOne CDx)

  This study assessed the presence of somatic variants via the FoundationOne CDx panel of commonly mutated cancer genes and measure tumor mutational burden using next-generation sequencing panels. It was performed on genomic DNA from FFPE tissue of tumor resections. Mutations were used to draw OncoPrints and to assess TMB in relation with response metrics.

  Study EGAS50000001139

• Single-cell RNA sequencing of metastatic colorectal cancer organoids treated with cetuximab

  Single-cell RNA sequencing was performed on metastatic colorectal cancer (mCRC) organoids derived from a cetuximab-sensitive patient-derived xenograft (PDX) model. The objective of this analysis was to investigate, at single-cell resolution, the transcriptional changes previously identified in bulk RNA-seq analyses of PDX models exposed to anti-EGFR therapeutic pressure.

  Study EGAS50000001460

• ChIP-seq data of H3K4me3, H3K27ac and H3K27me3 on multiple human embryonic tissues.

  The regulatory landscape of the human genome during organogenesis is undescribed for most tissues. We used ChIP-seq to survey histone modifications in 13 human embryonic tissues. We describe patterns of both common and tissue-specific marking of promoter activation and repression and use enhancer usage to infer regulatory pathways.

  Study EGAS00001003163

• Plasma whole genome sequencing from patients with stage IV colorectal cancer and microsatellite instability

  This study aims to explore genomic features of cancer in plasma WGS data from patients with advanced colorectal cancer. Cell-free DNA (cfDNA) was extracted from plasma using the QIAamp Circulating Nucleic Acid Kit. Libraries were prepared with 5 to 250 ng of cfDNA using the NEBNext DNA Library Prep Kit.

  Study EGAS00001006377

• Genomic Evolution of Breast Cancer Metastasis and Relapse

  Recurrent breast cancer is almost universally fatal. We characterize 170 patients locally relapsed or distant metastatic cancers using massively parallel sequencing. We identify that the relapse-seeding clone disseminates late from the primary tumor. TP53 and AKT1 appear to be enriched in ER-positive cancers predisposed to relapse. Mutation acquisition continues at relapse as the same mutation signatures continue to operate and new signatures, such as that caused by radiotherapy appear de novo. In 49% of cases we identify drivers mutations private to the relapse and these are sampled from a wider range of cancer genes, including SWI-SNF complex and JAK-STAT signaling.

  Dataset EGAD00001002697

• Deep Sequencing Studies for Cannabis and Stimulant Dependence

  Cannabis and stimulants are among the most widely used illicit drug in the United States, and their use is associated with substantial physical and psychiatric sequelae. Twin studies have shown a substantial genetic component to the etiology of cannabis and stimulant use disorders, but, genome-wide association studies using genotype data obtained from microarrays have yielded few robust results. The advent of increasingly economical whole genome sequencing provides new opportunities to identify trait-associated sequence variations. The present study proposes to identify sequence variants that affect stimulant and cannabis dependence in three cohorts. The three study cohorts were ascertained as part of the Mission Indian Study (PI Cindy Ehlers), the combined Yale-University of Connecticut Addiction Study samples (PI Joel Gelernter) and the San Francisco Family Study (PI Kirk Wilhelmsen). Because three populations with different continental origins were studied, the present study will also ascertain whether the major genetic risk factors for the traits of interest are shared or population-specific.

  Study phs001458

• NRG1 Fusions in KRAS Wild-type Pancreatic Cancer (H021)

  We used whole-genome and transcriptome sequencing to identify clinically actionable gene fusions in young adults with KRAS wild-type (KRASwt) pancreatic ductal adenocarcinoma (PDAC). These alterations included recurrent NRG1 rearrangements predicted to drive PDAC development through aberrant ERBB receptor-mediated signaling, and pharmacologic ERBB inhibition resulted in clinical improvement and remission of liver metastases in two patients with NRG1-rearranged tumors that had proved resistant to standard treatment. Our findings demonstrate that systematic screening of KRASwt tumors for oncogenic fusion genes will substantially improve the therapeutic prospects for a sizeable fraction of PDAC patients.

  Study EGAS00001002759

• Coenzyme Q10 (CoQ) in Huntington's Disease (HD) (2CARE)

  This is a multi-center, randomized, double-blind, placebo-controlled trial of CoQ involving 609 ambulatory subjects with HD who are not requiring skilled care or institutionalization. Eligible subjects were randomized to receive either CoQ 2400 mg/day or matching placebo. Subjects were followed prospectively and systematically for 60 months of double-blind observation. The primary outcome variable is a combination of time to death (for subjects who die) and the change from baseline to Month 60 in Total Functional Capacity (TFC) score (for subjects who survive). The primary hypothesis of the study is that chronic treatment of early-stage HD subjects with high-dosage CoQ will slow the progressive functional decline of HD.

  Study phs001065

• Metastatic Colorectal Adenocarcinoma Tumor Purity Assessment from Whole Exome Sequencing Data

  As molecular medicine wields greater and greater influence on cancer patient care, including therapeutic selection, it becomes increasingly important to understand the power and deficiencies of computational tools used in decision making processes. Here we use a set of unselected metastatic colorectal tumor samples in a head-to-head comparison between the calculation of stromal content by a board certified pathologist, versus that derived from whole exome sequencing and purity assessment by a variety of common computational methods. We find that in about 1/2 of the samples the computational methods each do a poor job of assessing the percent stromal contamination, and as a result, tumor variant allele frequencies (VAFs) are low or undetected, whereas analysis of organoids derived from the same tumors yielded much higher VAFs in keeping with their lower stromal content. The whole exome sequence of our samples is available via dbGaP, accession phs003059.v1.p1.

  Study phs003059

• Global Anaplastic Thyroid Cancer Initiative

  Thyroid cancer is the most common endocrine malignancy. Most thyroid cancers are of the well-differentiated (non-aggressive) phenotype, and are almost always cured with standard treatments. In contrast, anaplastic thyroid cancer (ATC) is rare, accounting for only 1% of thyroid cancers, however it is perhaps the most lethal human malignancy with an average survival of 3 to 6 months. ATC presents with dramatic and rapid onset of airway and esophageal blockage with frequent spread to the lungs. Interestingly, 21–79% of ATCs have coexisting areas or a previous history of well-differentiated cancers. Although this suggests a progression from well-differentiated cancers to ATC, to date there is little molecular conformation that such a progression exists versus de novo generation of ATC. As ATC is extremely rare and most cases are inoperable, there are a paucity of tissue samples for study at any one center. The Global Anaplastic Thyroid Cancer Initiative (GATCI) aims to unite international institutions in order to pool samples (ATC with or without a paired well-differentiated component) for a comprehensive analysis of the genomic landscape of this disease.

