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• Genetic and epigenetic characterization of adenoid cystic carcinoma

  Whole genome sequences of ACC primagrafts, Histone modification maps and transcription factor binding maps for ACC primagrafts and primary tumors. Processed ChIP-seq data is available on GEO under accession number GSE76465.

  Dataset EGAD00001001662

• Set_of_human_mesenchymal_CSA

  51 DNA methylation arrays of human samples initially diagnosed as mesenchymal chondrosarcoma. Microdissection of the cartilage and/or the small round cell component from the same sample may have occurred. As mentioned in the sample descriptions, the diagnoses of four samples have been revised. Additional molecular investigations were conducted for a subset of samples as described in the related publication.

  Dataset EGAD00010002515

• BIOMIROX

  This dataset regroups RNAseq of paired primary colorectal cancers and liver metastases extracted from 113 patients In Paris and Besançon University Hospitals. 216 FASTQ files from single-end 3' PolyA (QuantSeq 3′mRNA-Seq Kit FWD for Illumina (Lexogen)) RNAseq samples were generated On NOVASEQ 6000 (ILLUMINA).

  Dataset EGAD50000000443

• WES for CNV-verified CTCs from 2 patients with metastatic prostate cancer

  This dataset contains 4 paired fastq files sequenced by illumina Novoseq 6000. WES analysis (illumina platform, PE150, 100x coverage) was performed on a pool of CNV-verified CTCs that were enriched using high-throughout microfluidic device from entire leukopak from patients with metastatic prostate cancer (GU-1 and GU-2).

  Dataset EGAD50000001005

• Saliva_Fulani_Database

  In total, 90 DNA samples were genotyped on the Illumina Infinium H3Africa Consortium array (designed for 2,271,503 SNPs; using BeadChip type: H3Africa_2019_20037295_B1). Genotyping was performed at the SNP&SEQ Technology Platform (NGI/SciLifeLab Genomics, Sweden). Saliva Fulani dataset includes individuals from the following populations: 30 individuals from Senegal_FulaniLinguere, 30 individuals from Mauritania_FulaniAssaba, and 30 individuals from Mali_FulaniInnerDelta.

  Dataset EGAD50000000653

• Single-Cell Profiling of the Human Endometrium in Polycystic Ovary Syndrome: Uncovering Disease Signatures and Treatment Responses

  Single-nuclei map of human endometrial biopsies from women with and without PCOS to identify cell-type-specific disease signatures, compositional variations, and transcriptomic reversibility after a 16-week intervention with metformin or lifestyle. Single nuclei were extracted from 27 frozen endometrial biopsies for snRNA-seq using the 10X Genomics protocol.

  Dac EGAC50000000468

• HIV-phyloTSI: PANGEA (veSEQ-HIV)

  This dataset includes sample numbers TSI_0001 to TSI_0202 and TSI_0316 to TSI_0425 for the PANGEA (veSEQ-HIV) cohort of the study. Samples were sequenced using the Illumina NovaSeq system and the veSEQ-HIV method (see Bonsall, Golubchik et al 2020, DOI: 10.1128/JCM.00382-20). Each sample has a BAM file, and its associated reference file.

  Dataset EGAD50000001309

• HIV-phyloTSI: PANGEA (PCR amplicon)

  This dataset includes sample numbers TSI_0426 to TSI_0527 for the PANGEA (PCR amplicon) cohort of the study. Samples were generated by pooling four overlapping PCR amplicons (see Gall et al 2012, DOI: 10.1128/JCM.01516-12). The sequencing was conducted using the Illumina NovaSeq system. Each sample has a BAM file, and its associated reference file.

  Dataset EGAD50000001308

• WGS of thymic epithelial tumors and paired normal

  Among the 20 newly sequenced cases, we conducted additional whole-genome sequencing (WGS) on five out of eight CN-type thymomas, excluding three with low tumor cell fractions (< 0.1). Libraries for WGS were prepared using the TrueSeq DNA PCR-free Prep Kit following standard Illumina protocols.

  Dataset EGAD50000001160

• Dataset for melanoma-WHOLE_GENOME

  Rare cancer sequencing data of 22 runs in tumor/control pairs, which were uploaded to umbrella studies. The sequencing was always paired

  Dataset EGAD00001008889

• RNA-seq on neuroblastoma PDX model COG-N-519 treated with control miR-1283 and test miR-99b-5p mimics

  RNA-sequencing on neuroblastoma PDX model COG-N-519 treated with control miR-1283 and test miR-99b-5p mimics. Three samples from each of the treatment condition were analysed. Next-Seq platform was used for sequencing.

  Dataset EGAD00001007754

• Spatial transcriptomics of 1 untreated prostate cancer.

  Two sections of cryopreserved prostate cancer tissue from one untreated prostate cancer patient were profiled for spatial transcriptomics using the Visium Spatial library preparation protocol from 10x Genomics. The GRCh38 aligned sequencing reads from the two prostate cancer tissue sections are provided as BAM files.

  Dataset EGAD00001007921

• Low-coverage whole-genome sequencing (lcWGS) data of Genome in a Bottle (GIAB) reference samples

  This dataset contains low-coverage whole-genome sequencing (lcWGS) data generated from three GIAB reference samples (HG001–HG003) for method benchmarking and concordance analysis in FFPE-GWAS workflows. The data were generated using Illumina NovaSeq with paired-end 150bp reads and downsampled to 2x coverage.

  Dataset EGAD00001015533

• Combined Metabolic Activators Reduces Liver Fat in Nonalcoholic Fatty Liver Disease Patients

  Metagenomics data for "Combined Metabolic Activators Reduces Liver Fat in Nonalcoholic Fatty Liver Disease Patients". Samples were sequenced on NovaSeq6000(NovaSeq Control Software 1.7.0/RTA v3.4.4) with a 151nt (Read1)-10nt(Index1)-10nt(Index2)-151nt(Read2) setup using ‘NovaSeqXp’ workflow in ‘S4’ mode flow cell.

  Dataset EGAD00001008142

• Dataset for bone_cancer-WHOLE_GENOME

  Rare cancer sequencing data of 48 runs in tumor/control pairs, which were uploaded to umbrella studies. The sequencing was always paired

  Dataset EGAD00001008866

• Whole genome sequencing of GM09237 cells with and without folate depletion

  Two DNA samples extracted from GM09237 cell line cultured with either normal medium or medium with no folic acid for 5 days were sequenced using the BGISEQ500 platform (BGI whole genome 100 bp paired-end sequencing 60x) as well as PacBio Sequel long read sequencing.

  Dataset EGAD00001007732

• Small RNA sequencing from CSF extracellular vesicles - PD/CTR

  The dataset contains FASTQ files referring to the study "Small RNA sequencing from CSF extracellular vesicles - PD/CTR". For this project, RNA was isolated from CSF extracellular vesicles obtained by ultracentrifugation. Libraries were prepared with the TruSeq Small RNA library prep Illumina, and sequencing conducted in the Illumina HiSeq4000.

  Dataset EGAD00001006629

• Dataset for cancer_of_unknown_primary-EXON

  Rare cancer sequencing data of 62 runs in tumor/control pairs, which were uploaded to umbrella studies. The sequencing was always paired

  Dataset EGAD00001008870

• Dataset for GIST-WHOLE_GENOME

  Rare cancer sequencing data of 18 runs in tumor/control pairs, which were uploaded to umbrella studies. The sequencing was always paired

  Dataset EGAD00001008876

• Dataset for synovial_sarcoma-EXON

  Rare cancer sequencing data of 34 runs in tumor/control pairs, which were uploaded to umbrella studies. The sequencing was always paired

  Dataset EGAD00001008898

• Dataset for upper_gastrointestinal_tumor-WHOLE_GENOME

  Rare cancer sequencing data of 28 runs in tumor/control pairs, which were uploaded to umbrella studies. The sequencing was always paired

  Dataset EGAD00001008901

• PacBio HiFi sequencing of telobait-captured DNA from 68 patients

  PacBio HiFi sequencing was performed on 68 barcoded patients' genomic DNA after a telobait-capture protocol to enrich for telomeric regions. The sequencing reads of each patient were de-multiplexed and presented as patient-specific PacBio CCS BAM files. There are 56 new samples and 12 repeated samples from run 1.

  Dataset EGAD00001009397

• Leiomyosarcoma Cancer Transcriptome Sequencing

  RNA-Seq data (fastq raw read sequences) for French ICGC leiomyosarcoma cancer sequencing project, 78 samples representing 67 donors. Sequencing was performed on Illumina HiSeq. The libraries were then sequenced with a 2 x 75bp paired-end protocol to a minimum mean reads of 50 million.

  Dataset EGAD00001003192

• Whole exome Sequencing (WES) of multiple tumor biopsies, patient-derived spheroids and leukocyte DNA from colorectal cancer patients (BAM files)

  WES was performed using the KAPA-Hyper prep kit from Illumina (Roche, Basel, Switzerland) for library construction, followed by exome capture using Niblegen SeqCap EZ Human Exome Library v3.0 (Roche). Reads were mapped using BWA MEM against the humane reference genome HG19.

  Dataset EGAD00001003821

• Whole Exome Sequencing of 15 Human Embryonic Stem Cell Lines

  This dataset includes deep coverage (&gt;60x) whole exomes of 15 human embryonic stem cell lines. Genomic DNA was purified and fragmented using the Illumina Nextera system for library preparation and sequenced using 150bp paired-end reads. Sequencing reads were aligned to the hg19 reference genome using the BWA MEM alignment program.

