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• Biomarker analysis and treatment dynamics following preoperative ipilimumab plus nivolumab in locally advanced urothelial cancer from the phase 1B NABUCCO study

  In the current analysis of the full NABUCCO trial population (cohorts 1 and 2), we aimed to explore both potential biomarkers for response to combination ICB, as well as treatment dynamics to gain a better understanding of the effects of ICB on the urothelial cancer tumor microenvironment (TME).

  Study EGAS50000001781

• Alterations in the gut microbiome implicate key taxa and metabolic pathways across inflammatory arthritis phenotypes

  Musculoskeletal diseases affect up to 20% of adults worldwide. The gut microbiome has been implicated in inflammatory conditions, but large-scale metagenomic evaluations have not yet traced the routes by which immunity in the gut affects inflammatory arthritis. To characterize the community structure and associated functional processes driving gut microbial involvement in arthritis, the Inflammatory Arthritis Microbiome Consortium investigated 440 stool shotgun metagenomes comprising 221 adults diagnosed with rheumatoid arthritis, ankylosing spondylitis, or psoriatic arthritis and 219 healthy controls and individuals with joint pain without an underlying inflammatory cause. Diagnosis explained about 2% of gut taxonomic variability, which is comparable in magnitude to inflammatory bowel disease. We identified several candidate microbes with differential carriage patterns in patients with elevated blood markers for inflammation. Our results confirm and extend previous findings of increased carriage of typically oral and inflammatory taxa and decreased abundance and prevalence of typical gut clades, indicating that distal inflammatory conditions, as well as local conditions, correspond to alterations to the gut microbial composition. We identified several differentially encoded pathways in the gut microbiome of patients with inflammatory arthritis, including changes in vitamin B salvage and biosynthesis and enrichment of iron sequestration. Although several of these changes characteristic of inflammation could have causal roles, we hypothesize that they are mainly positive feedback responses to changes in host physiology and immune homeostasis. By connecting taxonomic alternations to functional alterations, this work expands our understanding of the shifts in the gut ecosystem that occur in response to systemic inflammation during arthritis.

  Dataset EGAD50000000567

• Genetic variability in exon 1 of the glucocorticoid receptor gene NR3C1 is associated with postoperative complications

  Patients having major surgery experience inflammation post-operatively, which may contribute to post-operative morbidity. Endogenous glucocorticoids (GCs) are an essential part of the stress response, but this response varies between individuals, which may in turn affect clinical outcome in general, and post-operative inflammation, specifically. Exon 1 of the NR3C1 gene, encoding the glucocorticoid receptor, contains an established region of differential regulation. DNA methylation patterns in this region have been found to differ between individuals. We investigated the methylation status and genotype in the Cytosine-phosphate-Guanine (CpG) island in exon 1 of NR3C1 in 24 patients who underwent major abdominal surgery and correlated it with post-operative complications. DNA was extracted from peripheral blood leukocytes and underwent targeted bisulfite sequencing of the CpG island. Complications were graded according to the Clavien-Dindo classification and 14 out of 24 had post-operative complications. Multifactorial and partial least square methods were used to analyse the data. A homogenous demethylated pattern was observed in all patients and no single CpG methylation was associated with post-operative complications. Four single nucleotide polymorphisms (SNPs) were significantly correlated with higher Clavien-Dindo scores. Genetic variability in the chr5:143,402,505-143,405,805 region of exon 1 of the glucocorticoid receptor gene NR3C1, but not DNA methylation, was associated with more severe post-operative complications in patients having major abdominal surgery. This indicates that the response to GCs may be of clinical importance for inflammatory conditions.

  Study EGAS00001005737

• Immunophenotyping in a COVID-19 Cohort (IMPACC) Transcriptomics and Genotyping Assays