  Study EGAS00001002234

• Urothelial Cancer - Genomic Analysis to Improve Patient Outcomes and Research (UC-GENOME): A Bladder Cancer Advocacy Network (BCAN)-Led Collaborative Research Pilot Study

  UC-GENOME is a real-world cohort of patients with metastatic urothelial carcinoma (UC). The study consisted of two co-equal aims: 1) to provide targeted DNA sequencing for clinical decision making at no cost to patients; and 2) to create a resource for collaborative translational science including a clinically annotated biobank. The submitted data represents the foundational analysis of 218 patients accrued at 7 academic medical centers. The analysis includes 176 patients with both targeted DNA sequencing and RNA sequencing. The genomic data was combined with clinical variables to model response to chemotherapy and immune checkpoint inhibitors (ICI). Due to additional sharing restrictions, data from one site can be found in phs003094.

  Study phs003066

• WES of Mino-VEN-R Mantle Cell Lymphoma Cells

  This project investigates the genetic basis of therapy resistance in mantle cell lymphoma (MCL) using whole exome sequencing (WES) of the Mino_VEN_R cell line, a model of resistance to pirtobrutinib, a non-covalent BTK inhibitor. Our study suggested that drug-tolerant persister (DTP) cells evade therapy through metabolic and phenotypic reprogramming. By analyzing the exome profile of resistant cells, this study aims to identify mutations associated with treatment escape and cellular plasticity. The findings will contribute to a better understanding of resistance mechanisms and support the development of more effective therapeutic strategies.

  Study EGAS50000001088

• Whole Genome sequencing of Angolan and Mozambican individuals

  To support the continued discovery and cataloguing of genomic variation in human populations and to further our understanding of the Bantu Expansion, we sequenced the genomes of 291 individuals from Cabinda, a northern exclave of Angola, and 49 individuals from Maputo, the capital of Mozambique. Utilising the power and flexibility of these whole-genome sequencing datasets, we discover rare variation, fine-scale population structure, and perform analyses using haplotype-based inference tools and our own model-based simulation framework to reconstruct complex dispersals of Bantu speak-ing populations across sub-Saharan Africa.

  Study EGAS00001007458

• Myeloproliferative_Disorder_Sequencing

  Agilent whole exome hybridisation capture will be performed on genomic DNA derived from 50 myeloproliferative disorder samples and matched normal DNA from the same patients. Three lanes of Illumina GA sequencing will be performed on the resulting 100 exome libraries and mapped to build 37 of the human reference genome to facilitate the identification of novel cancer genes. In addition, 500bp, NO_PCR total genomic libraries will be prepared from the same samples and five lanes of Illumina GA sequencing will be analysed to characterise genome wide, somatically acquired structural variation.

  Study EGAS00001000198

• Myeloproliferative_Disorder_Sequencing

  Agilent whole exome hybridisation capture will be performed on genomic DNA derived from 50 myeloproliferative disorder samples and matched normal DNA from the same patients. Three lanes of Illumina GA sequencing will be performed on the resulting 100 exome libraries and mapped to build 37 of the human reference genome to facilitate the identification of novel cancer genes. In addition, 500bp, NO_PCR total genomic libraries will be prepared from the same samples and five lanes of Illumina GA sequencing will be analysed to characterise genome wide, somatically acquired structural variation.

  Study EGAS00001000199

• University of Washington Cerebrospinal Fluid Biomarker Study for Parkinson disease

  There is a clear need to develop biomarkers for Parkinson disease (PD) diagnosis and monitoring disease progression. In this study we evaluated cerebrospinal fluid (CSF) proteins, which are known to be critically involved in PD or identified in our preliminary profiling studies, aptamers, and RNAs as potential PD biomarkers. Access to subjects for this study was via the Pacific Northwest Udall Center (PANUC) and the Alzheimer's Disease Research Center (ADRC) at the University of Washington and Oregon Health and Sciences University (OHSU). Using CSF samples from 30 well-characterized patients with PD and 30 age-, sex-matched healthy controls, we prepared RNA seq libraries and performed deep sequencing of all RNA species, including small and long RNA, mRNAs, noncoding RNAs and differentially spliced transcripts. We then tried several methods for RNAseq data analysis to optimize our analysis pipeline. We identified a total of 3381 transcripts corresponding to 182 long intergenic RNAs (LincRNAs), 11 microRNAs (miRNAs), 2861 protein-coding transcripts, 200 pseudogenes and 127 antisense RNAs; some of them were differentially expressed between PD and control groups. Selected differentially expressed RNAs have been validated in the same set of CSF samples using real-time PCR (RT-PCR). Further validations in independent, larger cohorts of samples are still ongoing. Our results obtained so far suggested that CSF proteins and RNAs could be used as good indexes for PD diagnosis and disease severity/progression. This study is a part of the NIDDS-funded Parkinson's Disease Biomarkers Program (PDBP).

  Study phs000901

• snRNA: A Cultured Leukemia Stem Cell Model Enables Validation of CDK6 as a Stemness Target Against Acute Myeloid Leukemia

  Acute myeloid leukemia (AML) represents a group of aggressive hematological malignancies, the clinical management of which is made challenging due to the persistence of rare and therapy resistant leukemia stem cells (LSCs) which serve as a source of disease relapse and poor outcomes. There are currently a paucity of methods to reliably enrich and study LSCs, hindering the development of therapies that specifically target LSCs. In this study, we deeply characterize the OCI-AML8227 culture model, which maintains a functional stemness hierarchy originating from its highly primitive CD34⁺CD38⁻ cells, to elucidate LSC biology and uncover LSC-specific therapeutic vulnerabilities. We analyzed both bulk and single-cell proteomics, transcriptomics, and epigenomics to generate a LSC protein-protein interaction network, which was then integrated with an LSC-focused small molecule screen using this model. From these findings, CDK6 was discovered as a therapeutic vulnerability specific to LSCs, which was validated in findings from the BEAT-AML cohort and a patient-derived xenograft (PDX) panel of AML samples through palbociclib treatment. Taken together, our studies validate CDK6 as a druggable vulnerability in LSCs, and authenticate OCI-AML8227 cells as a LSC target discovery engine.

