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• Mitochondrial Abnormalities in Schizophrenia and Bipolar Disorder

  Mitochondrial DNA structural variation is one proposed indicator of mitochondrial dysfunction. The large common deletion of mitochondrial DNA (mtDNA) increases with aging across multiple brain regions. We found other large deletions of mtDNA in brain at levels comparable to the common deletion (PMID: 30869147). Since mtDNA molecules replicate independently of nuclear division, the mtDNA copy number is a measure of mitochondrial health; levels are negatively correlated with age and all-cause morbidity. Complex I activity is another functional measure of mitochondria. We previously published a subset of this data from DLPFC (PMID: 29594135) for three indicators (common deletion, mtDNA copy number, Complex I activity). For this study, four indicators (common deletion, large deletions, mtDNA copy number, Complex I activity) were measured in four brain regions from subjects with schizophrenia (SZ) and bipolar disorder (BD) and compared to controls. The four brain regions were: the dorsolateral prefrontal cortex, superior temporal gyrus, primary visual cortex (V1), and nucleus accumbens.    

  Study phs002395

• Genome-Wide Association Study of Parkinson Disease: Genes and Environment

  This is a gene-environment study of Parkinson's disease. PD is a common, progressive, age-related, movement disorder that affects 1-2% of the people over the age of 65. The NeuroGenetics Research Consortium (NGRC) is the infrastructure of the study. Protocols and methods are standardized across NGRC clinics and labs as much as possible. The 2000 patients and 2000 control subjects selected for this GWAS were recruited at the NGRC-affiliated movement disorder clinics in Oregon, Washington, Georgia and New York. All 4000 subjects were white and all DNA samples were extracted from whole blood and unamplified. Seventy-five percent of subjects have data on cigarette smoking and caffeinated coffee consumption, which are inversely associated with PD risk. This study population represents the norm for clinical genetic studies of PD; i.e., NGRC estimates of risk to relatives, heritability, genotype frequencies, and exposure frequencies (see references) are very close to estimates from meta-analyses.

  Study phs000196

• A Comprehensive Platform for Analyzing Longitudinal Multi-Omics Data

  PALMO (Platform for Analyzing Longitudinal Multi-omics data) is a platform for analyzing longitudinal data from bulk as well as single cell. It allows to identify inter-, intra-donor variations in genes over longitudinal time points. The analysis can be done on bulk expression dataset without known cell type information or single cell with cell type or user defined groups. It allows to infer stable and variable features in a given donor and each cell type or a user defined group. The outlier analysis can be performed to identify technical/biological perturbed samples in a donor or a participant. Further, differential analysis can be performed to decipher time-wise changes in gene expression in a cell type. The data that is available in the dbGaP is the demo longitudinal samples used in the study, which includes hashed raw fastq files for single-cell RNA-sequencing (scRNA-seq) and non-hashed fastq files for single-cell ATAC-sequencing (scATAC) experiment.

  Study phs003203

• Epigenomics of Patient Outcomes after Aneurysmal SAH

  This project was focused on understanding the pathophysiology following aneurysmal subarachnoid hemorrhage (aSAH). DNA methylation is a key mechanism for regulation of gene expression and function in the adult brain and appears to play an important role in neuroprotection during ischemic events in the brain. Delayed cerebral ischemia (DCI), occurring during the acute phase following aSAH, is a major contributor to the complications that later develop; however, the pathophysiology of DCI and the development of complications is not known. We hypothesize that characterizing the methylome representing the CNS environment post aSAH will clarify the pathophysiology associated with DCI and patient outcomes. The aims of this project focused on the daily genome-wide methylomic changes that occur in DNA representing the CNS for the first 14 days after aSAH, as well as in peripheral blood in a subset of partcipants, and determining if this methylomic data impacts DCI and the development of complications after aSAH.

  Study phs001990

• Structurally Complex Osteosarcoma Genomes Exhibit Limited Heterogeneity within Individual Tumors and across Evolutionary Time

  A key characteristic of osteosarcoma is extensive and complex genomic rearrangements. However, published models explaining how these genomic rearrangements occur disagree about if these rearrangements occur early in tumor progression and then are stable afterwards, or if there is ongoing genomic instability. Previous studies have employed bulk sequencing technologies to characterize genomic alterations. A limitation of this approach is that it averages all changes within the bulk sample, essentially masking intra-sample heterogeneity and making evaluation of ongoing genomic instability difficult. To overcome this limitation and compliment previous work, we utilized single-cell whole genome sequencing to quantify somatic copy number alterations (SCNA). By interrogating individual cells within a sample, we were able to examine intra-sample heterogeneity. We found that the SCNA patterns between cells within a single sample were remarkably consistent, which supports the concept that the genomes of osteosarcoma tumors are relatively stable after early genome fragmentation events.

  Study phs003209

• Genetic Analysis of Latin American Cervical Cancer

  HPV16 is the most oncogenic type of human papillomaviruses (HPV). Integration of HPV into the human genome is an important mechanism of carcinogenesis but is absent in at least 30% of HPV16+ tumors. We applied long-read whole-genome sequencing (WGS) to cervical cancer cell lines and tumors to characterize HPV16 carcinogenesis in the absence of integration. WGS of HPV16+ cervical tumor samples from Latin America revealed that 11/20 tumors with only episomal HPV (EP) had intact monomer episomes. The remaining 9 EP tumors had multimer and rearranged HPV genomes. The majority (80%) of the HPV rearrangements and deletions disrupted the E1 and E2 genes, and EP tumors overexpressed the E6 and E7 viral oncogenes, a similar profile to tumors with HPV integration. Tumors with putative multimer HPV integrations display HPV multimers and concatemers of human and viral sequences. Our data uncovered a novel mechanism for HPV16 to cause cancer without integration through aberrant episomal replication, and forming rearranged, mutated, and multimer episomes.

