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• Persistent Mutation Burden Drives Sustained Anti-Tumor Immune Responses

  Tumor mutation burden is an imperfect proxy of tumor foreignness and has therefore failed to consistently demonstrate clinical utility in predicting responses in the context of immunotherapy. We evaluated mutations in regions of the genome that are unlikely to undergo loss and discovered that clonal mutations in single-copy regions and those present in multiple copies per cell constitute a persistent tumor mutation burden (pTMB) that is linked with therapeutic response to immune checkpoint blockade. Persistent mutations were retained in the context of tumor evolution under selective pressure of immunotherapy and tumors with a high pTMB content were characterized by a more inflamed tumor microenvironment. pTMB imposes an evolutionary bottleneck that cancer cells cannot overcome and may thus drive sustained immunologic tumor control in the context of immunotherapy.

  Study EGAS00001006660

• Genetics of gene expression in primary human immune cells

  The purpose of this study was to identify cell specific expression quantitative trait loci in freshly isolated highly purified primary B-cells and monocytes from healthy subjects of European ancestry. Cells were purified from Ficoll gradient prepared peripheral blood mononuclear cell fractions using positive selection via magnetic bead labelling of the B-cell marker CD19 and monocyte marker CD14. RNA was extracted from 287 B-cell samples and 288 monocyte samples. RNA was then hybridised to HumanHT-12 v4 BeadChips whole genome expression arrays (Illumina). Individuals were genotyped on HumanOmniExpress-12v1.0 BeadChips (Illumina) at 733202 genetic markers. Data presented include the raw expression values and Robust Spline Normalised values (RSN) for expression for each cell type per individual. Additional genotype data per individual is available on request.

  Study EGAS00000000109

• Hypermutation of the inactive X chromosome is a frequent event in cancer

  Mutation is a fundamental process in tumorigenesis. However the degree to which the rate of somatic mutation varies across the human genome and the mechanistic basis underlying this variation remain to be fully elucidated. As part of the ICGC PedBrain and Malignant Lymphoma (MMML-Seq) consortium we performed a cross-cancer comparison of whole genomes comprising a diverse set of childhood and adult tumors including both solid and hematopoietic malignancies. In addition we performed whole genome sequencing of clonally expanded hematopoietic stem/progenitor cells (HSPCs) from healthy individuals to compare somatic mutation rates.

  Study EGAS00001000565

• Gabriella Miller Kids First Pediatric Research Program in Genetics at the Intersection of Childhood Cancer and Birth Defects

  The Gabriella Miller Kids First Pediatric Research Program (Kids First) is a trans-NIH effort initiated in response to the 2014 Gabriella Miller Kids First Research Act and supported by the NIH Common Fund. This program focuses on gene discovery in pediatric cancers and structural birth defects and the development of the Gabriella Miller Kids First Pediatric Data Resource (Kids First Data Resource). All of the WGS and phenotypic data from this study are accessible through dbGaP and kidsfirstdrc.org, where other Kids First datasets can also be accessed. Birth defects and childhood cancer share biological pathways that are important for cell growth and division. We propose that sequencing pediatric patients suffering both conditions will allow us to discover the underlying genes and in turn advance our understanding of the causes of these devastating diseases.

  Study phs001846

• Homozygous Duplication Identified by Whole Genome Sequencing Causes LRBA Deficiency

  In more than one third of primary immunodeficiency (PID) patients, extensive genetic analysis including whole exome sequencing (WES) fails to identify the genetic defect. Whole genome sequencing (WGS) is able to detect variants missed by other genomics platforms, enabling the molecular diagnosis of otherwise unresolved cases. Here, we report two siblings, offspring of consanguineous parents, who experienced similar severe events encompassing early onset of colitis, lymphoproliferation and hypogammaglobulinemia, typical of lipopolysaccharide (LPS)-responsive and beige-like anchor protein (LRBA) or cytotoxic T-lymphocyte-associated protein 4 (CTLA4) deficiencies. WGS of these patients detected a 12.3 kb homozygous tandem duplication that was absent in control cohorts and is predicted to disrupt the reading frame of the LRBA gene.

