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• Childhood Cancer Data Initiative (CCDI): Pediatric In Vivo Testing Program - Neuroblastoma

  The goal of NCI's Pediatric In Vivo Testing Consortium (PIVOT) is to advance the development of effective treatments for pediatric cancers through preclinical in vivo testing of novel therapeutic agents. To design impactful experiments that can be rapidly translated to the clinic, PIVOT investigators require comprehensive genomic characterization of the patient-derived xenograft (PDX) models used across the consortium. This robust experimental design enhances collaboration with industry partners by providing proof-of-concept data for drugs in development. As part of this effort, neuroblastoma PDX models are being molecularly characterized to identify promising therapeutic candidates. The molecular profiling includes whole exome sequencing (WES), RNA-seq, MethylEPIC array, CytoSNP array, and DNA fingerprinting for quality control. Additionally, demographic and clinical data (e.g., diagnosis, disease site, disease status) are shared. These characterized PDX models, matched with patient tumors, guide model selection for preclinical drug testing.

  Study phs003163

• APOL1 Risk Variants Induce Metabolic Reprogramming of Podocytes in Patient-Derived Kidney Organoids

  Apolipoprotein L1 (APOL1) high-risk genotypes G1 and G2 are responsible for the increased risk of chronic kidney disease (CKD) in the African-American population, especially in the presence of interferon gamma (IFN-γ). Here, we applied single cell transcriptomics on kidney organoids generated from patient-derived induced pluripotent stem cells (iPSCs) to model human APOL1 nephropathy. iPSCs were generated from fibroblasts of two patients with APOL1 nephropathy homozygous for G1 or G2 risk variants, and an isogenic control (G0) was created by gene correction. Kidney organoids were generated according to previously published protocol (Takasato M et al. Nat. Protoc. 2016) and treated with IFN-γ for two days to induce APOL1. Twenty-four hours after IFN-γ removal, treated organoids from all three lines that were cultured in parallel were harvested for single cell transcriptomics.

  Study EGAS50000001223

• Determining genome-wide binding of ETS2 by CUT&RUN in primary human macrophages

  This dataset consists of sequencing data from an ETS2 CUT&RUN experiment in primary inflammatory (TPP) macrophages (n = 2). Pre-cultured TPP macrophages were harvested and processed immediately using the CUT&RUN Assay kit (Cell Signaling) according to the manufacturer’s instructions with the following modifications (essentially, avoiding the use of ConA-coated beads). Anti-ETS2 (ThermoFisher) or IgG control (Cell Signaling) antibodies were used for targeted digestion of chromatin. For each donor, 5x10^5 cells were pelleted, washed in Wash Buffer, and resuspended in Antibody Binding buffer. Cells were incubated with antibodies (1:100 dilution for anti-ETS2) for 2h at 4°C. After washing in Digitonin Buffer, cells were incubated with pA/G-MNase for 1h at 4°C. Cells were washed twice in Digitonin Buffer, resuspended in the same buffer and cooled for 5 minutes on ice. Calcium chloride was added to activate pA/G-MNase digestion and cells were incubated for 30 minutes at 4°C before Stop Buffer was added, and cells were incubated for 10 min at 37°C to release cleaved chromatin fragments. Supernatants were collected by centrifugation and DNA extracted using DNA Purification Buffers and Spin Columns (Cell Signaling). Library preparation was performed according to a protocols.IO protocol (dx.doi.org/10.17504/protocols.io.bagaibse) using the NEBNext Ultra II DNA Library Prep Kit. Size selection was performed using AMPure XP beads (Beckman Coulter) and fragment sizes were determined using an Agilent 2100 Bioanalyzer (High Sensitivity DNA kit). Equimolar pools of indexed libraries were sequenced on an Illumina NovaSeq 6000 (100bp PE reads). Raw data are provided as 100 bp paired-end Illumina reads.