  Study EGAS50000000786

• bulk ATACseq: A Cultured Leukemia Stem Cell Model Enables Validation of CDK6 as a Stemness Target Against Acute Myeloid Leukemia

  Acute myeloid leukemia (AML) represents a group of aggressive hematological malignancies, the clinical management of which is made challenging due to the persistence of rare and therapy resistant leukemia stem cells (LSCs) which serve as a source of disease relapse and poor outcomes. There are currently a paucity of methods to reliably enrich and study LSCs, hindering the development of therapies that specifically target LSCs. In this study, we deeply characterize the OCI-AML8227 culture model, which maintains a functional stemness hierarchy originating from its highly primitive CD34⁺CD38⁻ cells, to elucidate LSC biology and uncover LSC-specific therapeutic vulnerabilities. We analyzed both bulk and single-cell proteomics, transcriptomics, and epigenomics to generate a LSC protein-protein interaction network, which was then integrated with an LSC-focused small molecule screen using this model. From these findings, CDK6 was discovered as a therapeutic vulnerability specific to LSCs, which was validated in findings from the BEAT-AML cohort and a patient-derived xenograft (PDX) panel of AML samples through palbociclib treatment. Taken together, our studies validate CDK6 as a druggable vulnerability in LSCs, and authenticate OCI-AML8227 cells as a LSC target discovery engine.

  Study EGAS50000000787

• scATAC: A Cultured Leukemia Stem Cell Model Enables Validation of CDK6 as a Stemness Target Against Acute Myeloid Leukemia

  Acute myeloid leukemia (AML) represents a group of aggressive hematological malignancies, the clinical management of which is made challenging due to the persistence of rare and therapy resistant leukemia stem cells (LSCs) which serve as a source of disease relapse and poor outcomes. There are currently a paucity of methods to reliably enrich and study LSCs, hindering the development of therapies that specifically target LSCs. In this study, we deeply characterize the OCI-AML8227 culture model, which maintains a functional stemness hierarchy originating from its highly primitive CD34⁺CD38⁻ cells, to elucidate LSC biology and uncover LSC-specific therapeutic vulnerabilities. We analyzed both bulk and single-cell proteomics, transcriptomics, and epigenomics to generate a LSC protein-protein interaction network, which was then integrated with an LSC-focused small molecule screen using this model. From these findings, CDK6 was discovered as a therapeutic vulnerability specific to LSCs, which was validated in findings from the BEAT-AML cohort and a patient-derived xenograft (PDX) panel of AML samples through palbociclib treatment. Taken together, our studies validate CDK6 as a druggable vulnerability in LSCs, and authenticate OCI-AML8227 cells as a LSC target discovery engine.

  Study EGAS50000000788

• bulk RNA-seq: A Cultured Leukemia Stem Cell Model Enables Validation of CDK6 as a Stemness Target Against Acute Myeloid Leukemia

  Acute myeloid leukemia (AML) represents a group of aggressive hematological malignancies, the clinical management of which is made challenging due to the persistence of rare and therapy resistant leukemia stem cells (LSCs) which serve as a source of disease relapse and poor outcomes. There are currently a paucity of methods to reliably enrich and study LSCs, hindering the development of therapies that specifically target LSCs. In this study, we deeply characterize the OCI-AML8227 culture model, which maintains a functional stemness hierarchy originating from its highly primitive CD34⁺CD38⁻ cells, to elucidate LSC biology and uncover LSC-specific therapeutic vulnerabilities. We analyzed both bulk and single-cell proteomics, transcriptomics, and epigenomics to generate a LSC protein-protein interaction network, which was then integrated with an LSC-focused small molecule screen using this model. From these findings, CDK6 was discovered as a therapeutic vulnerability specific to LSCs, which was validated in findings from the BEAT-AML cohort and a patient-derived xenograft (PDX) panel of AML samples through palbociclib treatment. Taken together, our studies validate CDK6 as a druggable vulnerability in LSCs, and authenticate OCI-AML8227 cells as a LSC target discovery engine.

  Study EGAS50000000789

• Single-Nuclei Paired Multiomic Analysis of Young, Aged, and Parkinson's Disease Human Midbrain Reveals Age-Associated Glial Changes and Their Contribution to Parkinson's Disease

  Age is the primary risk factor for Parkinson's disease (PD), but how aging to change the expression and regulatory landscape of the brain remains unclear. Here, we present a single-nuclei multiomic study profiling shared gene expression and chromatin accessibility of young, aged and PD post-mortem midbrain samples. Combined multiomic analysis of midbrain nuclei along a pseudo-pathogenesis trajectory reveals that all glial cell types are affected by age, but microglia and oligodendrocytes are further altered in PD. We present evidence for a novel disease-associated oligodendrocyte subtype and identify genes lost over the aging and disease process, including CARNS1, that may predispose healthy cells to develop a disease-associated phenotype. Peak-gene association analysis from paired data identifies 89 PD-associated SNP loci, including five in MAPT, that only correlate with gene expression in disease-associated oligodendrocytes. Our study suggests a previously undescribed role for oligodendrocytes in aging and PD pathogenesis.

  Study phs002819

• National Cancer Institute (NCI) Early Onset Malignancies Initiative (EOMI): Molecular profiling of Breast, Colon, Kidney, Liver, Multiple Myeloma, and Prostate among Racially and Ethnically Diverse Populations

  The Early Onset Malignancies Initiative (EOMI) is focused on collecting specimens from racially and ethnically diverse population groups with six different types of cancer (breast, prostate, colon, liver, kidney, and multiple myeloma). This initiative is a partnership between the Center for Research Strategy, the Center for Cancer Genomics and the Division of Cancer (DCP). DCP's NCI Community Oncology Research Program (NCORP) is a critical partner. The acquisition of the cancer and matching normal biospecimens in this initiative are from newly diagnosed early onset cancer patients who identify as Non-Hispanic Black, Hispanic, American Indian or Alaska Native, or Non-Hispanic White. The Minority/Underserved NCORPs sites will collect the samples for this project. By carrying out this initiative in the NCORP's national network of investigators, cancer care providers, and research institutions, the EOMI will harness the community-based partnerships to improve participation among these racial/ethnic groups. The NCORP investigators, as participants in NCI's clinical trials network, will annotate the biologic samples with clinical information that will enhance the ability to answer questions about molecular determinants of early disease, treatment response, and/or prognosis. The EOMI will be a step forward in addressing racial/ethnic disparities and in understanding cancer in underserved populations.

