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• Childhood Cancer Data Initiative (CCDI): Integrating Longitudinal Clinical, Sociodemographic and Genomic Data into the NCCR

  The goal of this study is to contribute clinical and genomic data from a large institutional cohort of pediatric cancer patients who had tumor genomic profiling between 2013 and 2019 at Dana-Farber/Boston Children's Hospital Cancer and Blood Disorders Center. Clinical data include demographics, diagnosis (classified according to the International Classification of Diseases for Oncology (ICD-O-3.2), stage, and biospecimen associated data. Tumors were sequenced with OncoPanel, a targeted next-generation DNA sequencing panel of up to 447 cancer genes for detection of single-nucleotide variants (SNV), insertions, and deletions, and copy number alterations (CNA), as well as selected intronic regions for up to 60 genes for the detection of structural variants (SV). This dataset includes a patient and sample identifier (GENIE ID) that can be used to link the genomic data included in this dataset to additional longitudinal clinical cancer data on a subset of patients that was submitted to the National Childhood Cancer Registry (NCCR).

  Study phs002677

• Functional Genomic Landscape of Acute Myeloid Leukemia

  The implementation of targeted therapies for acute myeloid leukemia has been challenged by complex mutational patterns within and across patients as well as a dearth of pharmacologic agents for most mutational events. The initial findings from the Beat AML program were from a cohort of 672 tumor specimens collected from 562 patients. Additional patients have been added in subsequent versions. We assessed these specimens using whole exome sequencing, RNA-sequencing, and ex vivo drug sensitivity analyses. Our data reveal novel mutational events not previously detected in AML. We show association of drug response with mutational status, including instances of drug sensitivity that are specific to combinatorial mutational events. Integration with RNA-sequencing also revealed gene expression signatures, which predict a role of specific gene networks in drug response. Collectively, this report offers a dataset, accessible by the Beat AML data viewer (www.vizome.org), that can be leveraged to address clinical, genomic, transcriptomic, and functional inquiries into the biology of AML.

  Study phs001657

• Single-cell Analysis of Neoplastic Plasma Cells Identifies Myeloma Pathobiology Mediators and Potential Targets

  Multiple myeloma is a clonal plasma cell (PC) dyscrasia that arises from precursors and has been studied utilizing approaches focused on CD138+ cells. By combining single-cell (sc)RNA- with scB-cell receptor (BCR)-sequencing, we differentiate monoclonal/neoplastic from polyclonal/normal PCs, and find more dysregulated genes, especially in precursor patients, than by analyzing bulk PCs. To determine if this approach can identify oncogenes that contribute to disease pathobiology, MAD2L1 and MAT2A are validated as targets with drug-like molecules that suppress myeloma growth in pre-clinical models. Moreover, functional studies show a role of LAMP5, which is uniquely expressed in neoplastic PCs, in tumor progression and aggressiveness via interactions with c-MYC. Finally, a monoclonal antibody recognizing cell-surface LAMP5 shows efficacy as an antibody-drug conjugate and in a chimeric antigen receptor-guided T-cell format. These studies provide additional insights into myeloma biology and identify potential targeted therapeutic approaches that can be applied to reverse myeloma progression.

  Study EGAS50000000802

• Multiplexing cortical brain organoids for the longitudinal dissection of developmental traits at single cell resolution

  Dissecting human neurobiology at high resolution and with mechanistic precision requires a major leap in scalability, given the need for experimental designs to multiple individuals and, prospectively, population cohorts. To lay the foundation for this, we have implemented and benchmarked complementary strategies to multiplex brain organoids by pooling cells from different pluripotent stem cell lines (PSC) either during organoid generation (mosaic models) or before single cell-RNAseq library preparation (downstream multiplexing). We have also developed a new computational method, SCanSNP, and a consensus call to deconvolve cell identities, overcoming current criticalities in doublets prediction and low quality cells identification. We validated both multiplexing methods for charting neurodevelopmental trajectories at high resolution, thus linking specificity to genetic variation. Finally, we modelled their scalability across different multiplexing combinations and showed that mosaic organoids represent an enabling method for high-throughput settings. Together, this multiplexing suite of experimental and computational methods provides a highly scalable resource for disease modelling.

  Study EGAS50000000698

• Oncogenic FOXL2C134W has gain-of-function chromatin remodeling activity that reprograms glucocorticoid receptor occupancy to promote ovarian granulosa cell tumor growth

  Adult type ovarian granulosa cell tumors (AGCTs) are rare malignancies with near universal somatic mutation c.C402G (p.Cys134Trp) in FOXL2, a forkhead box-family transcription factor important for ovarian function. Relapsed AGCT is incurable and the mechanism of the unique FOXL2 mutation remains incompletely understood. To identify FOXL2C134W-dependent pharmacologic synergies, we created and characterized endogenous FOXL2 isogenic AGCT cells and an AGCT tumoroid biobank. A drug screen identified that glucocorticoids promote FOXL2C134W-dependent AGCT growth. Epigenetic investigation revealed that the Cys134Trp mutation exposes latent DNA sequence-specific pioneering activity in FOXL2, a unique oncogenic mechanism. FOXL2C134W pioneering activity redirects glucocorticoid receptor chromatin occupancy to drive hyaluronan synthase 2 gene expression and increase extracellular hyaluronan secretion. Treatment of AGCT models with hyaluronidase reduces viability and this effect can be rescued by dexamethasone. Thus, gain-of-function pioneering activity contributes to the oncogenic mechanism of FOXL2C134W and creates a potentially targetable synergy with glucocorticoid signaling.

  Study EGAS50000000622

• 1000 Genomes Used for Cloud Testing

  WARNING: This is a test data set. The phenotype data was not checked to match 1000 Genomes project. Use with caution.This study provides public access to a demonstration subset of 1000 genomes sequence data in dbGaP. It is intended to be used by software developers who design, implement and validate pipelines for dbGaP data. While this project distributes only public data, it uses dbGaP security mechanisms which include a project-specific security key and a decryption password. Since the data are public, the key and password for this project will be included by SRA into public demonstration packages that permit users to test and validate the security of their computational pipelines. Note that all public users of this data will be logged under the same project and account ID. The datasets attached to this project must be restricted to 1000 Genomes data identical to the project's public FTP site. To access these test data using SRA toolkit use prj_phs710EA_test.ngc.

  Study phs000710

• Uncovering Gene Regulatory Differences between Human and Chimpanzee Neural Cells

  A major challenge in human evolutionary biology is to pinpoint the genetic differences that underlie phenotypic changes in the human lineage, such as increased neuron number and a prolonged period of neuronal maturation. Here, we used human-chimpanzee tetraploid cells to distinguish changes in gene expression due to cis-acting sequence variants that change local gene regulation, from trans expression changes due to species differences in the cellular environment, in neural progenitor cells and excitatory neurons using RNA-seq and ATAC-seq. Using a CRISPR inhibition screen with scRNA-seq, transcription factor motif analyses with CUT&Tag, and downstream single-locus studies with RNA-seq, we further characterized cis-acting gene regulatory differences, including changes to FOS, TNIK, FOSL2, and MAZ, that influence neurogenesis and neuronal maturation. This study identifies specific genomic changes that may contribute to human neural specializations and provides a general framework for understanding genetic differences that underlie human traits.

