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• Genomic and transcriptomic determinants of therapy resistance and immune landscape evolution during anti-EGFR treatment in colorectal cancer

  Despite biomarker stratification, the anti-EGFR antibody cetuximab is only effective against a subgroup of colorectal cancers (CRC). This genomic and transcriptomic analysis of the cetuximab resistance landscape in 35 RAS wild-type CRCs identified associations of NF-1 and non-canonical RAS/RAF-aberrations with primary resistance and validated transcriptomic CRC-subtypes as non-genetic predictors of benefit. 64% of biopsies with acquired resistance harbored no genetic resistance drivers. Most of these had switched from a cetuximab-sensitive transcriptomic subtype pre-treatment to a fibroblast- and growth factor-rich subtype at progression. Fibroblast-supernatant conferred cetuximab resistance in vitro, confirming a major role for non-genetic resistance through stromal remodeling. Cetuximab treatment increased cytotoxic immune infiltrates and PDL1 and LAG3 immune-checkpoint expression, potentially providing opportunities to treat cetuximab-resistant CRCs with immunotherapy.

  Study EGAS00001003367

• COPD and neutrophils

  Chronic obstructive pulmonary disease (COPD) is a major respiratory disease characterized by small airway inflammation, emphysema and severe breathing difficulties. Low-grade systemic inflammation is an established hallmark of severe disease, however, the molecular changes in peripheral immune cells remain far from understood. We combined multi-color flow cytometry with single-cell RNA sequencing and showed that blood neutrophil numbers are significantly increased in COPD and they are a heterogeneous population. A transcriptomic state that expressed interferon response genes correlated with alveolar damage and acute exacerbations. Furthermore, bronchoalveolar neutrophils expressed gene signatures corresponding to certain blood neutrophil states. Last, our data in a murine model of cigarette smoke exposure demonstrated that bone marrow neutrophil progenitors are expanded in smoke-treated animals and display signs of immune activation. Our study provides evidence that COPD systemic inflammation may derive from an activated haematopoietic precursor compartment.

  Study EGAS00001006281

• COPD and neutrophils sc

  Chronic obstructive pulmonary disease (COPD) is a major respiratory disease characterized by small airway inflammation, emphysema and severe breathing difficulties. Low-grade systemic inflammation is an established hallmark of severe disease, however, the molecular changes in peripheral immune cells remain far from understood. We combined multi-color flow cytometry with single-cell RNA sequencing and showed that blood neutrophil numbers are significantly increased in COPD and they are a heterogeneous population. A transcriptomic state that expressed interferon response genes correlated with alveolar damage and acute exacerbations. Furthermore, bronchoalveolar neutrophils expressed gene signatures corresponding to certain blood neutrophil states. Last, our data in a murine model of cigarette smoke exposure demonstrated that bone marrow neutrophil progenitors are expanded in smoke-treated animals and display signs of immune activation. Our study provides evidence that COPD systemic inflammation may derive from an activated haematopoietic precursor compartment.

  Study EGAS00001006322

• COPD and neutrophils sc rhapsody

  Chronic obstructive pulmonary disease (COPD) is a major respiratory disease characterized by small airway inflammation, emphysema and severe breathing difficulties. Low-grade systemic inflammation is an established hallmark of severe disease, however, the molecular changes in peripheral immune cells remain far from understood. We combined multi-color flow cytometry with single-cell RNA sequencing and showed that blood neutrophil numbers are significantly increased in COPD and they are a heterogeneous population. A transcriptomic state that expressed interferon response genes correlated with alveolar damage and acute exacerbations. Furthermore, bronchoalveolar neutrophils expressed gene signatures corresponding to certain blood neutrophil states. Last, our data in a murine model of cigarette smoke exposure demonstrated that bone marrow neutrophil progenitors are expanded in smoke-treated animals and display signs of immune activation. Our study provides evidence that COPD systemic inflammation may derive from an activated haematopoietic precursor compartment.