  Study phs001952

• Proteomic Biomarkers of Progressive Fibrosing Interstitial Lung Disease: a Multicentre Cohort Analysis (PF-ILD Proteomics-BioLINCC)

  Data Access NOTE: Please refer to the “Authorized Access” section below for information about how access to the data from this accession differs from many other dbGaP accessions. Objectives: To identify novel plasma biomarkers of progressive fibrosing interstitial lung disease and develop a proteomic signature to predict this phenotype. Background: Progressive fibrosing interstitial lung disease (ILD) is a devastating condition characterized by parenchymal scar formation, leading to deteriorating lung function and early death. Whereas almost all patients with idiopathic pulmonary fibrosis (IPF) progress, a variable proportion of patients with other common ILDs, including connective tissue disease associated ILD, chronic hypersensitivity pneumonitis, and unclassifiable ILD, develop progressive fibrosing ILD. There are criteria that effectively identify those experiencing ILD progression. However, the criteria do not allow patients who are at risk to be identified before progression occurs. Several blood-based biomarkers have been linked to differential progression in patients with IPF and other fibrosing ILDs. Inflammatory signaling also appears to have a prominent role in fibrotic-predominant ILDs. As such, cytokines, interleukins, and other immune mediators might serve as useful biomarkers of progressive fibrosing ILD. The PF-ILD Proteomics study was a targeted investigation of inflammation-related proteins to identify and validate novel biomarkers of progressive fibrosing ILD in patients with fibrotic connective tissue disease-associated ILD, chronic hypersensitivity pneumonitis, and unclassifiable ILD. Participants: There were 589 participants. The discovery cohort comprised 385 participants and the validation cohort comprised 204 participants. Design: PF-ILD Proteomics was a multicenter cohort analysis study. Peripheral blood was collected from consenting patients and plasma was isolated according to center-specific protocols. Relative plasma concentrations for 368 biomarkers were determined with use of a semi-quantitative, targeted proteomic platform. Patients from UC Davis and UCSF comprised the discovery cohort and those from UTSW comprised the validation cohort. Participants who were alive with less than 10% relative decline in forced vital capacity (FVC) at 12 months-after blood draw were considered to have non-progressive ILD. Participants who died of any cause, underwent lung transplant, or experienced 10% or greater relative FVC decline within 12 months of blood draw were deemed to have progressive fibrosing ILD. Conclusions: 17 plasma biomarkers of progressive fibrosing interstitial lung disease were identified and showed consistent associations across ILD subtypes.

  Study phs003954

• Genome-Wide Characterization of Pancreatic Adenocarcinoma Patients Using Next Generation Sequencing

  In this study, we whole genome sequenced tumor/normal pairs from three pancreatic adenocarcinoma patients to separately characterize each patient with respect to somatic alterations. For 2 patients for whom tumor RNA was available, we also performed RNA sequencing to evaluate gene expression changes. While additional sequencing is needed to improve our understanding of the disease, the information acquired from this study contributes to our knowledge base on pancreatic cancer and helps to establish a foundation for identifying and developing more efficacious treatments for patients.

  Study phs000550

• Capture Hi-C identifies the chromatin interactome of colorectal cancer risk loci

  Multiple regulatory elements distant to their targets on the linear genome can influence the expression of a single gene through chromatin looping. Chromosome conformation capture implemented in Hi-C allows for genome-wide agnostic characterization of chromatin contacts. However, detection of functional enhancer-promoter interactions is precluded by its effective resolution that is determined by both restriction fragmentation and sensitivity of the experiment. Here we have developed a capture Hi-C (cHi-C) approach to allow an agnostic characterisation of these physical interactions on a genome-wide scale. Single nucleotide polymorphisms associated with complex diseases often reside within regulatory elements and exert effects through long-range regulation of gene expression. Applying this cHi-C approach to 14 colorectal cancer risk loci has allowed us to identify key long-range chromatin interactions in cis and trans involving these loci.

  Study EGAS00001001085

• Identification of Targetable FGFR Gene Fusions in Diverse Cancers

  In this study, patients with advanced cancer across all histologies were enrolled in our IRB approved clinical sequencing program, called MI-ONCOSEQ, to go through an integrative sequencing which includes whole exome sequencing of the tumor and matched normal, and transcriptome sequencing. Four index cases were identified which harbor gene rearrangements of FGFR2 including two cholangiocarcinoma cases, a metastatic breast cancer case, and a metastatic prostate cancer case. After extending our assessment of FGFR rearrangements across multiple tumor cohorts, including TCGA, we identified FGFR gene fusions with intact kinase domains of FGFR1, FGFR2, or FGFR3 in cholangiocarcinoma, breast cancer, prostate cancer, lung squamous cell cancer, bladder cancer, thyroid cancer, oral cancer, glioblastoma, and head and neck squamous cell cancer. All FGFR fusion partners tested exhibit oligomerization capability, suggesting a shared mode of kinase activation. Overexpression of FGFR fusion proteins in vitro induced cell proliferation, and bladder cancer cell lines that harbors FGFR3 fusion proteins exhibited enhanced susceptibility to pharmacologic inhibition in vitro and in vivo. Due to the combinatorial possibilities of FGFR family fusion to a variety of oligomerization partners, clinical sequencing efforts which incorporate transcriptome analysis for gene fusions are poised to identify rare, targetable FGFR fusions across diverse cancer types.

  Study phs000602

• Biallelic variants in the non-protein coding minor spliceosome components RNU6ATAC and RNU6ATAC cause syndromic monogenic autoimmune diabetes

  Non-protein coding genes are emerging as critical contributors to the aetiology of rare diseases, providing key insights into human biology and uncovering novel disease mechanisms. We identified 7 individuals from 4 families with early-onset diabetes (diagnosed <5 years) and immune dysregulatory features caused by biallelic variants in RNU6ATAC. RNU6ATAC encodes a small nuclear RNA (snRNA) acting as a catalytic component of the minor spliceosome, a protein-RNA complex mediating splicing of ~700 genes containing U12/minor-type introns. Variant screening of the other 64 minor spliceosome genes in 276 infants with diabetes identified 12 unrelated individuals with biallelic disease-causing variants in RNU4ATAC. Biallelic pathogenic RNU4ATAC variants are known to cause a variable spectrum of clinical features, which until now did not include diabetes. Clinically, 12/19 RNU6ATAC/RNU4ATAC patients had additional immune dysregulatory features, and 50% of patients tested were islet-autoantibody positive, strongly supporting an autoimmune aetiology for their diabetes. RNA-seq in 3 individuals with biallelic RNU6ATAC variants showed a pattern of intron retention in U12 intron-containing genes similar to that seen in RNU4ATAC-individuals (n=3), supporting a shared disease mechanism. Analysis of patients’ transcriptomic, methylation and immune data revealed impaired B cell development and maturation. We conclude that biallelic RNU6ATAC variants cause a novel syndrome of early-onset autoimmune diabetes and immune dysregulation. We further show that infancy-onset diabetes is a previously unrecognised feature of RNU4ATACopathy. Our work highlights the important role of two snRNAs critical to minor spliceosome function in immune system regulation, providing novel insights into the pathogenesis of autoimmune diabetes.