  Study phs004053

• ucfDNA workflows for molecular profiling of malignant disease

  Urinary cell-free DNA (ucfDNA) is a promising liquid biopsy analyte obtained by a non-invasive sampling method, particularly valuable in urological cancers due to the proximity of biofluids to the tumor site. However, extremely high fragmentation and low abundance of ucfDNA pose significant analytical challenges. Improper handling and storage can severely affect ucfDNA quality, necessitating optimized pre-analytical workflows for clinical applications. We evaluated multiple pre-analytical workflows, including urine stabilization approaches against unstabilized urine samples. Our results demonstrated that without stabilization, ucfDNA degraded rapidly and minimal quantities remaining after 72 hours. In contrast, urine stabilization preserved ucfDNA integrity, enabling successful downstream analyses, including digital PCR and next-generation sequencing, for mutation detection in cancer-related genes and genome wide copy number profiling. These findings underscore the critical role of stabilization for a reliable ucfDNA analysis and highlight its potential in molecular diagnostics as a complementary tool to plasma-based liquid biopsies.

  Study EGAS50000001093

• Identification and characterization of molecular markers in aging and neuronal disorders

  Supercentenarians, people who have reached 110 years of age, are a great model of healthy aging. Their characteristics of delayed onset of age-related diseases and compression of morbidity imply that their immune system remains functional. We performed single-cell transcriptome analysis of peripheral blood mononuclear cells (PBMCs), derived from supercentenarians and younger controls. We identified a marked increase of cytotoxic CD4 T-cells (CD4 CTLs) as a novel signature of supercentenarians. Furthermore, single-cell T-cell receptor sequencing of two supercentenarians revealed that CD4 CTLs had accumulated through massive clonal expansion. The CD4 CTLs exhibited substantial heterogeneity in their degree of cytotoxicity as well as a nearly identical transcriptome to that of CD8 CTLs. This indicates that CD4 CTLs utilize the transcriptional program of the CD8 lineage while retaining CD4 expression. Our study reveals that supercentenarians have unique characteristics in their circulating lymphocytes, which may represent an essential adaptation to achieve exceptional longevity by sustaining immune responses to infections and diseases.

  Study JGAS000230

• Exome sequencing in HIV+ Viremic Non-Progressors (VNPs) and HIV+ Progressors

  Viremic Non-Progressors (VNPs) maintain normal CD4+ T-cell counts despite uncontrolled HIV-1 replication, but mechanisms leading to CD4+ T-cell preservation are incompletely characterized. We aim to generate a comprehensive understanding of this infrequent phenotype by comparing rates of cellular infection, immunophenotype, genomics, single-cell transcriptomics, metabolomics, and levels of plasma biomarkers in 16 VNPs and 29 HIV+ Progressors. During chronic infection VNPs show lower frequency of HIV-1-infected cells in periphery, which is associated with reduced CCR5 expression and higher prevalence of CCR5Δ32 heterozygosity. The CD8+ T-cell compartment displays a less cytotoxic and less activated phenotype in VNPs. Moreover, despite similar viremia, we found lower bystander CD4+ T-cell death in the VNPs, together with weaker IFN responses, reduced plasma levels of zonulin (a biomarker of intestinal permeability), altered tryptophan catabolism, and preserved LPS responsiveness in vitro. Overall, a complex multifactorial mechanism, suggesting gut-associated lymphoid tissue preservation, underlies resistance to HIV pathogenesis in VNPs.

  Study EGAS50000000079

• Resequencing_candidate_genes_for_male_spermatogenic_impairment

  This study aims to identify novel candidate variants from human Y-chromosomal genes DAZ, BPY2 and CDY1 by resequencing the coding regions of these genes from male patients with spermatogenic impairment. The coding regions of the genes have been amplified by standard PCR, amplicon lengths range from 244 to 486 bp. A total of 61 amplicons were amplified for each of the 96 patients, totalling to approx. 25 kb per sample. Amplicons were quantified by gel electrophoresis and pooled in approx. equimolar concentrations per patient. For each of the 96 submitted samples, approx. 1 microgram of amplified DNA pool is provided in a total volume of 120 microlitres. The samples need to be indexed and libraries prepared for a PE250bp Illumina MiSeq run. 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 EGAS00001002157

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

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

  Study EGAS00001003751

• Whole_genome_sequencing_in_a_multiplex_Crohn_s_disease_family

  In 2009 we identified a four-generation family with over 700 members and 41 affected with Crohn's disease (CD). At the time we sequenced the exome of 6 affected individuals but did not identify any coding variants which appear to explain the high prevalence of disease. Since then we have collected DNA from a large number of additional family members, genotyped linkage arrays on the entire family to refine genomic regions shared by identity by descent and genotyped affected and unaffected members at known CD risk loci identified by Genome Wide Association Studies (GWAS). These analyses have confirmed that a significant unexplained excess of disease remains after accounting for all known genetic factors, and that several regions of the genome are shared by a large fraction of affected individuals. We therefore perform whole genomes sequencing from 8 individuals which will allow us to impute the complete sequence of nearly all the members of the two largest and most severely affected branches of the family.

  Study EGAS00001000060

• Engineering large chromosomal deletions by CRISPR-Cas9

  Arm-level chromosomal deletions are a prevalent and defining feature of cancer. A high degree of tumor-type and subtype specific recurrencies suggest a selective oncogenic advantage. However, due to their large size it has been difficult to pinpoint the oncogenic drivers that confer this advantage. Suitable functional genomics approaches to study the oncogenic driving capacity of arm-level deletions are limited. Here we present an effective technique to engineer arm-level deletions by CRISPR-Cas9 and create isogenic cell line models. We simultaneously induce double-strand breaks (DSBs) at two ends of a chromosomal arm and select the cells that have lost the intermittent region. Using this technique, we induced arm-level deletions on chromosome 11q (65 MB) and chromosome 6q (53 MB) in neuroblastoma cell lines. Such isogenic models enable further research on the role of arm-level deletions in tumor development and growth, and their possible therapeutic potential.

  Study EGAS00001005134

• Repli-seq data for 'Replication timing alterations are associated with mutation acquisition during tumour evolution in breast and lung cancer'

  The essential process of DNA replication timing during each cell cycle is highly regulated ensuring the correct duplication of the genome. The extent and importance of alterations in this process during malignant transformation has not been extensively explored. Here, we evaluate the impact of altered replication timing (ART) on cancer evolution by analysing replication-timing sequencing of cancer and normal cell lines and 952 whole-genome sequenced lung and breast tumours. We find 6%-18% of the cancer genome displays ART. Genomic regions with a change from early to late replication exhibit an increased mutation rate and distinct mutational signatures, while regions changing from late to early contain genes with increased expression and present a preponderance of APOBEC3-mediated mutation clusters and associated driver mutations. We demonstrate that ART is a relatively early event during cancer evolution and that ART may have a stronger correlation with mutation acquisition than alterations in chromatin structure.