  Dataset EGAD00001003446

• Germline genome sequencing samples from the Hereditary Cancer Syndromes (ICCon) Cancer Flagship

  A prospective study of individuals with suspicion of a hereditary cancer syndrome for whom previous clinical targeted genetic testing was either not informative or was not available. To identify pathogenic disease-causing variants explaining participant presentation, germline whole-genome sequencing and a comprehensive cancer virtual gene panel analysis were undertaken.

  Dataset EGAD00001011260

• COVID-19 Multiomics Atlas

  We provide a single-nuclei RNA-sequencing (snRNA-seq) dataset derived from four COVID-19 patients, generated using the 10x Chromium Next GEM Single Cell v3.1 kit. For our study, these were integrated with snRNA-seq data with 12 publicly available sc/snRNA-seq datasets, comprising organ donor lung samples (n=89) and COVID-19 lung tissue samples (n=51).

  Dataset EGAD00001015602

• The Genetics of Lung Cancer Susceptibility in Smokers

  Over 85% of all patients diagnosed with lung cancer report a history of tobacco use, though only 10% of tobacco smokers eventually develop lung cancer. Epidemiologic studies have shown that family members of patients with lung cancer have a higher risk of developing lung cancer than controls. In an effort to identify variants associated with tobacco induced lung cancer, we have sequenced germline DNA from affected and unaffected members of families with strong histories of tobacco related lung cancer.

  Study phs000728

• Genomic Characterization of African-American Prostate Cancer

  African-American men have the highest incidence and mortality rate from prostate cancer. This study represents a whole exome sequencing study of prostate cancer samples from African-American men. We performed exome sequencing and analysis of prostate tumors and matched normal tissues to identify somatic mutations and insertion/deletions across this cohort. All sequencing was performed at the Broad Institute. This study has the potential to identify novel recurrently mutated genes in prostate cancer and improve our understanding of prostate cancer in African-Americans.

  Study phs000945

• NHLBI TOPMed: Cleveland Clinic Atrial Fibrillation (CCAF) Study

  The Cleveland Clinic Atrial Fibrillation Study consists of clinical and genetic data of patients with atrial fibrillation and control cohorts from the Cleveland Clinic CV/Arrhythmia Biobank, including the Cleveland Clinic Lone Atrial Fibrillation GeneBank. The Cleveland Clinic Lone AF GeneBank Study has enrolled patients with lone AF, defined as AF in the absence of significant structural heart disease. The CV/Arrhythmia Biobank has also enrolled participants with non-lone atrial fibrillation. All patients provided written informed consent.

  Study phs001189

• Whole genome sequencing of glioblastoma reveals enrichment of non-coding constraint mutations in known and novel genes

  Glioblastoma (GBM) has one of the worst five-year survival rates of all cancers. While genomic studies of the disease have been performed, alterations in the non-coding regulatory regions of GBM have largely remained unexplored. We apply whole-genome sequencing (WGS) to identify non-coding mutations, with regulatory potential in GBM, under the hypothesis that regions of evolutionary constraint are likely to be functional, and somatic mutations are likely more damaging than in unconstrained regions.

  Study EGAS00001004379

• Lung_Cell_Atlas__Paediatric_RNA

  Single cell sequencing will be carried out by multiome profiling (RNAseq and ATACseq). Additonal modalities may be examined. Spatial profiling may involve Visium, Curio and other technologies. This data set will feed into a larger analysis of the human lungs over development, that aims to detail all the cell types of the human lungs and airways and will extend current knowledge by providing chromatin accessibility data that will allow us to link GWAS data and identify regulatory networks and then compare these against fetal and adult data sets

  Study EGAS00001008299

• Lung_Cell_Atlas__Paediatric_Spatial

  Single cell sequencing will be carried out by multiome profiling (RNAseq and ATACseq). Additonal modalities may be examined. Spatial profiling may involve Visium, Curio and other technologies. This data set will feed into a larger analysis of the human lungs over development, that aims to detail all the cell types of the human lungs and airways and will extend current knowledge by providing chromatin accessibility data that will allow us to link GWAS data and identify regulatory networks and then compare these against fetal and adult data sets

  Study EGAS00001008300

• Whole Genome Sequencing Data of High Grade Serous Ovarian Cancer

  Longitudinal whole genome sequencing data to study chemoresponse in ovarian cancer. These samples belong to an ongoing sample collection and the data already includes hundreds of samples from over 200 patients. Samples are from primary and metastatic tissues and ascites. All patients have been treated with platinum-taxane based chemotherapy and majority of them are diagnosed with high-grade serous ovarian cancer.

  Study EGAS00001006775

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

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

  Study EGAS50000000015

• Clonal_haematopoiesis_in_patients_with_AAA

  Recent advances in genomics have demonstrated that clonal haemopoiesis driven by leukaemia associated somatic mutations is a relatively common phenomenon that increases in frequency with advancing age. Whilst individuals with clonal haemopoiesis have an increased risk of developing haematological malignancies, they also have an increased mortality from other causes. Additionally, certain mutations are almost exclusively seen in individuals aged 70 years or older, whilst others are seen in individuals with non-haematological cancers including breast and ovarian. Recently, clonal haemopoiesis was found to be associated with a significantly increased risk of atherosclerotic cardiovascular disease. This association is thought to be causative with clonally-derived macrophages showing elevated expression of several chemokine and cytokine genes that contribute to atherosclerosis. Another vascular pathology, abdominal aortic aneurysm (AAA), increases with age and shares risk factors with atherosclerosis (including smoking, male sex, high cholesterol). However, the impact of these risk factors and the overlap between AAA and atherosclerosis is poorly understood. To investigate a possible link between clonal haemopoiesis and AAA, we will study DNA samples from 300 patients with AAA and up to 200 controls for evidence of clonal haemopoiesis. This will be done using target DNA enrichment with biotinylated RNA baits followed by high throughput sequencing.

  Study EGAS00001002873

• Identification and Molecular Characterization of Somatic Mutations in Malformations of Cortical Development

  Genetic mutations causing disease may be inherited, newly acquired in parental gametes and present in the zygote or acquired as somatic events at some point in development after fertilization. The burden and localization of an acquired mutation depend on when the mutation arises. As is the case for inherited genetic variation, there is accumulating evidence that somatic mutations can lead to severe tissue-specific disease. Malformations of cortical development (MCD) represent a group of disorders characterized by a range of morphological and structural abnormalities of the cerebral cortex reflecting errors in embryonic cortical development. MCD are associated with intellectual disability, as well as refractory epilepsy, and may require the surgical removal of the affected tissue. Inherited gene mutations involved in neuronal development explain only a fraction of MCD cases. In this project we sought to evaluate the hypothesis that somatic mutations disrupt embryonic cortical development and are responsible for a substantial fraction of MCD. Using high coverage next generation sequencing of protein-coding regions in DNA extracted from abnormal brain tissue and unaffected tissue (leukocytes) from patients with three forms of MCD, we sought to identify somatic mutations within each patient with MCD. Exome sequence data from study participants are provided to facilitate research into the genetic underpinnings of MCD.

  Study phs002128

• Mapping Systemic Lupus Erythematosus Heterogeneity at the Single Cell Level

  Patients with Systemic Lupus Erythematosus (SLE) display a complex blood transcriptome whose cellular origin is poorly resolved. Using single-cell RNA-seq, we profiled ~276,000 PBMCs from 33 children with SLE (cSLE) with different degrees of disease activity (DA) and 11 matched controls. Increased expression of Interferon-stimulated genes (ISGs) distinguished cSLE from healthy control cells. The high-ISG expression signature (ISGhi) derived from a small number of transcriptionally defined subpopulations within major cell types, including monocytes, CD4+ and CD8+ T cells, NK cells, cDCs, pDCs, B cells and especially plasma cells. Expansion of unique subpopulations enriched in ISGs and/or in monogenic Lupus-associated genes classified patients with the highest DA. Profiling of ~82,000 single PBMCs from adult SLE patients confirmed the expansion of similar subpopulations in patients with the highest DA. This study lays the groundwork for resolving the origin of the SLE transcriptional signatures and the disease heterogeneity towards precision medicine applications. Patient demographics, clinical and laboratory data and treatment are summarized and available. The genomic data for participant aHD2 will not be included in the dataset The study description is reprinted from Nehar-Belaid et. al. Nature Immunology, 2020, with permission from Nature Immunology Group

  Study phs002048

• Childhood Cancer Data Initiative (CCDI): Pediatric In Vivo Testing Program –Sarcoma, Kidney, and Liver Cancers

  The goal was to complete whole exome sequencing (WES) and RNA sequencing (RNA-Seq) on patient derived xenograft samples. Cancer in children is rare with approximately 15,700 new cases diagnosed annually in children 21 years or younger in the U.S. Through use of multimodality therapy (surgery, radiation therapy, and aggressive chemotherapy), 70% of patients will be 'cured' of their disease, and 5-year Event-Free Survival (EFS) exceeds 80%. Consequently, the number of patients that can be enrolled in phase I/II clinical trials is small, and most patients will have been extensively treated, hence drug/radiation resistant. Thus, preclinical studies that accurately translate into effective clinical therapy are an essential component of pediatric drug development. Our group has contributed to studies in the Pediatric Preclinical Testing Program (PPTP) and Pediatric Preclinical Testing Consortium (PPTC) that have led to clinical studies through Children's Oncology Group (COG). Of importance, we have developed and characterized over 330 Patient Derived Xenografts (PDX), developed from tumors both at diagnosis and relapse, that can be used to facilitate pediatric drug development as directed by FDA under the Research to Accelerate Cures and Equity for Children Act (RACE for Children Act).