  Study EGAS00001006323

• Digital tEchnology For Lung Cancer Treatment

  The aim of the DEFLeCT project (Digital tEchnology For Lung Cancer Treatment) is to generate a technological platform for precision medicine in order to set predictive personalised algorithms for patient diagnosis and therapy. All resectable patients having histologically confirmed stage IB-IIIA non-small cell lung cancer(NSCLC) will be enrolled in the PROMOLE study, a related and ongoing observational prospective clinical study, for tissue sampling. A large biobank of lung cancer samples and the corresponding healthy tissues and biological components (ie, blood, stools, etc.) with complete clinical, pathological and molecular information will be collected. The project will lay the basis of a knowledge hub and qualified technology aimed not only at answering the medical and scientific community's questions, but also meant to be useful to individual patients by predicting the response to adjuvant and second-line drugs in case of relapse of the disease.

  Study EGAS00001007219

• Organoid drug profiling identifies methotrexate as a therapy for SCCOHT, a rare pediatric cancer

  Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare and lethal tumor in adolescent and young adult patients. Currently, there is no standard-of-care treatment for these patients. Reliable models that represent this disease and can be used for translational research are scarce. To model SCCOHTs, we have established eight patient-derived tumoroid lines from tumor lesions of three patients with SCCOHT. The tumoroids recapitulate genomic and transcriptomic characteristics of the corresponding patient tumors and capture intrapatient tumor heterogeneity. Organoid drug profiling using a library of 153 clinical compounds identified methotrexate as an effective and selective drug against SCCOHTs with a clinically relevant IC50 of 35 nmol/L. RNA sequencing demonstrated that methotrexate induced TP53 pathway activation and apoptosis. These data underscore that organoid technology can support the design of therapeutic strategies for rare cancers.

  Study EGAS00001007911

• SweGen: a whole-genome data resource of genetic variability in a cross-section of the Swedish population

  The SweGen project represents a comprehensive map of genetic variation in the Swedish population. This Study contains four datasets where the first one contains whole-genome sequencing data in CRAM-format for 942 individuals from the Swedish Twin Registry, the second one contains genetic variant frequencies in VCF-format for the same individuals, the third one contains whole-genome sequencing data in CRAM-format for 58 individuals from the Northern Sweden Population Health Study and the fourth one contains genetic variant frequencies in VCF-format for the same individuals. The data, serving as a reference dataset, is a valuable and national resource for genetics research and clinical diagnostics and can be used, for instance, to increase understanding of both rare and complex disorders. It also serves as an international resource for larger studies of human population genetics.

  Study EGAS50000000906

• Beacon v2

  Beacon v2: a tool for data discovery Motivation In the era of data-driven health research and personalised medicine, human genomic data has become extremely valuable. These are also identifiable data, as they carry information pointing to a specific individual as well as their own family; and as such, they must be protected. This makes data discovery particularly challenging: this is where "Beacon" comes in. A "Beacon" is an API aiming to enable the search of genomic variants and associated information without jeopardising the privacy of the dataset. Here, we refer to its current version, namely version 2 (v2). Definition Beacon v2 is a term that can refer to different aspects. The EGA is playing a central role in the following aspects: The Beacon v2 protocol is a Global Alliance for Health and Genomics standard. The Beacon v2 Reference Implementation (B2RI) is an "out-of-the-box" Beacon instance developed with ELIXIR, which facilitates Beacon deployment. The EGA Beacon(s) are Beacons following the v2 standard and using the B2RI, deployed on top of data hosted at the EGA and allowing for their discovery. Resources Depending on whether you are visiting us a stakeholder (you need more general information about Beacon), a deployer /implementer (you want to have your own Beacon instance), or an EGA user (you want to query Beacon and start browsing data), you will be interested in the following resources: Your role Beacon aspect Documentation type Stakeholder Beacon v2 protocol Beacon website Beacon page on the GA4GH website Deployer/Implementer Beacon v2 protocol Read the docs: Beacon v2 standard technical description GitHub repository Beacon v2 standard Beacon v2 Reference Implementation Read the docs: B2RI technical description GitHub repository B2RI Guide to deploy Beacon using B2RI EGA user EGA Beacon EGA AF Browser

  Documentation about/projects-and-funders/beacon

• A Whole Genome Association Search for Type 2 Diabetes Genes in African Americans

