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• Discordant_Monozygotic_Twins_ALS (Epigenetics)

  We conducted a multi-omics study on a monozygotic twin pair discordant for amyotrophic lateral sclerosis. Data refers to 7 samples that are technical replicates from biological samples collected from the twins at two different time points (T1 and T2).

  Dataset EGAD00010002716

• Genome-wide association study for Bladder Cancer Risk

  This study funded by the National Cancer Institute (NCI) involves conducting a genome-wide association study of common genetic variants to identify markers of susceptibility to bladder cancer. This bladder GWAS has led to the discovery of three novel regions in the genome associated with bladder cancer risk. Cases were defined as individuals having histologically confirmed primary carcinoma of the urinary bladder, including carcinoma in situ (ICD-0-2 topography codes C67.0-C67.9 or ICD9 codes 188.1-188.9). Scan data were obtained from two case-control studies carried out in Spain and the United States (specifically, those in the Maine and Vermont components of the New England Bladder Cancer Study) and three prospective cohort studies in Finland and the United States (specifically Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study, Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial, and The American Cancer Society Cancer Prevention Study II Nutrition Cohort). We used data from 591,637 single nucleotide polymorphisms 3,532 affected individuals (cases) and 5,119 controls of European descent and replication including 8382 cases and 48275 controls from 16 studies. In a combined analysis, we identified three new regions associated with bladder cancer on chromosomes 22q13.1, 19q12 and 2q37.1: rs1014971, (P ≈ 8 x 10-12) maps to a non-genic region of chromosome 22q13.1, rs8102137 (P = 2 x 10-11) on maps to CCNE1 and rs11892031 (P = 1 x 10-7) maps to the UGT1A cluster on 2q37.1. We confirmed four previously identified genome-wide associations on chromosomes 3q28, 4p16.3, 8q24.21 and 8q24.3 (Rothman N et al., Nature Genetics, 2010, PMID: 20972438). Through meta-analysis with the MD Anderson Texas Bladder Cancer Study (TXBCS), we also identified a novel susceptibility locus that mapped to a region of 18q12.3, marked by rs7238033 (P = 8.7 x 10(-9); allelic odds ratio 1.20 with 95% CI: 1.13-1.28) and two highly correlated SNPs, rs10775480/rs10853535 (r(2)= 1.00; P = 8.9 x 10(-9); allelic odds ratio 1.16 with 95% CI: 1.10-1.22) (Garcia-Closas M et al, Human Molecular Genetics, 2011) For NCI-GWAS2, we performed genotyping on cases and controls for the New Hampshire component of the New England Bladder Cancer Study (NEBCS-NH). For the majority of new bladder cancer cases, we genotyped only cases from four case-control studies, the Los Angeles Bladder Cancer Study (LABCS), the French Center for Research on Prostate Diseases (CeRePP), the French Bladder Study (FBCS) and the Brescia Bladder Cancer Study (BBCS). We used existing control data from four cohort studies already genotyped and subjected to rigorous quality control metrics: the European Prospective Investigation Into Cancer and Nutrition Study (EPIC), Womens Health Initiative (WHI), Health Professionals Follow-up Study (HPFS), Nurses Health Study (NHS), which have been a part of Cancer Genetic Markers of Susceptibility (CGEMS). Meta-analysis of NCI-GWAS1, NCI-GWAS2 and a previously reported GWAS TXBCS-GWAS along with taqman replication, identified two new loci: rs10936599 on 3q26.2 (P = 4.53 x 10(-9)) and rs907611 on 11p15.5 (P = 4.11 x 10(-8)). Two notable loci were also identified that approached genome-wide statistical significance: rs6104690 on 20p12.2 (P = 7.13 x 10(-7)) and rs4510656 on 6p22.3 (P = 6.98 X 10(-7)); these require further studies for confirmation (Figueroa J et al, Human Molecular Genetics, 2013).

  Study phs000346

• SCANDARE MACARON

  Among gynecological cancers, high-grade serous ovarian cancer has the highest prevalence and more than 75% of patients have advanced stage at diagnosis with a 5-year survival of 40%. When the initial complete surgical removal is not possible (60% of patients), an interval surgery can be considered after three to four cycles of neoadjuvant chemotherapy to reduce the tumor mass. However, in approximately 50% of cases the tumor has little or no response to neoadjuvant chemotherapy. Therefore, identification of potential drug targets, biomarkers and/or pathways whose modulation can help in the prevention, interception, or curing of the disease is essential to address the unmet need. Therefore, MACARON project aims to address these issues through the identification of shared neoantigens arising out of somatic alterations and aberrant transcriptional programs in ovarian cancer DNA/RNA datasets.