  Study phs003160

• Hematopoietic Tet2 inactivation enhances the response to checkpoint blockade immunotherapy

  Somatic mutations inactivating TET2 are among the most common drivers of clonal hematopoiesis (CH). While TET2 inactivation is associated with monocyte-derived inflammation and improved chimeric antigen-receptor-T cell function, its impact on immunotherapy response is unknown. In murine models, hematopoietic Tet2 mutation enhanced the immune checkpoint blockade (ICB) response via the combined presence of phagocytes, CD4 and CD8 T cells. This effect was lost with myeloid- or T-cell restricted Tet2 inactivation, or in mice with 20% Tet2-mutant hematopoiesis. Mechanistically, in Tet2-mutant tumor-infiltrating leukocytes (TILs), ICB preferentially restricted cell states linked to tumor progression while inducing anti-tumor states. Tet2-mutant monocytes activated costimulatory programs, while Tet2-mutant T cells showed enhanced T cell memory signatures, alongside decreased exhaustion and regulatory phenotypes. This murine data was clinically relevant, since tumors from colorectal cancer and melanoma patients with TET2 driver mutation-CH (TET2-CH) showed enhanced immune infiltration, inflammation, and T cell activation. In melanoma patients treated with ICB, TET2-CH was associated with 6-fold greater odds of clinical benefit. Collectively, we demonstrate that hematopoietic Tet2 inactivation primes leukocytes for anti-tumor states associated with immunotherapy response and provides a potential biomarker for personalized therapy.

  Study EGAS50000001191

• METABRIC: Data from Batra et al (2021); DNA methylation landscapes of 1538 breast cancers reveal a replication-linked clock, epigenomic instability and cis-regulation

  DNA methylation is aberrant in cancer, but the dynamics, regulatory role and clinical implications of such epigenetic changes are still poorly understood. Here, RRBS-based profiles of 1538 breast tumors and 244 normal breast tissues from the METABRIC cohort are reported, facilitating detailed analysis of DNA methylation within a rich context of genomic, transcriptional, and clinical data. Tumor methylation from immune and stromal signatures are deconvoluted leading to the discovery of a tumor replication-linked clock with genome-wide methylation loss in non-CpG island sites. Unexpectedly, methylation in most tumor CpG islands follows two replication-independent processes of gain (MG) or loss (ML) that we term epigenomic instability. Epigenomic instability is correlated with tumor grade and stage, TP53 mutations and poorer prognosis. After controlling for these global trans-acting trends, as well as for X-linked dosage compensation effects, cis-specific methylation and expression correlations are uncovered at hundreds of promoters and over a thousand distal elements. Some of these targeted known tumor suppressors and oncogenes. In conclusion, the study demonstrates that global epigenetic instability can erode cancer methylomes and expose them to localized methylation aberrations in-cis resulting in transcriptional changes seen in tumors.

  Study EGAS00001004327

• MorphoITH: A Framework for Deconvolving Intra-Tumor Heterogeneity Using Tissue Morphology

  The ccRCC-ITH study WES dataset is derived from a morphology guided multi-regional sequencing dataset used to study the relationship between morphology and genetic evolution. It contains whole exome sequencing data of 18 tumor and 2 adjacent normal samples from 2 UTSW patients, who have consented to depositing their genomic data to public repository. Tumor samples come from different tumor sites, including primary tumor, thrombus and metastases. WES was performed using 75bp paired-end fragments at an average read depth > 50x on a NovaSeq 6000 platform (Illumina, San Diego, CA, USA). The raw data is in fastq format.

  Dataset EGAD50000001550

• Reference Panel for Imputation Analysis Based on Whole Genome Sequencing Data of 3,256 Japanese Individuals(BioBank Japan genotype data)

  This reference panel was constructed using whole genome sequencing data from 3,256 Japanese individuals and the 1000 Genomes Project. It provides high accuracy and utility in analyzing genetic polymorphisms, while also reflecting the genetic diversity specific to the Japanese population. This dataset is expected to contribute to the advancement of genetic research and personalized medicine.

  Study JGAS000746

• Evidence for Enhancer Activity in Intron 1 of TNFRSF1A Using CRISPR/Cas9 in Human Induced Pluripotent Stem Cell-derived Macrophages

  Use of CRISPR/Cas9 technology to study the TNFRSF1A gene, which plays a key role in autoimmune diseases such as ankylosing spondylitis, multiple sclerosis, and inflammatory bowel disease. By editing a specific regulatory element within the TNFRSF1A locus, we have identified the role of an enhancer element that is not well understood.

  Study EGAS50000000703

• PARADIGM: Combined ctDNA and serum PSA for dynamic monitoring of metastatic prostate cancer starting first-line treatment

  The prognosis of newly-diagnosed metastatic prostate cancer is highly variable. The PARADIGM prospective cohort study evaluated predictors of survival in blood collected at the start of each of the first six treatment cycles from 114 high-volume metastatic patients starting androgen deprivation therapy combined with docetaxel or an androgen receptor pathway inhibitor.

  Study EGAS50000001357

• Cancer genomics for elucidation of molecular mechanisms of carcinogenecis and progression in lung cancer

  The objective of this project is to analyze genomic aberrations and gene expression changes such as mutations, deletions, amplifications, and hypermethylation in human lung cancer cells at the somatic cell level, and to contrast these with clinicopathological information to elucidate the molecular mechanisms and characteristics of lung cancer development and progression at the genetic level.

  Study JGAS000756

• Multiregion Whole Exome sequencing of pHGG and DIPG

  The failure to develop effective therapies for paediatric glioblastoma (pGBM) and diffuse intrinsic pontine glioma (DIPG) is in part due to their intrinsic heterogeneity. Analysis of 142 sequenced cases revealed multiple tumour subclones, spatially and temporally co-existing in a stable manner as observed by multiple sampling strategies. This dataset provides multi region sequencing of high grade gliomas and diffuse intrinsic pontine gliomas from 15 patients. DNA was extracted from FFPE sections in 2-13 regions of each tumour and sequenced with Agilent SureSelect whole exome sequencing. Germline DNA was also sequenced in 14 cases. Data was aligned to hg19 with bwa and is provided as 79 separate BAM files.

  Dataset EGAD00001004114

• Role of Epigenetic Memory in Human Induced Pluripotent Stem Cells Pilot

  Fibroblasts have been shown to re-program into induced pluripotent stem (hiPS) cells, through over-expression of pluripotency genes. These hiPS cells show similar characteristics to embryonic stem cells including cell surface markers, epigenetic changes and ability to differentiate into the three germ layers. However it is unclear as to the extent of changes in gene expression through the re-programming process.. 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 (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/

  Dataset EGAD00001000828

• MediMer: A versatile do-it-yourself peptide-receptive MHC class I multimer platform for tumor neoantigen-specific T cell detection

  Peptide-loaded MHC class I (pMHC-I) multimers have revolutionized our capabilities to monitor disease-associated T cell responses with high sensitivity and specificity. To improve the discovery of T cell receptors (TCR) targeting neoantigens of individual tumor patients with recombinant MHC molecules, we developed a peptide-loadable MHC class I platform termed MediMer. MediMers are based on soluble disulfide-stabilized β2-microglobulin/heavy chain ectodomain single-chain dimers (dsSCD) that can be easily produced in large quantities in eukaryotic cells and tailored to individual patients’ HLA allotypes with only little hands-on time. Upon transient expression in CHO-S cells together with ER-targeted BirA biotin ligase, biotinylated dsSCD are purified from the cell supernatant and are ready to use. We show that CHO-produced dsSCD are free of endogenous peptide ligands. Empty dsSCD from more than 30 different HLA-A,B,C allotypes, that were produced and validated so far, can be loaded with synthetic peptides matching the known binding criteria of the respective allotypes, and stored at low temperature without loss of binding activity. We demonstrate the usability of peptide-loaded dsSCD multimers for the detection of human antigen-specific T cells with comparable sensitivities as multimers generated with peptide-tethered β2m-HLA heavy chain single-chain trimers (SCT) and wild-type peptide-MHC-I complexes prior formed in small-scale refolding reactions. Using allotype-specific, fluorophore-labeled competitor peptides, we present a novel dsSCD-based peptide binding assay capable of interrogating large libraries of in silico predicted neoepitope peptides by flow cytometry in a high-throughput and rapid format. We discovered rare T cell populations with specificity for tumor neoepitopes and epitopes from shared tumor-associated antigens in peripheral blood of a melanoma patient including a so far unreported HLA-C*08:02-restricted NY-ESO-1-specific CD8+ T cell population. Two representative TCR of this T cell population, which could be of potential value for a broader spectrum of patients, were identified by dsSCD-guided single-cell sequencing and were validated by cognate pMHC-I multimer staining and functional responses to autologous peptide-pulsed antigen presenting cells. By deploying the novel CHO producer cell-based dsSCD MHC-I MediMer platform, we hope to significantly improve success rates for the discovery of personalized neoepitope- specific TCR in the future by being able to also cover rare HLA allotypes.