  Study EGAS50000001565

• Integrative genomic analysis identifies key pathogenic mechanisms in primary mediastinal large B-cell lymphoma

  Primary mediastinal large B-cell lymphoma (PMBL) represents a clinically and pathologically distinct subtype of large B-cell lymphomas. Furthermore, molecular studies, including global gene expression profiling, have provided evidence that PMBL is more closely related to classical Hodgkin lymphoma (cHL). Although targeted sequencing studies have revealed a number of mutations involved in PMBL pathogenesis, a comprehensive description of disease-associated genetic alterations and perturbed pathways is still lacking. Here, we performed whole-exome sequencing of 95 PMBL tumors to inform on oncogenic driver genes and recurrent copy number alterations. The integration of somatic gene mutations with gene expression signatures provides further insights into genotype-phenotype interrelation in PMBL. We identified highly recurrent oncogenic mutations in the JAK-STAT and NF-kB pathways, and provide additional evidence of the importance of immune evasion in PMBL (CIITA, CD58, B2M, CD274, PDCD1LG2). Our analyses highlight the IRF-pathway as a putative novel hallmark with frequent alterations in multiple pathway members (IRF2BP2, IRF4, IRF8). In addition, our integrative analysis illustrates the importance of JAK1, RELB and EP300 mutations driving oncogenic signaling. The identified driver genes were significantly more frequently mutated in PMBL as compared to diffuse large B-cell lymphoma, whereas only a limited number of genes were significantly different between PMBL and cHL, emphasizing the close relationship between these entities. Our study, performed on a large cohort of PMBL, highlights the importance of distinctive genetic alterations for disease taxonomy with relevance for diagnostic work-up and therapeutic decision-making.

  Study EGAS00001003746

• Inhibition of CDK4/6 Promotes CD8 T Cell Memory

  Inhibitors of Cyclin-Dependent Kinase 4 and 6 (CDK4/6) have been recently deployed for the treatment of advanced breast cancer. Despite their success, the mechanism of action of these drugs is unclear. In mice, treatment with a CDK4/6 inhibitor improve T cell memory responses and protect mice against tumor rechallenge. We aimed to identify the correlates of this finding in human subjects. In this study, blood was collected from 5 breast cancer patients before and during treatment with the CDK4/6 inhibitors abemaciclib or palbociclib. Blood was also collected from 2 breast cancer patients who did not receive a CDK4/6 inhibitor. Recently activated CD8 T cells (CD45RO+ CD45RA+) were sorted and subjected to single-cell RNA sequencing.

  Study phs002448

• RNAseq samples of patients with anti-PD-1 resistant HNSCC from a non-randomized, open-label phase 1b clinical trial

  Immune checkpoint blockade (ICB) is an effective treatment for a subset of patients with head and neck squamous cell carcinoma (HNSCC); however, the majority remain refractory. In a nonrandomized, open-label Phase 1b clinical trial, participants with recurrent and/or metastatic (R/M) HNSCC who had progressed on ICB were treated with low-dose 5-azacytidine (5-aza) daily for either 5 or 10 days, in combination with durvalumab and tremelimumab. The primary objective was to determine the biologically effective dose of 5-aza. In this study, RNA sequencing (RNA-seq) was performed on baseline and on-treatment samples from eight participants, and transcriptomic changes were analyzed to assess the impact of low-dose 5-aza treatment.

  Study EGAS50000000728

• WES samples of patients with anti-PD-1 resistant HNSCC from a non-randomized, open-label phase 1b clinical trial

  Immune checkpoint blockade (ICB) is an effective treatment for a subset of patients with head and neck squamous cell carcinoma (HNSCC); however, the majority remain refractory. In a nonrandomized, open-label Phase 1b clinical trial, participants with recurrent and/or metastatic (R/M) HNSCC who had progressed on ICB were treated with low-dose 5-azacytidine (5-aza) daily for either 5 or 10 days, in combination with durvalumab and tremelimumab. The primary objective was to determine the biologically effective dose of 5-aza. In this study, whole exome sequencing (WES) was performed on baseline samples from 12 participants, and genomic alterations were analyzed to access the genetic background of these participants.

  Study EGAS50000000729

• GENEVA Genes and Environment Initiatives in Type 2 Diabetes (Nurses' Health Study/Health Professionals Follow-up Study)

  Type 2 diabetes mellitus (T2D) affects approximately 21 million individuals in the U.S., or almost 10% of the U.S. adult population. Because diabetes is determined by both genetic and environmental factors, a better understanding of the etiology of diabetes requires a careful investigation of gene-environment interactions. The Nurses&#39; Health Study (NHS) and Health Professionals&#39; Follow-up Study (HPFS) are well-characterized cohort studies of women and men for whom stored blood and DNA samples are available as well as detailed information on dietary and lifestyle variables. The major goals of the project include: 1. To conduct a GWA analysis among 3,000 cases of T2D and 3,000 healthy controls in NHS/HPFS cohorts. 2. To use information on the joint effects of genes and a list of carefully selected environmental exposures at the initial screening stage to test gene-environment interactions. This approach optimizes our power to detect variants that have a sizeable marginal effect and those with a small marginal effect but a sizeable effect in a stratum defined by an environmental exposure. For this analysis, we have developed a joint test of genetic marginal effect and gene-environment interaction. This flexible two-degree-of-freedom test generally provides greater power than standard methods and has the potential to uncover both marginal genetic effects and stratum-specific effects. The Version 1 (v1) dbGaP release of data from the GENEVA Diabetes Study (NHS/HPFS) includes data from the NHS only. The Version 2 (v2) dbGaP release includes data from both the NHS and HPFS. This study is part of the Gene Environment Association Studies initiative (GENEVA, http://www.genevastudy.org) funded by the trans-NIH Genes, Environment, and Health Initiative (GEI). The overarching goal is to identify novel genetic factors that contribute to type 2 diabetes mellitus through large-scale genome-wide association studies of well-characterized cohorts of nurses and health professionals. Genotyping was performed at the Broad Institute of MIT and Harvard, a GENEVA genotyping center. Data cleaning and harmonization were done at the GEI-funded GENEVA Coordinating Center at the University of Washington.

  Study phs000091

• COMPARE study: participants typed during UK Biobank version 2 array development phase

  The COMPARE study enrolled 29,066 British blood between donors between February 2016 and March 2017, the study aim is to find the optimum technology for haemoglobin screening (ISRCTN 90871183). All participants were at the time of recruitment active blood donors. The 4,796 participants in this dataset have consented to join the NIHR BioResource. Genotyping data was produced using the Thermo Fisher Scientific Axiom Genotyping platform. The UK Biobank version 2 array design was used, content on this array has been added to allow for accurate DNA based identification of human blood group antigens.