  Study EGAS50000000145

• ARST17B2-Q Germline and Somatic Genetic Landscape of Pediatric Rhabdomyosarcoma

  Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children. While these malignancies display aberrant myogenic differentiation, relatively little is known about genetic susceptibility to RMS, or how genetic variants influence subsequent somatic events and may be used in risk stratification strategies. A small percentage of cases are associated with mutations in TP53 (Li-Fraumeni syndrome), HRAS (Costello syndrome), and PTCH1 (nevoid basal cell carcinoma syndrome/Gorlin syndrome), suggesting the genetic origins of childhood RMS. In spite of this, little work has been done to characterize genetic susceptibility to this malignancy. We plan to leverage samples collected as part of D9902 to conduct one of the largest germline genomic studies of RMS. We anticipate that once genetic associations are identified, researchers can use the information to develop better strategies to detect, treat, and prevent childhood RMS.

  Study phs003192

• Massachusetts General Hospital (MGH) Atrial Fibrillation Study

  The Massachusetts General Hospital (MGH) Atrial Fibrillation Study was initiated in 2001. The study has enrolled serial probands, unaffected and affected family members with atrial fibrillation. At enrollment participants undergo a structured interview to systematically capture their past medical history, AF treatments, and family history. An electrocardiogram is performed; the results of an echocardiogram are obtained; and blood samples are obtained. The Massachusetts General Hospital (MGH) Atrial Fibrillation Study is utilized in the following dbGaP substudies. To view genotypes, analysis, other molecular data, and derived variables collected in these substudies, please click on the following substudies below or in the "Substudies" box located on the right hand side of this top-level study page phs001001 Massachusetts General Hospital (MGH) Atrial Fibrillation Study. phs001116 MGH AF CHARGE-S phs001117 MGH AF Exome Sequencing phs001118 MGH AF Medical Resequencing

  Study phs001001

• Somatic L1 Retrotransposition in Colorectal Tumors

  The purpose of this study is to ascertain the locations of somatic LINE-1 retrotransposition events in human colon tumor samples by pooling multiple tumor samples from different patients and performing a targeted resequencing assay (Ewing and Kazazian, Genome Research 2010) to sequence the 3' flanking regions of all insertions in the pooled sample. The result is compared to the result of applying the same method to pooled normal samples from the same patients as were used in the pooled tumor sample and selecting sites that show an insertion in the tumor but not in the normaltissue and do not correspond to any known non-reference LINE-1 insertion allele. The selected sites are then validated by site-specific PCR and capillary sequencing to confirm that they represent LINE-1 insertions and to obtain breakpoint sequences.

  Study phs000536

• MP2PRT: Identification of Genetic Changes Associated with Relapse and/or Adaptive Resistance in Patients Registered as Favorable Histology Wilms Tumor on AREN03B2

  The Molecular Profiling to Predict Response to Treatment (MP2PRT) program is part of the NCI's Cancer Moonshot Initiative. The aim of this program is the retrospective characterization and analysis of biospecimens collected from completed NCI-sponsored trials of the National Clinical Trials Network and the NCI Community Oncology Research Program. This study, titled "Identification of Genetic Changes Associated with Relapse and/or Adaptive Resistance in Patients Registered as Favorable Histology Wilms Tumor on AREN03B2", performs genomic characterization (WGS 30X, Total RNAseq, miRNAseq) on a discovery set of 70 trio cases (normal tissue, tumor tissue at time of diagnosis, tumor tissue at time of relapse) from patients who relapsed with Favorable Histology Wilms Tumor. Prioritized findings from the discovery set will be validated using Targeted Sequencing in an independent validation set of 47 relapse samples.

  Study phs001965

• The genomic complexity of sporadic and inherited retinoblastoma with a matched orthotopic xenograft

  Retinoblastoma is a pediatric cancer of the developing retina. All retinoblastomas are believed to initiate with biallelic inactivation of the RB1 gene. To identify subsequent genetic lesions in retinoblastoma, we performed whole genome sequencing of tumor and normal DNA of 4 children with retinoblastoma and one matched orthotopic xenograft. Both alleles of RB1 were inactivated in the tumor samples. 3 of the patients had sporadic retinoblastoma and one patient had inherited retinoblastoma. Overall, there were few single nucleotide changes in coding regions of the genome and some of the tumors had few chromosomal lesions. There were very few new genetic lesions in the xenograft compared to the primary tumor. These data suggest that the genome in retinoblastoma is more stable than previously believed and there are relatively few recurrent genetic lesions in known cancer pathways other than the RB1 pathway.