  Dataset EGAD00001011349

• National Cancer Institute (NCI) Prostate Cancer Genome-Wide Association Study for Uncommon Susceptibility Loci (PEGASUS)

  This genome-wide association study was funded by the National Cancer Institute (NCI) to identify uncommon susceptibility loci for prostate cancer. A total of 4,600 prostate cancer cases and 2,840 controls of European ancestry from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial were genotyped using the Illumina HumanOmni2.5 and passed rigorous quality control filters. Additional genotype data (available in dbGap under other accession numbers) from 101 independent controls of European ancestry scanned with the HumanOmni2.5 were also included, resulting in a total of 4,600 cases and 2,941 controls for the published analysis. SNPs from the most promising regions, as determined by rank p-value, under multiple different models as well as select candidate genes were taken forward for replication using a custom Iselect chip in 6,575 cases and 6,392 controls of European ancestry. Results from the primary scan after imputation were then meta-analyzed with the Iselect results as well as results from previous GWAS. In a combined meta-analysis of the primary scan together with the custom Iselect replication and a previous GWAS, thirteen loci reached genome-wide significance (P < 5 x 10-8) for prostate cancer overall; however, each of them confirmed a previously reported locus. Although they did not reach genome-wide significance, we found evidence for two new suggestive loci at chromosome 16q22.2 (PKD1L3, rs12597458, P = 9.67 x 10-8) and 6p22.3 (CDKAL1, rs12198220, P = 2.13 x 10-7). In a combined case-only analysis of 12,518 prostate cancer cases, we identified two loci associated with Gleason score, a pathological measure of disease aggressiveness: rs35148638 at 5q14.3 (RASA1, P=6.49x10-9) and rs78943174 at 3q26.31 (NAALADL2, P=4.18x10-8). In a stratified case-control analysis, the SNP at 5q14.3 appears specific for aggressive prostate cancer (P=8.85x10-5) with no association for non-aggressive prostate cancer compared to controls (P=0.57). Only the cases and controls genotyped on the HumanOmni2.5 specifically for this study are included under this accession number. Controls (n=101) genotyped with the HumanOmni2.5 for another study are posted under a different accession number. Please note that the majority of prostate cancer cases and controls genotyped in CGEMS (and posted under a different accession number) are included in this study.

  Study phs000882

• Epigenomic priming of immune genes implicates oligodendroglia in multiple sclerosissusceptibility

  Multiple sclerosis (MS) is characterized by a targeted attack on oligodendroglia (OLG)and associated myelin by immune cells, which are thought to be the main drivers of MS susceptibility. Assessing chromatin accessibility and the transcriptome simultaneously at the single cell level, we found that immune genes exhibit a primedchromatin state in mouse and human OLG in a non-disease context, compatible withrapid transitions to immune-competent states in MS. We identified transcription factors as BACH1 and STAT1 involved in immune gene regulation in oligodendrocyteprecursor cells (OPCs). A subset of immune genes present bivalency of H3K4me3/H3K27me3 in OPCs, with Polycomb inhibition leading to their increased activation upon interferon-gamma (IFNg) treatment. Some MS susceptibility single-nucleotide polymorphisms (SNPs) overlap with these regulatory regions in mouse andhuman OLG, and treatment of mouse OPCs with IFNg leads to chromatin architecture remodeling at these loci and altered expression of interacting genes. Our data indicates that susceptibility for MS may involve OLG, which therefore constitute novel targets for immunological-based therapies for MS.

  Study EGAS00001005911

• National Heart Lung and Blood Institute Exome sequencing in SCID

  Analysis of the molecular etiologies of severe combined immunodeficiency (SCID) has led to important insights into the control of immune cell development. Most cases of SCID result from either X-linked or autosomal recessive inheritance of mutations in a known causative gene. However, in some cases, the molecular etiology remains unclear. To identify the cause of SCID in a patient known to lack the protein tyrosine phosphatase CD45, we utilized single nucleotide polymorphisms (SNP) arrays and whole exome sequencing. The patient's mother was heterozygous for an inactivating mutation in CD45, while the paternal alleles lacked mutations. The patient exhibited a single CD45 mutation identical to the maternal allele. Patient SNP array analysis revealed no change in copy number but loss of heterozygosity for the entire length of chromosome 1 (Chr1), indicating that disease was caused by uniparental disomy (UPD) with isodisomy of the entire maternal Chr1 bearing the CD45 mutation. Non-lymphoid blood cells and other mesoderm and ectoderm-derived tissues retained UPD of the entire maternal Chr1 in this patient who had undergone successful bone marrow transplantation. Exome sequencing revealed mutations in 7 additional genes bearing nonsynonymous SNPs predicted to have deleterious effects. These findings represent the first reported case of SCID caused by UPD and suggest UPD should be considered in SCID and other recessive disorders, especially when the patient appears homozygous for an abnormal gene found in only one parent. Evaluation for alterations in other genes affected by UPD should also be considered in such cases.