  Study phs002810

• Single cell chromatin accessibility allows analysis of the transposable element landscape, revealing shared features of immune tissue-residency

  Tissue adaptation is required for regulatory T (Treg) cells to function within organs. Whether this program shares similarities between different tissue-localized immune populations is poorly understood. Here, we addressed this by analyzing single-cell chromatin accessibility data, including the transposable element (TE) landscape, of CD45+ immune cells from different tissues. We identified features of organ-specific tissue adaptation across different immune cells. Focusing on tissue-Treg cells, we found that the Treg tissue adaptation program was conserved in other tissue-localized immune cells, such as amphiregulin-producing Th17 cells. Accessible TEs can act as regulatory elements but their contribution to tissue adaptation is unclear. TE landscape analysis revealed an enrichment of specific transcription factor binding motifs in TE regions within accessible chromatin peaks. TEs, specifically from the LTR family, were located in enhancer regions and associated with tissue adaptation. These findings broaden our understanding of immune tissue-residency, an important step towards organ-specific immune interventions.

  Study EGAS50000000350

• Base-excision repair pathway shapes 5-methylcytosine deamination signatures in pan-cancer genomes

  Transition of cytosine to thymine in CpG dinucleotides is the most frequent type of mutation in cancer. This increased mutability is commonly attributed to spontaneous deamination of 5-methylcytosine (5mC), which is normally repaired by the base-excision repair (BER) pathway. However, the contribution of 5mC deamination in the increasing diversity of cancer mutational signatures remains poorly explored. Here, we integrate mutational signatures analysis in a large series of tumor whole genomes with lineage-specific epigenomic data to draw a detailed view on 5mC deamination in cancer. We uncover tumor type-specific patterns of 5mC deamination signatures in CpG and non-CpG contexts. We demonstrate that the BER glycosylase MBD4 preferentially binds to open chromatin domains, which correlates with lower mutational burden in these domains. We validate our findings by modelling BER deficiencies in isogenic cell models. Overall, we establish MBD4 as the main actor responsible for 5mC deamination repair in humans.

  Study EGAS50000000536

• IL-17B uses IL-17RA and IL-17RB to induce Type-2 inflammation from human lymphocytes

  IL-17 family cytokines are critical to host defense responses at cutaneous and mucosal surfaces. Whereas IL-17A, IL-17F, and IL-17C induce overlapping inflammatory cascades to promote neutrophil-mediated immunity, IL-17E/IL-25 drives type 2 immune pathways and eosinophil activity. Genetic and pharmacological studies reveal the significant contribution these cytokines play in antimicrobial and autoimmune mechanisms. However, little is known about the related family member, IL-17B, with contrasting reports of both pro- and anti-inflammatory function in rodents. We demonstrate that in the human immune system, IL-17B is functionally similar to IL-25 and elicits type 2 cytokine secretion from innate type 2 lymphocytes, NKT, and CD4+ CRTH2+ Th2 cells. Like IL-25, this activity is dependent on the IL-17RA and IL-17RB receptor subunits. Furthermore, IL-17B can augment IL-33–driven type 2 responses. These data position IL-17B as a novel component in the regulation of human type 2 immunity.

  Study EGAS50000000579

• Pyjacker identifies enhancer hijacking events in acute myeloid leukemia including MNX1 activation via deletion 7q

  Acute myeloid leukemia with complex karyotype (ckAML) is characterized by high genomic complexity, including frequent TP53 mutations and chromothripsis. We hypothesized that the numerous genomic rearrangements could reposition active enhancers near proto-oncogenes, leading to their aberrant expression. We developed pyjacker, a computational tool for the detection of enhancer hijacking events, and applied it to a cohort of 39 ckAML samples. Pyjacker identified motor neuron and pancreas homeobox 1 (MNX1), a gene aberrantly expressed in 1.4% of AML patients, often as a result of del(7)(q22q36) associated with hijacking of a CDK6 enhancer. MNX1-activated cases show significant co-occurrence with BCOR mutations and a gene signature shared with t(7;12)(q36;p13) pediatric AML. We demonstrated that MNX1 is a dependency gene, as its knockdown in a xenograft model reduces leukemia cell fitness. In conclusion, enhancer hijacking is a frequent mechanism for oncogene activation in AML.

  Study EGAS50000000743

• Parent-of-origin dependent DNA methylation and gene expression in the human placenta

  DNA methylation is globally reprogrammed after fertilization and the parental genomes have similar DNA methylation profiles after implantation except at the germline differentially methylated regions (gDMRs). We, and others, have previously shown that there are a large number of transient gDMRs in human blastocysts, whose differential methylation is lost in embryonic tissues after implantation. In this study we employed genome-wide allelic DNA methylation analyses of highly purified trophoblast cells from human placentas. ~40% of the transient-in-embryo gDMRs maintained their parent-of-origin-dependent biased allelic methylation. RNA sequencing-based allelic expression analyses revealed that some of the placental-specific gDMRs were associated with novel imprinted genes. This approach identified the first examples of X-linked gDMRs specific to the placenta. These findings highlight the unique regulation of allelic DNA methylation in the human placenta, which is important for understanding normal placental development and the pathogenesis of pregnancy complications.

  Study JGAS000038

• Single cell transcriptomic analysis of the immune cell compartment in the human small intestine and in Celiac disease

  Celiac disease is an autoimmune disorder in which ingestion of dietary gluten triggers an immune reaction in the small intestine leading to destruction of the lining epithelium. Current treatment focusses on lifelong adherence to a gluten-free diet. Gluten-specific CD4+ T cells and cytotoxic intraepithelial CD8+ T cells have been proposed to be central in disease pathogenesis. Here we use unbiased single-cell RNA-sequencing and explore the heterogeneity of CD45+ immune cells in the human small intestine. We show altered myeloid cell transcriptomes present in active celiac lesions. CD4+ and CD8+ T cells transcriptomes show extensive changes and we define a natural intraepithelial lymphocyte population that is reduced in celiac disease. We show that the immune landscape in Celiac patients on a gluten-free diet is only partially restored compared to control samples. Altogether, we provide a single cell transcriptome resource that can inform the immune landscape of the small intestine during Celiac disease.