  Study EGAS00001007773

• Serial assessment of measurable residual disease in medulloblastoma liquid biopsies

  Nearly one-third of children with medulloblastoma, a malignant embryonal tumor of the cerebellum, succumb to their disease. Conventional response monitoring by imaging and cerebrospinal fluid (CSF) cytology remains challenging and a marker for measurable residual disease (MRD) is lacking. Here, we show the clinical utility of CSF-derived cell-free DNA (cfDNA) as a biomarker of MRD in serial samples collected from children with medulloblastoma (123 patients, 476 samples) enrolled on a prospective trial. Using low-coverage whole-genome sequencing, tumor-associated copy-number variations (CNVs) in CSF-derived cfDNA are investigated as an MRD surrogate. MRD is detected at baseline in 85% and 54% of patients with metastatic and localized disease, respectively. The number of MRD-positive patients decline with therapy, yet those with persistent MRD have significantly higher risk of progression. Importantly, MRD detection precedes radiographic progression in half who relapse. Our findings advocate for the prospective assessment of CSF-derived liquid biopsies in future trials for medulloblastoma.

  Study EGAS00001005592

• Genome-wide Rare Variant Score Associates With Morphological Subtypes of Autism Spectrum Disorder

  Defining different genetic subtypes of Autism Spectrum Disorder (ASD) can help predict developmental outcomes. Based on minor physical and major congenital anomalies, we categorized 325 Canadian children with ASD into dysmorphic and non-dysmorphic subgroupings. We developed a method to calculate a genome-wide rare variant score (GRVS) from whole-genome sequencing (WGS) data for each ASD proband. GRVS is a sum of the number of variants in morphology-associated coding and non-coding regions, weighted by their effect sizes. Probands with dysmorphic ASD had a significantly higher GRVS compared to those with non-dysmorphic ASD (P= 0.027). Using the polygenic transmission disequilibrium test, we observed an over-transmission of ASD-associated common variants in non-dysmorphic ASD probands (P= 2.9×10-3). We replicated our findings using 442 ASD probands that had accompanying morphology data in the Simons Simplex Collection. Our findings provide support for an alternative genomic classification of ASD subgroups using morphology data, which may inform intervention protocols.

  Study EGAS00001005753

• cfRRBS on cfDNA from pediatric cancer

  In the clinical management of pediatric solid tumors, histological examination of tumor tissue obtained by a biopsy remains the gold standard to establish a conclusive pathological diagnosis. The DNA methylation pattern of a tumor is known to correlate with the histopathological diagnosis across cancer types and is showing promise in the diagnostic workup of tumor samples. This methylation pattern can be detected in the cell-free DNA. Here, we provide proof-of-concept of histopathologic classification of pediatric tumors using cell-free reduced representation bisulfite sequencing (cf-RRBS) from retrospectively collected plasma and cerebrospinal fluid samples. We determined the correct tumor type in 49 out of 60 (81.6%) samples starting from minute amounts (less than 10 ng) of cell-free DNA. We demonstrate that the majority of misclassifications were associated with sample quality and not with the extent of disease. Our approach has the potential to help tackle some of the remaining diagnostic challenges in pediatric oncology in a cost-effective and minimally invasive manner.

  Study EGAS00001004194

• SMARCB1 loss activates patient-specific distal oncogenic enhancers in malignant rhabdoid tumors

  Malignant rhabdoid tumor (MRT) is a highly malignant and often lethal childhood cancer. MRTs are genetically defined by bi-allelic inactivating mutations in SMARCB1, a member of the BRG1/BRM-associated factors (BAF) chromatin remodeling complex. Mutations in BAF complex members are common in human cancer, yet their contribution to tumorigenesis remains in many cases poorly understood. Here, we studied derailed regulatory landscapes as a consequence of SMARCB1 loss in the context of MRT. Our multi-omics approach on patient-derived MRT organoids revealed a dramatic reshaping of the regulatory landscape upon SMARCB1 reconstitution. Chromosome conformation capture experiments subsequently revealed patient-specific looping of distal enhancer regions with the promoter of the MYC oncogene. This intertumoral heterogeneity in MYC enhancer utilization is also present in patient MRT tissues as shown by combined single-cell RNA-seq and ATAC-seq. We show that loss of SMARCB1 drives patient-specific epigenetic reprogramming underlying MRT tumorigenesis.

  Study EGAS00001007590

• Genomic catastrophes frequently arise in esophageal adenocarcinoma and drive tumorigenesis.

  Oesophageal adenocarcinoma (EAC) incidence is rapidly increasing in Western countries. A better understanding of EAC underpins efforts to improve early detection and treatment outcomes. While large EAC exome sequencing efforts to date have found recurrent loss-of-function mutations, oncogenic driving events have been underrepresented. Here we use a combination of whole-genome sequencing (WGS) and single-nucleotide polymorphism-array profiling to show that genomic catastrophes are frequent in EAC, with almost a third (32%, n=40/123) undergoing chromothriptic events. WGS of 22 EAC cases show that catastrophes may lead to oncogene amplification through chromothripsis-derived double-minute chromosome formation (MYC and MDM2) or breakage-fusion-bridge (KRAS, MDM2 and RFC3). Telomere shortening is more prominent in EACs bearing localized complex rearrangements. Mutational signature analysis also confirms that extreme genomic instability in EAC can be driven by somatic BRCA2 mutations. These findings suggest that genomic catastrophes have a significant role in the malignant transformation of EAC.

  Study EGAS00001000750

• X chromosomal genetic variants are associated with childhood obesity

  Current genetic association studies are usually focused on autosomal variants only, and the sex chromosomes are often neglected. In recent years, a number of statistical techniques and strategies have been widely described making much easier overcoming X-chromosome technical hurdles and including this region within genetic studies. Tenomodulin (TNMD) is a Xq22 chromosome anti angiogenic locus which has been recently linked to different obesity-related phenotypes. These results have not been replicated to date. Given these facts, we have conducted a genetic association analysis in Spanish children population including seven TNMD SNPs as potential candidate markers for obesity and metabolic dysfunctions. Additionally genotypes for another locus located in the X chromosome, the SLC6A14, have been included in the dataset. A total of 915 DNA samples from 258 normal weight, 177 overweight and 480 obese Spanish children (438 males, 477 females) were genotyped for seven TNMD SNPs and one SLC6A14 SNP. Associations with anthropometric measurements and glucose metabolism were investigated.

  Study EGAS00001002738

• Exome and RNA sequencing data from 32 ocular and extraocular sebaceous carcinomas

  Sebaceous carcinomas (SeC) are cutaneous malignancies that, in rare cases, metastasize and prove fatal. Here we report whole exome sequencing on 32 SeC, revealing distinct mutational classes that explain both cancer ontogeny and clinical course. A UV-damage signature predominated 10/32 samples, while 9 were instead defined by microsatellite instability (MSI) mutations. UV-damage SeC exhibited poorly differentiated, infiltrative histopathologycompared to MSI signature SeC (p = 0.003), features previously associated with dissemination. Strikingly, UV-damage SeC transcriptomes and anatomic distributionclosely resembling those of cutaneous squamous cell carcinomas (SCC), implicating sun-exposed keratinocytes as a cell of origin. Like SCC, this UV-damage subclass harbors a high somatic mutation burden with >50 mutations/Mb, predicting immunotherapeutic response. In contrast, ocular SeC acquire far fewer mutations without a dominant signature, but show frequent truncating mutations in the ZNF750 epidermal differentiation regulator. Our data exemplify how different mutational processes convergently drive histopathologically related but clinically distinct cancers.