  Study phs000479

• whole-genome sequencing in 17 ESCC cases and whole-exome sequencing in 71 cases

  Esophageal cancer is one of the most aggressive cancers and the sixth leading cause of cancer death worldwide1. Approximately 70% of the global esophageal cancers occur in China and over 90% histopathological forms of this disease are esophageal squamous cell carcinoma (ESCC)2-3. Currently, there are limited clinical approaches for early diagnosis and treatment for ESCC, resulting in a 10% 5-year survival rate for the patients. Meanwhile, the full repertoire of genomic events leading to the pathogenesis of ESCC remains unclear. Here we show a comprehensive genomic analysis in 158 ESCC cases, as part of the International Cancer Genome Consortium (ICGC) Research Projects (http://icgc.org/icgc/cgp/72/371/1001734). We conducted whole-genome sequencing in 17 ESCC cases and whole-exome sequencing in 71 cases, of which 53 cases and additional 70 ESCC cases were subjected to array comparative genomic hybridization (a-CGH) analysis.

  Study EGAS00001000709

• Genome-Wide Association Study of Genetic Susceptibility for Graft-vs-Host Disease Cohort 1

  Allogeneic hematopoietic stem cell transplantation (Allo-HSCT) is the only curative therapy for many advanced hematologic malignancies. Allo-HSCT is associated with significant morbidities and mortality, mainly because of the graft-versus-host disease (GVHD) caused by donor T cells recognizing antigens present in recipient tissues, and initiating an alloimmune response resulting in damage to many organs including the skin, gastrointestinal (GI) tract, and liver in recipient. More than half of all Allo-HSCT recipients develop different degrees of GVHD (grades I-IV). About 20% of recipients develop severe GVHD (grades III-IV) that is associated with a very high morbidity and mortality. The most important factor determining the severity of GVHD is the genetic disparities between donors and recipients, as is reflected in human leukocyte antigen (HLA) haplotypes that are routinely checked for donor selection. Even when donors and recipients are HLA-identical, many recipients develop severe GVHD. As a result, non-HLA antigens are important determinants of acute GVHD. An interesting and unique aspect of GVHD is that it is the consequence of an interaction between antigens present in one individual with the immune system of another individual. As a result, genotypes of both donor and recipient, and their interactions affect the pathogenesis of GVHD. To determine the genetic risk factors for GVHD, in the first aim (discovery phase), we will conduct Genome-Wide Association Studies (GWAS) in 3,000 patients who underwent Allo-HSCT and in their respective donors (6000 DNA samples) that are provided to us by the Center for International Blood and Marrow Transplant Research (CIBMTR), a research collaboration between the NMDP and Medical College of Wisconsin. In the second aim, we will validate the association between high risk genotypes detected in the first aim and severe GVHD in 1,750 donors and 1,750 recipients of Allo-HSCT, and perform the joint analysis with the discovery samples. In the third aim, we will investigate the functional effect of SNPs detected and validated to be significantly correlated with the severity of acute GVHD in mixed lymphocyte reaction (MLR), as an ex vivo surrogate for an alloimmune response.

  Study phs002185

• High Frequency Ventilation in Premature Infants (HIFI-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 evaluate the hypothesis that high frequency oscillatory ventilation in preterm infants would reduce the incidence of mortality and pulmonary complications compared to conventional mechanical ventilation.Background: With the introduction of mechanical ventilation in preterm infants, mortality and morbidity significantly improved but remained high. The improvement in survival that accompanied the use of mechanical ventilation also brought about an increase in the incidence of pulmonary complications. The principal complication occurs in the form of bronchopulmonary dysplasia. Barotrauma and oxygen toxicity are considered to be in the pathogenesis for this disorder. Considerable interest in high frequency ventilation for preterm infants was generated when animal studies indicated high frequency ventilation to be effective in promoting gas exchange without apparent adverse effects. High Frequency Ventilation (HFV) delivers small tidal volumes at high frequencies of 4 to 15 Hz, and animal studies had indicated that HFV was associated with effective gas exchange, less barotrauma, and lower mean airway pressure. However, the efficacy and safety of HFV in preterm infants had not been studied. The HIFI Planning Phase was initiated in August 1984, and recruitment and intervention began in February, 1986. Follow-up studies continued thru September, 1988.Participants: A total of 673 infants were enrolled.Conclusions: Bronchopulmonary dysplasia incidence was similar in the two groups as was mortality and the need for ventilatory support during the first 28 days. There was a significantly greater rate of pneumoperitoneum of pulmonary origin in the high frequency group as was a greater incidence rate of intracranial hemorrhage. (HIFI Study Group, 1989, PMID: 2643039)