  Study EGAS00001003751

• Lenalidomide Resistance in del(5q) Myelodysplastic Syndrome Follows Loss of RUNX1/TP53-mediated Megakaryocytic Differentiation

  Interstitial deletion of the long arm of chromosome 5 (del(5q)) is the commonest structural genomic variant in myelodysplastic syndromes (MDS). Lenalidomide (LEN) is the treatment of choice for patients with del(5q) MDS, but half of the responding patients become resistant within two years. TP53 mutations are detected in ~20% of patients who become resistant to LEN. Our data show that patients who become resistant to LEN harbor either TP53 or RUNX1 mutations or loss of RUNX1 expression. Here we show that LEN-induced degradation of IKZF1 permits a RUNX1/GATA2 complex to drive megakaryocytic differentiation and consequent del(5q) MDS progenitor cell death via CRBN-mediated CSNK1A1 degradation. Overexpression of GATA2 is able to restore LEN sensitivity in the context of RUNX1 or TP53 mutations by enhancing LEN-induced megakaryocytic differentiation. Screening for TP53 and RUNX1 mutations or downregulation should identify patients resistant to LEN, and strategies to activate GATA2 may resensitize del(5q) MDS cells to LEN

  Study EGAS00001004113

• Dual targeting of polyamine synthesis and uptake in diffuse intrinsic pontine gliomas

  Diffuse intrinsic pontine glioma (DIPG) is an incurable malignant childhood brain tumour, with no active systemic therapies and a 5-year survival of less than 1%. Polyamines are small organic polycations that are essential for DNA replication, translation and cell proliferation. Ornithine decarboxylase 1 (ODC1), the rate limiting enzyme in polyamine synthesis, is irreversibly inhibited by difluoromethylornithine (DFMO). Herein we show that polyamine synthesis is upregulated in DIPG, leading to sensitivity to DFMO. DIPG cells compensate for ODC1 inhibition by upregulation of the polyamine transporter SLC3A2. Treatment with the polyamine transporter inhibitor AMXT 1501 reduced uptake of polyamines in DIPG cells, and co-administration of AMXT 1501 and DFMO led to potent in vitro activity, and significant extension of survival in three aggressive DIPG orthotopic animal models. Collectively, these results demonstrate the potential of dual targeting of polyamine synthesis and uptake as a therapeutic strategy for incurable DIPG.

  Study EGAS00001004905

• Improving CLL Vγ9Vδ2-T cell fitness for cellular therapy by ex vivo activation and ibrutinib

  We studied whether Vγ9Vδ2-T cells can exploited as autologous effector lymphocytes in chronic lymphocytic leukemia (CLL). Healthy controls (HC) Vγ9Vδ2-T cells were activated by and had potent cytolytic activity against CLL cells, however CLL-derived Vγ9Vδ2-T cells proved dysfunctional with respect to effector cytokine production and cytotxicity. Dysfunction of Vγ9Vδ2-T cells was reversible upon activation with autologous monocyte-derived dendritic cells (mODCs). RNA sequencing confirmed that Vγ9Vδ2-T cells from CLL patients have a transcriptional profile that is distinct from HC Vγ9Vδ2-T cells prior to ex vivo expansion, although the profile after ex vivo expansion is similar between CLL and HC Vγ9Vδ2-T cells. Gene expression profiling implicated alterations in both synapse formation and exhaustion as conceivable contributors to compromised Vγ9Vδ2-T cell function in CLL patients. Taken together, CLL-mediated dysfunction of autologous Vγ9Vδ2-T cells is fully reversible, resulting in potent cytotoxicity towards CLL cells.

  Study EGAS00001003193

• Next_gen_seq_of_eye_cancers

  Retinoblastoma (RB), the commonest eye cancer in children was the first cancer for which a genetic cause was identified: the Rb1 gene is a tumour suppressor gene that is mutated in RB. The Rb1 gene defect alone does not predict the clinical outcome. We propose to study other possible mechanisms: 1. Stepwise further mutations occur in RB, increasing its carcinogenesis. We will sequence the whole genome in RB tissue, and relate the different genes expressed to the treatments used. 2. Extracellular matric proteins contribute to a tumour permissive environment for RB to continue to grow. This includes Samll Leucine Rich Proteoglycans (SLRP), a family of 15 secreted extracellular matrix proteins involved in eye development. 3. Cancer stem cells (CSC), a subpopulation of treatment resistant cells, drive RB tumours, and whether these stem cells can be manipulated for new therapies. The aim of this study is to assist finding targeted diagnostic techniques and treatments for RB.

  Study EGAS00001002309

• Whole Exome sequencing of Gingivo-buccal Cancer : ICGC-India Project_Batch04

  Whole Exome Sequencing of Gingivo-buccal Cancer: ICGC-India ProjectAs a part of the ICGC, India has undertaken genomic studies on gingivobuccal cancer of the oral cavity, which is the most prevalent form of cancer among men in India. There are various known environmental (life-style) correlates of this cancer, the most important of which are tobacco chewing and HPV infection. Exome of paired DNA samples – isolated from the tumor tissue and from the blood of 47 patients – have been performed to catalog germline and somatic mutations. Association between each observed genomic alteration and exposure to environmental risk factors is being explored. Detailed clinical characterization of the patients, collection of data on demographic and environmental exposures, and isolation of DNA samples from blood and tumor tissues collected from each patient are being done at the Advanced Centre for Research, Treatment and Education on Cancer, Mumbai. Whole exome sequencing is being performed at the National Institute of Biomedical Genomics, Kalyani.