  Study phs000352

• Combinatorial Indexed 10x Genomics Single-Cell ATAC-seq on Human Cerebral Cortex

  Single-cell chromatin accessibility profiling (scATAC) using droplet fluidics (10x Genomics) is inherently limited in throughput due to the number of available indexed droplets. This study leverages single-cell combinatorial indexing workflows with modified adapter designs to enable indexed tagmentation and superloading of pre-indexed nuclei into the 10x Genomics scATAC workflow, enabling a substantial increase in the number of cell profiles that can be obtained per channel. This workflow, 10x single-cell combinatorial indexed ATAC-seq (txsciATAC), is demonstrated on human brain tissue (middle frontal gyrus), along with mouse brain tissue to enable doublet and crosstalk assessment. This study includes all human data and includes a single preparation taken through nuclei isolation and indexed tagmentation using 96 indexes then split to produce two datasets, one targeting 20k cells and one targeting 70k, each using a single channel of the 10x Chromium controller.

  Study phs003497

• Genetic Analysis of Skin Cells

  Cutaneous squamous cell carcinoma (cSCC) is a form of skin cancer originating from keratinocytes in the skin. They have high mutation burdens, primarily driven by UV-radiation-induced DNA damage. The order in which mutations undergo selection during the evolution of cSCC is not known. A subset of cSCCs grow out of benign neoplasms called actinic keratoses. To better understand the evolution of cSCC, we identified cases of cSCCs adjacent to actinic keratoses. From these cases, we separately microdissected the surrounding normal skin, the actinic keratosis, and the cSCC, and we performed targeted DNA-sequencing on the tissue from each area. We reconstructed tumor phylogenies and performed spatial transcriptomics on the 10X FFPE Visium platform on a subset of cases. Collectively, these studies revealed the mutational and gene expression changes that arise during the evolution of cSCC.

  Study phs003282

• Genomic Sequencing of Ewing Sarcoma

  Pediatric Ewing sarcoma is a pediatric cancer that primarily arises from the bone. It is characterized by chimeric fusions of the EWS gene and an ETS family transcription factor. In this study, we performed massively parallel sequencing of a larger collection of Ewing sarcoma tumors to define the genomic landscape of this disease. We found that these tumors are among of the most genetically normal cancers currently characterized. There was also a marked absence of recurrent mutations in immediately targetable signaling transduction pathway genes. In this study we answer outstanding questions about ETS transcription factor expression, effects of treatment on mutational burden in Ewing sarcoma tumors, and describe patterns of tumor evolution. We also found that loss-of-function mutations in STAG2 were present in approximately 15% of Ewing sarcoma tumors and loss of STAG2 expression was associated with disease metastasis in this patient cohort.

  Study phs000804

• Tissue-specificity and co-expression analyses identify human long non-coding RNAs related to inherited retinal disease genes

  The role of long non-coding RNAs (lncRNAs) in biological and pathological processes is still poorly understood. In this study, we aimed to identify lncRNAs that potentially contribute to retinal biology and Inherited Retinal Disease (IRD) by using two complementary strategies, tissue-specificity and location in topologically associating domains (TADs) containing IRD genes on one hand, and co-expression analyses on the other, applied to human retinal omics datasets. This combined approach resulted in the selection of 11 Retina Enriched IRD-gene Related (REIR) lncRNAs, one of which is novel. In-depth in silico and experimental characterization of REIRs identified novel REIR isoforms and confirmed retina-predominant (often photoreceptor-specific) expression as well as predicted functional association with visual function. Long-read direct cDNA sequencing (ONT) of three post-mortem human retina samples was used to delineate the novel REIR isoforms.

  Study EGAS50000000963

• Genetic landscape of pediatric Retinoblastoma

  Retinoblastoma is a pediatric cancer of the developing retina. All retinoblastomas are believed to initiate with biallelic inactivation of the RB1 gene. To identify subsequent genetic lesions in retinoblastoma, we performed whole genome sequencing of tumor and normal DNA of 4 children with retinoblastoma and one matched orthotopic xenograft. Both alleles of RB1 were inactivated in the tumor samples. 3 of the patients had sporadic retinoblastoma and one patient had inherited retinoblastoma. Overall, there were few single nucleotide changes in coding regions of the genome and some of the tumors had few chromosomal lesions. There were very few new genetic lesions in the xenograft compared to the primary tumor. These data suggest that the genome in retinoblastoma is more stable than previously believed and there are relatively few recurrent genetic lesions in known cancer pathways other than the RB1 pathway.

  Study EGAS00001000346

• Assessment_of_genetic_and_epigenetic_variation_in_human_IPS_cells_RNA

  In order to progress human induced pluripotent stem cells (hiPSCs) towards the clinic, several outstanding questions must be addressed. It is possible to reprogram different somatic cell types into hiPSCs and from studies in the mouse, it appears that an epigenetic memory of the starting cell type is carried over to hiPSCs. However a comprehensive comparative study of the characteristics of these hiPSCs has been missing from the literature. Importantly studies which aimed to address these aspects of hiPSCs have used cells from different patients. In order to avoid this important confounding variable and to keep the genetic background constant, tissue samples were procured from the patients and reprogrammed to iPS cells. The transcriptomes of these iPS cells will be compared. Protocol: primary cultures of cells were reprogrammed to iPS cells. RNA was extracted using a standard column extraction kit.