  Study EGAS50000000065

• Chromatin immunoprecipitation linked to next-generation whole genome sequencing (ChIP-Seq) for H3K36me3 in paediatric high grade glioma cell lines KKNS4 and SF188 with and without a G34V mutation in H3F3A

  Glioblastomas of children and young adults have a median survival of only 12-15months and are clinically and biologically distinct from histologically similar cancers in older adults1. They are defined by highly specific mutations in the gene encoding the histone H3.3 variant H3F3A2, occurring either at or close to key residues marked by methylation for regulation of transcription – K27 and G34. We performed chromatin immunoprecipitation linked to next-generation whole genome sequencing (ChIP-Seq) for H3K36me3 in order to test the hypothesis that, rather than total H3K36me3, the G34V mutation may instead result in differential binding of the trimethyl mark throughout the genome. Compared with H3F3A wild-type SF188 paediatric GBM cells, H3K36me3 was found to be significantly differentially bound in KNS42 cells at 5130 distinct regions of the genome corresponding to 156 genes. Concurrent whole genome DNA sequencing demonstrated that this was not confounded by copy number alterations. The cerebral hemispheric-specific G34 mutation drives a distinct expression signature through differential genomic binding of the K36 trimethylation mark (H3K36me3). The transcriptional program induced recapitulates that of the developing forebrain, and involves numerous markers of stem cell maintenance, cell fate decisions and self-renewal. Critically, H3F3A G34 mutations cause profound upregulation of MYCN, a potent oncogene which is causative of glioblastomas when expressed in the correct developmental context. This driving aberration is selectively targetable in this patient population by inhibiting kinases responsible for stabilisation of the protein.

  Study EGAS00001001437

• Effect of Breast Feeding on Immunologic Priming in Young Infants

  The mechanisms generating immunoglobulin heavy chain (IgH) biodiversity result in over potentially unique immunoglobulin sequences within an individual. However, over the course of B cell development, B cell receptor (BCR) selection constrains the repertoire significantly. In newborn infants compared to adults, developmental regulation of terminal deoxynucleotidyl transferase (TdT) activity in the bone marrow, selective use of V, D and J gene segments in the IgH locus during fetal life, and immaturity of somatic hypermutation (SHM) and class switch recombination (CSR) mechanisms are likely to contribute to a less diverse IgH repertoire, although the extent of repertoire biodiversity in newborns has not been extensively examined. Furthermore, the fetal IgH repertoire is tightly controlled and for the most part independent of environmental antigenic influences. As a result, the neonatal repertoire, in contrast to older children and adults, is less impacted by the selective pressures of the microbiome, pathogen exposure, and environmental antigens. Evidence for developmental differences in TdT activity is seen in shorter CDR3 lengths and decreased junctional diversity in BCR in both term and preterm newborns. Next Generation Sequencing (NGS) is a sensitive approach to evaluate the neonatal IgH repertoire and assess the relative contribution of each aspect of IgH rearrangement and affinity maturation to overall IgH biodiversity prior to and following isotype class switch. NGS and bioinformatics accurately assess biodiversity by determining the number of unique sequences within the IgH repertoire. Combined with novel analytic tools, NGS provides an approach to compare the extent of somatic hypermutation (SHM), N insertions, V/D/J gene segment usage, and CDR3 length between newborns and adults. Taken together, these measures can be used to assess the earliest events in B cell development using the newborn Ig transcriptome to evaluate the IgM, IgG, and IgA IgH repertoires. The goal of this study was to define the extent of IgH biodiversity in newborns and examine the factors that contribute to the generation of biodiversity during early life. Establishment of the bioinformatics pipeline can be applied to examine the immune deficiency, response to vaccine and infection at molecular population level.

  Study phs002073

• HCA_Thymus_Disease_DiGeorge_Transplant_RNA

  Single cell transcriptomics study of thymic transplant biopsies Allogeneic thymus transplantation is the only curative therapy for complete DiGeorge Syndrome (cDGS), a rare severe primary immunodeficiency characterised by athymia. GOSH is one of only two centres worldwide to offer this treatment. Despite a lack of major histocompatibility complex (MHC)-matching between donor and host, transplanted thymus becomes repopulated by recipient bone marrow derived precursor cells and supports development of functional T-cells. The mechanisms underlying thymopoiesis in this context are poorly understood, but over time we observe reconstitution of T-cell immunity, with the ability to produce host naïve T-cells showing a broad T-cell receptor (TCR) repertoire and to generate MHC-restricted T-cell proliferative responses. Although lifesaving, the achieved immunological reconstitution is typically not complete with circulating T-cell numbers usually remaining below the age related normal ranges. Additionally, we observe persistence of donor-derived T-cells of unknown clinical significance. To gain more insight into the mechanisms by which MHC-mismatched transplanted thymus supports T-cell development with self-tolerance, as well as into the basis of suboptimal T-cell immunity, we now aim to investigate immune reconstitution after thymus transplantation in further detail by using single-cell transcriptomics, applied to thymic transplant biopsies and peripheral blood samples collected during standard post-transplant patient care. By identifying which lineages of host- derived cells repopulate the thymic tissue after transplantation, we will be able to address the role of MHC in positive and negative T-cell selection during T-cell differentiation. We will also be able to clarify the exact ontogeny of the persistent donor T-cells, as well as their possible role. Understanding the mechanisms of action of HLA-mismatched transplanted thymus will contribute to treatment optimisation. Additionally, our research provides a unique opportunity to further investigate key immunological concepts, such as tolerance and autoimmunity, challenging existing paradigms in thymus immunology. 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 (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/

  Study EGAS00001004025

• A novel recurrent mutation in MITF predisposes to familial and sporadic melanoma

  We conducted whole-genome sequencing of probands from several melanoma families, identifying one individual carrying a novel germline variant (c.G1075A, NM_000248.3; p.E318K, NP_000239.1; rs149617956) in the melanoma lineage-specific oncogene MITF. While the variant cosegregated with melanoma in some, but not all cases in the family, linkage analysis of 31 families subsequently identified to carry the variant generated a LOD score of 2.7 under a dominant model, suggesting E318K as a possible intermediate risk variant. Consistent with this, E318K was significantly associated with melanoma in a large Australian case-control sample, giving an odds ratio (OR) of 2.33, 95% CI 1.21-4.70 (case and control carrier frequency, 0.0165 and 0.0072, respectively; P=0.008). Likewise, it was similarly associated in an independent case-control sample from the United Kingdom (UK P=0.012; combined P=0.0003, OR 2.19, 95% CI 1.41-3.45). In the Australian sample, the variant allele was significantly over-represented in cases with a family history of melanoma (OR 2.95, 95% CI 1.23-6.92), multiple primary melanomas (OR 4.22, 95% CI 1.52-10.91), or both (OR 8.37, 95% CI 2.58-23.80). The variant allele was also associated with increased nevus count (combined P=0.002, OR 2.54, 95% CI 1.42-4.55) and non-blue eye color (combined P=0.008, OR 2.01, 95% CI 1.11-3.81). Functional analysis of E318K showed that MITF encoded by the variant allele had impaired sumoylation and differentially regulated several MITF targets. These data indicate that MITF is a melanoma predisposition gene and highlights the utility of whole-genome sequencing to identify novel rare variants associated with disease susceptibility.

  Study phs000419

• Telomerase activation by genomic rearrangements in high-risk neuroblastoma

  Neuroblastoma is a malignant pediatric tumor of the sympathetic nervous system1. Roughly half of these tumors regress spontaneously or are cured by limited therapy. By contrast, high-risk neuroblastomas have an unfavorable clinical course despite intensive multimodal treatment, and their molecular basis has remained largely elusive2-4. We have performed whole-genome sequencing of 56 neuroblastomas (high-risk, n=39; low-risk, n=17) and discovered recurrent genomic rearrangements affecting a chromosomal region (5p15.22) proximal of the telomerase reverse transcriptase gene (TERT). These rearrangements occurred only in high-risk neuroblastomas (12/39, 31%) in mutually exclusive fashion with MYCN amplifications and ATRX mutations, which are known genetic events in this tumor type1,2,5. In an extended case series (n=217), TERT rearrangements defined a subgroup of high-risk tumors with particularly poor outcome. Despite the large diversity of these rearrangements, they all induced massive transcriptional upregulation of TERT. In the remaining high-risk tumors, TERT expression was also elevated in MYCN-amplified tumors, whereas alternative lengthening of telomeres was present in neuroblastomas without TERT or MYCN alterations, suggesting that telomere lengthening represents a central mechanism defining this subtype. The 5p15.22 rearrangements juxtapose the TERT coding sequence to strong enhancer elements, resulting in massive chromatin remodeling and DNA methylation of the affected region. Supporting a functional role of TERT, neuroblastoma cells bearing rearrangements or amplified MYCN exhibited both upregulated TERT expression and enzymatic telomerase activity. In summary, our findings show that remodeling of the genomic context abrogates transcriptional silencing of TERT in high-risk neuroblastoma and places telomerase activation in the center of transformation in a large fraction of these tumors.

  Study EGAS00001001308

• BLUEPRINT: Epigenetic programming during monocyte to macrophage differentiation and trained innate immunity

  Monocyte differentiation into macrophages represents a cornerstone process for host defense. Concomitantly, immunological imprinting of either tolerance or trained immunity determines the functional fate of macrophages and susceptibility to secondary infections. Transcriptomes (RNA-Seq) and epigenomes (ChIP-Seq H3K4me1,H3K4me3,H3K27ac) in four primary cell types: monocytes, in vitro differentiated naive, tolerized and trained macrophages were characterized. Inflammatory and metabolic pathways were modulated in macrophages, including decreased inflammasome activation, and pathways functionally implicated in trained immunity were identified. Strikingly, B-glucan training elicits an exclusive epigenetic signature, revealing a complex network of enhancers and promoters. Analysis of transcription factor motifs in DNase I hypersensitive sites at cell-type specific epigenetic loci unveiled differentiation and treatment specific repertoires. Altogether, this study provides a resource to understand the epigenetic changes that underlie innate immunity in humans.