  Study EGAS00001003748

• DEMENTIA-SEQ: WGS in Lewy Body Dementia and Frontotemporal Dementia

  Lewy body dementia, amyotrophic lateral sclerosis/frontotemporal dementia, and multiple system atrophy are age-related, neurodegenerative syndromes that are poorly understood. Delineating the genetic risk that is driving the pathophysiology of these neurological diseases is fundamental for understanding disease mechanisms and for developing disease-modifying treatments. In version 1 of the study/dbGaP deposition, we performed a whole-genome sequencing study consisting of 7,403 total samples, including 2,633 genomes from patients with Lewy body dementia, 2,641 frontotemporal dementia patients, and 1,980 neurologically healthy controls. Of these, 6,907 were uploaded to dbGaP as the basis of the DementiaSeq, phs001963 dataset. The data relating to these samples are available on dbGaP. In version 2 of this study/dbGaP deposition, we made much of these data available on Anvil. More specifically, data for 6,254 of these samples were also uploaded to the ALS Compute platform on AnVIL. The data for the remaining 653 samples are only available on dbGaP. The dbGaP/AnVIL Table lists the availability of dbGaP and AnVIL for each individual sample: phd008475.In version 3 of the study/dbGaP deposition, we added whole-genome sequence data generated using DNA samples obtained from 683 patients diagnosed with multiple system atrophy.

  Study phs001963

• Molecular analysis of post-colonoscopy CRC (PCCRC)

  Background: Post-colonoscopy colorectal cancers (PCCRCs, i.e. CRC diagnosed after a colonoscopy that excluded cancer) pose a challenge in clinical practice. In a retrospective cohort study, we compared clinical and molecular features of PCCRCs and prevalent CRCs. Methods: PCCRCs were defined according to the WEO classification, as cancers occurring within 10 years after a complete index colonoscopy, which excluded CRC. Whole genome chromosomal copy number changes and mutation status of genes commonly affected in CRC (APC, KRAS, BRAF, FBXW7, PIK3CA, NRAS, SMAD4 and TP53) were examined by low-coverage WGS and targeted sequencing, respectively. MSI and CIMP status were also determined. Results: In total, 122 PCCRCs and 98 prevalent CRCs were examined. PCCRCs are more often located proximally in the colon (p&lt;0.001), non-polypoid appearing (p=0.004), early stage (p=0.009), and poorly differentiated (p=0.006) compared to prevalent CRCs. PCCRCs contain less frequently 18q deletions (p&lt;0.001) than prevalent CRCs. MSI (p=0.029) and CIMP (p=0.014) are more frequently observed in PCCRCs. Conclusion: Although no PCCRC specific pathway could be defined, PCCRCs’ molecular features are more associated with MSI and hypermethylation pathways than canonical CIN pathway. The clinical and molecular features observed in PCCRCs support the hypothesis that sessile serrated lesions and non-polypoid CRNs are contributors to the development of these cancers."

  Study EGAS00001004686

• Genetic Legacy of Punan Hunter-Gatherer Groups in Indonesian Borneo

  Punan Batu (the “Cave Punan”), the last living nomadic hunter-gatherer (HG) group who still literally live under karst rock shelters in Borneo, is the least-known hunter-gatherer society in Asia. To provide insights on the origin and adaptation of the Cave Punan, here we present the autosomal genome-wide SNPs study of the Cave Punan, including other Punan groups who speak different language from the Cave Punan, which are transitioning into a more sedentary lifestyle.

  Study EGAS00001004471

• Center for Common Disease Genomics (CCDG) - Cardiovascular: eMERGE - Northwestern Cohort

  The National Human Genome Research Institute (NHGRI) has funded the Centers for Common Disease Genomics (CCDG), a collaborative large-scale genome sequencing effort to comprehensively identify rare risk and protective variants contributing to common disease phenotypes and to better understand the general principles of genomic architecture underlying common, complex inherited diseases. This study contains variant calls derived from the whole genome sequence data of an early-onset coronary artery disease case-control cohort selected from the NUgene Project biobank at Northwestern University. Case status was assigned based on the presence of myocardial infarction, coronary artery stenosis greater than 70% in at least one coronary artery, and/or revascularization (coronary angioplasty with or without stent placement or coronary artery bypass grafting) at an early age. In this study "early age" is defined as men 60 years of age or younger and women 70 years of age or younger.

  Study phs001913

• Type 1 Diabetes Genetics Consortium (T1DGC): Multi-Ethnic ImmunoChip Study

  Type 1 diabetes (T1D) is characterized by an autoimmune attack that destroys the insulin-producing pancreatic beta cells and is driven by diverse genetic and environmental factors. Between 8-100 chromosome regions are known to contain variants that alter T1D risk, substantially fewer than many other common diseases. Less is known about the contribution of T1D risk alleles in non-European populations, despite recent increases in T1D diagnoses in multiple non-European ancestry groups. To address these gaps in T1D genetics, we doubled the sample size from the previous largest T1D association study, genotyped ancestrally diverse T1D cases, controls, and affected families with the Illumina ImmunoChip array, and imputed additional variants using a large haplotype reference panel. After quality filtering, a total of 61,427 participants and 140,333 genotyped ImmunoChip variants were included in analysis, providing dense coverage in 188 autosomal regions ("ImmunoChip regions") and sparse genotyping in other regions of the genome. Each participant was assigned to one of five ancestry groups using k-means clustering of ImmunoChip genotype principal components: European (EUR, N = 47,319), African Admixed (AFR, N = 4,290), Finnish (FIN, N = 6,991), East Asian (EAS, N = 588) and Other Admixed (AMR, N = 2,239). In total, 16,159 T1D cases, 25,386 controls (unrelated) and 6,143 trio families (i.e., an affected child and both parents) were genotyped and included in association analyses. Imputation with the National Heart, Lung, and Blood Institute (NHLBI) Trans-Omics for Precision Medicine (TOPMed) multi-ethnic reference panel was used to improve discovery power and fine-mapping resolution. After imputation, the number of variants in ImmunoChip regions with imputation R-squared &gt; 0.8 and MAF &gt; 0.005 in each ancestry group was 322,084 (AFR), 166,274 (EUR), 163,612 (FIN), 137,730 (EAS) and 188,550 (AMR). Imputed genotypes were compared in the same participants who have whole genome sequencing data, resulting in high concordance. Unrelated cases and controls (N = 41,545) were analyzed initially, assuming an additive inheritance model. T1D trio families (N = 6,143 trios, some trio families were multiplex and analyzed as multiple trios) were analyzed separately, with meta-analysis of case-control and trio results used for discovery of regions associated with T1D (p &lt; 5&#215;10-8). Summary-level data at each SNP (genotype and imputed) for type 1 diabetes (outcome) are provided in dbGaP.