  Study phs004032

• A Phase 2 Study of Tipifarnib in Large Granular Lymphocyte (LGL) Leukemia

  LGL leukemia can be divided into three subsets including the following: αβ or γδT-LGL and NK-LGL leukemia. All three subtypes will be enrolled using a two-stage design. The primary endpoint of the study is assessment of overall clinical response. Correlative laboratory studies will be performed aimed at determining the mechanism of response to treatment. Thirteen participants will be accrued in the first stage at a dose of 300 mg BID administered intermittently every other week (i.e., 7 days on and 7 days off). If there are two or more responders, the protocol will be extended to a second stage of the study and accrual will be extended to 25 evaluable participants. Allowing for 10% rate of ineligibility due to unexpected events and dropout, we will accrue 14 patients in the first stage and 27 patients in total. Participants that withdraw from the study for reason unrelated to toxicity, will be replaced. There are two potential stopping rules for toxicity. If 3 or more participants out of the 13 enrolled in the first stage experiences grade IV neurotoxicity, the study will be stopped due to excessive toxicity. Dose reductions have been incorporated for hematologic toxicity. Treatment of T and NK LGL leukemia with immunosuppressive agents such as low-dose methotrexate generally require from four to six months for a clinical response and sometimes much longer. Therefore, in participants who show clinical improvement with less than grade three toxicity, tipifarnib treatment will be continued for as many as four additional months (12 months total). After the first 8 months, response will be assessed. The protocol treatment will be discontinued in participants with progression of disease. A long-term follow up will be performed for five years in patients that receive a complete clinical response. The long-term follow up will consist of vital signs, weight, CBCs, serum chemistries, and physical examination at six month intervals.

  Study phs000594

• ENU_CCK_81_cetuximab_pilot_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.

  Study EGAS00001001743

• 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

  Study EGAS00001001744

• ENU_NCI_H508_Cetuximab_SecondRound

  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

  Study EGAS00001001745

• Genetic analysis in an inherited cardiac arrhythmia

  To identify a causative gene for an inherited cardiac arrhythmia, exome sequence analysis was conducted in 6 patients and 5 controls.

  Study JGAS000041

• In vitro reconstitution of epigenetic reprogramming in the human germ line

  Epigenetic reprogramming resets parental epigenetic memories and differentiates primordial germ cells (PGCs) into mitotic pro-spermatogonia or oogonia, ensuring sexually dimorphic germ-cell development for totipotency. In vitro reconstitution of epigenetic reprogramming in humans remains a fundamental challenge. Here, we establish a robust strategy for inducing epigenetic reprogramming and differentiation of pluripotent stem cell (PSC)-derived human PGC-like cells (hPGCLCs) into mitotic pro-spermatogonia or oogonia, coupled with their extensive amplification (~>1010-fold). Strikingly, bone morphogenetic protein (BMP) signalling is a key driver of these processes: BMP-driven hPGCLC differentiation involves an attenuation of the mitogen-activated protein kinase/extracellular-regulated kinase (MAPK/ERK) pathway and both de novo and maintenance DNA methyltransferase (DNMT) activities, likely promoting replication-coupled, passive DNA demethylation. On the other hand, hPGCLCs deficient in tens-eleven translocation (TET) 1, an active DNA demethylase abundant in human germ cells, differentiate into extraembryonic cells, including amnion, with de-repression of key genes bearing bivalent promoters; these cells fail to fully activate genes vital for spermatogenesis and oogenesis, with their promoters remaining methylated. Our study elucidates the framework of epigenetic reprogramming in humans, making a fundamental advance in human biology, and through the generation of abundant mitotic pro-spermatogonia and oogonia-like cells, represents a milestone for human in vitro gametogenesis (IVG) research and its potential translation into reproductive medicine.