  Study EGAS00001000367

• Ongoing_mutagenesis_RNAseq

  One of the key questions to be explored is whether the biological processes generating specific mutational signatures continue to operate in the human cancer cell lines or simply reflect past mutagenic activity which is no longer operative. To address this question, we have extracted mutational signatures from 1,000 cancer cell lines of diverse cancer types. Several cell lines with mutational signatures of interest were selected, subcloned over a defined period of time and their genomes sequenced. The increased load of the mutations representative of a specific mutational signature within the genome of a subclone when compared to its parental clone was informative of the on-going mutational processes. To further study the recent observation that some of the clones belonging to a same cell line acquired differencet numbers of mutations over a set period of time, their RNA will be subjected to RNA-sequencing to study their differences.

  Study EGAS00001002364

• MicroRNA expression in malignant and benign breast tissue – the Norwegian Women and Cancer study

  The Norwegian Women and Cancer study (NOWAC) is a prospective study which started in 1991 and includes 172 000 Norwegian women aged 30-70 years. The study is based on questionnaires with information on variables of importance to breast cancer risk. Later, about 49 500 samples of peripheral blood have been collected (the NOWAC postgenome cohort). Participants in the NOWAC postgenome cohort with a diagnosis of breast cancer have been identified, and breast cancer cases in Northern Norway diagnosed in 2004-2008 were included in this pilot study. Formalin-fixed paraffin-embedded (FFPE) tumor tissue was retrieved from the pathology labs, tissue cores were collected and RNA extracted. As normal controls, FFPE tissue from benign breast specimens (breast reductions) was included in the study. Microarray analyses of microRNA expression were perfomed by Exiqon using the 7th generation miRCURY LNA microRNA microarray system.od- to be deleted

  Study EGAS00001002671

• Genetic makeup of agnospheres

  Agnospheres are cultures of cancer stem cells isolated from tissue biopsies from patients with Cancer of Unknown Primary (CUPs). The latter is a lethal malignancy (median survival <1 year), representing approximately the 3% of all cancers, and characterized by metastatic dissemination in the absence of a primary tumor recognizable by a standardized protocol including thorough body imaging and histopathological analysis. Agnospheres are long-term propagated in culture and, after subcutaneous injection into immunocompromised mice, they display high tumorigenicity and quickly reproduce the clinical presentation of the original tumor, featuring a multi-organ metastatic pattern and poorly differentiated histology. The goal of the project is to analyse the mutational profile of agnospheres in detail, as to verify its correspondance with that of the original tumors. Genetic information will be exploited to investigate the genetic drivers of the CUP phenotype, in particular the hypermetastatic ability and the differentiative block.

  Study EGAS00001004868

• Molecular patterns of response and treatment failure after frontline venetoclax combinations in older patients with AML

  This study assessed molecular determinants of response in a cohort of patients with AML that were treated with venetoclax in combination with either DNA methyltransferase inhibitors or low dose cytarabine. RNA sequencing was performed on 31 patients from three different response classes [10 Group A - Durable remission (n=10), Group B - Relapsed (n=10) and Group C - Refractory (n=11)]. Library preparation and sequencing was performed at the Australian Genome Research Facility, using the Truseq Stranded mRNA library kit. Technical and batch replicate samples are included, and these replicates are designated in the sample name. Gene count data are provided with the original publication. The use of the sequencing data is subject to a data transfer agreement and is restricted to ethically approved research into blood cell malignancies and cannot be used to assess germline variants.

  Study EGAS00001003820

• Transcriptional_Consequences_of_Copy_Number_Changes_MY_HDBR_200531

  Every normal human cell has two copies of each non-sex chromosome. The gain or loss of an extra copy underlies many health conditions, including developmental syndromes and cancer. Ultimately, it is the patterns of genes that are turned on and off that determines which proteins a cell produces and its biological function. Despite the importance of changes in chromosome number (known as aneuploidy or copy number changes), little is known about how these changes impact patterns of gene expression. This project will aim to fill this gap by creating an atlas of patterns of gene expression in cells from developmental tissues with aberrant numbers of chromosomes. These gene expression profiles will then be compared to the patterns of expression in the same cells with two copies of each chromosome, directly measuring the precise, cell specific, consequences of copy number change on gene expression.