  Study phs002468

• OncoArray: Follow-up of Ovarian Cancer Genetic Association and Interaction Studies (FOCI)

  The Follow-up of Ovarian Cancer Genetic Association and Interaction Studies (FOCI) was one of five projects funded in 2010 as part of the NCI's Genetic Associations and Mechanisms in Oncology (GAME-ON) initiative (http://epi.grants.cancer.gov/gameon/). FOCI represents a collective effort that builds upon the strengths and history of collaboration inherent in the Ovarian Cancer Association Consortium (OCAC), a multidisciplinary group comprised of epidemiologists, genetic epidemiologists, statistical geneticists, molecular and cell biologists and clinicians that was formed in 2005. The other four funded GAME-ON projects were: the ColoRectal TransdisciplinaryStudy (CORECT), Elucidating Loci Involved in Prostate Cancer Susceptibility (ELLIPSE), Discovery, Biology, and Risk of Inherited Variants in Breast Cancer (DRIVE), and Transdisciplinary Research in Cancer of the Lung (TRICL). As part of our aim to discover, expand, and replicate ovarian cancer susceptibility loci, the GAME-ON projects and other consortia formed the OncoArray network (http://epi.grants.cancer.gov/oncoarray/) to develop and genotype a new custom genotyping array in large numbers of cancer cases and controls (over 400,000 samples) across multiple cancer types. The FOCI data includes over 50,000 ovarian cancer cases and controls genotyped with the Oncoarray at the Center for Inherited Disease Research (CIDR). Genotype calling and quality control procedures were performed under a standardized protocol across the Oncoarray consortium, and over 490,000 SNPs passed QC and are included under this dbGaP submission.

  Study phs001882

• Uveal Melanoma Immunogenomics Predict Immunotherapy Resistance and Susceptibility

  Immunotherapy using immune checkpoint inhibition (ICI) has shown success in treating metastatic cutaneous melanoma but has limited efficacy against metastatic uveal melanoma (UM), a rare variant arising from the immune privileged eye. To better understand this immune resistance, we performed comprehensive immunogenomic profiling of 100 human UM metastases using clinicogenomics, bulk and single cell transcriptomics, T cell receptor (TCR) repertoire analysis, and tumor infiltrating lymphocyte (TIL) potency assessment. We found that over half of these metastases harbored TIL with potent autologous tumor specificity, despite having low tumor mutational burden and resistance to prior immunotherapies, including ICI and the bispecific T cell engager tebentafusp. These T cell infiltrated metastases displayed activated antigen presenting cells, chronic interferon signaling, and diverse TCR repertoires. However, we observed strikingly low intratumoral TCR clonality and transcriptionally non-proliferative TIL within the tumor microenvironment even after ICI and tebentafusp therapy, demonstrating that these immunotherapies were insufficient to induce proliferation of the tumor reactive TIL. To harness the therapeutic potential of these quiescent TIL, we developed rapid tumor transcriptomic profiling to enable their selective in vivo identification and ex vivo liberation to counter their growth suppression. We demonstrate that adoptive transfer of these transcriptomic selected TIL can promote tumor immunity in patients with metastatic UM when other immunotherapies are incapable.Data that will be available through dbGaP includes raw bulk tumor transcriptomic sequencing data.

  Study phs003330

• The Medical Genome Reference Bank: a whole genome data resource of 4,000 healthy elderly individuals.

  Allele frequency data from human reference populations is of increasing value for filtering and assignment of pathogenicity to genetic variants. Aged and healthy populations are more likely to be selectively depleted of pathogenic alleles, and therefore particularly suitable as a reference populations for the major diseases of clinical and public health importance. However, reference studies of the healthy elderly have remained under represented in human genetics. We have developed the Medical Genome Reference Bank (MGRB), a large scale comprehensive whole genome dataset of confirmed healthy elderly individuals, to provide a publicly accessible resource for health related research, and for clinical genetics. It also represents a useful resource for studying the genetics of healthy aging. The MGRB comprises 4,000 healthy, older individuals with no reported history of cancer, cardiovascular disease or dementia, recruited from two Australian community based cohorts. DNA derived from blood samples will be subject to whole genome sequencing. The MGRB will measure genome wide genetic variation in 4,000 individuals, mostly of European decent, aged 60 to 95 years (mean age 75 years). The MGRB has committed to a policy of data sharing, employing a hierarchical data management system to maintain participant privacy and confidentiality, whilst maximizing research and clinical usage of the database. The MGRB will represent a dataset of international significance, broadly accessible to the clinical and genetic research community.

  Study EGAS00001003511

• Targeting the p53 pathway to treat Malignant Rhabdoid and High-Risk Atypical Teratoid Rhabdoid Tumors

  Rhabdoid tumors (RTs) predominantly affect young children and are among the deadliest pediatric solid tumors. Despite multimodal therapy consisting of surgery, radiation, and chemotherapy, children with these tumors have median survival of less than one year. RTs can arise throughout the body, including the central nervous system (CNS) where they are called atypical teratoid rhabdoid tumors (AT/RTs), and in extra-CNS locations such as the kidneys and other soft tissues where they are designated malignant RTs (MRTs). We previously identified MDM2 and MDM4 as therapeutic vulnerabilities in RTs and showed that treatment with the MDM2 inhibitor idasanutlin increased survival in mice bearing MRT xenografts. However, the therapeutic potential of idasanutlin in CNS RT tumors is unknown. Single agent therapies are prone to resistance and show limited clinical benefit on their own. Therefore, we sought to identify combination strategies incorporating idasanutlin that would be effective in both CNS and extra-CNS RTs. Here, we show that the XPO1 inhibitor selinexor increased nuclear retention of p53 and potentiated idasanutlin-induced p53 pathway activation and cytotoxicity in AT/RT and MRT cell lines in vitro. Importantly, combination therapy limited acquired resistance through TP53 mutation. In vivo, combination therapy was well-tolerated, reduced tumor burden, and increased survival in orthotopic models of both AT/RT and MRT. Our results demonstrate that combining idasanutlin with selinexor is a promising therapeutic strategy for children with rhabdoid tumors.