  Over 2.8 million African Americans have type 2 diabetes mellitus (T2DM). This represents approximately 13% of the African American population and a significant proportion of the 21 million Americans living with diabetes. On average, an African American individual is twice as likely to have T2DM as a European American peer. Our research group has been actively involved in the study of African American diabetes genetics for over 15 years. We hypothesize that genes contributing to the development of T2DM in African Americans exist and can be located using modern molecular genetic methods. With the exception of TCF7L2(Transcription factor 7-like 2) evidence to date suggests variants that contribute T2DM risk in European-derived populations are not significant contributors to African American T2DM risk. We have performed a SNP-based Whole Genome Association (WGA) analysis on the Affymetrix 6.0 in a case control population of over 1000 African American T2DM cases and over 1000 non-diabetic controls. The DNAs have been collected from participants using uniform criteria from North Carolina and neighboring states. Genotype data will be subjected to extensive genetic analysis with the goal of defining a priority list of SNPs for genotyping in independent populations for confirmation and further detailed analysis.

  Study phs000140

• Finding the way towards the eradication of therapy-related myeloid neoplasms

  Therapy-related neoplasms are directly caused by the drugs used to eradicate a previous cancer. It is well known that a subset of drugs designed to kill cancer cells through DNA-damage-induced apoptosis can intrinsically, as secondary effect, cause DNA-damage in other cells, thus inducing a neoplasm. Those neoplasms have especially bad prognosis. Why are these drugs still in use? Because for many diseases we do not have anything better, at the moment. Approximately 0.5-1% of the kids treated for various types of cancers develop a therapy-related myeloid neoplasm (tMN) as a result of the treatment. Despite having the same origin, their prognostic and molecular features are different from the adult ones, and a complete understanding of the pathogenesis of tMN in children is still missing. A total of 84 paediatrics neoplasms have been profiled by either Whole Genome or Whole Exome sequencing by Jason R. Schwartz and his colleagues, in a collaborative effort guided at the St. Jude Children's hospital, in Memphis. They identified a mean of 28 somatic mutations per patient, a number which is significantly bigger than the number of mutations found in paediatrics primary neoplasms, as depicted in the original paper's figure 1b, shown here. Their sequencing data identified that Ras/MAPK pathway mutations, alterations in RUNX1 or TP53, and KMT2A rearrangements as the most frequent drivers of the disease. Clonal evolution analysis (the comparative study of the behaviour of cells harbouring different mutations) highlighted that, unlike in adults’ tMN, there were not pre-existing leukemic clones, and virtually all mutated cells were found arising as a direct consequence of cytotoxic therapy. This represents yet another important difference between adult and paediatric tMN. This important study have been published in Nature communications in February 2021. The sequencing data have been deposited at EGA under the study number EGAS00001004850. Thanks to this, other researchers around the world could re-use it to uncover more information, integrate and validate their studies. Revealing the molecular features underlying the development of cancers is the only way towards the development of new generation targeted therapies, which will allow us to finally drop the cytotoxic drugs eliciting such unwanted and catastrophic secondary effects as tMN. It is not an overstatement to say that, while improving the treatment of primary tumours, we could entirely eradicate therapy-related neoplasms right from their origin. Looking forward.

  Blog eradication-of-therapy-related-myeloid-neoplasms

• Efficacy of two different FGFR-inhibitors in a patient with extrahepatic cholangiocarcinoma harboring an FGFR2 mutation

  Cholangiocarcinomas (CCAs) is a type of cancer with few effective systemic therapies. Elucidation of the molecular landscape of the disease from genomic studies based on next generation sequencing (NGS) has contributed to the introduction of new targeted therapies. One of these treatments consists of a class of small molecules that target members of the FGFR family of receptor tyrosine kinases. These drugs are effective and have been approved for cholangiocarcinomas with fusions or rearrangements of FGFR genes. In contrast, the role of these inhibitors in cholangiocarcinomas with mutations in FGFR genes is less well defined. We report here a patient with a cholangiocarcinoma bearing a FGFR2 p.Ser252Trp mutation. The patient was treated with two different FGFR inhibitors, as the first caused ocular toxicity. She obtained clinical benefit from both. This case illustrates the efficacy of FGFR inhibitors on cholangiocarcinoma with specific point mutations. This is the first case to report the clinical benefit of these drugs in FGFR2 p.Ser252Trp mutation. Clinical benefit can be sustained, as seen in our patient. Our case also shows that FGFR inhibitors-induced adverse effects, such as ocular toxicities, may not recur after re-challenge with an alternative drug of the same class.