  Study JGAS000690

• Limited Association between HRR Gene Alterations and HRD in Molecular Tumor Board Cancer Samples: Who should be tested for HRD?

  Alterations in Homologous Recombination Repair (HRR) Pathway genes have been found to be associated with HR-Deficiency (HRD), which is an approved biomarker for PARP Inhibitor (PARPi) treatment. The aim of a Molecular Tumor Board (MTB) is to identify molecular alterations in cancer patients with advanced tumors that may suggest off-label treatment options. So far, few studies have analyzed the presence of HRR gene mutations and their association with HRD outside of clinical studies. Currently, no data on HRD testing in the setting of a MTB have been published. For the present study, a cohort of 237 patients encompassing 24 different tumor entities was collected from the MTB of the Comprehensive Cancer Center Erlangen-EMN. We show that an elevated Genomic Instability Score (GIS ≥ 42) can occur in samples with and without mutations in HRR-related genes. Overall, 38.1% of cancer samples with BRCA1/2 mutations, 10.9% of tumors with alterations in HRR genes other than BRCA1/2, and 4.3% of cancer samples without HRR gene mutations harbored an elevated GIS. Notably, our data show that various inactivating BRCA1/2 mutations are not associated with an elevated GIS. Taken together, panCancer assessment of HRD in addition to BRCA1/2 and other HRR gene mutational analysis is recommended to guide decisions regarding PARPi treatment. Further studies are needed to establish thresholds for GIS in non-ovarian cancer entities. Finally, HRD can be observed in 4.3% of BRCA1/2 and other HRR gene wildtype cancer samples, and may emerge as an independent biomarker for PARPi in the future.

  Study EGAS00001008063

• Mucociliary Clearance Consortium (MCC) Rare Genetic Disorders of the Airways: Cross-section Comparison of Clinical Features, and Development of Novel Screening and Genetic Test

  We have established a consortium of 7 geographically-dispersed clinical research sites that are designed to study rare diseases of the airways, which involve defects in clearance of mucus secretions from the airways (defective "mucociliary clearance"). These sites will collaborate in diagnostic, genetic, and other studies in patients with impairments of mucociliary clearance, including primary ciliary dyskinesia (PCD), variant cystic fibrosis (CF), and pseudohypoaldosteronism (PHA). These disorders reflect genetic defects in airway host-defense, and typically result in chronic infection of the airways. Patients with these disorders of the conducting airways and sinuses have delayed (or incorrect) diagnoses, because diagnostic tests are not readily available. These patients may also have sub-optimal management of their clinical disease, because the cause of these disorders is not well-defined, and treatment regimens are usually not driven by evidence-based medicine. This current protocol is designed to employ a systematic approach to the diagnostic evaluation of these patients with chronic airways disease, which will yield precise diagnoses in individual patients, and will be associated with development of better diagnostic techniques, including genetic testing. In addition, we will compare/contrast clinical features (phenotype) across these disorders. A rigorous cross-sectional comparison of the clinical features will provide better understanding of the clinical disease of these disorders; in turn, this will lead not only to a better standard of clinical care, but will also assist in the identification of novel therapeutic approaches. The patient population for these studies includes individuals carrying a tentative diagnosis of the three disorders (PCD, variant CF or PHA), plus individuals suspected to have one of these disorders, but with inadequate or inconclusive diagnostic tests. Individuals in this latter category must have a preliminary clinical evaluation to evaluate for other more common disorders that may have similar manifestations including classical CF, immunodeficiency, asthma, and severe gastroesophageal reflux. We have an informal agreement with a network of pulmonologists across the United States to perform clinically-indicated (not research) preliminary clinical testing, if not directly available to patients who inquire about these studies. Blood will be collected for DNA to test for genetic mutations. The blood samples will be processed to establish a cell line (lymphocyte transformation) for a source of DNA for future genetic studies, in participants with disease. For participants unable to provide a blood sample, a buccal sample will be obtained for DNA.

