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• Multicenter Study of Hydroxyurea (MSH)

  This study aimed to determine whether or not treatment with hydroxyurea titrated to maximum tolerated doses would reduce the frequency of vaso-occlusive (painful) crises by at least 50% in 299 men and women between 18 and 50 years old with a diagnosis of sickle cell anemia by gel electrophoresis conducted by a Core Laboratory. A secondary objective investigated correlations of fetal hemoglobin (HbF) levels and other patient or treatment characteristics with the occurrence of vaso-occlusive (painful) crises, and the effect of treatment on the quality of life.This controlled trial made hydroxyurea the first drug of proven benefit in preventing vaso-occlusive pain crisis and acute chest syndrome caused by sickle cell disease, with additional findings including reduced mortality in adult patients taking hydroxyurea for frequent painful sickle cell episodes after 9 of years follow-up. No significant side-effects of hydroxyurea therapy were noted.Instructions for requesting individual-level data are available on BioData Catalyst at https://biodatacatalyst.nhlbi.nih.gov/resources/data/. Apply for data access in dbGaP. Upon approval, users may begin accessing requested data in BioData Catalyst. For questions about availability, you may contact the BioData Catalyst team at https://biodatacatalyst.nhlbi.nih.gov/contact.

  Study phs002348

• National Heart, Lung and Blood Institute: Regulation of Motile Cilia Assembly in Lung Disease

  This study of 59 primary ciliary dyskinesia (PCD) patients utilized whole-exome capture sequencing to help identify variants that may be causative for PCD. Our goal was to provide insights into disease pathophysiology in samples, most of which had no obvious phenotype from transmission electron microscopy. This class of patients has been understudied. The patient samples were collected through UNC or under the auspices of Genetic Disorders of Mucociliary Clearance Consortium (GDMCC), which consists of eight geographically diverse clinical research sites across North America. It collectively studies inherited respiratory diseases related to impaired mucociliary clearance and airway host defense, which result in chronic suppurative respiratory diseases. The goal is to enhance diagnostic capabilities as the Consortium has been pivotal in the identification and/or characterization of 34 primary ciliary dyskinesia-associated genes. In this phase of the work, we used immunocytochemistry in patient samples and in shRNA hTEC cultures to show the localization of the CFAP57 protein to cilia and the role of a short region in trafficking of CFAP57 into the cilia. This work was complemented by proteomic studies in the Chlamydomonas reinhardtii

  Study phs002035

• Genomic Analysis of Prostate Tumor Heterogeneity in Metastasis

  To investigate the molecular changes, mutations, and signaling pathways that characterize the initial steps of prostate cancer metastasis to the lymph nodes, we analyzed 19 discrete lymph node (LN) metastases, 97 primary tumor foci, 39 benign lymph nodes, and 10 normal adjacent prostate tissue samples from 43 patients enrolled in a clinical trial (NCT01808222) of extended lymphadenectomy and metastasis excision guided by [18F]-fluciclovine PET imaging for high risk, newly diagnosed prostate cancer conducted at Emory University. These patients fell within high or very high-risk groups (T3a, Gleason score 8-10, or PSA greater than 20 ng/ml). Of these patients, 16 had LN metastases at least 4 mm in diameter, and 20 patients had no metastases. For metastatic patients, we performed RNA and Whole Exome Sequencing (WES) on three primary tumor foci, one benign LN, and all LN metastases greater than 4mm in diameter. For non-metastatic patients, we sequenced two primary tumor foci and one benign LN. In total, RNAseq was performed on 165 tissue samples from 43 patients, and WES was performed on 137 samples from 35 patients.

  Study phs003404

• CONNECTS Master Protocol for Clinical Trials targeting Macro- and Micro-Immuno-Thrombosis, Vascular Hyperinflammation, and Hypercoagulability and Renin-Angiotensin-Aldosterone System (RAAS) in Hospitalized Patients with COVID-19 (ACTIV-4 Host Tissue)

  ACTIV 4 Host Tissue is a shared-placebo clinical trial platform evaluating therapies targeting the host response to COVID-19 in hospitalized patients. The overarching goal of the platform was to find effective strategies for inpatient management of patients with COVID-19. Therapeutic goals for patients hospitalized for COVID-19 include hastening recovery and preventing progression to critical illness, multiorgan failure, or death. Our objective is to determine whether modulating the host tissue response improves clinical outcomes among patients with COVID-19. Three trials were implemented to investigate three agents: TXA-127, TRV-027, and Fostamatinib. These agents all impact the host tissue response in COVID-19 via a number of unique mechanisms, including potential beneficial effects on the RAAS system and formation of neutrophil extracellular traps (NETs). Each trial evaluated the efficacy of these agents' ability to impact the host tissue response and improve outcomes in patients hospitalized with COVID-19. We found no evidence that any of the three agents significantly improved clinical outcomes as measured by the primary outcome, oxygen free days through day 28.