  Study EGAS50000000015

• A recessive PRDM13 mutation results in congenital hypogonadotropic hypogonadism and cerebellar hypoplasia

  The PRDM13 (PR Domain containing 13) putative chromatin modifier and transcriptional regulator functions downstream of the transcription factor PTF1A, which controls GABAergic fate in the spinal cord and neurogenesis in the hypothalamus. Here, we report a novel, recessive syndrome associated with PRDM13 mutation. Patients exhibited intellectual disability, ataxia with cerebellar hypoplasia, scoliosis and delayed puberty with congenital hypogonadotropic hypogonadism (CHH). Expression studies revealed Prdm13/PRDM13 transcripts in the developing hypothalamus and cerebellum in mouse and human. An analysis of hypothalamus and cerebellum development in mice homozygous for a Prdm13 mutant allele revealed a significant reduction in the number of Kisspeptin (Kiss1) neurons in the hypothalamus and PAX2+ progenitors emerging from the cerebellar ventricular zone. The latter was accompanied by ectopic expression of the glutamatergic lineage marker TLX3. Prdm13-deficient mice displayed cerebellar hypoplasia, normal gonadal structure, but delayed pubertal onset. Together, these findings identify PRDM13 as a critical regulator of GABAergic cell fate in the cerebellum and of hypothalamic kisspeptin neuron development, providing a mechanistic explanation for the co-occurrence of CHH and cerebellar hypoplasia in this syndrome. To our knowledge, this is the first evidence linking disrupted PRDM13-mediated regulation of Kiss1 neurons to CHH in humans.

  Study EGAS00001005878

• Cloning_of_the_breakpoint_of_a_novel_translocation_associated_with_T_acute_lymphoblastic_leukaemia

  Single case of T-ALL carrying t(4;6), a novel translocation.

  Study EGAS00001000520

• Whole Transcriptome Sequencing of Resectable Stage III/IV Melanoma Evaluated After Starting Hu14.18-IL2 Predicts Outcome

  Background: We analyzed whole transcriptome sequencing in tumors from 23 patients with stage III or IV melanoma from a pilot trial of the anti-GD2 immunocytokine, hu14.18-IL2, to identify predictive immune and/or tumor biomarkers in melanoma patients at high risk for recurrence. Methods: Patients were randomized to receive the first of 3 monthly-courses of hu14.18-IL2 immunotherapy either before (Group A) or after (Group B) complete surgical resection of all known disease. Tumors were evaluated by histology and whole transcriptome sequencing. Results: We report here that tumor infiltrating lymphocyte (TIL) levels directly associate with relapse-free survival (RFS) and overall survival (OS) in resected tumors from Group A, where early responses to the immunotherapy agent could be assessed. TIL levels directly associated with a previously reported immune signature which associated with RFS and OS, particularly in Group A tumors. In Group A tumors there were decreased cell cycling gene RNA transcripts, but increased RNA transcripts for repair and growth genes. We found that outcome (RFS and OS) was directly associated with several immune signatures and immune-related RNA transcripts and inversely associated with several tumor growth-associated transcripts, particularly in Group A tumors. Most of these associations were not seen in Group B tumors. Conclusion: We interpret these data to signify that both immunologic and tumoral cell processes, as measured by RNAseq analyses detected shortly after initiation of hu14.18-IL2 therapy are associated with long term survival and could potentially be used as prognostic biomarkers in tumor resection specimens obtained after initiating neoadjuvant immunotherapy. Note: RNA sequences and expression data can be found at NCBI GEO GSE133713