  Study phs000595

• HTAN Pilot Project: Single-Cell Transcriptomics Toolbox for Fresh and Frozen Human Tumors (Lung, Breast, Ovarian, Melanoma, Neuroblastoma, Sarcoma, Glioblastoma, Glioma, and Leukemia)

  Single cell transcriptomics is a powerful tool to map the complex tumor microenvironment, providing unprecedented resolution into cell types, cell states, cell interactions, and tumor heterogeneity. Depending on their tissue site and whether processing begins from a fresh or frozen sample, different tumors require different optimizations in order to obtain high quality single cell transcriptomic data. In this study, we profiled a range of tumor types, varying in cell-of-origin, solid and non-solid forms, patient ages, and transitions. The tumors also further varied in their tissue site and in their sample collection method. To enable profiling of such diverse samples, we developed a systematic toolbox for single cell RNA-Seq and single nucleus RNA-Seq of fresh and frozen clinical tumor samples. We validated this toolbox for 216,490 cells and nuclei extracted from 39 samples across 23 tumors (some tumors were split into multiple samples). The 23 tumors represented eight unique tumor types. This toolbox comprises both experimental and computational protocols as well as guidelines for comparing and selecting protocols for the biological problem of interest.

  Study phs001983

• NINDS-Genome-Wide Genotyping in Parkinson's Disease: First Stage Analysis and Public Release of Data

  Epidemiological studies have estimated a cumulative prevalence of PD of greater than 1 per thousand. When prevalence is limited to senior populations, this proportion increases nearly 10-fold. The estimated genetic risk ratio for PD is approximately 1.7 (70% increased risk for PD if a sibling has PD) for all ages, and increases over 7-fold for those under age 66 years. The role for genes contributing to the risk of PD is therefore significant. This study utilized the well characterized collection of North American Caucasians with Parkinson's disease, and neurologically normal controls from the sample population which are banked in the National Institute of Neurological Disorders and Stroke (NINDS Repository) collection for a first stage whole genome analysis. Genome-wide, single nucleotide polymorphism (SNP) genotyping of these publicly available samples was originally done in 267 Parkinson's disease patients and 270 controls, and this has been extended to include genome wide genotyping in 939 Parkinson's disease cases and 802 controls. The NINDS repository was established in 10-2001 towards the goal of developing standardized, broadly useful diagnostic and other clinical data and a collection of DNA and cell line samples to further advances in gene discovery of neurological disorders. All samples, phenotypic, and genotypic data are available to the research community including to academics and industry scientists. In addition, well characterized neurologically normal control subjects are a part of the collection. This collection formed the basis of this first stage study by Fung et al., and the expanded study by Simon-Sanchez et al. The genotyping data was generated and provided by the laboratory of Dr. Andrew Singleton NIA, and Dr. John Hardy NIA (NIH Intramural, funding from NIA and NINDS). Important links to apply for individual-level data Data Use Certification Requirements (DUC) Apply here for controlled access to individual level data Participant Protection Policy FAQ

  Study phs000089

• TK-EPN862 - Patient-dervied xenograft model of Posterior Fossa A Ependymoma - RNAseq

  Ependymomas (EPN) are the third most common malignant brain cancer in children. Treatment strategies for pediatric EPN have remained unchanged over recent decades, with 10-year survival rates stagnating at just 67% for children aged 0-14 years. Moreover, patients who survive treatment for the most common subtype of pediatric EPN (posterior fossa A (PFA)), often suffer long-term neurological side effects as a result of therapy. It is evident that there is a need for safer, more effective treatments for pediatric EPN patients. There are ten distinct subgroups of EPN, each with their own molecular and prognostic features. To identify and facilitate the testing of new treatments for EPN, in vivo laboratory models representative of the diverse molecular subtypes are required. Here, we describe the establishment of a patient-derived orthotopic xenograft (PDOX) model of PFA EPN, derived from a metastatic cranial lesion. Patient and PDOX tumors were analyzed using immunohistochemistry, DNA methylation profiling, whole genome sequencing (WGS) and RNA sequencing. Both patient and PDOX tumors classified as PFA EPN by methylation profiling, and shared similar histological features consistent with this molecular subgroup. RNA sequencing revealed that gene expression patterns were maintained across the primary and metastatic tumors, as well as the PDOX. Copy number profiling revealed gains of chromosomes 7, 8 and 19, and loss of chromosomes 2q and 6q in the PDOX and matched patient tumor. No clinically significant single nucleotide variants were identified, consistent with the low mutation rates observed in PFA EPN. Overexpression of EZHIP RNA and protein, a common feature of PFA EPN, was also observed. Despite the aggressive nature of the tumor in the patient, this PDOX was unable to be maintained past two passages in vivo. Others who have successfully developed PDOX models report some of the lowest success rates for EPN compared to other pediatric brain cancer types attempted, with loss of tumorigenicity not uncommon, highlighting the challenge in propagating these tumors in the laboratory. Here, we discuss our collective experiences with PFA EPN PDOX model generation and propose potential approaches to improve future success in establishing preclinical EPN models