  Study phs002557

• Resuscitation Outcomes Consortium Pragmatic Trial of Airway Management in out-of-Hospital Cardiac Arrest (ROC PART-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 determine the effect of an initial airway management strategy using laryngeal tube (LT) insertion, compared with endotracheal intubation (ETI), on survival among adults with out-of-hospital cardiac arrest (OHCA).Background: Out-of-hospital cardiopulmonary arrest (OHCA) affects more than 350,000 adults in the United States each year, with only a low percentage of patients surviving to hospital discharge. Emergency medical services (EMS) paramedics commonly perform ETI or insertion of supraglottic airways (SGAs), such as the LT, on patients with OHCA to facilitate oxygenation and protect the lungs from aspiration of vomitus. Because SGA insertion is rapid, simple, and requires less training compared to ETI, many EMS agencies have incorporated this as the primary method of ventilation during OHCA resuscitation. However, the optimal method for OHCA advanced airway management is unknown.Participants: A total of 3004 patients were included; 1505 assigned to initial LT and 1499 assigned to initial ETI.Design: PART was a multicenter cluster-crossover randomized trial. The trial included 27 EMS agencies associated with US sites of the Resuscitation Outcomes Consortium (ROC). The EMS agencies were grouped into 13 randomization clusters. Each cluster selected a crossover interval of 3 or 5 months. Within each cluster, treatment assignments for consecutive intervals were computer-randomized in blocks of 2 to ensure balanced exposure to both airway groups. Crossovers between study groups could occur more than once. Treatment assignments were initial LT insertion or initial ETI. Neuromuscular blocking agents or video laryngoscopy was permitted for initial intubation efforts. The trial did not limit the number of initial LT insertion or ETI attempts. If the initial insertion efforts were unsuccessful, EMS personnel performed rescue airway management using any available airway technique. EMS personnel followed local protocols for confirmation of airway placement and management of OHCA, including field termination of resuscitation efforts. Patients receiving bag-valve mask (BVM) ventilation only were retained in their assigned treatment group per intention-to-treat principles. The trial did not prescribe clinical care at the receiving hospitals, including use of EMS airway, targeted temperature management, percutaneous coronary intervention, or the timing of withdrawal of life-sustaining therapy.The primary outcome was 72-hour survival. Secondary outcomes included return of spontaneous circulation, survival to hospital discharge, and favorable neurological status at hospital discharge (Modified Rankin Scale score ≤3). Conclusions: Among adults with OHCA, a strategy of initial LT insertion was associated with significantly greater 72-hour survival compared with a strategy of initial ETI. These findings suggest that LT insertion may be considered as an initial airway management strategy in patients with OHCA, but limitations of the pragmatic design, practice setting, and ETI performance characteristics suggest that further research is warranted.

  Study phs003902

• JAK Inhibitor Withdrawal Causes a Transient Proinflammatory Cascade: A Potential Mechanism for Major Adverse Cardiac Events

  This is a study of mesenchymal stromal cells (MSCs) from salivary glands. The salivary glands were derived from participants who had dry eye or dry mouth symptoms but did not have evidence of systemic autoimmune disease (sicca controls). The aim of the study was to determine the effects of Type I and Type II Janus kinase (JAK) inhibitors (JAKinibs) withdrawal on these cells in vitro. The MSCs were treated in vitro with a) IFN-gamma (10 ng/mL) for the entire duration, b) IFN-gamma (10 ng/mL) and withdrawal of ruxolitinib (1 µM), c) IFN-gamma (10 ng/mL) and withdrawal CHZ-868 (1 µM), and d) IFN-gamma (10 ng/mL) and ruxolitinib (1 µM) for the entire duration. For the drug (CHZ-868 and ruxolitinib) conditions, after IFN-gamma treatment for 48 hours, we washed the cells with PBS and treated them with standard growth media with 0.01% DMSO, 10 ng/mL IFN-gamma + 0.01% DMSO, or 10 ng/mL IFN-gamma + JAKinib for 48 hours. For withdrawal conditions, we washed the cells twice and then treated them with standard growth media with either 0.01% DMSO or with 10 ng/mL IFN-gamma + 0.01% DMSO for 24 hours before harvest.

  Study phs003915

• Disorders/Differences of Sex Development (DSD) Study Performed at UCLA in Collaboration with the DSD-Translational Research Network (DSD-TRN), with the Support of the Gabriella Miller Kids First Pediatric Research Program