  Study EGAS00001002869

• Understanding human fetal pancreas development using subpopulation sorting and RNA sequencing

  To decipher the populations of cells present in the human fetal pancreas and their lineage relationships, we developed strategies to isolate pancreatic progenitors, endocrine progenitors and endocrine cells. Transcriptome analysis of the individual populationsrevealed a large degree of conservation among vertebrates in the drivers of gene expression changes occurring at different steps of differentiation, althoughnotably, sometimes, different members of the same gene family are expressed. The transcriptome analysis establishes a resource to identify novel genes and pathways involved in human pancreas development. Single cell profiling further captured intermediate stages ofdifferentiation and enabled us to decipher the sequence of transcriptional events occurring during human endocrine differentiation. Furthermore, we evaluate how well individual pancreatic cells derived in vitro from human pluripotent stem cells mirror the natural processoccurring in human fetuses. This comparison uncovers a few differences at the progenitor steps, a convergence at the steps of endocrine induction and the current inability to fully resolve endocrine cell subtypes in vitro.

  Study EGAS00001003127

• Comparison of 3 protocols for deriving pancreatic progenitors from hPSC with RNA-seq and ATAC-seq

  Several distinct differentiation protocols for deriving pancreatic progenitors (PP) from human pluripotent stem cells have been described but it remains to be shown how similar the PP are across protocols, and how well they resemble their in vivo counterparts. Here we evaluated three differentiation protocols; performed RNA and ATAC-seq on isolated PP derived with these, and compared them to fetal human pancreas populations. This enabled us to define a shared transcriptional and epigenomic signature of the PP, including several genes not previously implicated in pancreas development. Furthermore, we identified a significant and previously unappreciated cross-protocol variation of the PP through multi-omics analysis and demonstrate how such information can be applied to refine differentiation protocols for derivation of insulin-producing beta-like cells. Together, our study highlights the importance of a detailed characterization of defined cell populations derived from distinct differentiation protocols, and provides a valuable resource for exploring human pancreatic development.

  Study EGAS00001003513

• Preeclampsia InterPregGen Consortium: Large-scale GWAS meta-analysis of maternal preclampsia cases and controls from Europe and Central Asia. Plus extension of earlier European fetal preeclampsia GWAS meta-analysis (see EGAS00001001048) by adding Central Asian fetal preeclampsia cases and controls. Datasets provided under this study are GWAS meta-analysis summary statistics and individual level GWAS genotype data. Related InterPregGen Consortium data are also provided under studies EGAS00001000416 and EGAS00001000417 (whole genome sequence data for 100 unrelated Uzbeks and 100 unrelated Kazakhs) and EGAS00001001048 (European fetal preeclampsia GWAS summary statistics and genotype data

  Preeclampsia (PE) is a syndrome affecting pregnant mothers and fetus/babies characterised by hypertension and proteinuria, and is a leading cause of maternal and fetal death and of premature births worldwide. The InterPregGen Consortium was funded by a European Framework 7 (FP7) grant and grew out of the WTCCC3 GWAS comparing ~2000 UK PE mothers with ~6000 common UK controls. The EGAS00001001266 study includes two components the FP7 InterPregGen project: (a) GWAS case-control meta-analysis of maternal PE cases from Europe (UK, Iceland, Norway, Denmark, Finland) and Central Asia (Kazakhstan, Uzbekistan); (b) GWAS case-control meta-analysis of PE fetal (baby) cases from Europe (UK, Iceland, Norway, Denmark) and Central Asia (Kazakhstan, Uzbekistan)

  Study EGAS00001001266

• Chromosomal copy number heterogeneity predicts survival rates across cancers

  Survival rates of cancer patients vary widely within and between malignancies. While genetic aberrations are at the root of all cancers, individual genomic features cannot explain these distinct disease outcomes. In contrast, intra-tumour heterogeneity (ITH) has the potential to elucidate pan-cancer survival rates and the biology that drives cancer prognosis1,2. Unfortunately, a comprehensive and effective framework to measure ITH across cancers is missing3. Here, we introduce a scalable measure of chromosomal copy number heterogeneity that predicts patient survival across cancers. We show that the level of ITH can be derived from a single-sample copy number profile. Using gene-expression data we demonstrate that ongoing chromosomal instability underlies the observed heterogeneity. Analysing 11,534 primary cancer samples from 35 different malignancies, we find that copy number heterogeneity can be accurately deduced and predicts cancer survival across tissues of origin and stages of disease. Our results provide a unifying molecular explanation for the different survival rates observed between cancer types.

  Study EGAS00001004702

• Resident memory CD8 T cells persist for years in human small intestine

  Resident memory CD8 T cells (Trm) have been shown to provide effective protective responses in the small intestine (SI) in mice. A better understanding of the generation and persistence of SI CD8 Trm cells in humans may have implications for intestinal immune-mediated diseases and vaccine development. Analyzing normal and transplanted human SI we demonstrated that the majority of SI CD8 T cells were bona fide CD8 Trm cells that survived for over 1 year in the graft. Intraepithelial and lamina propria CD8 Trm cells showed a high clonal overlap and a repertoire dominated by expanded clones, conserved both spatially in the intestine and over time. Functionally, lamina propria CD8 Trm cells were potent cytokine-producers, exhibiting a polyfunctional (IFN-γ+ IL-2+ TNF-α+) profile, and efficiently expressed cytotoxic mediators after stimulation. These results suggest that SI CD8 Trm cells could be relevant targets for future oral vaccines and therapeutic strategies for gut disorders.

  Study EGAS00001003676

• DNA Methylation loss coupled with mitotic cell division promotes immune evasion of tumours with high mutation load

  Mitotic cell division increases tumour mutation burden and copy number load with a positive and inverse correlation, respectively, with the clinical benefit of immunotherapy. Markers of cell division correlate also with genomic demethylation involving methylation loss in late-replicating partial methylation domains. Here we find that immunomodulatory pathway genes are concentrated in these domains and transcriptionally repressed in demethylated tumours with CpG island promoter hypermethylation. Global methylation loss correlated with immune evasion signatures independently of mutation burden and aneuploidy. Methylome data of our cohort (n = 60) and a published cohort (n = 81) in lung cancer and a melanoma cohort (n = 40) consistently demonstrated that genomic methylation alterations counteract the contribution of high mutation burden and increase immunotherapeutic resistance. Higher predictive power was observed for methylation loss than mutation burden. We also found that genomic hypomethylation correlates with the immune escape signatures of aneuploid tumours. Hence, DNA methylation alterations implicate epigenetic modulation as a combination regimens for precision immunotherapy.