  Study EGAS00001006844

• Institut Curie Neuroblastoma Whole Genome Sequencing Diagnosis Relapse

  Neuroblastoma, a clinically heterogeneous pediatric cancer, is characterized by distinct genomic profiles but few recurrent mutations. As neuroblastoma is expected to have high degree of genetic heterogeneity, study of neuroblastoma's clonal evolution with deep coverage whole-genome sequencing of diagnosis and relapse samples will lead to a better understanding of the molecular events associated with relapse. Samples were included in this study if sufficient DNA from constitutional, diagnosis and relapse tumors was available for WGS. Whole genome sequencing was performed on trios (constitutional, diagnose and relapse DNA) from eight patients using Illumina Hi-seq2500 leading to paired-ends (PE) 90x90 for 6 of them and 100x100 for two. Expected coverage for sample NB0175 100x100bp was 30X for tumor and constitutional samples. For the seven other patients expected coverage was 80X for tumor samples with PE 100x100, 100X in the other tumor samples and 50X for all constitutional samples (see table 1). Following alignment with BWA (Li et al., Oxford J, 2009 Jul) allowing up to 4% of mismatches, bam files were cleaned up according to the Genome Analysis Toolkit (GATK) recommendations (Van der Auwera et al., Current Protocols in Bioinformatics, 2013, picard-1.45, GenomeAnalysisTK-2.2-16). Variant calling was performed in parallel using 3 variant callers: GenomeAnalysisTK-2.2-16, Samtools-0.1.18 and MuTect-1.1.4 (McKenna et al., Genome Res, 2010; Li et al., Oxford J, 2009 Aug; Cibulskis et al., Nature, 2013). Annovar-v2012-10-23 with cosmic-v64 and dbsnp-v137 were used for the annotation and RefSeq for the structural annotation. For GATK and Samtools, single nucleotide variants (SNVs) with a quality under 30, a depth of coverage under 6 or with less than 2 reads supporting the variant were filter out. MuTect with parameters following GATK and Samtools thresholds have been used to filter our irrelevant variants. .SNVs within and around exons of coding genes overlapping splice sites.. Then,variants reported in more than 1% of the population in the 1000 genomes (1000gAprl_2012) or Exome Sequencing Project (ESP6500) have been discarded in order to filter polymorphisms. Finally, synonymous variants were filtered out. MuTect focuses on somatic by filtering with constitutional sample. Mpileup comparison between constitutional and somatic DNAs allowed us to focus also on tumor specific SNVs with GATK and Samtools. Finally, every SNV called by our pipeline and also supported in any constitutional samples were filtered our in order to prevent putative constitutional DNA coverage deficiency. Then we analyzed CNVs (copy number variants) with HMMcopy-v0.1.1 (Gavin et al., Genome Res, 2012) and control-FREEC-v6.7 (Boeva et al., Bioinformatics 2011) with a respective window of 2000bp and 1000 bp, and auto-correction of normal contamination of tumor samples for Control-FREEC. Finally we explored Structural variants (SVs) including deletions, inversions, tandem duplications and translocations using DELLY-v0.5.5 with standard parameters (Rausch et al., Oxford J, 2012). In tumors, at least 10 supporting reads were required to make a call and 5 supporting reads for the sample NB0175 with a coverage of only 40X (see table 2). To predict SVs in constitutional samples for subsequent somatic filtering, only 2 supporting reads were required in order not to miss one. To identify somatic events, all the SVs in each normal sample were first flanked by 500 bp in both directions and any SVs called in a tumor sample which was in the combined flanked regions of respective normal sample was removed (see graph 1). Deletions with more than 5 genes impacted or larger than 1Mb and inversions or tandem duplications covering more than 4 genes, were removed. We focused on exonic and splicing events for deletions, inversions, and tandem duplications. For translocation, we keep all SVs that occurred in intronic, exonic, 5'UTR, upstream or splicing regions. Bioinformatics detection of variations with Deep sequencing approach Once PE reads merged and adaptors trimmed by SeqPrep with default parameters, merged reads were aligned via the BWA (Li H. and Durbin R. 2009 PMID 19451168) allowing up to 1 differences in the 22-base-long seeds and reporting only unique alignments. Only reads having a mapping quality 20 or more have been further analysed. Variant calling software was not used, since we aimed to predict variations at low frequencies, observed in less than 1% of reads. Such variants require a custom approach. Using DepthOfCoverage functions of the Genome Analysis Toolkit (GATK) v2.13.2 (McKenna A, et al., 2010 Genome Research PMID: 20644199), we focused on high quality coverage of bases A, C, G and T at the targeted variant position. Depth of coverage of each base following a mapping quality higher than 20 and a base quality higher than 10 have been taken into account in order to focus only on high quality data. Aiming to determine the background level of variability at the studied regions, 10 control samples were included in the analysis. The same approach and filtering criteria have been applied as introduced above over the entire amplicons. In order to highlight variants, for each sample the frequencies of each bases at each amplicon position were then compared to those observed in the set of controls. Statistical analyses were performed with the R statistical software (http://www.R-project.org). Fisher’s exact two-sided tests with a Bonferroni correction were performed to compare percentages of bases between the data sets, i.e. for a given base between a case and the controls. Finally, significant variations were filtered-in once (i) a significant increase in the percentage of avariant base and (ii) a significant decrease in the percentage of it's reference base following our p.values criteria was observed (p.val < 0.05).