  Study EGAS00001005100

• Combination_Immune_Checkpoint_Inhibition_in_Australian_Rare_Cancers_WES

  Combination immune checkpoint inhibition (ICI) with anti-CTLA-4 and anti-PD-1 blockade has demonstrated significant clinical activity across tumour types. Rare cancer patients have limited treatment options due to the scarcity of studies of novel treatment options, so they are often offered chemotherapies untested in their disease. ONJ2016-001/CA209-538 is a prospective, multicentre clinical trial of combination ICI (ipilimumab and nivolumab) in patients with advanced rare cancers, including biliary tract, adrenocortical, rare gynaecological and neuroendocrine cancers (https://clinicaltrials.gov/ct2/show/NCT02923934). The primary endpoint is clinical benefit rate (complete response + partial response + stable disease >3 months) by RECIST 1.1. This study involves generation and analysis of pre-treatment formalin fixed paraffin embedded (FFPE) tumour DNA sequencing data, paired with germline DNA sequencing data, to potentially identify genomic biomarkers that may associate with clinical benefit or other clinical efficacy / toxicity metrics.

  Study EGAS00001005709

• Vento_Placental_Cell_Atlas

  The Human Cell Atlas initiative is an ambitious global research effort which aims to describe every cell in the human body across all developmental stages to generate a reference map to accelerate progress in science and medicine particularly relating to human development and disease. The initiative is led by investigators based at the Wellcome Sanger Institute and the Broad Institute of MIT and Harvard and funding support from the Wellcome and NIH. This specific project will assess human development. We aim to interrogate the cellular composition and molecular regulators underpinning development and maturation through single cell RNA-sequencing/spatial transcriptomics and computational algorithms to predict cellular developmental trajectories and cell-cell interactions. We will subsequent validate these findings in situ using allied imaging technologies e.g. immunohistochemistry and RNAscope and in vitro culture of human intestinal organoids (HIOs).

  Study EGAS00001004187

• COPD and neutrophils

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

  Study EGAS00001006281

• COPD and neutrophils sc

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

  Study EGAS00001006322

• COPD and neutrophils sc rhapsody

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

  Study EGAS00001006323

• Rare coding variants in lupus risk genes

  Systemic lupus erythematosus (SLE) is the prototypic systemic autoimmune disease. It is thought that many common variant gene loci of weak effect act additively to predispose to common autoimmune diseases, while the contribution of rare variants remains unclear. Here we describe that rare coding variants in lupus-risk genes are present in most SLE patients and healthy controls. We demonstrate the functional consequences of rare and low frequency missense variants in the interacting proteins BLK and BANK1, which are present alone, or in combination, in a substantial proportion of lupus patients. The rare variants found in patients, but not those found exclusively in controls, impair suppression of IRF5 and type-I IFN in human B cell lines and increase pathogenic lymphocytes in lupus-prone mice. Thus, rare gene variants are common in SLE and likely contribute to genetic risk.

  Study EGAS00001003548

• Short and long-read sequencing of Brugada syndrome samples

  Genome-wide association studies (GWAS) are instrumental in identifying loci with an impact on human traits and disease. Typically, however, most GWAS information is considered redundant as it is based on neighboring single-nucleotide variants (SNVs) in strong linkage disequilibrium (LD). In this context, besides the most significant hit (lead SNV) in every trait- or disease-associated locus, the rest of GWAS hits are often marginally reported, examined, or exploited. To interrogate the value of integrating the information provided by the full set of GWAS hits and fine-mapping haplotypes containing these SNVs, here we focused on a locus repeatedly associated with traits of the cardiac electrical conduction system and arrhythmia (SCN5A-SCN10A). We found that the same SNV can exhibit differing associations depending on haplotype. Thus, these analyses provide corroborative evidence that assuming redundancy among neighboring GWAS hits has the risk of missing critical disease-risk associations.

  Study EGAS00001004927

• Substantial somatic genomic variation and selection for BCOR mutations in human induced pluripotent stem cells