  Study phs001947

• PAGE: Global Reference Panel

  Stanford contributed samples to the PAGE study that can act as a population reference dataset across the globe. Therefore this dataset includes reference individuals, without phenotypes, chosen to help infer ancestry that will help us understand the diverse samples available in PAGE. The complete dataset comprises individuals of European, African, Asian, Oceanian, and Native American descent, from a total of over 50 populations. A subset of these individuals from Puno, Peru and Easter Island (Rapa Nui), Chile, are included in the PAGE samples that were whole genome sequenced in 2015. Additional details are available in the Study Acknowledgments. The Global Reference Panel comprises 6 sample sets: A population sample of Andean individuals primarily of Quechuan/Aymaran ancestry from Puno, Peru A population sample of Easter Island (Rapa Nui), Chile Individuals of indigenous origin from Oaxaca, Mexico Individuals of indigenous origin from Honduras Individuals of indigenous origin from Colombia Individuals of indigenous origin from the Nama and Khomani KhoeSan populations of the Northern Cape, South Africa In addition, we genotyped publicly available samples that will be hosted on the Bustamante lab website (https://bustamantelab.stanford.edu/). These comprise large public datasets to provide an open reference dataset for the world: The additional related individuals from the Americas in the Human Genome Diversity Panel (H952) plus all additional samples from the Americas A subset of the unrelated individuals from the Maasai in Kinyawa, Kenya (MKK) dataset from the International Hapmap Project hosted at Coriell Additional samples will be available for restricted use with a data access agreement with the Bustamante Lab. This study is part of the Population Architecture using Genomics and Epidemiology (PAGE) study (phs000356).

  Study phs001033

• Columbia University Study of Caribbean Hispanics with Familial and Sporadic Late Onset Alzheimer's disease

  Compared to Caucasians residing in the same community the incidence rate of Alzheimer's disease is approximately twice as high in Caribbean Hispanics. Moreover, Caribbean Hispanics represent a homogenous population with only a few founders. Replication of genetic associations in other ethnic groups provides supporting evidence that a putative gene is involved in the disease pathogenesis, and when different allelic variants within the same genes are associated with disease it can help to localize the pathogenic variant. SORL1 is an example of a candidate gene that was first identified in Hispanics and then confirmed in multiple ethnic and racial groups in a meta-analysis. For this project, we are genotyping 704 individuals in families multiply affected by Alzheimer's disease (166 families). These families were recruited in the United States, Puerto Rico and the Dominican Republic. In addition, we are genotyping 2491 individuals (960 patients with sporadic Alzheimer's disease and 1531 unrelated controls) phenotyped in a similar fashion totaling 3195 individuals. Both cohorts are followed at regular intervals of 18 to 24 months, and potential phenotypes available other than those related to Alzheimer's disease include body mass index, measured blood pressure, neurological history and examinations. More importantly, both studies are funded through 2014 and additional phenotypes could be added in successive waves. We propose a genome wide association (GWA) study of Alzheimer's disease and longitudinal changes in cognition and other age-related neurological and medical phenotypes. The goal will be to identify the chromosomal locations of genes underlying this disease and its related endophenotypes.

  Study phs000496

• Center Common Disease Genomics [CCDG] - Cardiovascular: Partners Biobank

  This study is a part of NHGRI's Center for Common Disease Genomics, a collaborative large-scale genome sequencing effort to comprehensively identify rare risk and protective variants contributing to multiple common disease phenotypes. Current estimates anticipate that the CCDG program will perform whole genome sequencing of 140K individuals and whole exome sequencing of 225K individuals over the course of the project. The Cardiovascular Disease working group of the CCDG considered five diseases: early-onset coronary artery disease (EOCAD), stroke, atrial fibrillation, congestive heart failure and type 2 diabetes. CAD is the leading cause of death in the world and common variant association studies show that our understanding of the underlying molecular mechanisms is incomplete (e.g, >2/3 of the 63 common variants previously mapped for CAD do not directly relate to known risk factors). CAD is representative of a class of common diseases with onset at middle age. When CAD occurs early in life, there is a stronger inherited component. In addition, there is empirical evidence that a burden of rare coding alleles in individual genes contribute to risk for CAD. Source: https://ccdg.rutgers.edu/sites/default/files/CCDG_CVD_EOCAD_STROKE_FINAL.pdf For this study, The Broad Institute of MIT and Harvard generated genetic data for ~13,500 individuals from the Partners Biobank, including using whole exome sequencing and whole genome genotyping (Infinium Global Screening Array), with 550 samples from patients with myocardial infarction, a type of EOCAD. Partners Biobank, launched in 2010, is a biobank composed of samples from Partners hospitals, including Massachusetts General Hospital and Brigham and Women's Hospital. The Biobank has enrolled >100K individuals to study how genes, lifestyle, and other factors affect people's health and contribute to disease.