  Study EGAS00001002852

• Heritable pulmonary arterial hypertension in a large Iberian family

  Data from a study of a large Iberian family (n=65 subjects, 5 generations) affected by pulmonary arterial hypertension (PAH) and segregating with the BMPR2 missense mutation p.Arg491Gln (rs137852749, c.1472G>A). PAH is a rare disease characterized by an abnormal rise in mean pulmonary arterial pressure (> or equal to 25 mmHg at rest), which, in turn, leads to a progressive increase in pulmonary vascular resistance and ultimately to death, due to right ventricular failure. Heritable PAH has an overall prevalence below 1 case per million adults and is defined by either the presence of a known genetic defect linked to the disease or a positive family history. Heritable PAH is inherited as an autosomal dominant disease. However, not all BMPR2 mutation carriers develop the disease, highlighting the presence of reduced penetrance. In this family, there are 22 mutation carriers from which 8 were diagnosed with heritable PAH and the other 14 were healthy at the time of examination.

  Study EGAS00001003123

• Molecular evolution and clinical trajectories of prostate cancer identifies novel markers for risk stratification

  Prostate cancer is a highly heterogeneous disease that is thought to develop over many years. Identifying the earliest somatic changes can give important insights into the tumour evolution and aid in stratifying high- from low-risk diseases. Here we pursued integrative whole-genome, transcriptome and methylome-based analysis of early-onset prostate cancer patients. Characterisation of genomic alterations across 270 PCa tumours revealed age-related genomic alterations and mutation signatures including BRCAness and APOBEC. We used methylation- and expression-data to identify four molecular subgroups, which included a highly aggressive tumour subgroup that frequently involved recurrent duplications and increased expression of ESRP1. Analysis of 12,000 tissue-microarray tumour samples demonstrated that ESRP1 is a candidate biomarker associated with faster proliferation rate and shorter time to relapse. We combine the patterns of molecular co-occurrence, risk-stratification and subgroup information to deconvolute tumor heterogeneity, which reveal complex but recurrent clinical trajectories of prostate cancer.

  Study EGAS00001002923

• Mutations in the RAS/MAPK pathway drive replication repair deficient hypermutated tumors and confer sensitivity to MEK inhibition

  The RAS/MAPK pathway is an emerging targeted pathway across a spectrum of both adult and pediatric cancers. Typically, this is associated with a single, well-characterized point mutation in an oncogene. Hypermutant tumors which harbor many somatic mutations may obscure the interpretation of such targetable genomic events. We find that replication repair deficient (RRD) cancers which are universally hypermutant and affect children born with RRD cancer predisposition, are enriched for RAS/MAPK mutations (p=10-8). These mutations are not random, exist in subclones, and increase in allelic frequency over time. The RAS/MAPK pathway is activated both transcriptionally and at the protein level in patient derived RRD tumors and these tumors responded to MEK inhibition in vitro and in vivo. Treatment of patients with RAS/MAPK hypermutant gliomas reveal durable responses to MEK inhibition. Our observations suggest that hypermutant tumors may be addicted to oncogenic pathways resulting in favorable response to targeted therapies.

  Study EGAS00001005008

• Systematic comparative analysis of single-nucleotide variants detection methods from single-cell RNA sequencing data

  Systematic interrogation of single nucleotide variations (SNVs) is one of the most promising approaches to delineate the cellular heterogeneity and phylogenetic relationships at the single cell level. While SNV detection from abundant single cell RNA sequencing (scRNA-seq) data is applicable and cost-effective in identifying expressed variants, inferring sub-clones, and deciphering genotype-phenotype linkages, there is a lack of computational methods specifically developed for SNV calling in scRNA-seq. Although variant callers for bulk RNA-seq have been sporadically used in scRNA-seq, the performances of different tools have not been assessed. Here, we performed a systematic comparison of seven tools including SAMtools, the GATK pipeline, CTAT, FreeBayes, MuTect2, Strelka2 and VarScan2, using both simulation and scRNA-seq datasets, and identified multiple elements influencing their performance. Our study provided the first benchmarking to evaluate the performances of different SNV detection tools for scRNA-seq data.

  Study EGAS00001003883

• Rare occurrence of Aristolochic Acid Mutational Signatures in Oro-Gastrointestinal Tract Cancers

  Aristolochic Acids (AAs) are a family of carcinogenic phytochemical compounds commonly found in plants of Aristolochia and Asarum genus. Comprehensive genomic profiling of genitourinary and hepatobiliary cancers has highlighted the widespread prevalence of Aristolochic Acid (AA) signatures in cancer patients across parts of Asia, particularly in Taiwan. The aim of our study was to determine in Oro-Gastrointestinal Tract (OGITC) cancers, the prevalence, role and significance that AA plays as a driver of tumorigenesis as AA containing products are commonly administered orally. This would suggest a possible etiological relationship between cancers of OGITC. However, in this study the rarity of AA mutational signatures in OGITC suggests that AA is unlikely to drive carcinogenesis in OGITC through direct exposure. Our study is valuable to show that AA exposure is not an equal driver of tumorigenesis in different organs and represents an important piece of information in the field.

  Study EGAS00001005909

• Exome sequencing of synchronous colorectal cancers

  Approximately 4% of colorectal cancer (CRC) patients have at least two simultaneous cancers in the colon. Due to the shared environment, these synchronous CRCs (SCRCs) provide a unique setting to study colorectal carcinogenesis. Understanding whether these tumors are genetically similar or distinct is essential when designing therapeutic approaches. We performed exome sequencing of 47 primary cancers and corresponding normal samples from 23 patients. Additionally, we carried out a comprehensive mutational signature analysis to assess whether tumors had undergone similar mutational processes and the first immune cell score analysis (IS) of SCRC to analyze the interplay between immune cell invasion and mutation profile in both lesions of an individual. The tumor pairs shared only few mutations, favoring different mutations in known CRC genes and signaling pathways, and displayed variation in their signature content. Two tumor pairs had discordant mismatch repair statuses. In majority of the pairs, IS varied between primaries. Differences were not explained by any clinicopathological variable or mutation burden.