  Study EGAS00001003731

• Evolutionary predictability of genetic versus non genetic resistance to anticancer drugs in melanoma

  Therapy resistance arises from heterogeneous drug-tolerant persister cells or minimal residual disease (MRD) through genetic and nongenetic mechanisms. A key question is whether specific molecular features of the MRD ecosystem determine which of these two distinct trajectories will eventually prevail. We show that, in melanoma exposed to MAPK therapeutics, emergence of a transient neural crest stem cell (NCSC) population in MRD concurs with the development of nongenetic resistance. This increase relies on a GDNF-dependent signaling cascade, which activates the AKT survival pathway in a focal adhesion kinase (FAK)-dependent manner. Ablation of the NCSC population through FAK inhibition delays relapse in patient-derived tumor xenografts. Strikingly, all tumors that ultimately escape this treatment exhibit resistance-conferring genetic alterations and increased sensitivity to ERK inhibition. These findings identify an approach that abrogates the nongenetic resistance trajectory in melanoma and demonstrate that the cellular composition of MRD deterministically imposes distinct drug resistance evolutionary paths.

  Study EGAS00001005314

• Contribution of allelic imbalance to colorectal cancer

  Point mutations in cancer have been extensively studied but chromosomal gains and losses have been more challenging to interpret due to their unspecific nature. Here we examine high-resolution allelic imbalance (AI) landscape in 1699 colorectal cancers, 256 of which have been whole genome sequenced (WGSed). The imbalances pinpoint 38 genes as plausible AI targets based on previous knowledge, and unbiased CRISPR-Cas9 knockout and activation screens identified altogether 79 genes within AI peaks regulating cell growth. Genetic and functional data implicates loss of TP53 as a sufficient driver of AI. The WGS highlights an influence of copy number aberrations on the rate of detected somatic point mutations. Importantly, the data reveal several associations between AI target genes, suggesting a role for a network of lineage-determining transcription factors in colorectal tumorigenesis. Overall, the results unravel the contribution of AI in colorectal cancer and provide a plausible explanation why so few genes are commonly affected by point mutations in cancers.

  Study EGAS00001002966

• Exome sequencing of familial high-grade serous ovarian carcinoma reveals heterogeneity for rare candidate susceptibility genes

  High-grade serous ovarian carcinoma (HGSOC) has a significant hereditary component, approximately half of which cannot be explained by known genes. To discover genes, we analyse germline exome sequencing data from 516 BRCA1/2-negative women with HGSOC, focusing on genes enriched with rare, protein-coding loss-of-function (LoF) variants. Overall, there is a significant enrichment of rare protein-coding LoF variants in the cases (p < 0.0001, chi-squared test). Only thirty-four (6.6%) have a pathogenic variant in a known or proposed predisposition gene. Few genes have LoF mutations in more than four individuals and the majority are detected in one individual only. Forty-three highly-ranked genes are identified with three or more LoF variants that are enriched by three-fold or more compared to GnomAD. These genes represent diverse functional pathways with relatively few involved in DNA repair, suggesting that much of the remaining heritability is explained by previously under-explored genes and pathways.

  Study EGAS00001004235

• A microRNA-signature that correlates with cognition and is a target against cognitive decline

  While some individuals age without pathological memory impairments, others develop age-associated cognitive diseases. Since changes in cognitive function develop slowly over time in these patients, they are often diagnosed at an advanced stage of molecular pathology, a time point when causative treatments fail. Thus, there is great need for the identification of inexpensive and minimal invasive approaches that could be used for screening with the aim to to identify individuals at risk for cognitive decline that can then undergo further diagnostics and eventually stratified therapies. In this study we use an integrative approach combining the analysis of human data and mechanistic studies in model systems to identify a circulating 3-microRNA signature that reflect key processes linked to neural homeostasis and informs about cognitive status. We furthermore provide evidence that expression changes of this signature represent multiple mechanisms de-regulated in the aging and diseased brain and are a suitable target for RNA therapeutics.

  Study EGAS00001005627

• Single-cell RNA-seq of bronchoalveolar lavage (BAL) fluid of late stage severe COVID-19 patients

  COVID-19-induced ‘acute respiratory distress syndrome’ (ARDS) is associated with prolonged respiratory failure and high mortality, but the mechanistic basis of lung injury remains incompletely understood. Here, we analyzed pulmonary immune responses and lung pathology in two cohorts of patients with COVID-19 ARDS using functional single cell genomics, immunohistology and electron microscopy. We describe an accumulation of CD163-expressing monocyte-derived macrophages, that acquired a profibrotic transcriptional phenotype during COVID-19 ARDS. Gene set enrichment and computational data integration revealed a significant similarity between COVID-19-associated macrophages and profibrotic macrophage populations identified in idiopathic pulmonary fibrosis. COVID-19 ARDS was associated with clinical, radiographic, histopathological, and ultrastructural hallmarks of pulmonary fibrosis. Exposure of human monocytes to SARS-CoV-2, but not Influenza A virus or viral RNA analogs, was sufficient to induce a similar profibrotic phenotype in vitro. In conclusion, we demonstrate that SARS-CoV-2 triggers profibrotic macrophage responses and pronounced fibroproliferative ARDS.

  Study EGAS00001005634

• Myoepithelial progenitors as founder cells of hyperplastic human breast lesions upon PIK3CA transformation

  The myoepithelial (MEP) lineage of human breast comprises bipotent and multipotent progenitors in ducts and terminal duct lobular units (TDLUs). We here assess whether this heterogeneity impacts on oncogenic PIK3CA transformation. Single cell RNA sequencing (scRNA-seq) and multicolor imaging reveal that terminal ducts represent the most enriched source of cells with ductal MEP markers including a-smooth muscle actin (a-SMA), keratin K14, K17 and CD200. Furthermore, we find neighboring CD200high and CD200low progenitors within terminal ducts. When sorted and kept in ground state conditions, their CD200low and CD200high phenotypes are preserved. Upon differentiation, progenitors remain multipotent and bipotent, respectively. Immortalized progenitors are transduced with shp53 and mutant PIK3CA. Upon transplantation, CD200low MEP progenitors distinguish from CD200high by the formation of multilayered structures with a hyperplastic inner layer of luminal epithelial cells. We suggest a model with spatially distributed MEP progenitors as founder cells of biphasic breast lesions with implications for early detection and prevention strategies.

  Study EGAS00001005933

• Homologous recombination DNA repair deficiency and PARP inhibition activity in primary triple negative breast cancer

  Triple negative breast cancer (TNBC) encompasses molecularly different subgroups, with a subgroup harboring evidence of defective homologous recombination (HR) DNA repair. Within a phase 2 window clinical trial, RIO trial (EudraCT 2014-003319-12), we investigate the activity of PARP inhibitors in 43 patients with untreated TNBC. The primary endpoint, decreased Ki67, occurs in 12% of TNBC. Multiple different approaches identify HR deficiency in the majority of TNBC, 69% with the mutational-signature-based HRDetect assay. Cancers with mutational signatures of HR deficiency have a functional defect in HR. Following rucaparib treatment there is no association of Ki67 change with HR deficiency. In contrast, early circulating tumor DNA dynamics identify activity of rucaparib in cancers with mutation-signatures of HR deficiency, with rucaparib inducing expression of interferon response genes in HR deficient cancers. The majority of TNBCs have a defect in DNA repair, identifiable by mutational signature analysis, that may be targetable with PARP inhibitors.