  Study phs002018

• Genome Studies in Hereditary Spastic Paraplegia

  Next-generation sequencing technology is opening up new opportunities to rethink the way we identify disease causing genetic variation. An early application, whole exome sequencing, has now been established by a small number of research labs, including ours. Exome sequencing allows obtaining a near complete set of protein coding genomic variation in single individuals for less than $5,000. Promising targets for exome sequencing studies are Mendelian diseases, such as hereditary spastic paraplegias (HSP). HSP comprise a genetically very heterogeneous set of neurological disorders with currently 39 different HSP chromosomal loci being reported; yet, the identified genes explain only 60% of the genetic effect at best. Traditional methods of gene identification require linkage analysis of large families, but face increasing difficulties to identify such extended pedigrees for rare HSP forms. However, the innovative approach described in this application will overcome some of these limitations and utilize relatively small pedigrees for highly effective gene identification. We will apply exome sequencing, which will characterize all coding changes and flanking exonic variation in two individuals of a family. We have developed a multi-tiered strategy to reduce the number of identified novel variants to the very causative change in an individual family. We propose to study at least 60 HSP families, which are too small to yield conclusive results with linkage analysis. If the developing technology permits we will consider a larger sample or perform whole genome sequencing. Beyond the important benefit to genetics of HSP, this study will allow us to further establish this new method, which will benefit a large range of additional disease studies.

  Study phs001080

• ChiLDReN/BA: Genetic Studies of Biliary Atresia in the Childhood Liver Disease Research Network

  Biliary atresia (BA) is a progressive necroinflammatory process initially involving the extra-hepatic biliary tree. Little is known about the factors that cause BA or the factors that influence disease progression. A variety of genetic, autoimmune, and environmental influences have been hypothesized to be important. Most studies to date have focused on the neonate and young child with BA, yet the older surviving child with BA can provide important information about genetics as well as natural history.The Childhood Liver Disease Research Network (ChiLDReN) conducts two longitudinal and observational studies that include BA patients: Biliary Atresia Study in Infants and Children (BASIC) and A Prospective Database of Infants with Cholestasis (PROBE). Using samples from participants in these two protocols, we have formed the largest known data set of biliary atresia patients in the world. ChiLDReN is performing a series of genomic analyses, with subsequent analyses being released as subsequent versions of this registration, phs003356. Version 1 concerns PKD1L1.About the PKD1L1 Analysis (phs003356.v1): While multiple factors have been implicated in the perinatal biliary injuries that characterize BA, a definitive etiology has not yet been established. This study is part of a larger project to characterize the largest cohort of pediatric BA patients through whole-exome sequencing (WES). In this analysis, we examine the WES of those with various laterality defects to determine whether genetic factors could be identified to explicate the etiopathogenesis of BA in biliary atresia splenic malformation (BASM) syndrome. We specifically explored variations in the PKD1L1 gene, which recently has been identified in mouse models as playing a role in laterality.

  Study phs003356

• Lung Cancer Genetic Study Among Asian Never Smokers

  The Lung Cancer Genetic Study Among Asian Never Smokers includes data from four population-based studies conducted among Asian women: the Shanghai Women's Health Study (SWHS), the Hwasun Cancer Epidemiology Study (HCES1 and HCES2), the Female Lung Cancer Consortium in Asia (FLCCA, including sFLCA), and the Guangzhou Lung Cancer Study (GLCS). Shanghai Women's Health Study (SWHS): The SWHS is a population-based prospective cohort study of approximately 75,000 adult women who were recruited between 1997 and 2000. The cohort has been followed by a combination of record linkage and active follow-ups. Lung cancer patients identified in the SWHS and non-cases were included in the current study.Hwasun Cancer Epidemiology Study-Lung Cancer (HCES1 and HCES2): The HCES is a hospital-based case-control study whose goal is to identify factors of the cancer development and clinical progression in a Korean population. Included in this project were 299 female lung cancer cases from HCES2, who were diagnosed between April 2004 and February 2013 at Chonnam National University Hwasun Hospital, a cancer specified hospital in Jeollanam-do province, South Korea. Controls were randomly selected from women with no previous cancer diagnosis at enrollment in the Namwon Study and the Dong-gu study, ongoing community-based cohort studies in South Korea. A total of 1,103 controls (273 from HCES1 and 830 from HCES2) were genotyped by MEGA. Guangzhou Lung Cancer Study (GLCS): The GLCS is a case-control study including never-smoking women lung cancer cases and controls from Guangzhou, China.In this study, the DNA samples of 1,195 subjects from SWHS and GLCS were genotyped using whole exome sequencing (WES), and the DNA samples of 7,174 subjects from SWHS, HCES1, HCES2, FLCCA, and sFLCA were genotyped using the Multi-Ethnic Global Array (MEGA).