  Dataset EGAD00001001356

• Most HCCs in Taiwan show the mutational signature of aristolochic acid

  Plants in the genus Aristolochia contain the mutagen aristolochic acid (AA) and have been widely used in traditional medicines and for weight loss. AA binds covalently to genomic DNA and induces a highly distinctive mutational signature. While AA involvement in urinary-tract cancers in Taiwan is known, the possible role of AA in hepatocellular carcinomas (HCCs) in Taiwan has not been examined. Here, we whole-exome sequenced 98 unselected HCCs from Taiwan and analyzed the mutational signatures for evidence of AA mutagenesis. Remarkably, more than 78% of HCCs showed strong evidence of AA mutagenesis, often associated with high mutation burdens. Non-synonymous mutations in genes known to be HCC driver genes were detected. Importantly, we elucidated the potential of immunotherapy in this cohort of liver cancer patients.

  Study EGAS00001002301

• ABIS_1_MeDIP-seq

  We investigated changes in whole genome DNA-methylation in a group of 48 healthy five-year-old children differentiated by their hair cortisol levels. By combining this novel biomarker for chronic stress with methylated DNA immunoprecipitation sequencing (MeDIP-seq), we found that high cortisol were associated with a genome-wide decrease in DNA-methylation targeted to specific zinc finger transcription factor binding sites, repetitive elements and genes important for neurodevelopment and calcium transport. Large scale hypomethylation of repetitive regions, as well as a deficient calcium transport, have been reported in many stress related diseases, as well as in many cancers and biological aging. Thus our findings may aid in our understanding of how susceptibility to these diseases develops.

  Study EGAS00001001099

• Germline Genetic Variants in Cancer-Susceptibility Genes in Patients with Osteosarcoma

  We conducted whole-exome sequencing of germline DNA from patients with osteosarcoma to estimate the frequency of pathogenic/likely pathogenic germline genetic variants in known cancer-susceptibility genes in a large population of osteosarcoma patients unselected for family history.

  Study phs002444

• Mutational_burden_in_skin_following_UV_treatment_Nanoseq

  We wish to assess the changes in mutational burden in patients under going UV treatment for psoriasis. Using duplex sequencing we will assess mutational burden in traditionally sun exposed (arm) and non-sun exposed (buttock) skin epidermis both pre and post UV treatment.

  Study EGAS00001007681