  Study EGAS00001003474

• An isogenic human iPSC model unravels neurodevelopmental abnormalities in SMA

  Whether neurodevelopmental defects underlie the selective neuronal death that characterizes neurodegenerative diseases is becoming an intriguing question. To address it, we focused on the motor neuron (MN) disease Spinal Muscular Atrophy (SMA), caused by reduced levels of the ubiquitous protein SMN. Taking advantage of the first isogenic human induced pluripotent stem cell-derived SMA model that we have generated and a spinal cord organoid system, here we report that the relative and temporal expression of early neural progenitor and MN markers is altered in SMA. Furthermore, the corrected isogenic controls only partially reverse these abnormalities. These findings raise the relevant clinical implication that SMN-increasing treatments might not fully amend SMA pathological phenotypes. The approach we have taken demonstrates that the discovery of new disease mechanisms is greatly improved by using human isogenic models. Moreover, our study implies that SMA has a developmental component that might trigger the MN degeneration.

  Study EGAS00001007259

• Northern Ireland COhort for the Longitudinal study of Ageing

  The Northern Ireland COhort for the Longitudinal study of Ageing (NICOLA) is a representative sample of ~8,500 people from across Northern Ireland. The study, which was set up in 2012, aims to understand what it is like to grow older in Northern Ireland. • NICOLA has a strong focus on molecular biomarkers so there is complementary genetic, epigenetic and transcriptomic data available for a subset of individuals. • We inherit much of our DNA from our parents while a small amount of this material changes as we get older. In NICOLA we have 551,839 directly genotyped and 18,148,478 imputed Single Nucleotide Polymorphisms (SNPs) currently available for 2969 participants. • Summary statistics for the association of these gene polymorphisms with ~30 phenotypes were generated. • Epigenetics provides a link between our inherited DNA and environmental influences from a person’s diet, medication and lifestyle. NICOLA has the epigenetic quality controlled profiles of 1984 individuals arising from variations in DNA methylation at 862,927 genetic sites.

  Study EGAS00001007915

• EGAD00000000054

  NCI-H209 is an immortal cell line derived from a bone marrow metastasis of a patient with small cell lung cancer, taken before chemotherapy. The specimen showed histologically typical small cells with classic neuroendocrine features. NCI-BL209 is an EBV-transformed B-cell line derived from the same patient as the small cell lung cancer cell line, NCI-H209

  Dataset EGAD00000000054

• Molecular Genetics of Secondary Histiocytic/Dendritic Sarcoma

  This is a comprehensive genomic analysis of a rare set of secondary histiocytic/dendritic sarcomas from the consult service of the Hematopathology section of the Laboratory of Pathology, NCI, NIH.

  Study phs001942

• Whole exome sequencing of a cold agglutinin disease patient

  We performed whole exome sequencing of bone marrow monoclear cells derived from a cold agglutinin disease patient. Aim of our study is to elucidate the pathogenesis of hemolytic anemia.

  Study JGAS000612

• Whole exome sequencing of a cold agglutinin disease patient

  We performed whole exome sequencing of bone marrow monoclear cells derived from a cold agglutinin disease patient. Aim of our study is to elucidate the pathogenesis of hemolytic anemia.

  Study JGAS000583

• Amplicon sequencing of duodenal adenoma

  The aim of this study is to analyze the methylation and mutation status of non-ampullary duodenal lesions in order to detect the genetic changes for predicting the progression to adenocarcinomas.

  Study JGAS000352

• Veterans Administration (VA) Million Veteran Program (MVP) Summary Results from Omics Studies

  MVP is an ongoing prospective cohort study and mega-biobank in the Department of Veterans Affairs Healthcare System designed to study genetic influences on health and disease among veterans.

  Study phs001672

• FLT3 is genetically essential for ITD-mutated leukemic stem cells but dispensable for human HSCs

  bulk RNA sequencing of AML patients It contains 18 samples from primary AML patients. Half of the samples are control samples and half of the samples are FLT3-ITD knock-out (edited for the FLT3-ITD mutation). It is using Illumina high-throughput technology

  Dataset EGAD50000000636

• GeoMx digital spatial profiling of NGS mRNA expression in pre-treatment biopsies from patients.

  This DAC is created to define the data controller (the person that determines the purposes for which and the means by which personal data is processed) for the following study: GeoMx digital spatial profiling of NGS mRNA expression in pre-treatment biopsies from patients with metastatic triple-negative breast cancer treated with PARP inhibitors.

  Dac EGAC50000000774

• DAC for Cornell-NCI DLBCL NGS Genomic Project

  Genome-wide sequencing experiments were conducted on 103 DLBCL biopsy samples, of which the datasets (called Cornell-NCI DLBCL cohort) are available for authorized scientists. The Center of Technology Licensing at Cornell University is in charge of this data access policy and approval. Particularly, Cornell University will email a DAA to each requestor to have their institution sign before access is granted

  Dac EGAC50000000704

• Resolution and methylation patterns of supernumerary marker chromosomes

  Herein we study the structure of ring and marker chromosomes in 10 carriers. The aim is to gain understanding of the formation and function of ring and marker chromosomes.

  Study EGAS50000001466

• Impact of DIS3 Aso on BCR repertoir in human buffy coat purified B-Cells

  The aim is to identify difference in the BCR of Aso DIS3 treated cells compared to Control Aso. Using extracted DNA from human B-cells

  Study EGAS50000001107

• RNA sequencing of Korean ER positive breast cancer females aged under 35 years old.