  Study phs002366

• Rapid Early Action for Coronary Treatment (REACT-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: This multicenter controlled community study developed and evaluated the impact of a community educational intervention program on participant delay time from onset of symptoms of an acute myocardial infarction (AMI) to arrival at a hospital emergency department.Background: Although early reperfusion or thrombolytic therapy can reduce morbidity and mortality following an AMI, delayed access to medical care in participants is relatively common. Mean delay times from symptom onset to hospital arrival range from more than 4 hours to 24 hours, and the largest component of prolonged delay is participant recognition and action.Participants: A total of 20 communities from 5 field centers in the U.S. were pair-matched (10 pairs) according to geographic proximity and demographic characteristics. After initiation of a 4 month baseline surveillance period, one community in each pair was randomly selected to receive the intervention. The baseline surveillance period was followed by an 18 month community intervention and surveillance period. The community surveillance captured a total of 59,944 adults aged 30 years or older presenting to hospital emergency departments with chest pain, of whom 20,364 met study criteria for suspected acute coronary heart disease (CHD) at admission and discharged with a CHD diagnosis.Conclusions: Delay times were decreased in the intervention and reference communities. The results showed that the multicomponent community intervention program did not differentially reduce delay time from onset of AMI symptoms to arrival at a hospital, but did significantly increase the use of Emergency Medical Services by these participants in the intervention communities. (PMID:10872014).

  Study phs003885

• National Emphysema Treatment Trial (NETT-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. Available Data: The current release of the NETT study dataset includes follow-up data through May of 2013.Objectives: To compare lung-volume-reduction surgery with medical therapy for severe emphysema, and to identify participant selection criteria for lung volume reduction surgery.Background: Lung-volume-reduction surgery has been proposed as a palliative treatment for severe emphysema. Effects on mortality, the magnitude and durability of benefits, and criteria for the selection of participants have not been established.Participants: A total of 1,218 participants with severe emphysema underwent pulmonary rehabilitation and were randomly assigned at 17 centers to undergo lung-volume-reduction surgery (bilateral stapled wedge resection) or to receive continued medical treatment. Participants were randomized after a 6-10 week pulmonary rehabilitation period and participants with a forced expiratory volume in one second (FEV1) that was 20 percent or less of predicted and a homogeneous distribution of emphysema or carbon monoxide diffusing capacity 20 percent or less of predicted were not eligible for randomization due to poor post-surgery prognosis for death or functional improvement.Conclusions: Overall, lung-volume-reduction surgery increases the chance of improved exercise capacity but does not confer a survival advantage over medical therapy. It does yield a survival advantage for participants with both predominantly upper-lobe emphysema and low base-line exercise capacity. Participants previously reported to be at high risk and those with non-upper-lobe emphysema and high base-line exercise capacity are poor candidates for lung-volume-reduction surgery, because of increased mortality and negligible functional gain. (NEJM 2003;348:2059-2073).

  Study phs004077

• Involvement of the FGF8/FGF Receptor Signaling Pathway in the Maintenance and Progression of Fusion-Positive Rhabdomyosarcoma

  In our previous work, we used a myoblast model of fusion-positive rhabdomyosarcoma (FP-RMS) to demonstrate that FGF8, a target of the PAX3-FOXO1 (P3F) transcription factor, is essential for tumorigenicity driven by P3F. When aberrantly expressed, FGF8 can also sustain tumorigenicity in recurrent tumors that are independent of P3F. In this study, we report that FGF8, along with its receptors FGFR1 and FGFR4, is often highly expressed in FP-RMS tumors. We found that high levels of FGF8 expression in FP-RMS cells correlate with increased sensitivity to an FGFR4 inhibitor and a pan-FGFR inhibitor. Conversely, downregulating FGF8 led to a loss of sensitivity to these inhibitors. Interestingly, when FGF8 was upregulated in myoblasts, it resulted in decreased FGFR4 expression and sensitized the cells to an FGFR1 inhibitor and a pan-FGFR inhibitor. The downregulation of FGFR4 expression mediated by FGF8 could be reversed by inhibiting FGFR1, MEK, or ERK, thereby defining a signaling pathway through which FGF8 exerts its regulatory effects. Additionally, we discovered that high FGF8 expression in P3F-independent recurrent tumors is due to a rearrangement of viral long terminal repeat (LTR) sequences into the 3' untranslated region (UTR) of FGF8, leading to increased stability of FGF8 mRNA. These findings indicate that FGF8 plays an oncogenic role in FP-RMS through FGFR4 and may also exert oncogenic effects in P3F-independent relapses via FGFR1. Our study highlights the functional significance of FGF8 in FP-RMS and supports the rationale for preclinical investigations of FGFR inhibitors in treating this type of cancer.