  Human Induced Pluripotent Stem Cells (hiPSC) are an established patient-specific model system where opportunities are emerging for cell-based therapies. We compared and contrasted hiPSCs derived from different tissues, skin and blood, in the same individual. We show extensive single-nucleotide mutagenesis in all hiPSC lines, although fibroblast-derived hiPSCs (F-hiPSCs) are particularly heavily mutagenized by ultraviolet (UV)-related damage. We utilized genome sequencing data on 454 F-hiPSCs and 44 blood-derived hiPSCs (B-hiPSCs) to gain further insights. Across 324 whole genome sequenced (WGS) F-hiPSCs derived by the Human Induced Pluripotent Stem Cell Initiative (HipSci), UV-related damage is present in ~72% of cell lines, sometimes causing substantial mutagenesis (range 0.25-15 per Mb). Furthermore, we find remarkable genomic heterogeneity between independent F-hiPSC clones derived from the same reprogramming process in the same donor, due to oligoclonal populations within fibroblasts. Combining WGS and exome-sequencing data of 452 HipSci F-hiPSCs, we identify 272 predicted pathogenic mutations in cancer-related genes, of which 21 genes were hit recurrently three or more times, involving 77 (17%) lines. Notably, 151 of 272 mutations were present in starting fibroblast populations suggesting that more than half of putative driver events in F-hiPSCs were acquired in vivo. In contrast, B-hiPSCs reprogrammed from erythroblasts show lower levels of genome-wide mutations (range 0.28-1.4 per Mb), no UV damage, but a strikingly high prevalence of acquired BCOR mutations in ~57% of lines, indicative of strong selection pressure. All hiPSCs had otherwise stable, diploid genomes on karyotypic pre-screening, highlighting how copy-number-based approaches do not have the required resolution to detect widespread nucleotide mutagenesis. This work strongly suggests that models for cell-based therapies require detailed nucleotide-resolution characterization prior to clinical application.

  Dataset EGAD00001007029

• UM

  metabolite levels provided by UM platform (Creative Dynamics Inc, NY, USA) (the data is raw abundance. Mapping was applied on log10 transformed data)

  Dataset EGAD00010002146

• Center of Medical Genetics Ghent - lab BMN

  This is a DAC created to contain datasets generated in lab BMN, part of the Center of Medical Genetics Ghent, Belgium.

  Dac EGAC50000000351

• Genome-wide association study in multiple human prion diseases suggests genetic risk factors additional to PRNP

  We conducted GWAS of sporadic CJD, variant CJD, iatrogenic CJD, inherited prion disease, kuru and resistance to kuru despite attendance at mortuary feasts. After quality control we analysed 2000 samples and 6015 control individuals (provided by the Wellcome Trust Case Control Consortium and KORA-gen), for 491032-511862 SNPs in the European study. Association studies were done in each geographical and aetiological group followed by several combined analyses.

  Study EGAS00000000097

• ONGOING CHROMOSOMAL INSTABILITY ACROSS ANEUPLOID SUBTYPES OF CHILDHOOD B-CELL ACUTE LYMPHOBLASTIC LEUKEMIA ASSOCIATES WITH DISEASE PROGRESSION

  Single-cells from primary cB-ALL samples were isolated using an inverted microscope coupled to a micromanipulator equipped with glass capillary for cell collection. A minimum of 20 cells were isolated per sample in microdrops of 2.5 μl of phosphate buffered saline (PBS) with 0.5% polyvinylpyrrolidone. Cell lysis and DNA amplification was performed using the SurePlex DNA Amplification System (Illumina). Genomic DNA was subsequently fragmented and tagged with the VeriSeq PGS transposome and the TruSeq Index adapters by PCR for library preparation (VeriSeq PGS Library Prep Kit, Illumina). Equal volumes of normalized libraries were pooled and sequenced on an Illumina MySeq platform with 1×75-bp single-end sequencing. Reads were subsequently aligned to the human reference genome (GRCh38/hg38) using Bowtie2 (version 2.2.4).

  Dataset EGAD50000000029

• Next Generation Mendelian Genetics: Familial Combined Hyperlipidemia

  The NHGRI Next Generation Mendelian Genetics project uses exome resequencing to identify variants in unsolved Mendelian diseases. The research study procedures included the collection of a fasting blood sample, 2 medical history/life style questionnaires and a measurement of subjects' waist circumference that were completed many years ago. Blood samples were analyzed for metabolic markers including cholesterol, HDL, triglycerides and APOE. Genetic tests targeted known and novel genes and polymorphisms associated with carotid artery disease.

  Study phs000538

• Tamoxifen Response at Single Cell Resolution in Estrogen Receptor Positive Primary Human Breast Tumors

  Primary breast tissue, normal and cancerous, was collected immediately after resection. The tissue was dissociated and treated with 10uM tamoxifen or control media for 12 hours in suspension. Single cell libraries were then created using a 10x Genomics gel bead droplet-based kit and sequenced via Illumina sequencing platforms. Differences in cell response to tamoxifen was observed between cell types and distinct responsive and unresponsive cell populations were determined.

  Study phs003186

• Anonymized germline variants of prospectively characterized clinical cancer specimens

  These clinical specimens represent solid tumors and matched blood controls that were collected as part of patients' routine care at Memorial Sloan Kettering Cancer Center. They were sequenced on the targeted platform MSK-IMPACT. Here, we performed germline variant calling on the normal blood specimens and assessed their zygosity in the concomitant tumor specimens for comprehensive exploration of the landscape of pathogenic germline variants in patients with advanced cancer.