  IMPACC (IMmunoPhenotyping Assessment in a COVID-19 Cohort) is a prospective longitudinal cohort study (NCT04378777) launched in May 2020 in response to the worldwide pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It was funded by the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institute of Health (NIH). Patient enrollment and sample analysis involved 20 hospitals associated with 15 U.S. biomedical research centers and 11 centralized Core immunoassay laboratories.The study aimed to enable the identification of potential biomarkers and inform future therapeutic interventions using a longitudinal approach encompassing the whole disease course for a comprehensive understanding of the contributions of the pathogen and host immune response in modulating the manifestations, severity, and post-acute sequelae of the infection. IMPACC enrolled close to 1200 adult symptomatic, molecularly confirmed hospitalized COVID-19 patients in the study within 48 hours of their hospital admission. Clinical data and biological samples (blood, mid-turbinate nasal swabs, and esophageal aspirant) were collected according to minimal risk guidelines at enrollment and on days 4, 7, 14, 21, and 28. Biological samples were collected at 3-month intervals up to 12 months after hospital discharge to assess functional and immunologic recovery measures. Sample collection, processing, and storage procedures were standardized across sites, and samples were transported to centralized assay-specific core laboratories (Core Labs) in batches for testing and analysis. The description of outcome severity was not limited to survival versus death but encompassed a clinical trajectory approach using 5 groups leveraging longitudinal data based on time in the hospital, disease severity by ordinal scale based on the degree of respiratory illness, and presence or absence of limitations at discharge. Disease severity was assessed based on the degree of respiratory illness using a 7-point ordinal scale adapted from the World Health Organization COVID-19 and NIAID disease ordinal severity scales. DNA for genetic analyses was collected from whole blood at a single time point. To identify any genomic determinants of severe COVID-19 disease, single-nucleotide polymorphism (SNP) genotyping and exome sequencing were conducted to assess genetic variants associated with individual susceptibility to severe disease. In addition, IMPACC included bulk transcriptomic analysis of upper airway (nasal swaps) samples, lower airway (esophageal aspirant) samples, and peripheral blood mononuclear cells (PBMCs) to evaluate dynamic changes in cellular composition and cellular response during the course of the disease. Reads were aligned to the GRCh38 human reference genome. Additional information for the IMPACC study has been submitted to The Immunology Database and Analysis Portal (ImmPort) under study accession SDY1760. Further information and requests for resources and reagents should be directed to and will be fulfilled by the Lead Contact, Dr. Steven Kleinstein (steven.kleinstein@yale.edu).

  Study phs002686

• Efficacy of a Therapeutic Treatment Trial in Angelman Syndrome

  This study has been designed to evaluate the possible therapeutic benefits of L-5-methyltetrahydrofolate (Metafolin), vitamin B12, creatine and betaine in children with Angelman Syndrome (AS). This study is based on the hypotheses 1) that dietary manipulation may increase global DNA methylation; 2) that increased methylation of the paternal chromosome in AS participants may increase expression of the Angelman gene causing clinical benefit; and 3) that dietary interventions with Metafolin in conjunction with creatine, betaine, and vitamin B12 would represent little risk, but some chance for benefit. The dietary regimen is felt to be quite benign and safe. The clinical response will be measured by recording: changes in seizure activity, changes in communication skills, changes in developmental skills and changes in behavioral patterns as indicated by formal developmental assessments and clinical evaluations. We will assess the progress of the participants by monitoring their changes from baseline throughout their participation in the study and measure their improvement in particular in the developmental parameters. As a secondary aim, we plan to measure the biochemical response to these compounds by obtaining levels of homocysteine, methionine, S-adenosyl-methionine (SAM), and S-adenosyl-homocysteine (SAH). The molecular response will be measured by global DNA methylation analysis. As an exploratory aim, we hope to use control data we have previously obtained from a double blind placebo-controlled trial done in the past using betaine and folic acid to compare the development of those children who have and those who have not received medications. More specifically, we wish to compare differences in the rate of development for those children who have never received study medications (from the first trial) with those who have received medications from the present trial. Developmental parameters used in the previous trial will be consistent with those used in the present trial in order to permit these comparisons. The previous trial was conducted at Baylor College of Medicine, Rady San Diego Children's Hospital and Boston Children's Hospital whereas a group of AS participants received folic acid and betaine or placebo in a randomized double-blind basis. All the participants for the study will include patients who have a documented molecular diagnosis of AS. The participants will be seen at Baylor College of Medicine, Rady Children's Hospital of San Diego, Boston Children's Hospital and the Greenwood Genetics Center at 0 months and at 12 months for follow-up. Clinical and relevant historical data will be collected during the clinical visit and examination and also by reviewing medical and laboratory records. This information will then be entered into a HIPAA compliant clinical research database.

  Study phs000701

• High-Resolution Spatial Transcriptomics Uncover Epidermal-Dermal Divergences in Merkel Cell Carcinoma: Spatial Context Reshapes the Gene Expression Landscape

  Merkel cell carcinoma (MCC) is an aggressive malignancy with neuroendocrine differentiation marked by high plasticity, often manifesting as rapid therapy resistance. Although the cell-of-origin is presumed to be epithelial, epidermal localization of MCC is rarely observed, largely because in situ MCC is typically an incidental finding. Nevertheless, a subset of MCC tumors exhibits epidermotropism, wherein tumor cells are present in the epidermis. The behavior of cancer cells is profoundly influenced by the tumor microenvironment and interactions with neighboring cells. Notably, the normal counterparts of the cancer’s cell-of-origin have been shown to attenuate tumor aggressiveness. Thus, epidermotropic MCC presents a unique opportunity to explore the potential role of surrounding keratinocytes in modulating tumor cell behavior. While the epidermotropic tumor nests share histological resemblance with their dermal counterparts, their transcriptomic profiles remain unexplored. Here, we employed high-definition spatial and single cell transcriptomics to dissect the gene expression profiles of epidermotropic MCC cells, comparing them to MCC cells in the tumor core and those adjacent to blood vessels. Notably, epidermotropic MCC cells exhibit a transcriptomic signature reminiscent of cutaneous squamous cell carcinoma, characterized by upregulation of genes encoding keratins, S100A proteins, as well as calmodulin-like proteins 3 and 5. Mechanistically, this keratinocytic differentiation is associated with enhanced p63 activity, leading to the upregulation of PERP. Collectively, our study demonstrates that MCC cells can adopt a keratinocytic differentiation program in response to microenvironmental cues, underscoring the remarkable phenotypic plasticity of this malignancy and the importance of the tumor microenvironment for tumor characteristics.