  Study EGAS00001007680

• MutWP6__CRUK_Grand_Challenge_Mutographs_of_Cancer__oncology_agents

  he Mutographs project aims to advance our understanding of the causes of cancer through studies of mutational signatures. Led by Mike Stratton, together with Paul Brennan, Ludmil Alexandrov, Allan Balmain, David Phillips and Peter Campbell, this large-scale international research endeavour was awarded a Cancer Research UK Grand Challenge. Within Mutographs, work lead by the Sanger Institute will investigate whether detection of somatic mutations and mutational signatures in circulating white blood cells can be developed into a practical, generic system for surveying and monitoring multiple different endogenous and exogenous exposures, providing an ‘observatory’ on somatic mutational processes in humans. Whole genome sequences are generated at the Wellcome Sanger Institute (Illumina HiSeqX). Somatic mutational signatures are subsequently extracted by non-negative matrix factorisation methods. Through an enhanced understanding of cancer aetiology, Mutographs unprecedented effort is anticipated to outline modifiable risk factors, lead to new approaches to prevent cancer, and provide opportunities to empower early detection, refine high-risk groups and contribute to further therapeutic development.

  Study EGAS00001004125

• MILK-Omics: Systems Biology of Human Milk and Its Links to Maternal and Infant Health

  The primary objective of the project is to generate a systems-level view of human milk in the context of healthy mothers and their term infants. The study uses biospecimens and clinical data from the Mothers and Infants LinKed for Healthy Growth Study (MILk Study), a prospective observational cohort of approximately 500 exclusively breastfeeding women and their infants who are followed to 6 months of age. The project focuses on mature milk samples collected at 1 month postpartum and infant gut microbiome samples collected at 1 and 6 months of age. Specific Aim 1 is to identify maternal genetic and clinical factors that shape human milk gene expression. Using bulk and single-cell RNA sequencing of the milk cell pellet and genotypes from maternal DNA, we will identify novel genetic determinants of the milk transcriptome and assess potential modification of these genetic associations by gestational weight gain, diet, and other clinical factors. Specific Aim 2 is to describe key features of the normative human milk biosystem and their interactions with one another. Specifically, machine learning techniques will be used to characterize interaction networks and correlational structures among the following features of human milk: transcriptomics, microbiomes, oligosaccharides, metabolomics, lipidomics, and milk macronutrient composition. Specific Aim 3 is to establish how the milk biosystem is related to variation in infant gut microbiomes and health. dbGaP will house the maternal genotype and milk transcriptomics data.The infant microbiome sequence data are associated with BioProject PRJNA1019702.

  Study phs003408

• International Cancer Proteogenomics Consortium (ICPC): Proteogenomics of East-Asian Breast Cancer

  The incidence of invasive breast cancer is rapidly increasing in East Asia, enriching in younger patients and luminal disease. We presented a deep proteogenomic landscape of a prospectively enrolled early-stage cohort in Taiwan to uncover the etiology, age-related subtype and oncogenic vulnerabilities underlying the heterogeneous disease. Multilayer proteogenomic architecture revealed distinct endogenous and environmental carcinogen-associated mutagenesis, linking APOBEC (apolipoprotein-B mRNA editing enzyme, catalytic polypeptide-like) cytidine deaminase and DBAC (dibenz[a,j] acridine) signatures to significantly elevated hormone biosynthesis and chemical carcinogenesis in younger patients, and identifying a novel subset of high mutation burden and immune escape potentially beneficial from combined epigenetic therapy and immunotherapy. A proteomics-informed classification resolves luminal heterogeneity, defines high-risk recurrent luminal disease and nominates biomarkers and actionable druggable pathways. Furthermore, proteogenomics profile distinguished a young luminal population susceptible to exogenous carcinogen and having DNA repair deficiency. This study illuminates the age-related molecular subtypes and oncogenic vulnerabilities, providing a proteogenomics-transformative guide for patient stratification and precision therapeutics beyond clinical staging.

  Study phs003150

• Single-cell analysis of airway samples identifies immune cell activation correlating with COVID-19 disease severity

  To investigate the immune response and mechanisms associated with severe COVID-19, we performed single-cell RNA-seq on nasopharyngeal and bronchial samples from 19 clinically well-characterized patients with moderate or critical disease and from 5 healthy controls. We identified airway epithelial cell types and states vulnerable to SARS-CoV-2 infection. In COVID-19 patients, epithelial cells showed an average threefold increase in expression of the SARS-CoV-2 entry receptor ACE2, which correlated with interferon signals by immune cells. Compared with moderate cases, critical cases exhibited stronger interactions between epithelial and immune cells, as indicated by ligand–receptor expression profiles, and activated immune cells , including inflammatory macrophages expressing CCL2, CCL3, CCL20, CXCL1, CXCL3, CXCL10, IL8, IL1B and TNF . The transcriptional differences in critical cases compared with moderate cases likely contribute to clinical observations of heightened inflammatory tissue damage, lung injury and respiratory failure. Our data suggest that pharmacologic inhibition of the CCR1 and/or CCR5 pathways may suppress immune hyperactivation in critical COVID-19.

  Study EGAS00001004481

• 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

• Carboxylesterase 1 mediates a distinctive metabolic profile of dendritic cells to attain an inflammatory phenotype

  The metabolic profile of dendritic cells (DCs) shapes their phenotype and functions. Carboxylestrase 1 (CES1) enzyme is highly expressed in mononuclear myeloid cells however its exact role in DCs is elusive. We used a CES1 inhibitor (WWL113) and genetic overexpression to explore the role of CES1 in DCs differentiation in inflammatory models. CES1 expression was analyzed during CD14+ monocytes differentiation to DCs (MoDCs) using quantitative PCR. CES1 Inhibitor (WWL113) was applied during MoDCs differentiation. Surface markers, secreted cytokines, lactic acid production, phagocytic and T cell polarization capacity were analyzed. Transcriptomic and metabolic profile were assessed with RNA-sequencing and mass spectrometry. Cellular respiration was assessed with seahorse respirometry. Transgenic mice were used to assess CES1 overexpression in DCs in inflammatory models. CES1 expression peaks early during MoDCs differentiation. Pharmacological inhibition of CES1 led to higher expression of CD209, CD86 and MHCII. WWL113 treated MoDCs secreted higher quantities of IL6, IL8, TNF and IL10 and demonstrated stronger phagocytic ability and higher capacity to polarize Th17 differentiation in autologous DCs-T cells co-culture model. Transcriptomic profiling revealed enrichment of multiple inflammatory and metabolic pathways. Functional metabolic analysis shows impaired maximal mitochondrial respiration capacity, increased lactate production and decreased intracellular amino acids and TCA intermediates. Transgenic human CES1 overexpression in murine DCs generated less inflammatory phenotype and increased resistance to T cell mediated colitis. In conclusion, CES1 inhibition directs DCs differentiation towards more inflammatory phenotype, that shows stronger phagocytic capacity and supports Th17 skewing. This is associated with disrupted mitochondrial respiration and amino acids depletion.

  Study EGAS50000000230