  Study EGAS00001004405

• Somatic_mutation_profiling_of_intestinal_crypts_from_IBD_Full_STDY

  Following on from our pilot study we will investigate further the role that somatic mutations in intestinal stem cells play in IBD. We will use laser capture microdissection to ascertain epithelial cells from an individual crypts/vilus. We will extract DNA from these and use a new low-input material library prep methods to make accurate libraries for sequencing. We will perform 15X whole-genome sequencing of crypts biopsied from patients. Biopsies have been taken from inflammed and noninflammed patches to compare mutation rates and mutational signatures. We will also test if crypts from inflammed patches of a single patient are clonal (either within a given inflammed patch or across inflammed patches). We will quantify the rate of cancer driver mutations in inflammed and non-inflammed crypts. 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 EGAS00001003249

• Comprehensive genomic and transcriptomic analysis of three synchronous primary tumours and a recurrence from a head and neck cancer patient

  Synchronous primary malignancies occur in a small proportion of head and neck squamous cell carcinoma patients. Here, we analysed three synchronous primaries and a recurrence from one patient, by comparing the genomic and transcriptomic profiles among the tumour samples and determining the recurrence origin. We found remarkable levels of heterogeneity among the primary tumours, and through the patterns of shared mutations, we traced the origin of the recurrence. Interestingly, the patient carried germline variants which might have predisposed him to carcinogenesis, together with a history of alcohol and tobacco consumption. Mutational signature analysis confirmed the impact of alcohol exposure, with Signature 16 present in all tumour samples. Characterisation of immune cell infiltration highlighted an immunosuppressive environment in all samples, which exceeded the potential activity of T cells. Studies such as the one described here have important clinical value and contribute to personalised treatment decisions for patients with synchronous primaries and matched recurrences.

  Study EGAS00001004857

• RNA-seq on patient-derived, stage II, CRC cell lines

  The gut microbiome is a key player in the immunomodulatory and pro-tumorigenic microenvironment in colorectal cancer (CRC). It is well established that Fusobacterium’s virulence factors are responsible for its pro-tumorigenic properties, however the role of its metabolic cross-talk with the tumor remains unexplored. Here we use in vitro, in vivo, and in silico methods to describe a novel microbe-host interaction keystone: formate. Omics data reveals molecular signatures, linking a metabolically driven CRC phenotype with Fusobacteria. We observed a metabolic shift towards increased F. nucleatum formate secretion in gut-on-chip model co-cultures with patient-derived CRC cells, along with an accelerated cancer glutamine metabolism. We show that high formate levels trigger AhR signaling, increase cancer stemness and cellular invasion. Finally, we observed an expansion of Th17 cells accompanying F. nucleatum-induced tumorigenesis. Moving beyond observational studies, we applied new experimental approaches for gaining ecosystem-level mechanistic understanding of F. nucleatum’s role in cancer pathogenesis.

  Study EGAS00001005948

• Arriba: accurate and efficient detection of gene fusions from RNA-Seq (H021)

  The identification of gene fusions from RNA sequencing data is a routine task in cancer research and precision oncology. However, despite the availability of many computational tools, fusion detection remains challenging. Existing methods suffer from poor prediction accuracy and are computationally demanding. We developed Arriba, a novel fusion detection algorithm with high sensitivity and short runtime. When applied to a large collection of published pancreatic cancer samples (n=803), Arriba identified a variety of driver fusions, many of which affected druggable proteins, including ALK, BRAF, FGFR2, NRG1, NTRK1, NTRK3, RET, and ROS1. The fusions were significantly associated with KRAS wild-type tumors and involved proteins stimulating the MAPK signaling pathway, suggesting that they substitute for activating mutations in KRAS. In addition, we confirmed the transforming potential of two novel fusions, RRBP1-RAF1 and RASGRP1-ATP1A1, in cellular assays. These results demonstrate Arriba’s utility in both basic cancer research and clinical translation.

  Study EGAS00001003554

• The Genetic Landscape of Ocular Adnexa MALT Lymphoma Reveals Frequent Aberrations in NFAT and MEF2B Signaling Pathways

  A comprehensive constellation of somatic non-silent mutations and copy number (CN) variations in ocular adnexa marginal zone lymphoma (OAMZL) is unknown. By utilizing whole-exome sequencing in 69 tumors we define the genetic landscape of OAMZL. Mutations and CN changes in CABIN1 (30%), RHOA (26%), TBL1XR1 (22%), and CREBBP (17%) and inactivation of TNFAIP3 (26%) were among the most common aberrations. Candidate cancer driver genes cluster in the B-cell receptor (BCR), NFkB, NOTCH and NFAT signaling pathways. One of the most commonly altered genes is CABIN1, a calcineurin inhibitor acting as a negative regulator of the NFAT and MEF2B transcriptional activity. CABIN1 deletions enhance BCR-stimulated NFAT and MEF2B transcriptional activity, while CABIN1 mutations enhance only MEF2B transcriptional activity by impairing binding of mSin3a to CABIN1. Our data provide an unbiased identification of genetically altered genes that may play a role in the molecular pathogenesis of OAMZL and serve as therapeutic targets.

  Study EGAS00001006631

• High-resolution, patient-level dissection of IL-23 blockade in cutaneous psoriasis

  Psoriasis vulgaris and other chronic inflammatory diseases improve markedly with therapeutic blockade of IL-23 signaling in T cells, but the genetic mechanisms of response remain poorly understood. We single-cell transcriptomically profiled CD45+ immune cells isolated from lesional psoriatic skin before and after IL-23 blockade. In clinically responsive patients, a psoriatic transcriptional signature in skin-resident memory T cells was sharply attenuated. In contrast, poorly responsive patients were distinguished by enduring T17 cell activation, a mechanism distinct from alternative cytokine signaling or downstream resistance. Spatial transcriptomic analysis suggests that successful IL-23 blockade requires dampening of > 90% of IL-17-induced signaling in lymphocyte-adjacent keratinocytes, an unexpectedly high threshold. We also detected a subset of persistent, disease-specific T17 abnormalities in responsive patients, revealing an irreversible cell identity that may necessitate ongoing IL-23 inhibition. Collectively, our data establishes a patient-level paradigm for dissecting response to immunomodulatory treatments.

  Study EGAS00001007373

• Unraveling mutagenic processes influencing the tumor mutational patterns of individuals with Constitutional Mismatch Repair Deficiency

  Constitutional mismatch repair deficiency (CMMRD), caused by bi-allelic germline variants in one of the mismatch repair (MMR) genes, is a childhood cancer predisposition syndrome that often results in the development of multiple tumors early in life. A better understanding of mutational processes driving subsequent CMMRD tumors could advance optimal treatment. Therefore, we performed a genomic characterization of 41 tumors from 17 individuals with CMMRD. Mutational patterns in these tumors were found to be influenced by multiple factors, including the affected MMR genes, tumor types and somatic polymerase proofreading mutations. Temozolomide treatment left prominent mutational signatures in two second primary hematologic malignancies. Furthermore, a novel indel signature was found in 54% of the tumors, characterized by one base pair cytosine insertions in cytosine homopolymers. In conclusion, the analysis of sequential tumors in individuals with CMMRD reveals diverse mutational patterns influenced by the underlying mutated MMR gene, tumor type and treatment history.