  Corresponding data set is composed of RNA sequencing of Korean ER positive breast cancer under 35 years old. This set provides 50 alignment files of 50 tumor samples. This is a part of total project data set.

  Dataset EGAD00001003243

• Chondromyxoid_fibroma

  Chondromxoid fibroma is a benign tumour of bone with unknown underlying pathogenesis. To determine pathognomic genomic event in chondromyxoid fibroma whole genome sequencing will be undertaken to reconstruct rearrangements and find underlying mutations.

  Study EGAS00001000533

• Poikiloderma_syndrome_RNAseq

  We will sequence the RNA of lymphoblast samples, transformed with EBV, which have poikiloderma syndrome with mutations in c16orf57. The aim of the experiment is to characterise RNA structural effects in this disease.

  Study EGAS00001000250

• Dissecting_global_protective_immune_response_to_dengue_virus_at_a_single_cell_resolution

  1) This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute please see http://www.sanger.ac.uk/datasharing/

  Study EGAS00001004980

• Targeted-capture sequencing (bam files) of 81 samples of myxofibrosarcoma and 44 matched pairs

  Myxofibrosarcoma (MFS) is a rare subtype of sarcomas in the elderly, whose genetic basis is poorly understood. To elucidate it, the Targeted-capture sequencing was performed.

  Dataset EGAD00001007826

• Center for Common Disease Genomics [CCDG] - Cardiovascular: SWISS-AF/SWISS-AF-PVI/BEAT-AF

  This study is a part of NHGRI's Centers for Common Disease Genomics (CCDG), which is 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 sequence approximately 140K whole genomes and 225K whole exomes during the life of the project. The Cardiovascular Disease working group of the CCDG considered five diseases: early-onset coronary artery disease (EOCAD), stroke, atrial fibrillation (AF), congestive heart failure and type 2 diabetes. AF will affect between 6-12 million individuals in the US by 2050. AF is also associated with increased risks of stroke, dementia, heart failure, death, and high health care costs. Many risk factors for AF have been identified, including advancing age, cardiovascular disease (CVD), and CVD risk factors. However, there is little knowledge how to prevent AF. Furthermore, therapies for AF are only partially effective, and are themselves associated with substantial morbidity. Previously, heritable forms of AF have been considered rare; yet in the last decade, it has been established that AF, and in particular early-onset forms of AF, are heritable. Genome-wide association studies (GWAS) provide a powerful tool to identify common variants underlying disease risk. The AFGen Consortium currently consists of investigators from more than 25 studies with >20,000 individuals with AF and >100,000 without AF. In the latest analyses, 14 loci have been identified for AF1. Broadly, the loci implicate genes related to cardiopulmonary development, cardiac-expressed ion channels, and cell signaling molecules. Source: https://ccdg.rutgers.edu/sites/default/files/CCDG_CVD_EOAF_FINAL_w_link.pdf Three collections were brought together to form Swiss atrial fibrillation cases: SWISS-AF, SWISS-AF-PVI, and BEAT-AF. SWISS-AF is a prospective observational, multicentric cohort study in Switzerland to increase our knowledge on structural brain damage and its changes over time in patients with atrial fibrillation. Overall, 2400 patients with documented atrial fibrillation aged >65 years will be included and followed on a yearly basis. SWISS-AF-PVI is a registry of patients with atrial fibrillation undergoing catheter-based ablation of atrial fibrillation (pulmonary vein isolation) to determine long-term success rates of catheter-based ablation of atrial fibrillation (pulmonary vein isolation) and to evaluate factors associated with long-term success of catheter-based ablation of atrial fibrillation (pulmonary vein isolation). BEAT-AF is a prospective observational, multicenter cohort study in Switzerland. Overall, 1550 patients with documented atrial fibrillation were enrolled in seven study centers. The main aim of this study is to investigate the therapy and the medical consequences of patients with atrial fibrillation. Samples from all three collections were sent to The Broad Institute of MIT and Harvard to generate genetic data using whole exome sequencing and whole genome genotyping (Infinium Global Screening Array); all cases with atrial fibrillation.

  Study phs002242

• Genome-Wide Association Studies of Prematurity and Its Complications

  Preterm labor resulting in the delivery of a premature child is a complex problem with an enormous impact on individuals, families and society. An estimated 500,000 children are born prematurely in the U.S. each year, and 5 million worldwide die annually of prematurity and its complications. Prematurity is also the single largest contributor to disability-adjusted life years, a measure of the lifetime impact of a disease. Despite the importance of the problem and its disproportionate occurrence in poor and minority populations, its underlying etiology (or etiologies) remains unknown; the single best predictor for preterm delivery is a previous preterm birth. The largest single cause of prematurity is spontaneous preterm labor, and suspected triggers for this include infection, stress, poor nutrition and genetic factors. Family and twin studies provide strong evidence that genetic factors underlie about 40% of the risk for prematurity. A major challenge in studying genetic factors in prematurity is maternal/uterine factors, fetal/placental factors, or both may influence risk. Thus, any approach to studying preterm birth should account for both infant and maternal risk, environmental covariates and interactions. The Danish National Birth Cohort (DNBC) is a well-established, prospective cohort that enrolled women early in pregnancy, prior to any adverse pregnancy outcomes, to minimize bias in data collection and sampling. See details at: http://www.ssi.dk/English. The DNBC followed over 100,000 pregnancies beginning in the first trimester and has extensive biological material and epidemiologic data on health outcomes in both mother and child. The current study posted on dbGaP contains data from a genome-wide case/control study using approximately 1,000 preterm mother-child pairs from the DNBC most with spontaneous onset of labor or preterm premature rupture of membranes (PPROM), along with 1,000 control pairs where the child was born at ~40 weeks' gestation. After data cleaning some small changes in case/control status and other variables resulted in minor changes in numbers of cases or controls in certain categories. Environmental variables are being used as covariates in the analysis. To replicate positive findings, we are using additional mother-child pairs from the DNBC and from the general Danish population, as well as 2200 samples coming primarily from an African-American population known to have high rates of preterm labor and delivery. This group includes over 1000 mostly very low birthweight infants, over 500 infant term controls, 326 term mother/baby pairs and 180 preterm mother/baby pairs. The data from these additional cohorts will be available in separate dbGaP postings. The study is expected to yield a better understanding of the biology of parturition, identify common genetic factors that play a role in preterm birth and its complications and suggest environmental modifications that can prolong gestation, with the goal of improving both neonatal and adult outcomes. This study is part of the Gene Environment Association Studies initiative (GENEVA, http://www.genevastudy.org) funded by the trans-NIH Genes, Environment, and Health Initiative (GEI). The overarching goal is to identify novel genetic factors that contribute to prematurity and its complications through large-scale genome-wide association studies of a well-characterized cohort of Danish mothers and babies. Genotyping was performed at the Johns Hopkins University Center for Inherited Disease Research (CIDR). Data cleaning and harmonization were done at the GEI-funded GENEVA Coordinating Center at the University of Washington.