  Dataset EGAD00001001011

• SC_DDD-G-5

  Post-QC (pre-imputation) genotype data for N=2,166, a subset of trios described in EGAD00010001602. These data form N=722 complete trios in which the proband has a neurodevelopmental phenotype (Niemi et al. Nature 2018). Includes HPO phenotype terms for patients. Samples were genotyped on the Illumina HumanOmniExpress BeadChip

  Dataset EGAD00010001606

• RNASeq Whole Transcriptome Expression Profiles of NFE2 and PF4 as Translational Biomarkers for BET Inhibition-Induced Thrombocytopenia in Preclinical and Clinical Studies

  Longitudinal blood samples for exploratory biomarker analysis were collected from 51 out of 83 patients enrolled in CA011-001 (NCT02419417) study of BMS-986152, totaling 425 samples collected on three different dosing schedules (A, B, and C). Whole transcriptome expression profiling was performed on the collected blood samples using RNASeq, with Illumina TruSeq library preparation and paired sequencing. Gene expression data was quantified as transcripts per million (TPM).

  Dataset EGAD50000001659

• RNA-seq data for proximal and distal human LHBT UZH (CH)

  This dataset contains bulk RNA-seq data from 15 patients who underwent rotator cuff repair surgery, yielding paired proximal and distal samples of the long head of the biceps tendon (30 samples total). The submission includes 90 files, consisting of R1 and R2 FASTQ files for each sample as well asprocessed .TXT files containing gene-level counts generated after genome alignment. Raw sequencing reads were generated on an Illumina platform, aligned to the human reference genome GRCh38.p13, and quantified at the gene level.

  Dataset EGAD50000002095

• CRUK Accelerator: Non-small cell lung cancer whole exome and RNA sequencing

  Whole exome and RNASeq raw sequencing data for a cohort 24 patients with non-small cell lung cancer, 15 adenocarcinoma (8 female, 7 male) and 9 squamous cell carcinoma(5 female, 4 male). Median age at diagnosis was 69. Tumour tissue and PBMCs were used for whole exome sequencing and RNA sequencing. This data was generated as part of a study funded by a Cancer Research UK Centres Network Accelerator Award Grant (A21998).

  Dataset EGAD00001007934

• CITEseq data

  Single-cell whole transcriptome and antibody expression for bone marrow samples from Cohorts A and B. CITEseq protocol was followed. 37 and 77 surface markers were measured in each cohort, respectively (see Supplementary Table 1). For details on cell sorting prior scRNAseq see the methods section of the manuscript.

  Dataset EGAD00001010187

• Identification of neoantigen from MSI-CRC patient derived organoids and its application for targeting by autologous T cells

  Targeting neoantigens expressed only by tumor cells enable tumor destruction without unexpected damages to healthy tissues. Here, we identified neoantigens from microsatellite instable (MSI) colorectal cancer (CRC) patient-derived organoids by genomics and immunopeptidomics approches. The neoantigens in this study were predicted from frame-shift mutation by whole-genome sequencing and confirmed its presentation on organoids surface class I HLA molecules by mass spectrometry. We utilized these neoantigens to isolate neoantigen-specific CD8 T cells from autologous PBMC, and proved tumor organoids killing ability of the CD8 T cells, whereas it did not attack normal organoids. This study provides a platform to identify neoantigen from patient-derived cancer organoids and a model to validate T cell recognition, which could be useful for adoptive CD8 T cell transfer treatment for MSI-CRC patient.

  Study EGAS00001006633

• EPIC arrays data for chemotherapy response project

  In this study, a total of 300 patients with MIBC receiving chemotherapy were included; 62 received NAC before cystectomy and 245 received first-line chemotherapy upon detection of locally-advanced (T4b) or metastatic disease. Treatment response, defined as pathological downstaging (&amp;lt; pTa,CIS,N0) after NAC or complete or partial response after first-line treatment (RECIST criteria). DNA methylation analysis was performed using DNA from 72 patients. We used 500 ng genomic DNA for bisulfite conversion followed by whole-genome amplification prior to hybridization to EPIC BeadChip (Illumina, San Diego, CA) overnight as described by the manufacturer and then scanned with the Illumina iSCAN system. Data provided here consist of 144 idat files.

  Study EGAS00001004515

• Human data for chromatin accessibility (ATAC-Seq and scATAC-Seq) and transcriptome (RNA-Seq and scRNA-Seq) in eight B-cell precursors, from HSC to Naive B cells

  We generated paired transcriptomic (RNA-Seq) and chromatin accessibility (ATAC-Seq) profiles from 8 immune cell populations representing the early lymphoid hematopoietic differentiation stages along the B cell lineage: HSC, CLP, pro-B, pre-B, Immature B, Transitional B, Naive B CD5-, Naive B CD5+. Cell populations were isolated from healthy adult human bone marrow precursors and peripheral blood (n=13) following a predefined sorting strategy. For each donor, a subset of different cell type populations was obtained. Additionally, to explore the continuous dynamic of RNA and ATAC, we generated a single-cell sample of human CD34+ B cell precursors.

  Study EGAS00001007296

• Raw ONT R9 data: Rapid brain tumor classification from sparse epigenomic data

  This dataset contains 75 Nanopore sequencing experiments using a MinION sequencer and R9 flow cells from 51 patient biopsies. Gzipped tar files containing all fast5 files per sample are provided.

  Dataset EGAD50000000832

• SEF tumor sequencing data

  This dataset contains samples from 8 patients with Sclerosing epithelioid fibrosarcoma. All 8 samples have whole exome tumor data and tumor RNAseq data. 3 samples also have matched normal dna sequence data.

  Dataset EGAD00001011100

• CTCF ChIP-seq of human acute leukemias

  CTCF ChIP-seq of 39 primary samples derived from human acute leukemias, namely AML, T-ALL and mixed myeloid/lymphoid leukemias with CpG Island Methylator Phenotype (CIMP).

  Dataset EGAD00001011059

• Unmapped sequencing reads of EGAD00001007002

  Bam files of unmapped sequencing reads of samples in EGAD00001007002. When utilized in combination with corresponding aligned bam files in dataset EGAD00001007002, they contain all sequencing reads of samples.

  Dataset EGAD00001007647

• Breast cancer sequential sampling study

  This study aims to whole genome sequence DNA derived from breast cancer patients who received neo-adjuvany chemotherapy. All patients had multiple biopsies performed before chemotherapy. Patients who had residual disease after the course of treatment underwent a further biopsy. We aim to characterise the mutations involved.

  Dataset EGAD00001000387

• High density copy number analysis and whole exome sequencing of unselected chronic lymphocytic leukemia cases and of paired chronic lymphocytic leukemia and Richter Syndrome cases

  Analysis of the chronic lymphocytic leukemia coding genome: role of NOTCH1 mutational activation The pathogenesis of chronic lymphocytic leukemia (CLL), the most common leukemia in adults, is still largely unknown since the full spectrum of genetic lesions that are present in the CLL genome, and therefore the number and identity of dysregulated cellular pathways, have not been identified. By combining next-generation sequencing and copy number analysis, we show here that the typical CLL coding genome contains less than 20 clonally represented gene alterations/case, including predominantly non-silent mutations and fewer copy number aberrations. These analyses led to the discovery of several genes not previously known to be altered in CLL. While most of these genes were affected at low frequency in an expanded CLL screening cohort, mutational activation of NOTCH1, observed in 8.3% of CLL at diagnosis, was detected at significantly higher frequency during disease progression toward Richter transformation (31.0%) as well as in chemorefractory CLL (20.8%). Consistent with the association of NOTCH1 mutations with clinically aggressive forms of the disease, NOTCH1 activation at CLL diagnosis emerged as an independent predictor of poor survival. These results provide initial data on the complexity of the CLL coding genome and identify a dysregulated pathway of diagnostic and therapeutic relevance. Genetic Lesions associated with Chronic Lymphocytic Leukemia transformation to Richter Syndrome Richter syndrome (RS) derives from the rare transformation of chronic lymphocytic leukemia (CLL) into an aggressive lymphoma, most commonly of the diffuse large B cell type (DLBCL). The molecular pathogenesis of RS is only partially understood. By combining whole-exome sequencing and copy-number analysis of 9 CLL-RS pairs and of an extended panel of 43 RS cases, we show that this aggressive disease typically arises from the predominant CLL clone by acquiring an average of ~20 genetic lesions/case. RS lesions are heterogeneous in terms of load and spectrum among patients, and include those involved in CLL progression and chemorefractoriness (TP53 disruption and NOTCH1 activation) as well as some not previously implicated in CLL or RS pathogenesis. In particular, disruption of the CDKN2A/B cell cycle regulator locus is associated with ~30% of RS cases. Finally, we report that the genomic landscape of RS is significantly different from that of de novo DLBCL, suggesting that they represent distinct disease entities. These results provide insights into RS pathogenesis, and identify dysregulated pathways of potential diagnostic and therapeutic relevance.

  Study phs000364

• Similarity and diversity of the tumor microenvironment in multiple metastases: critical implications for overall and progression-free survival of high-grade serous ovarian cancer.