  Study EGAS00001007660

• Somatic mutation and selection at epidemiological scale - TwinsUK_TargetedNanoSeq_Buccal

  Targeted NanoSeq in buccal epithelium obtained longitudinally from a number of donors. A custom-designed panel of ~200 genes will be used to achieve high depth coverage (aiming for ~1000X at panel sites).As we age, many tissues become colonised by microscopic clones carrying somatic driver mutations. Some of these clones represent a first step towards cancer whereas others may contribute to ageing and other diseases. However, our understanding of the clonal landscapes of human tissues, and their impact on cancer risk, ageing and disease, remains limited due to the challenge of detecting somatic mutations present in small numbers of cells. Here, we introduce a new version of nanorate sequencing (NanoSeq), a duplex sequencing method with error rates of less than 55 per billion base pairs, which is compatible with whole-exome and targeted gene sequencing. Deep sequencing of polyclonal samples with single-molecule sensitivity enables the simultaneous detection of mutations in large numbers of clones, yielding accurate somatic mutation rates, mutational signatures and driver mutation frequencies in any tissue. Applying targeted NanoSeq to 1,042 non-invasive samples of oral epithelium and 371 samples of blood from a twin cohort, we found an unprecedentedly rich landscape of selection, with 46 genes under positive selection driving clonal expansions in the oral epithelium, over 62,000 driver mutations, and evidence of negative selection in some genes. The high number of positively selected mutations in multiple genes provides high-resolution maps of selection across coding and non-coding sites, a form of in vivo saturation mutagenesis. Multivariate regression models enable mutational epidemiology studies on how carcinogenic exposures and cancer risk factors, such as age, tobacco or alcohol, alter the acquisition and selection of somatic mutations. Accurate single-molecule sequencing has the potential to unveil the polyclonal landscape of any tissue, providing a powerful tool to study early carcinogenesis, cancer prevention and the role of somatic mutations in ageing and disease.

  Dataset EGAD00001015618

• Somatic mutation and selection at epidemiological scale - TwinsUK_TargetedEMSeq_Blood

  Development of a targeted methylation assay to determine the cell-type composition of a sample. As we age, many tissues become colonised by microscopic clones carrying somatic driver mutations. Some of these clones represent a first step towards cancer whereas others may contribute to ageing and other diseases. However, our understanding of the clonal landscapes of human tissues, and their impact on cancer risk, ageing and disease, remains limited due to the challenge of detecting somatic mutations present in small numbers of cells. Here, we introduce a new version of nanorate sequencing (NanoSeq), a duplex sequencing method with error rates of less than 5 per billion base pairs, which is compatible with whole-exome and targeted gene sequencing. Deep sequencing of polyclonal samples with single-molecule sensitivity enables the simultaneous detection of mutations in large numbers of clones, yielding accurate somatic mutation rates, mutational signatures and driver mutation frequencies in any tissue. Applying targeted NanoSeq to 1,042 non-invasive samples of oral epithelium and 371 samples of blood from a twin cohort, we found an unprecedentedly rich landscape of selection, with 46 genes under positive selection driving clonal expansions in the oral epithelium, over 62,000 driver mutations, and evidence of negative selection in some genes. The high number of positively selected mutations in multiple genes provides high-resolution maps of selection across coding and non-coding sites, a form of in vivo saturation mutagenesis. Multivariate regression models enable mutational epidemiology studies on how carcinogenic exposures and cancer risk factors, such as age, tobacco or alcohol, alter the acquisition and selection of somatic mutations. Accurate single-molecule sequencing has the potential to unveil the polyclonal landscape of any tissue, providing a powerful tool to study early carcinogenesis, cancer prevention and the role of somatic mutations in ageing and disease.

  Dataset EGAD00001015623

• Somatic mutation and selection at epidemiological scale - TwinsUK_TargetedEMSeq_Buccal

  Development of a targeted methylation assay to determine the cell-type composition of a sample. As we age, many tissues become colonised by microscopic clones carrying somatic driver mutations. Some of these clones represent a first step towards cancer whereas others may contribute to ageing and other diseases. However, our understanding of the clonal landscapes of human tissues, and their impact on cancer risk, ageing and disease, remains limited due to the challenge of detecting somatic mutations present in small numbers of cells. Here, we introduce a new version of nanorate sequencing (NanoSeq), a duplex sequencing method with error rates of less than 5 per billion base pairs, which is compatible with whole-exome and targeted gene sequencing. Deep sequencing of polyclonal samples with single-molecule sensitivity enables the simultaneous detection of mutations in large numbers of clones, yielding accurate somatic mutation rates, mutational signatures and driver mutation frequencies in any tissue. Applying targeted NanoSeq to 1,042 non-invasive samples of oral epithelium and 371 samples of blood from a twin cohort, we found an unprecedentedly rich landscape of selection, with 46 genes under positive selection driving clonal expansions in the oral epithelium, over 62,000 driver mutations, and evidence of negative selection in some genes. The high number of positively selected mutations in multiple genes provides high-resolution maps of selection across coding and non-coding sites, a form of in vivo saturation mutagenesis. Multivariate regression models enable mutational epidemiology studies on how carcinogenic exposures and cancer risk factors, such as age, tobacco or alcohol, alter the acquisition and selection of somatic mutations. Accurate single-molecule sequencing has the potential to unveil the polyclonal landscape of any tissue, providing a powerful tool to study early carcinogenesis, cancer prevention and the role of somatic mutations in ageing and disease.

  Dataset EGAD00001015622

• Prevention and Early Treatment of Acute Lung Injury (PETAL) Acetaminophen in Sepsis: Targeted Therapy to Enhance Recovery (ASTER) (PETAL ASTER-BioLINCC)