  Study EGAS00001008157

• RNA-seq of uncultured CD112high and CD112low long-term(LT) human hematopoietic stem cells (HSC) and cultured and lentiviral transduced (CTRL, INKA1-OE) LT- and short-term HSC from umbilical cord blood

  We performed RNA-sequencing to elucidate the biological pathways (1) altered by INKA1 overexpression in LT-HSC and ST-HSC that may contribute to the induced transient restraint in generating proliferative hematopoietic output in vivo and in vitro; and (2) that underlie the differential in vitro priming and regeneration phenotypes of CD112high and CD112low LT-HSC. Therefore, we prospectively isolated indicated subpopulations from 3 independent human umbilical cord blood pools and subjected them either to RNA-sequencing directly or following culture, lentiviral transduction and purification of the transduced cell fractions.

  Study EGAS00001004768

• WGS, DuplexSeq and NanoSeq genomic data from histologically normal tissue in cancer patients

  The extent to which mutagenic and non-mutagenic processes, including cancer treatment, contribute to somatic evolution in histologically normal tissue remains unclear. We subjected 168 cancer-free normal samples representing 16 different organs from 22 patients with metastatic cancer enrolled in the PEACE research autopsy study to high-depth duplex panel sequencing (coverage >20,000x). In every sample we identified somatic mutations (range 170 - 2,978) at exceedingly low variant allele frequencies (median VAF 0.0000323), consistent with a patchwork of mutated cells in normal tissue. By analysing the mutational spectra of each sample, we extracted 16 distinct single base substitution mutational signatures, reflecting somatic mutational processes that have moulded the genomes of normal cells. Signatures were found to be associated with diverse aetiologies, including alcohol-related mutation acquisition in liver tissue, smoking-induced mutagenesis in lung and cardiac tissue, and multiple distinct treatment-induced processes, which correlated with treatment and its duration. On average, in this cohort in which patients had each received several lines of anti-cancer therapy, exogenous sources, including treatment-related mutagenesis, underpinned >40% of mutations in liver samples, yet <10% in brain samples. Finally, we observed clear differences in the extent and effects of selection in different tissues, with positive selection in certain tissues, including lung (TP53, EGFR and PIK3CA), liver (NF2L2) and spleen (BRAF, NOTCH2), and limited selection in others, such as brain and cardiac. Over 25% of driver mutations in normal tissue exposed to systemic anti-cancer therapy, including mutations in TP53, could be attributed to treatment-induced mutagenesis. Immunotherapy, while not associated with mutagenesis, was linked to an excess of driver mutations in PPM1D and TP53, illustrating how non-mutagenic treatment can sculpt somatic evolution. Our study reveals the rich tapestry of mutational processes and driver mutations in cancer-free normal tissue, and the profound impact of cancer therapeutic and life-time environmental exposures on normal tissue somatic evolution.

  Study EGAS00001008326

• Ciliopathies Exome Sequencing Initiative

  The study is aimed at identifying new genes involved in pediatric brain disorders from inbred families originating predominantly in the Middle East. Each patient analyzed to date has a specific and highly unique neurodevelopmental disorder that is likely to be recessive in nature. Many patients have one of the diseases along the "ciliopathy" spectrum of diseases, with evidence of kidney failure, retinal blindness and cerebellar ataxia.

  Study phs000288

• Whole Genome Profiling to Detect Schizophrenia Methylation Markers

  Schizophrenia (SCZ) is a devastating psychiatric disorder. The aim of this study was to detect DNA methylation (5meC) profiles in whole blood associated with SCZ. The sample consisted of schizophrenia cases and controls selected from national population registers in Sweden. We employed MBD protein-based enrichment of the methylated DNA fraction, followed by single end sequencing (50 bp reads) on the SOLiD platform. To improve methylome-wide coverage we used an existing protocol variant, which increases the relative number of fragments from CpG poor regions. To analyze the data, we used an analysis pipeline described elsewhere7, that was designed specifically for MBD-seq and included alignment, quality control (QC) of reads and samples, coverage calculations for the 26,752,702 autosomal CpGs in the reference genome using a non-parametric estimate of the fragment size distribution, an in silico experiment to identify CpGs in loci with alignment problems, a 2-stage adaptive algorithm to combine data from correlated adjacent CpG sites in "blocks", principal component analysis (PCA), association testing, bioinformatics annotation and network analysis. After QC, 1459 subjects with on average 32.4 million high quality reads remained. Association testing was performed on 4.3 million high quality blocks after regressing out possible assay related technical artifacts, sex/age, and unmeasured confounders through the PCA components.

  Study phs000608