  The tumor microenvironment is pivotal in influencing cancer progression and metastasis. Different cells co-exist with high spatial diversity within a patient, yet their combinatorial effects are poorly understood. We investigate the similarity of the tumor microenvironment of 192 local metastatic lesions in 61 ovarian cancer patients. An ecologically inspired measure of microenvironmental diversity derived from multiple metastasis sites is correlated with clinicopathological characteristics and prognostic outcome. We demonstrate a high accuracy of our automated analysis across multiple sites. A low level of similarity in microenvironmental composition is observed between ovary tumor and corresponding local metastases (stromal ratio r = 0.30, lymphocyte ratio r = 0.37). We identify a new measure of microenvironmental diversity derived from Shannon entropy that is highly predictive of poor overall (p = 0.002, HR = 3.18, 95% CI = 1.51-6.68) and progression-free survival (p = 0.0036, HR = 2.83, 95% CI = 1.41-5.7), independent of and stronger than clinical variables, subtype stratifications based on single cell types alone and number of sites. Although stromal influence in ovary tumors is known to have significant clinical implications, our findings reveal an even stronger impact orchestrated by diverse cell types. Quantitative histology-based measures can further enable objective selection of patients who are in urgent need of new therapeutic strategies such as combinatorial treatments targeting heterogeneous tumor microenvironment.

  Study EGAS00001002065

• C3 SNPs and outcome after lung transplantation

  Background: Development of chronic rejection is still a severe problem and causes high mortality rates after lung transplantation (LTx). Complement activation is important in the development of acute rejection (AR) and bronchiolitis obliterans syndrome, with C3 as a key complement factor. Methods: Since a single nucleotide polymorphism (SNP) in the C3 gene (rs2230199) is associated with long-term outcome after solid organ transplantation, we investigated this SNP in relation to LTx. In addition, we looked at local production of C3 by analyzing bronchoalveolar lavage fluid (BALF) of LTx patients using isoelectric focusing (IEF). Results: We demonstrated the presence of C3 in BALF and showed that this is produced by the donor lung based on the genotype of SNP rs2230199. We also analyzed donor and patient SNP configurations and observed a significant association between the SNP configuration in patients and episodes of AR during 4-years follow-up. Survival analysis showed a lower AR-free survival in homozygous C3 slow patients (p=0.005). Furthermore, we found a significant association between the SNP configuration in donors and BOS development. Patients receiving a graft from a donor with at least one C3 fast variant for rs2230199 had an inferior BOS-free survival (p=0.044). Conclusions: In conclusion, our data indicate local C3 production by donor lung cells. In addition, a single C3 SNP present in recipients affects short-term outcome after LTx, while this SNP in donors has an opposite effect on long-term outcome after LTx. These results could contribute to an improved risk stratification after transplantation.

  Study EGAS00001003843

• A Single Complex Agpat2 Allele In A Patient With Partial Lipodystrophy

  Genetic lipodystrophies are a group of rare syndromes associated with major metabolic complications - including severe insulin resistance, type 2 diabetes mellitus, and hypertriglyceridemia - which are classified according to the distribution of adipose tissue. Lipodystrophies can be present at birth or develop during life and can range from local to partial and general. With at least 18 different genes implicated so far, definite diagnosis can be challenging due to clinical and genetic heterogeneity. In an adult female patient with clinical and metabolic features of partial lipodystrophy we identified via whole genome sequencing a single complex AGPAT2 allele [V67M;V167A], functionally equivalent to heterozygosity. AGPAT2 encodes for an acyltransferase implicated in the biosynthesis of triacylglycerol and glycerophospholipids. So far homozygous and compound heterozygous mutations in AGPAT2 have only been associated with generalized lipodystrophy. A SNP risk score analysis indicated that the index patient is not predisposed to lipodystrophy based on her genetic background. The partial phenotype in our patient is therefore more likely associated to the genetic variants in AGPAT2. To test whether the resulting double-mutant AGPAT2 protein is functional we analysed its in vitro enzymatic activity via mass spectrometry. The resulting AGPAT2 double mutant is enzymatically inactive. Our data support the view that the current classification of lipodystrophies as strictly local, partial or generalized may have to be re-evaluated and viewed more as a continuum, both in terms of clinical presentation and underlying genetic causes. Better molecular understanding of lipodystrophies may lead to new therapies to treat adipose tissue dysfunction in common and rare diseases.

  Study EGAS00001003177

• Endogenous CD4+ T Cells Recognize Neoantigens in Lung Cancer Patients, including KRAS and ERBB2 (Her2) Driver Mutations

  Neoantigen-specific T cell responses were characterized in 4 patients with non-small cell lung cancer. Candidate neoantigens were identified by sequencing tumor and normal DNA from each patient, and ranking single nucleotide variants by expression. Multiple T cell responses were isolated, and in two patients with lung adenocarcinoma, CD4+ T cell responses to recurrent oncogenic mutations in KRAS and Her2 were identified.

  Study phs001805

• Laser Capture Microscopy (LCM)-RNAseq for Topological Mapping of Synovial Pathology during Rheumatoid Arthritis

  Synovial tissue from the hip or knee was collected from rheumatoid arthritis (RA) and osteoarthritis (OA) patients at the time of joint replacement surgery. Samples were analyzed using laser capture microdissection (LCM) followed by RNA-seq to evaluate the transcriptome in distinct synovial compartments. Results indicated that synovial compartments have both shared and distinct transcriptional signatures that correspond to key pathways relevant to RA pathogenesis.

  Study phs003587

• Whole genome sequencing of pheochromocytoma and paraganglioma arising from germline SDHB mutations

  Paired-end 150 basepair whole genome sequencing of 94 SDHB-deficient non-metastatic and metastatic pheochromocytoma and paraganglioma. Libraries were prepared using the Illumina® TruSeq™ DNA Nano library preparation method according to the manufacturer’s instructions at The University of Melbourne Centre for Cancer Research (UMCCR) using 200ng input DNA and a 550 base pair insert size. Samples were sequenced in separate batches on the Illumina® Nova-Seq 6000 according to manufacturer’s instructions (Illumina, USA). Included in this dataset are FASTQ format files containing raw read data, CRAM format files containing reads aligned to GRCh38, and VCF format files containing germline variants calls.

  Dataset EGAD50000000502

• WES analysis of tumor samples from ER+ breast cancer patients treated with CDK4/6 inhibitor

  We performed whole exome sequencing of paired fresh frozen tumor from 4 ER+ advanced breast cancer patients. Samples were obtained for each patient prior to combined CDK4/6 inhibitor and endocrine therapy and at disease progression (N=8). DNA was extracted using the Maxwell® RSC FFPE and Tissue DNA Kit (Promega). WES was performed at the Department of Molecular Medicine, Aarhus University Hospital on matched tumor DNA (derived from primary fresh frozen and FFPE tissue) and buffy coat DNA. Libraries of tumors and matching germline DNA were prepared using 50 ng DNA and captured by Twist Comprehensive Exome with custom spike-ins, sequenced on the Illumina NovaSeq 6000 platform to an average coverage of 413x (range: 148-515x). The dataset include the analysis data files (vcf files).

  Dataset EGAD50000000622

• ISCAPE V(D)J libraries from HA-specific single memory B cells of four Influenza A exposed individuals

  Peripheral blood mononuclear cells were used to produce paired, full-length IGM, IGK and IGL V(D)J libraries from HA-binding single memory B cells using the ISCAPE (Individualized Single Cell Analysis of Paired Expressed antigen receptors) technique. Locus-specific multiplexed nested PCR with primer sets targeting the 5’ UTR/leader and 3’ constant region was performed before well and plate indexing and paired chain sequencing with an Illumina MiSeq instrument. Expressed total IGM, IGK and IGL V(D)J libraries from each donor were acquired and analyzed to define personalized IG allele content. The fastq file names include the donor and a numerical plate index for the HA-specific ISCAPE BCR HC and LC V(D)J libraries.

  Dataset EGAD50000002019

• Evolutionary trajectories and clonal migration underlying tumor progression and lymph node metastasis in resectable lung cancer

  In this prospective study, targeted deep sequencing was performed on a total of 160 primary tumors (474 regions) and 112 lymph nodes from 125 patients with stage I-III lung cancer (LuCaTH). Progressive evolution at clonal divergence scale was observed while specific driver events were positively selected for clonal sweeps during tumor development. Between-region genetic divergence (BRGD) of tumors were assessed and positively correlated with tumor differentiation. A machine learning algorithm was employed to evaluate clinicopathological and molecular parameters of primary tumors underlying lymph node metastasis. By analyzing clonal lineages and metastatic trajectories across multiple nodal stations, we unraveled a common sequential LNM seeding pattern but with divergent modes of clonal spread.

  Dataset EGAD00001007587

• Pooled Single-Cell RNA-Seq of iPSC-Derived Neural Stem Cells from ADHD and Control Individuals

  This dataset contains FASTQ files from pooled single-cell RNA sequencing (scRNA-seq) of neural stem cells (NSCs) derived from induced pluripotent stem cells (iPSCs). The iPSCs were reprogrammed using the non-integrative Sendai virus system (CytoTune-iPS 2.0), introducing OCT3/4, SOX2, KLF4, and cMYC. Donor somatic cells included keratinocytes, PBMCs, and lymphoblastoid cell lines from individuals with ADHD and age-matched healthy controls (6–18 years). iPSCs underwent standard quality control, including immunocytochemistry, qRT-PCR, mycoplasma testing, and SNP genotyping. NSCs were produced via neural induction and validated by qRT-PCR and immunostaining for PAX6, SOX2, NESTIN, TUJ1, and FOXG1. Sequencing was performed on the Illumina NovaSeq 6000.