  Data Access NOTE: Please refer to the “Authorized Access” section below for information about how access to the data from this accession differs from many other dbGaP accessions. Access to Biospecimens is through the NHLBI Biologic Specimen and Data Repository Information Coordinating Center (BioLINCC). Biospecimens from PETAL ASTER include plasma, urine and whole blood. Please note that use of biospecimens in genetic research is subject to a tiered consent. Objectives: To determine whether acetaminophen increases days alive and free of organ dysfunction in sepsis participants compared with placebo.Background: Acetaminophen (paracetamol) has many effects that can be beneficial in sepsis treatment, including analgesia, antipyresis, cyclooxygenase-2 inhibition, as well as a potent and specific hemoprotein reduction that can block hemoglobin-induced oxidation of lipids and other substrates. The majority of sepsis participants experience elevated circulating cell-free hemoglobin levels, which is associated with development of organ dysfunction including acute respiratory distress syndrome (ARDS) and death.Acetaminophen has been found in observational studies to be associated with improved survival in critically ill sepsis participants with elevated plasma cell-free hemoglobin, and small clinical trials have had positive sepsis participant outcomes such as reduced plasma biomarkers of lipid peroxidation and improved kidney function. However, a large, randomized trial of acetaminophen administration for treatment of fever in participants with suspected infection did not show a mortality benefit. The NHLBI PETAL Network initiated ASTER as a larger phase trial to examine the utility of plasma cell-free hemoglobin level as a biomarker for future sepsis trials and whether acetaminophen would increase the number of days alive and free of organ support for participants with sepsis and respiratory or circulatory organ dysfunction. Participants: A total of 447 participants were enrolled and randomized, 227 to the acetaminophen arm and 220 to the placebo arm. Data from 40 participants who were randomized to the Vitamin C arm, which was stopped early (see Design section below), is also included.Design: ASTER was a phase 2b multicenter, randomized, double-blind trial. The study originally had a 3-arm platform trial in which participants were randomized 1:1:1 to treatment with intravenous acetaminophen, vitamin C, or a common placebo. The vitamin C arm of the trial was stopped after enrolling 79 participants due to external clinical trial data for vitamin C.Participants randomized to the acetaminophen arm received acetaminophen at the dose of 1 g in 100 mL diluent (or 15 mg/kg if actual body weight was Conclusions: Intravenous acetaminophen was considered to be safe but did not significantly improve days alive and free of organ support in critically ill sepsis participants. There was no significant interaction between cell-free hemoglobin levels and acetaminophen.

  Study phs003900

• Capturing the Genetic Diversity of the Himba Population

  The Himba people are a semi-nomadic, Bantu-speaking pastoralist group from the northwestern Kunene region of Namibia. Because of their limited population size, restricted geographic distribution, and endogamy, founder populations represent an ideal system for genetic analyses due to reduction of the confounding environmental and cultural variables. The original study used genotype data and demographic interview data to understand family dynamics and ancestry in a population of Himba pastoralists. HLA allele calls and genome-wide methylation array data were later generated for a subset of the initial dataset for 2 additional studies. These 3 molecular datasets, available through dbGaP, are relevant to broader studies of ancestry, allele frequencies and the relationship of Himba to other ethnic groups in sub-Saharan Africa. The Himba population provides a unique opportunity to study questions regarding extra-pair paternity and mate selection because Himba culture allows both men and women, married and not, to take multiple partners. Previous estimates of extra-pair paternity rates in human populations have been very low, but these estimates lack global and cultural diversity in population representation. Thus, investigating the rate of extra-pair paternity in the Himba greatly aids in understanding the global variation in non-paternity rates among human populations. Saliva samples were collected from parents and children, and were genotyped on Illumina SNP array platforms (MEGAex and H3Africa). In total, 678 individuals' genotype array data are deposited. Paternity results were de-identified and protected by a double blind protocol (no researcher has full knowledge of individual paternity results). Due to the sensitive nature of this study, paternity assertions are not available for access. For a subset of 360 individuals, HLA class 1 (A, B, C) and class 2 (DPA1, DPB1, DQA1, DQB1, DRB1) genes were targeted for DNA sequencing using a probe-based capture method. HLA alleles at the four field resolution were determined from the sequence capture using the consensus calls obtained from two algorithms: NGSengine® 2.10.0 (GenDX, Utrecht, the Netherlands) and HLA Explore™ (Omixon Biocomputing Ltd. Budapest, Hungary). These data were used to investigate evidence for mate selection based on HLA dissimilarity in the Himba. Himba cultural norms permit concurrent arranged marriages and chosen sexual partnerships allowing us to directly test for evidence of disassortative mate selection based on HLA genotype. Due to the sensitive nature of this study, partnership data are not available for access.For a subset of 51 Himba individuals methylation array data was generated from the saliva-derived DNA. These data were generated in order to investigate the accuracy of epigenetic age predictors in this population and to construct population-specific epigenetic age predictors in a subsequent publication. Chronological ages are available for these 51 individuals.

  Study phs001995

• Beyond BRCA deficiency: Clinical and molecular predictors of survival in patients with BRCA-deficient tubo-ovarian high-grade serous carcinoma

  Homologous recombination DNA repair deficient (HRD) tumors account for about 50% of tubo-ovarian high-grade serous carcinomas (HGSC) and are associated with a high response to platinum-based chemotherapy. However, a subset of patients with HRD tumors have unexpected resistance to chemotherapy and experience short survival. Our study compared BRCA-deficient and proficient HGSC among patients with short (<3 years, the lowest quartile of overall survival (OS)) versus longer-term (>3 year OS) to identify prognostic markers and potential therapeutic opportunities. Primary tumors from a cohort of patients with advanced-stage HGSC (n=154) enriched for those with HRD tumors and short survival (n=42) were analyzed using whole-genome sequencing, bulk RNA-sequencing, and DNA methylation profiling. A subset of HRD tumors (n=143) were characterized for immune cell densities by multiplex immunofluorescence. Clinicopathological features were assessed in 1,389 patients with HGSC, including 282 with pathogenic germline BRCA variants (gBRCApv). Findings were validated in two international HGSC cohorts: the Ovarian Tumor Tissue Analysis consortium (n=5,875) and Multisciplinary Ovarian Cancer Outcome Group (n=895). In gBRCApv-carriers, residual disease following surgical cytoreduction was not associated with shorter OS unlike in non-carriers where it was strongly associated. While most patients with gBRCApv had a more favorable OS compared to non-carriers, a survival advantage was not apparent in those with variants located outside of BRCA1 exon 10/23 and BRCA2 exon 11/27. Patient survival correlated with HRD score, such that those with a score ≥63 had significantly longer OS compared to those with HRD scores of 42-63 and <42. While higher HRD scores were associated with better survival outcomes, most gBRCApv carriers with a short survival had tumor HRD scores that exceeded the threshold typically considered predictive of a good response to carboplatin or PARP inhibitors. BRCA2-deficient HGSC with loss of the tumor suppressor NF1 was associated with exceptionally favorable outcome (median OS 17 years), whereas amplification of both PIK3CA and RAD21, was associated with poor outcome in BRCA2-deficient HGSC (median OS 2.9 years). The density of tumor-infiltrating CD8+ PD-1+ T cells was prognostic for OS in gBRCApv-carriers. In summary, rather than simply the presence or absence of a germline BRCA pathological variant influencing patient survival, the co-occurrence of specific somatic gene alterations, the extent of immune cell infiltration, the level of homologous recombination deficiency, and BRCA-variant location may modify clinical outcomes in patients with BRCA-deficient HGSC. Analysis of exceptional outcome patients, in this case gBRCApv-carriers with an atypically short survival, may identify determinants of outcome applicable to the wider HGSC patient population.

  Study EGAS00001008059

• The evolution of ovarian high grade serous carcinoma from STIC lesions

  We performed Ampliseq on 11 samples on a targeted panel of 17 genes.

  Study EGAS50000000361

• Psoriatic_arthritis

  This is a pilot single cell mRNA sequencing experiment to study immune cells in psoriatic arthritis.

  Study EGAS00001002104