  Study phs000103

• Targeted_sequencing_of_genes_recurrently_mutated_in_AML

  Background Massively parallel sequencing technology has transformed cancer genomics. It is now feasible, in a clinically relevant time-frame, for a clinically manageable cost, to screen DNA from patient tumours for mutations essentially genome-wide. The challenge for personalised medicine will be to increase the sample size to thousands or tens of thousands of well-characterised cases in order to attain sufficient statistical power to stratify patients accurately across the complexity and genomic heterogeneity expected for most of the common tumour types. Currently, whole genome sequencing on this scale is not feasible, and targeted sequencing of relevant portions of the genome will be required. Pilot data We have developed protocols for large-scale, multiplexed sequencing of 100-200 genes in thousands of samples. Essentially, using robotic technology, genomic DNA from the cancer specimen is processed into sequencing libraries with unique DNA barcodes, thereby allowing sequencing reads to be attributed to the sample they derive from. Currently, these sequencing libraries can be generated in a 96-well format using fully automated protocols, and we are exploring methods to expand this to a 384-well format. The sequencing libraries are pooled and hybridized to custom sets of RNA baits representing the genomic regions of interest. Sequencing of the pulled-down libraries is done in pools of 48-96 samples per lane of an Illumina Hi-Seq. This protocol is already implemented at the Sanger Institute. We have published proof that somatic mutations in novel cancer genes can be identified from exome-wide sequencing. In unpublished pilot data, we have established the feasibility of robotic library production, custom pull-down, and multiplexed sequencing of barcoded libraries for 100 known myeloid cancer genes across 760 myelodysplasia samples. Highlights of the data thus far analysed reveal that the coverage is remarkably even between samples; when 96 samples are run, average coverage per lane of sequencing is ~250, with 90-95% of targeted exons covered by >25 reads; known mutations can be discovered in the data set; and the protocol is amenable to whole genome amplified DNA. The bioinformatic algorithms for identification of substitutions and indels in pull-down data are well-established; we have pilot data proving that copy number changes, LOH and genomic rearrangements in specific regions of interest can also be identified by tiling of baits across the relevant loci. Proposal We propose to apply this methodology to 10000 samples from patients with AML enrolled in clinical trials over the last 10-20 years. Oncogenic point mutations and potentially genomic rearrangements will be identified, and linked to clinical outcome data, with a view to undertaking the following sorts of analyses: • Identification of co-occurrence, mutual exclusivity and clusters of driver mutations. • Correlation of prognosis with driver mutations and potentially gene-gene interactions • Exploration of genomic markers of drug response Ultimately, we would like to be in a position to release the mutation data together with matched clinical outcome data to genuine medical researchers via a controlled access approach, possibly within the COSMIC framework (www.sanger.ac.uk/genetics/CGP/cosmic/). The vision here is to generate a portal whereby a clinician faced with an AML patient and his / her mutational profile can obtain a ‘personalised’ prediction of outcome, together with a fair assessment of the uncertainty of the estimate. With a sufficient sample size, there would also be the potential to develop decision support algorithms for therapeutic choices based on such data.

  Study EGAS00001000408

• Natural History, Pathogenesis and Outcome of Melorheostosis

  Melorheostosis is a rare osteosclerotic disease resulting in exuberant excessive bone growth with a characteristic radiographic appearance often described as "dripping candle wax". As a result of these bony formations, patients report mild to moderate pain that interferes with their routine activities. It is usually diagnosed on radiographs but bone biopsy may be performed to exclude other osteosclerotic diseases and/or osteosarcoma. Deformities, limb-length discrepancy, muscle atrophy, neurological deficit have been reported as complications. A subset of patients have somatic mutations in MAP2K1. The cause of this disease is not known in all patients, the natural history poorly described and there is no clearly-defined systemic therapy. We propose a prospective observational study to investigate the natural history and pathogenesis of the disease. Subjects will undergo standardized initial evaluation and medically indicated testing. Skin biopsies may be performed to test for known mutations related to melorheostosis, and if negative affected bone and/or skin may be sent for genetic testing for acquired somatic mutations in genes that control bone homeostasis. Enrolled subjects will be followed every two to three years for assessment of disease progression and receive clinically indicated testing and treatment. The study of this rare bone disease offers the potential to generate new insights, provide answers as well as generate new questions into the biology of the skeletal and mineral metabolism.