  Dataset EGAD00001015644

• metastatic uveal melanoma tumour biopsies

  Tumour biopsies were obtained from uveal melanoma patients pre and 16 days post treatment with tebentafusp. Biopsies, which were either snap frozen or put in RNA later, were analysed by bulk RNA sequencing (50 million reads per sample) using the Illumina NovaSeq system.

  Study EGAS50000000864

• metastatic uveal melanoma tumour biopsies (n=35)

  Tumour biopsies were obtained from uveal melanoma patients (n = 35) pre and 16 days post treatment with tebentafusp. Biopsies, which were either snap frozen or put in RNA later, were analysed by bulk RNA sequencing (50 million reads per sample) using the Illumina NovaSeq system.

  Study EGAS50000000836

• single cell RNA-seq of small cell lung cancer tumors

  This study investigated the transcriptomic profile of small cell lung cancer from 10 patients. Tumors were rapidly dissociated after the surgical procedure. Libraries were constructed using the VDJ NextGEM v1.1 10x Genomics Chromium kit. Samples were sequenced on a NextSeq 550 sequencer (Illumina).

  Study EGAS50000001400

• Deep whole genome ctDNA chronology of treatment-resistant prostate cancer

  Circulating tumor DNA (ctDNA) in blood plasma is an emerging tool for clinical cancer genotyping and longitudinal disease monitoring. We performed deep whole-genome sequencing of serial plasma and synchronous metastases in patients with aggressive prostate cancer. We comprehensively assess all classes of genomic alterations and demonstrate that ctDNA harbors multiple dominant populations whose evolutionary histories frequently indicate whole-genome doubling and shifts in mutational processes. Although tissue and ctDNA showed concordant clonally-expanded cancer driver alterations, each individual metastasis contributed only a minor share of total ctDNA. By comparing serial ctDNA before and after clinical progression on potent androgen receptor (AR) pathway inhibitors, we reveal population restructuring converging solely on AR augmentation as the dominant genomic driver of acquired treatment-resistance. Finally we leverage nucleosome footprints in ctDNA to infer mRNA abundance in synchronously biopsied metastases, including treatment-induced changes in AR pathway transcriptional activity.

  Dataset EGAD00001008460

• Development of Novel Histiocytic Sarcoma Organoid Model for Drug Discovery

  Histiocytic sarcoma is an extremely rare and aggressive hematopoietic malignancy. Its pathogenesis remains poorly understood and effective treatments are lacking. We treated a patient with histiocytic sarcoma of soft tissue in Osaka International Cancer Institute and established an organoid culture from a resected tumor specimen using a modified air���liquid interface method. After serial passaging, the organoid was successfully xenografted into NOD-scid IL2Rgnull (NSG) mice. The established organoid retained key histological features and genetic characteristics of the original tumor. This organoid model offers a novel and reliable platform for studying the biology of histiocytic sarcoma and may contribute to the development of future therapeutic strategies.

  Study JGAS000807

• HuBMAP: KULMAP - Human Kidney, Urinary Tract, and Lung Mapping Center

  The major goal of the Human Kidney, Urinary Tract, and Lung Mapping Center (KULMAP) is to generate multi-omic and spatially resolved molecular anatomical maps of the human bladder, ureter and kidneys (BUKMAP) and the lung airways and parenchyma (LAPMAP) at a single cell resolution. This entails sequencing of the transcriptomes and epigenomes of dissociated single cells in a massively parallel manner. These profiles will then inform on highly multiplexed RNA in situ imaging for spatial mapping of hundreds of molecular targets in the tissue sections, at a subcellular resolution. These spatial molecular maps will serve as scaffolds for computational registration of cell types and the associated transcriptome/chromatin maps to the tissue space. The combination of sequencing single dissociated cells and multiplexed in situ mapping will allow the construction of detailed spatial maps for these large organs.

  Study phs002249

• Genome-Wide Analysis of Splenic Marginal Zone Lymphoma

  Splenic Marginal Zone Lymphoma (SMZL) is a B-cell malignancy of unknown pathogenesis and thus orphan of targeted therapies. By integrating whole-exome sequencing and copy-number analysis of 8 paired tumor-normal DNAs from patients with SMZL, we show that the typical SMZL exome carries ~30 genetic alterations. Targeted resequencing of selected candidates in an extended panel of 40-117 samples revealed activating mutations of NOTCH2, a gene required for marginal-zone (MZ) development, as the most frequent and SMZL-specific lesion, accounting for approximately 20% of cases. Additional altered genes suggest that deregulation of signaling pathways normally involved in MZ development (NOTCH, NF-kappa B, and B-cell receptor) represents a critical event in SMZL pathogenesis. These findings have direct implications for the treatment of SMZL patients since drugs are available which can target NOTCH as well as other pathways deregulated in this disease.

  Study phs000502

• Host Response to Respiratory Infections

  In this study, we describe a strategy to identify undiagnosed respiratory viral infections through screening nasopharyngeal (NP) swabs for the chemokine CXCL10, which is highly induced in the nasopharynx as part of the host antiviral response. Using this strategy, we conducted two screens: first, we screened NP swabs collected at Yale New Haven Hospital (YNHH) in January 2017 from patients with undiagnosed respiratory viral infections and identified patients infected with seasonal coronaviruses and the relatively uncommon influenza C virus. Second, we screened samples from the beginning of March 2020 in the weeks before YNHH tested for SARS-CoV-2 and identified four patients that had undiagnosed SARS-CoV-2 infections. Sequences uploaded as part of this study include samples with rhinovirus, human coronavirus NL63, and 8 samples as part of the January 2017 screen for undiagnosed respiratory viral infections.

  Study phs002442

• Nature and Contribution of Noncoding, Regulatory Mutations in Neurodevelopmental Disorders

  This dbGaP study contains variant call files generated from whole-genome sequencing data of families with autism. The variant callers include FreeBayes, GATK, Platypus, and Strelka2. A family-level VCF file, from each caller, is provided for each family in the study. The families included in this study are from the Simons Simplex Collection (SSC), the Study of Autism Genetics Exploration (SAGE), and The Autism Simplex Collection (TASC); sequencing was performed at the New York Genome Center, as part of the Centers for Common Disease Genomics (CCDG) Consortium. The analysis to generate the variant callsets was supported by a K99 Pathway to Independence grant to Dr. Tychele Turner (1K99MH117165-01). *Access to phenotype data at the individual level for Simons Simplex Collection (SSC) subjects can be requested from SFARI Base: https://www.sfari.org/resource/sfari-base/.

  Study phs001874

• NCI-Maryland Prostate Cancer Case-Control Study

  The study seeks to examine the genetic and ancestral basis of prostate cancer-associated inflammation using a genome-wide association approach. The study population are the participants of the NCI Maryland Prostate Cancer Case-Control study. This study recruited both African American and European American men, and investigated the causes for the excessive burden of prostate cancer among African American men in more general terms. We measured 82 blood-based immune-oncology markers, and genotyped the participants using the HumanOmni5-Quad BeadChip, which provides a significant genome coverage for genetically-admixed and diverse populations, to evaluate the genetic basis and evidence for causality of any immune-inflammation marker that is associated with prostate cancer risk. We want to assess how germline genetics influence the abundance levels of these 82 markers in African American and European American men, which may contribute to differences between them.

  Study phs002939

• CIDR/NICHD Genetic Basis of Recessive Pediatric Brain Diseases - Group 2

  The purpose of this study is to identify new genetic causes of recessive forms of pediatric neurodevelopmental disorders (NDDs) including Cerebellar hypoplasia (CBH), Lissencephaly (LIS), Microcephaly (MIC), Corpus callosum hypoplasia (CCH), Pontocerebellar hypoplasia (PCH), Pontine tegemental cap dysplasia (PTCD), and Aicardi syndrome among many others. Using whole exome sequencing on one or two affected members per family, we are able to identify many pathogenic genes for these families. Using Human SNP Linkage Scans, which takes advantage of the Illumina HumanCore Array, and parametric linkage analysis software (Genehunter, Allegro, and others), we seek to identify pathogenic loci utilizing 60-70 families per year. Through the combination of parametric linkage analysis with exome sequencing and bioinformatics approaches, we will refine our search for superior sensitivity and accuracy when investigating candidate genes and identifying causative mutations for disease.

  Study phs001267

• Methylation Profiles of Cell-Free DNA Using Nanopore Sequencing

  Epigenetic characterization of cell-free DNA (cfDNA) is an emerging approach for detecting and characterizing diseases such as cancer. We developed a strategy using nanopore-based single-molecule sequencing to measure cfDNA methylomes. This approach generated up to hundreds of millions of reads for a single cfDNA sample from cancer patients, an order of magnitude improvement over existing nanopore sequencing methods. We developed a single-molecule classifier to determine whether individual reads originated from a tumor or immune cells. Leveraging methylomes of matched tumors and immune cells, we characterized cfDNA methylomes of cancer patients for longitudinal monitoring during treatment.Control subjects consist of healthy individuals without a positive diagnosis of cancer. cfDNA was obtained through purification of plasma from blood draws. Genomic DNA (gDNA) was derived from extraction of primary tumor tissue or from leukocytes from blood draws.