  The Gabriella Miller Kids First Pediatric Research Program (Kids First) is a trans-NIH effort initiated in response to the 2014 Gabriella Miller Kids First Research Act and supported by the NIH Common Fund. This program focuses on gene discovery in pediatric cancers and structural birth defects and the development of the Gabriella Miller Kids First Pediatric Data Resource (Kids First Data Resource). Both childhood cancers and structural birth defects are critical and costly conditions associated with substantial morbidity and mortality. Elucidating the underlying genetic etiology of these diseases has the potential to profoundly improve preventative measures, diagnostics, and therapeutic interventions. Whole Genome Sequence (WGS) and phenotypic data from this study are accessible through dbGaP and kidsfirstdrc.org, where other Kids First datasets can also be accessed. Disorders/Differences of Sex Development (DSD) are congenital conditions in which development of chromosomal, gonadal, or anatomic sex is atypical. DSD are chronic medical conditions collectively affecting ~1% of the population, frequently requiring life-long care by multiple specialists, and carrying a significant public health burden. Some are associated with life-threatening events, such as adrenal crises in Congenital Adrenal Hyperplasia (CAH). DSD are also associated with increased infertility, cancer, gender dysphoria risks, psychosocial distress and pervasive challenges to health-related quality of life (HRQoL) for patients and families. DSD are broadly classified into three categories: sex chromosome DSD, 46,XY DSD and 46,XX DSD, and further classified according to the type of gonad found in the patient (ovary, testis, ovotestis). We were able to increase significantly the diagnostic success for DSD using Whole Exome Sequencing (WES), with the identification of disease-causing and likely pathogenic variants in a third of a cohort of 46,XY patients. We have therefore proposed a shift in the diagnostic approach to DSD to use next-gen sequencing as a first-line clinical test, which could lead to faster and more accurate diagnosis, and orient further clinical management, limiting unnecessary, costly, and often invasive endocrine testing and imaging. However many remain unexplained (over half of the XY cases, a significant minority of XX cases, including most ovotesticular DSD, and most syndromic cases). In addition, the very large phenotypic variability in cases with known variants in the same gene is unexplained. We here propose to use Whole-Genome Sequencing (WGS), which dramatically improves upon exome sequencing, covering both coding and non-coding parts of the genome more uniformly, as an approach to not only improve diagnostic yield, but also to identify novel genes and regulatory elements involved in DSD.

  Study phs001178

• METSIM (METabolic Syndrome In Men) Study

  The METSIM Study includes 10,197 men, aged from 45 to 73 years, randomly selected from the population register of the town of Kuopio, Eastern Finland, and examined in 2005-2010. The aim of the study is to investigate genetic and non-genetic factors associated with the risk of type 2 diabetes (T2D), cardiovascular disease (CVD), and insulin resistance-related traits in a cross-sectional and longitudinal setting. Study protocol includes collection of data on CVD risk factors (smoking, exercise, diet, history of chronic diseases including coronary heart disease, stroke, cardiac failure, medication, history of diabetes or early onset coronary heart disease in the family), questionnaire on the FINDRISC Score, measurement of height, weight, waist, hip, blood pressure, and bioimpedance for the evaluation of fat percentage. July 2016 - The first study release (v1) included phenotype and whole exome sequencing (WES) data of n=982 participants in substudy: Type 2 Diabetes Genetic Exploration by Next-Generation Sequencing in Multi-Ethnic Samples (T2D-GENES) Project 1: Metabolic Syndrome in Men Study (METSIM) - phs001100.v2.p1. The second study release (v2) included phenotype data for the entire METSIM cohort and made two additional substudies available, phs000919.v1.p1 and phs000752.v1.p1. The third study release (v3) made three subcutaneous adipose biopsy substudies available, phs003385.v1.p1, phs003386.v1.p1, and phs003387.v1.p1.The fourth study release (v4) added phenotype data for the subcutaneous adipose biopsies, made two additional substudies available, phs01579.v1.p1 and phs004033.v1.p1, and is utilized in the following dbGaP sub-studies. To view genotypes, other molecular data, and derived variables collected in these sub-studies, please click on the following sub-studies below or in the "Sub-studies" section of this top-level study page phs000743 METSIM Study. phs000752 METSIM FinMetSeq Exome Sequencing phs000919 METSIM GWAS and Exome Chip phs001100 METSIM T2D-GENES Exome Sequencingphs001579 METSIM CCDG Whole Genome Sequencingphs003385 METSIM Subcutaneous Adipose Needle Biopsy RNA-Seq phs003386 METSIM Subcutaneous Adipose Needle Biopsy ATAC-Seq phs003387 METSIM Subcutaneous Adipose Surgical Biopsy RNA-Seqphs004033 METSIM Metabolomics

  Study phs000743

• Recursive splicing in long vertebrate genes

  Recent studies have shown that expression of many genes with exceptionally long introns in the mammalian brain can be perturbed by regulatory factors linked to neurodevelopmental or neurodegenerative disorders1-3, suggesting unique regulatory mechanisms. Here we identify functional recursive splice sites (RSS) in long introns of genes expressed in the brain. These RSS are highly conserved in genes with extreme length across diverse vertebrate species and permit step-wise removal of long introns via recursive splicing. Recursive splicing requires initial definition of a “recursive exon” that is located downstream of RSS, and most often contains premature stop codons. Moreover, we show that RSS create a splicing switch driven by splice site competition in order to distinguish primary mRNA isoforms from alternative isoforms that are prevalent in long genes. The recursive exon is not detectable in the dominant mRNA isoform due to recursive splicing, but is completely included when cryptic promoters or other cryptic exons are used. Thus, by coupling inclusion of recursive exons with the use of cryptic elements, RSS act to distinguish new mRNA isoforms emerging from long genes.

  Study EGAS00001001170