  Study phs001976

• Foregut Microbiome and Risk of Gastric Intestinal Metaplasia, and Gastric Cancer Risk

  The study is composed of two sub-studies. The first study, conducted by NYU Grossman School of Medicine, is a case-control study of 89 cases with gastric intestinal metaplasia (IM) and 89 matched controls who underwent upper gastrointestinal endoscopy at three sites affiliated with NYU Langone Health. Shotgun metagenomic sequencing using oral wash samples from the 89 case-control pairs and antral mucosal brushing samples from 55 case-control pairs were conducted. The other study, conducted by Vanderbilt University Medical Center, is a prospective case-control study on the oral microbiome and gastric cancer risk, utilizing shotgun metagenomic sequencing data of pre-diagnostic buccal samples from 319 Asians, 118 African Americans and 51 European Americans. This study includes data from three population-based studies: the Southern Community Cohort Study (SCCS), the Shanghai Women's Health Study (SWHS), and the Shanghai Men's Health Study (SMHS). The SWHS and SMHS include 74,941 women aged 40-70 years and 61,480 men aged 40-74 years, respectively, who were permanent residents of Shanghai and recruited to the cohorts between 1997 and 2006. The SCCS is an ongoing prospective cohort study, including ~86,000 participants recruited during 2002 and 2009 from 12 Southeastern states. Nearly 67% of study participants are African Americans (AAs) and the remaining are European American (EA) subjects.

  Study phs002566

• NHLBI GO-ESP: Family Studies (JHMI-Molecular Genetics of Atypical Cystic Fibrosis (CF) Study)

  The NHLBI "Grand Opportunity" Exome Sequencing Project (GO-ESP), a signature project of the NHLBI Recovery Act investment, was designed to identify genetic variants in coding regions (exons) of the human genome (the "exome") that are associated with heart, lung and blood diseases. These and related diseases that are of high impact to public health and individuals from diverse racial and ethnic groups will be studied. These data may help researchers understand the causes of disease, contributing to better ways to prevent, diagnose, and treat diseases, as well as determine whether to tailor prevention and treatments to specific populations. This could lead to more effective treatments and reduce the likelihood of side effects. GO-ESP is comprised of five collaborative components: 3 cohort consortia - HeartGO, LungGO, and WHISP - and 2 sequencing centers - BroadGO and SeattleGO. Cystic fibrosis (CF) patients without detectable disease-causing mutations in CFTR present a clinical phenotype very similar to, but possibly discrete from, classic CF. We hypothesize that the phenotype of these atypical CF patients is not due only to mutations in the carbonic anhydrase gene CA12 or in the genes encoding the epithelium sodium ion channel ENaC, but is due to mutations in novel genes that have yet to be associated with CF. The goal of this study is to determine the molecular etiology of this atypical CF.

  Study phs000556

• Gabriella Miller Kids First Pediatric Research Program: An Integrated Clinical and Genomic Analysis of Treatment Failure in Pediatric Osteosarcoma

  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 childhood 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. 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. Although the survival of children with relapsed osteosarcoma is very poor, little is known about the etiology of treatment failure in this disease. The purpose of this project is to perform whole genome sequencing on serial samples from patients with osteosarcoma obtained before treatment, after treatment, and at relapse/metastasis in order to identify the mutations and pathways that are drivers of drug resistance. If successful, our results may help identify patients at high risk for treatment failure and may yield new treatments for children who cannot currently be cured.

  Study phs001714

• Targeted Sequencing of GWAS Loci in Cleft Lip and Palate

  Nonsyndromic cleft lip and palate (NSCL/P) is a complex disorder caused by both genetic and environmental factors and has been the focus of an extensive effort to identify genetic risk factors. A number of candidate gene studies have been performed but have not been widely replicated. To date, four independent genome wide association studies have been performed as well as a meta-analysis. Together these studies have identified many loci associated with NSCL/P. The goal of this project is to use targeted sequencing to further characterize these regions and to progress from the association signals identified by GWAS to the identification of causative genes and/or variants. This study is part of the GWASeq project, a collaboration of five disease studies, which will sequence genomic regions from GWAS to characterize the genetic variation underlying these diseases and to compare study design and methods for the follow-up of GWAS studies by sequencing. The goal of this study is to sequence 1000+ NSCL/P case-parent trios from China and the Philippines and 400 trios of European ancestry. Targeted sequencing was performed on intervals ranging between 60kb to 1Mb surrounding 13 genes/loci previously associated with NSCL/P including: IRF6, MAFB, ARHGAP29, 8q24, PAX7, VAX1, NTN1, NOG, FOXE1, MSX1, BMP4, FGFR2, PTCH1.

  Study phs000625

• MSK SPECTRUM - SPatiotemporal Evolution of Cancer Traced Using Multimodalities

  MSK SPECTRUM is a multi-modal, interdisciplinary prospective study of spatiotemporal determinants of high-grade serous ovarian cancer (HGSOC) evolution, treatment and response. Accounting for ~80% of ovarian cancers, HGSOC is the most lethal gynecological malignancy and is a cancer of major unmet clinical need. Challenges in disease management relate to several unresolved questions about disease biology and diagnostic modalities. Prospective longitudinal collection of tissues and blood from laparoscopic biopsies and debulking surgeries enable multi-modal molecular measurements. The program brings together formidable expertise at Memorial Sloan Kettering Cancer Center (MSKCC) across the disciplines of high-resolution genomics and computer science, radiology and radiomics, surgery, tissue banking and sample preparation, medical oncology, immuno-oncology and high-resolution tissue profiling to generate a comprehensive and integrative dataset that will allow us to address the following major aims: i) characterize malignant and immune diversity at diagnosis, ii) survey the co-evolution of malignant cells and the immune response, and iii) stratify patients on standard-of-care and investigational compounds based on their genomic and transcriptomic signatures and changes to relevant genes (TP53, CCNE1, BRCA1/2, CDK12). The goal is to create a framework to utilize integrated multi-modal data as a route to advanced diagnostics and to ultimately establish a proof-of-concept for integrated diagnostics.

  Study phs002857