  Study phs002950

• CIDR/NICHD Genetic Basis of Recessive Pediatric Brain Diseases

  The purpose of this study is to identify new genetic causes of recessive forms of pediatric neurodevelopmental disorders (NDDs) including cerebellar hypoplasia (CBH), lissencephaly (LIS), microcephaly (MIC), corpus callosum hypoplasia (CCH), pontocerebellar hypoplasia (PCH), pontine tegmental cap dysplasia (PTCD), and Aicardi syndrome among many others. Using whole exome sequencing on one or two affected members per family, we are able to identify many pathogenic genes for these families. Using Human SNP Linkage Scans, which takes advantage of the Illumina HumanCore Array, and parametric linkage analysis software (Genehunter, Allegro, and others), we seek to identify pathogenic loci utilizing 60-70 families per year. Through the combination of parametric linkage analysis with exome sequencing and bioinformatics approaches, we will refine our search for superior sensitivity and accuracy when investigating candidate genes and identifying causative mutations for disease.

  Study phs001060

• CIDR NICHD Genetic Basis of Recessive Pediatric Brain Diseases - Group 4

  The purpose of this study is to identify new genetic causes of recessive forms of pediatric neurodevelopmental disorders (NDDs) including Cerebellar hypoplasia (CBH), Lissencephaly (LIS), Microcephaly (MIC), Corpus callosum hypoplasia (CCH), Pontocerebellar hypoplasia (PCH), Pontine tegmental cap dysplasia (PTCD), and Aicardi syndrome among many others. Using whole exome sequencing (WES) on one or two affected members per family, we are able to identify many pathogenic genes for these families. Using Human SNP Linkage Scans, which takes advantage of the Illumina HumanCore Array, and parametric linkage analysis software (Genehunter, Allegro, and others), we seek to identify pathogenic loci utilizing 60-70 families per year. Through the combination of parametric linkage analysis with exome sequencing and bioinformatics approaches, we will refine our search for superior sensitivity and accuracy when investigating candidate genes and identifying causative mutations for disease.

  Study phs001822

• CIDR NICHD Genetic Basis of Recessive Pediatric Brain Disease - Group 3

  The purpose of this study is to identify new genetic causes of recessive forms of pediatric neurodevelopmental disorders (NDDs) including Cerebellar hypoplasia (CBH), Lissencephaly (LIS), Microcephaly (MIC), Corpus callosum hypoplasia (CCH), Pontocerebellar hypoplasia (PCH), Pontine tegmental cap dysplasia (PTCD), and Aicardi syndrome among many others. Using whole exome sequencing (WES) on one or two affected members per family, we are able to identify many pathogenic genes for these families. Using Human SNP Linkage Scans, which takes advantage of the Illumina HumanCore Array, and parametric linkage analysis software (Genehunter, Allegro, and others), we seek to identify pathogenic loci utilizing 60-70 families per year. Through the combination of parametric linkage analysis with exome sequencing and bioinformatics approaches, we will refine our search for superior sensitivity and accuracy when investigating candidate genes and identifying causative mutations for disease.

  Study phs001510

• Platinum Pedigree Consortium Long-Read Sequencing

  Platinum Pedigree Consortium includes whole genome sequencing of blood-derived DNA using five technologies on a 4-generation family. This is the CEPH-Utah (CEU) family 1463 and includes 4 grandparents from 1st generation, 2 parents from 2nd generation, 5 children from 3rd generation, 9 individuals from the 4th generation representing 2 branches of the 3rd generation, and their 2 additional parents. Family was not selected for disease, rather large size to study genetic transmission and human variation.Data available through dbGaP include raw sequence data: PacBio HiFi reads in unaligned BAM formats, Ultra-Long Oxford Nanopore (ONT) reads in FASTQ formats, Illumina sequencing, strand-seq and Element sequencing data in FASTQ format. Additionally, alignment files for HiFi reads mapped to the GRCh38 and CHM13v2.0 reference genomes, as well as de novo genome assemblies generated for this project are included.

  Study phs003793

• A capture methyl-seq protocol with improved efficiency and cost-effectiveness using pre-pooling and enzymatic conversion

  The opportunities for sequencing-based methylome analysis of clinical samples are increasing. To reduce its cost and the amount of genomic DNA required for library preparation, we aimed to establish a capture methyl-seq protocol, which adopts pre-pooling of multiple libraries before hybridization capture and TET2/APOBEC-mediated conversion of unmethylated cytosine to thymine. We compared a publicly available dataset generated by the standard Agilent protocol of SureSelect XT Human Methyl-Seq Kit and our dataset obtained by our modified protocol, EMCap, that adopted sample pre-pooling and enzymatic conversion. We confirmed that the quality of DNA methylation data was comparable between the two datasets. As our protocol, EMCap, is more cost-effective and reduces the amount of input genomic DNA, it would serve as a better choice for clinical methylome sequencing.

  Study JGAS000605

• Whole-genome sequencing in 14 cases and whole-exome sequencing in 90 cases of Chinese ESCC

  Esophageal cancer is one of the most aggressive cancers and the sixth leading cause of cancer death worldwide1. Approximately 70% of the global esophageal cancers occur in China and over 90% histopathological forms of this disease are esophageal squamous cell carcinoma (ESCC)2-3. Currently, there are limited clinical approaches for early diagnosis and treatment for ESCC, resulting in a 10% 5-year survival rate for the patients. Meanwhile, the full repertoire of genomic events leading to the pathogenesis of ESCC remains unclear. Here we show a comprehensive genomic analysis in 158 ESCC cases, as part of the International Cancer Genome Consortium (ICGC) Research Projects (http://icgc.org/icgc/cgp/72/371/1001734). We conducted whole-genome sequencing in 14 ESCC cases and whole-exome sequencing in 90 cases.

  Study EGAS00001001487

• RA-Map, A multi-omic survey of whole blood and subsets in early rheumatoid arthritis and vaccine study controls

  Rheumatoid arthritis (RA) is a chronic inflammatory disorder of unknown aetiology characterised by synovial inflammation with variable disease severity and drug responsiveness. To investigate the molecular heterogeneity and pathogenesis of RA, we performed a comprehensive clinical and molecular profile of 267 RA patients for up to 18 months to establish a high quality biobank of barcoded samples that included plasma, serum, peripheral blood cells, whole blood RNA, RNA from lymphocyte and monocyte subsets, genomic DNA and urine. We have performed extensive multi-omic immune phenotyping, including genomic, metabolomic, proteomic, transcriptomic and auto-antibody profiling. We anticipate that these detailed clinical and molecular data will serve as a fundamental resource for the development and application of targeted therapies for RA and reveal further insights into disease pathogenesis and therapeutic response.

  Study EGAS00001004424

• Plasma MicroRNA Signatures of Aging

  Background. MicroRNAs are small non-coding RNAs that regulate gene expression post-transcriptionally and show differential expression in various tissues with aging phenotypes. Detectable in circulation, extracellular microRNAs reflect (patho)physiological processes and hold promise as biomarkers for healthy aging and age-related diseases. This study aimed to explore plasma extracellular microRNAs as biological aging indicator and their associations with health outcomes using population-level data. Methods. We quantified plasma expression levels of 2,083 extracellular microRNAs using targeted RNA-sequencing in 2,684 participants from the population-based Rotterdam Study cohort. The training and test sets included 1,930 participants from the advanced-aged initial and second subcohort (RS-I/RS-II; median age: 70.6), while the validation set comprised 754 participants from the middle-aged fourth subcohort (RS-IV; median age: 53.5). Based on 591 microRNAs well-expressed in plasma, we examined differential expression of microRNAs with chronological age, PhenoAge –a composite score of age and nine multi-system blood biomarkers–, the frailty index, and mortality. Next, elastic net models were employed to construct composite microRNA-based aging biomarkers predicting chronological age (mirAge), PhenoAge (mirPA), frailty index (mirFI), and mortality (mirMort). The association of these aging biomarkers with different age-related health outcomes was assessed using Cox Proportional Hazard, linear regression, and logistic regression models in the test and validation sets. Results. We identified 188 microRNAs differentially expressed with chronological age within the RS-I/RS-II advanced-aged population (ntraining=1158, ntest=772), of which 177 microRNAs (94.1%) were replicated in the middle-aged RS-IV subcohort (nvalidation=754). Moreover, 227 miRNAs showed robust associations with PhenoAge, 61 with FI, and 16 with ten-year mortality independent of chronological age. Subsequently, we constructed four plasma microRNA-based aging biomarkers: mirAge with 108, mirPA with 153, mirFI with 81, and mirMort with 50 miRNAs. Elevated scores on these microRNA-based aging biomarkers were associated with unfavorable health outcomes, including lower subjective physical functioning and self-reported health and increased mortality and frailty risk, but not with first- or multi-morbidity. Overall, larger effect estimates were observed for mirPA, mirFI, and mirMort compared to mirAge. Conclusions. This study describes distinct plasma microRNA-aging signatures and introduces four microRNA-based aging biomarkers with potential to identify accelerated aging and age-related decline, providing insights into the intricate process of human aging.

  Study EGAS00001008117

• Arcagen – thoracic malignancies

  Arcagen is an EORTC/SPECTA pan-European project that aims to recruit 1000 rare cancer patients from different tumour domains of EURACAN. This study collected samples from advanced or metastatic rare cancer from patients older than 12, and analysed them using Foundation Medicine next-generation sequencing (NGS) panels (FoundationOne CDx for FFPE samples or FoundationOne Liquid CDx for blood samples). Here we are submitting the dataset that contain NGS files from rare thoracic malignancies (n=102)

  Dataset EGAD50000000168