  Study phs001858

• Molecular genetic analysis of inherited kidney dysfunction

  Samples were chosen for sequencing from a set of probands from pedigrees with apparently inherited forms of focal segmental glomerulosclerosis (FSGS). Several genes have been identified which when mutated cause FSGS under both recessive and dominant inheritance patterns. These known genes are estimated to explain less than 50% of inherited FSGS. We chose samples from individuals in which previous analyses of known disease genes failed to identify likely disease-causing mutations.

  Study phs000484

• The Genomic Landscape of Juvenile Myelomonocytic Leukemia

  This study analyzed samples from 29 patients with juvenile myelomonocytic leukemia (JMML) using whole exome sequencing. Each patient had a paired germline tissue along with a diagnostic leukemia sample. Germline tissue types included buccal mucosa, cordblood, Epstein-Barr virus immortalized cell lines and fibroblasts from either skin or bone marrow. Leukemia samples were either blood or bone marrow. Seven of the 29 patients also had a relapsed leukemia sample available for exome analysis.

  Study phs000973

• Genome Sequencing of Large, Multigenerational CEPH/Utah Families

  Blood-derived DNA samples were collected from 603 members of large, multigenerational families, collected as part of the Centre d'Etude du Polymorphisme Humain (CEPH) consortium. These DNA samples were sequenced (using Illumina HiSeq technology) to a median genome-wide depth of 30X. Sequenced reads from each individual were aligned to the human reference genome (hg19), generating CRAM files for each individual. Variant calls in VCF format were obtained using the Genome Analysis Toolkit (GATK).

  Study phs001872

• Whole Genome Sequencing of Waldenstrom's Macroglobulinemia

  Whole genome sequencing was conducted on 10 tumor/germline paired samples along with 20 additional unpaired tumor samples from patients with Waldesntrom's macroglobulinemia. Tumor lymphoplasmacytic lymphoma cells were obtained from CD19+ selected bone marrow mononuclear cells. Germline tissue was obtained from CD19 depleted peripheral blood mononuclear cells. High molecular weight DNA was then submitted for whole genome sequencing with Complete Genomics and aligned to HG19/NCBI human reference build 37.

  Study phs000740

• Genomic Profiling of Relapsed and Refractory Childhood Cancers

  Through clinical trials focused on molecularly guided therapy in pediatric cancers (NCT01355679, NCT01802567, NCT02162732), the Beat Childhood Cancer Consortium performed paired tumor/normal whole exome sequencing and/or tumor mRNA sequencing for 202 pediatric or adolescent young adult patients with rare, relapsed and refractory cancers (including neuroblastoma, Ewing sarcoma, osteosarcoma, rhabdomyosarcoma, ependymoma, glioma, and other rare solid tumors). A subset of these patients had multiple biopsies sequenced, including longitudinal profiling.

  Study phs002238

• Multiregional Single-Cell Transcriptomic Analysis of Liver Cancer

  In this study, we performed single-cell transcriptomic profiling of human liver tissues collected from hepatocellular carcinoma and intrahepatic cholangiocarcinoma patients. A total of seven primary liver cancer patients enrolled in this study. Samples were collected from multiple regions, including tumor core, tumor border and adjacent non-tumor tissue. The 10x Genomics platform was used to generate single cell 5' libraries. The Illumina NovaSeq 6000 platform was employed for sequencing.

  Study phs003117

• Immune Dysregulation in Human Subjects with Heterozygous Germline Mutations in

  We identified germline heterozygous mutations in CTLA4 in members of four families with severe immune dysregulation. Human CTLA4 haploinsufficiency caused dysregulation of FoxP3+ regulatory T (Treg) cells and lymphocytic infiltration of target organs, mimicking Ctla4 homozygous mice. Patients also exhibited a B cell phenotype, with progressive loss of B cells and accumulation of autoreactive CD21lo B cells. This study demonstrates a critical quantitative role for CTLA-4 in human immune homeostasis.

  Study phs000797

• NHLBI TOPMed: Pathways to Immunologically Mediated Asthma (PIMA)

  Study designed to further our understanding of the pathogenesis of asthma exacerbations in children. Children enrolled in the study (n=217) were all asthmatic and primarily Hispanic white. The children were followed for 18 months until they experienced an asthma exacerbation or completed the follow-up without an exacerbation. The time to the first asthma exacerbation was considered the outcome. The acute and convalescent immune phenotype of each asthma exacerbation was documented.

  Study phs001727

• LCM-isolated buccal epithelial cell sequencing

  Single buccal epithelial cells were dissected and collected on an adhesive cap with laser capture microdissection (LCM) with approximately 13-60 cells per cap. Each adhesive cap containing 13-60 cells was independently processed with QIAamp DNA micro kit (Qiagen) for DNA extraction. The NEBNext ultra II FS DNA library kit was used to prepare DNA libraries with low starting material. Paired-end whole genome sequencing reads were obtained with the NovaSeq.