  Study phs004009

• RNAseq: Acquired non-permissive bone marrow microenvironment impairs hematopoietic stem cell proliferation and maintenance and B-cell development post-HSCT

  Defects in B-cell reconstitution upon hematopoietic stem-cell (HSC) transplantation (HSCT) are a common observation, yet the mechanism remains unexplained. The bone marrow (BM) stroma, including mesenchymal stromal cells (MSCs), guides HSC maintenance and B-lymphopoiesis by secreting crucial cytokines. We report acquired, permanent, selective and complete B-cell deficiency in the context of full donor-chimerism in a patient with X-linked lymphoproliferative disease and aimed to identify the contribution of the BM-microenvironment in disrupted B-cell reconstitution post-HSCT. We studied longitudinal BM samples from the patient and his identical twin, both of whom underwent HSCT with the same donor with opposite outcomes in B-cell reconstitution. In the index patient BM, we observed progressive loss of proliferation of HSCs and a selective block at the pre-BI cell stage. In vitro modeling studies showed limited survival of patient-HSCs and a relative accumulation of pre-B cells. Patient-derived MSCs failed to support survival and proliferation of HSCs and B-cell development of healthy-HSCs which was correlated with reduced CXCL12 levels. Using bulk RNA-sequencing of MSCs and in vitro functional studies, we showed global changes in the patients’ MSCs and a progressive loss of CXCL12 expression. Indeed, survival of patients HSCs improved supplementing in vitro development culture with CXCL12, suggesting a contribution of defective CXCL12 signaling to the phenotype. In summary, our data show that an acquired defect in the BM-stromal microenvironment and exhaustion of HSCs and committed progenitors may cause a permanent non-permissive state for normal B-cell development.

  Study EGAS50000001437

• ATAC-seq: Acquired non-permissive bone marrow microenvironment impairs hematopoietic stem cell proliferation and maintenance and B-cell development post-HSCT

  Defects in B-cell reconstitution upon hematopoietic stem-cell (HSC) transplantation (HSCT) are a common observation, yet the mechanism remains unexplained. The bone marrow (BM) stroma, including mesenchymal stromal cells (MSCs), guides HSC maintenance and B-lymphopoiesis by secreting crucial cytokines. We report acquired, permanent, selective and complete B-cell deficiency in the context of full donor-chimerism in a patient with X-linked lymphoproliferative disease and aimed to identify the contribution of the BM-microenvironment in disrupted B-cell reconstitution post-HSCT. We studied longitudinal BM samples from the patient and his identical twin, both of whom underwent HSCT with the same donor with opposite outcomes in B-cell reconstitution. In the index patient BM, we observed progressive loss of proliferation of HSCs and a selective block at the pre-BI cell stage. In vitro modeling studies showed limited survival of patient-HSCs and a relative accumulation of pre-B cells. Patient-derived MSCs failed to support survival and proliferation of HSCs and B-cell development of healthy-HSCs which was correlated with reduced CXCL12 levels. Using bulk RNA-sequencing of MSCs and in vitro functional studies, we showed global changes in the patients’ MSCs and a progressive loss of CXCL12 expression. Indeed, survival of patients HSCs improved supplementing in vitro development culture with CXCL12, suggesting a contribution of defective CXCL12 signaling to the phenotype. In summary, our data show that an acquired defect in the BM-stromal microenvironment and exhaustion of HSCs and committed progenitors may cause a permanent non-permissive state for normal B-cell development.

  Study EGAS50000001438