  Study EGAS50000000098

• Single-cell RNA sequencing of pediatric Hodgkin Lymphoma to study the inhibition of T cell subtypes

  Here, we applied single-cell RNA-sequencing (scRNA-seq) on isolated HRS cells and the immune cells from the same pediatric classical Hodgkin Lymphoma (cHL) tumors. Specifically, 13 cHL patients and 3 reactive lymph node control samples were included in this cohort. This allowed us to identify genes of cell surface proteins that are consistently overexpressed in HRS cells and can potentially be used as targets for antibody-drug conjugates or CAR T cells. Finally, we identify potential interactions by which HRS cells inhibit T cells, among which the Galectin-1/CD69 and HLA-DRA/LAG3 interactions. However, high levels of inter-patient heterogeneity of the interaction strength were observed. In conclusion, this study identifies new potential therapeutic targets for cHL and highlights the importance of studying heterogeneity when identifying therapy targets.

  Dataset EGAD50000000626

• Whole genome and transcriptome sequencing of cancer of unknown primary tumours

  Whole genome and transcriptome sequencing of cancer of unknown primary tumours was used to determine yield of clinical biomarkers for a molecular guided trial or for resolving cancer type of origin. This study includes profiling of germline DNA and tumour DNA and RNA by whole genome and transcriptome sequencing. All samples are in BAM format aligned with GRCh38 reference genome. This dataset includes: 1. Whole genome sequencing (WGS) of 78 cancer of unknown primary tumour samples and 73 matched germline DNA. 2. Whole transcriptome sequencing (WTS) of 69 cancer of unknown primary tumour samples (matched to WGS cases) 3. Whole genome sequencing of 22 cell-free DNA samples from cancer of unknown primary patients and matched Germaine DNA(8 samples matched to tumour WGS)

  Dataset EGAD50000000656

• Characterisation of Cyr61-enriched myeloid angiogenic cells

  We previously demonstrated the enrichment of an angiogenic precursor cell population from peripheral blood mononuclear cells by CYR61, a protein of the CCN family. In vivo, CYR61 mediates the binding of leukocytes and particular monocyte populations at sites of vascular inflammation. Here, we present an in vitro enrichment system mimicking (patho)physiology and at the same time representing an effective tool for enrichment of the CYR61-binding blood cells and analyzed this cell population in depth.

  Study EGAS50000000533

• Transcriptome Sequencing PPGL (2)

  RNA-Seq data (n=81) library preparation was performed as previously reported by Calsina et al 2023 using QuantSeq 3' mRNA-Seq Library Prep Kit FWD for Illumina (Lexogen, 015). The prepared libraries were subsequently sequenced on NovaSeq™ system (Illumina). To combine the new CNIO samples (n=81) with the CNIO+TCGA dataset generated in Calsina et al., 2023, RNA data were processed using ComBat-seq as described in that same article.

  Study EGAS50000000013

• Targeting Heterochromatin Eliminates Malignant Stem Cells in Chronic Myelomonocytic Leukemia Through Reactivation of Retroelements and Innate Immune pathways

  Hematopoietic stem cell (HSC) aging involves heterochromatin reorganization. These repressive marks together with DNA methylation are essential for suppressing transposable elements (TEs). In this study we analyze heterochromatin and transcriptomic changes occurring at genes and TEs in HSCs from chronic myelomonocytic leukemia, a severe myeloid malignancy affecting the elderly, compared to age-matched cells, and in the presence or absence of a combination of epidrugs.

  Study EGAS50000000367

• Reconstitution of Human Brain Cell Diversity in Organoids via Four Protocols [scRNAseq]

  Single-cell RNA-sequencing of brain organoids at day 120 grown in four distinct growth protocols designed to generate dorsal (D) and ventral (V) forebrain, midbrain (M) and striatum (S) tissue using eight different pluripotent stem cell lines. Per per cell line-protocol combination two organoids (biological replicates) were grown. For cell line 176 the experiment was conducted in two independent biological replicates (repititions E1 and E2).

  Study EGAS50000000662

• Targeting Heterochromatin Eliminates Malignant Stem Cells in Chronic Myelomonocytic Leukemia Through Reactivation of Retroelements and Innate Immune pathways

  Hematopoietic stem cell (HSC) aging involves heterochromatin reorganization. These repressive marks together with DNA methylation are essential for suppressing transposable elements (TEs). In this study we analyze heterochromatin and transcriptomic changes occurring at genes and TEs in HSCs from chronic myelomonocytic leukemia, a severe myeloid malignancy affecting the elderly, compared to age-matched cells, and in the presence or absence of a combination of epidrugs.

  Study EGAS50000000688