  Study phs003708

• Atezolizumab Plus Chemotherapy With or Without Bevacizumab in Advanced Biliary Tract Cancer: Clinical and Biomarker Data From the Randomized Phase II IMbrave151 Trial

  PURPOSE Biliary tract cancers (BTCs) harbor an immunosuppressed tumor microenvironment (TME) and respond poorly to PD-1/PD-L1 inhibitors. Bevacizumab (anti-VEGF) plus chemotherapy can promote anticancer immunity, augmenting response to PD-L1 inhibition. PATIENTS AND METHODS This randomized, double-blind, proof-of-concept Phase II study enrolled patients (n=162) with previously untreated advanced BTC (IMbrave151; NCT04677504). Patients were randomized 1:1 to receive 3-weekly cycles of atezolizumab (1200 mg) plus bevacizumab (15 mg/kg) or atezolizumab plus placebo until disease progression or unacceptable toxicity. All patients received cisplatin (25 mg/m2) plus gemcitabine (1000 mg/m2; CisGem) on Days 1 and 8 every 3 weeks for up to 8 cycles. Stratification of patients was by disease status, geographic region, and primary tumor location. The primary endpoint was progression-free survival (PFS). No formal hypothesis testing was performed. Exploratory correlative biomarker analysis was undertaken using transcriptome analysis (n=95) and mutation profiling (n=102) on baseline tumor samples. RESULTS Between February and September 2021, 162 patients were enrolled. Median PFS was 8.3 months in the bevacizumab arm and 7.9 months in the placebo

  Study EGAS50000000387

• Single cell atlas of large B-cell lymphoma

  Large B-cell lymphomas (LBCL) are clinically and biologically heterogeneous lymphoid malignancies, shaped by complex tumor and microenvironments that play a critical role in disease progression. There has been no direct and comprehensive single-cell characterization of tumor microenvironment in LBCL that simultaneously captures lymphoid, myeloid, and stromal populations across a sufficiently large cohort to reveal reproducible and biologically meaningful patterns. Here, we performed single-nucleus multiome profiling, coupled with bulk DNA and RNA sequencing, on 232 tumor and control biopsies to comprehensively map cell subpopulations of LBCL. Through this integrative approach, we identified Lymphoma Microenvironment Archetype Profiles (LymphoMAPs)—distinct, reproducible patterns defined by the co-occurrence of functionally specialized cell subsets. We further characterized the cell-cell communication pathways that shape these transcriptional phenotypes within archetypes. Importantly, we discovered associations between specific LymphoMAPs and clinical and molecular features of LBCL, including response to CD19 CAR T-cell therapy. Our study provides a valuable resource of lymphoid, myeloid, and non-hematopoietic cell states in LBCL and offers a framework for understanding how the abundance and functional state of cells within the tumor microenvironment may drive inter-patient variability in therapeutic outcome.

  Study EGAS50000001022

• Investigation of molecular diagnosis by molecular biological analysis using next-generation sequencer for actionable endocrine diseases (including neoplastic diseases)

  Fructose-1,6-bisphosphatase (FBPase) deficiency, caused by an FBP1 mutation, is an autosomal recessive disorder characterized by hypoglycemic lactic acidosis. Due to the rarity of FBPase deficiency, the mechanism by which the mutations cause enzyme activity loss still remains unclear. Here we identify compound heterozygous missense mutations of FBP1, c.491G>A (p.G164D) and c.581T>C (p.F194S), in an adult patient with hypoglycemic lactic acidosis. The G164D and F194S FBP1 mutants exhibit decreased FBP1 protein expression and a loss of FBPase enzyme activity. The biochemical phenotypes of all previously reported FBP1 missense mutations in addition to G164D and F194S are classified into three functional categories. Type 1 mutations are located at pivotal residues in enzyme activity motifs and have no effects on protein expression. Type 2 mutations structurally cluster around the substrate binding pocket and are associated with decreased protein expression due to protein misfolding. Type 3 mutations are likely nonpathogenic. These findings demonstrate a key role of protein misfolding in mediating the pathogenesis of FBPase deficiency, particularly for Type 2 mutations. This study provides important insights that certain patients with Type 2 mutations may respond to chaperone molecules.

  Study JGAS000625

• FLT3-targeting and places FLT3 as an ideal therapeutic target to selectively eradicate LSCs, while sparing HSC.

  CRISPR/Cas9 FLT3 knock-out (FLT3-KO) in human HSCs and LSCs followed by functional xenograft assays to test their ability to regenerate human hematopoiesis and leukemia, respectively. FLT3-KO in HSCs from human fetal liver, cord blood and adult bone marrow showed no impairment in multilineage hematopoiesis in primary and secondary xenografts. By contrast, FLT3-KO LSCs from 6 of 7 FLT3-ITD mutated AMLs were able to generate short-term engraftment but were completely exhausted by 12 weeks. Thus, FLT3 is essential for LSC long-term propagation. This dependency was unique to FLT3-ITD AML samples as non-FLT3-ITD AML samples generated leukemic grafts upon FLT3-KO. Transcriptomic analysis revealed that FLT3-KO induced downregulation of DNA repair and cell cycle checkpoints, uniquely in FLT3-ITD AML, but not in healthy HSCs or other AMLs. Our research highlights a critical distinction between healthy HSCs and LSCs: whereas healthy hematopoiesis proceeds unperturbed upon FLT3-KO, FLT3-ITD leukemogenesis is impaired through elimination of LSCs. This evidence underscores the necessity for more potent FLT3-targeting and places FLT3 as an ideal therapeutic target to selectively eradicate LSCs, while sparing HSC.

  Study EGAS50000000437

• Whole genome and transcriptome analysis of medullary thyroid cancer

  Medullary thyroid cancer is the neoplasm of the calcitonin-producing parafollicular cells of the thyroid gland. The hormone calcitonin acts to lower the blood calcium level, counteracting the effects of the parathyroid hormone; it can also serve as a biomarker for the presence or recurrence of medullary thyroid cancer. Surgery is the only curative treatment for this cancer. Targeted therapeutics vandetanib and cabozantinib are approved for the treatment of aggressive and metastatic tumors that are not amenable to surgery. The use of these multikinase inhibitors are supported by the observed overactivation of the RET oncoprotein in a large sub-population of medullary thyroid cancers; however, not all patients carry oncogenic alterations of this kinase. Hence, there is a need for molecular characterization of medullary tumors on the genomic scale with the aim of identifying targetable mutations. Here, we describe the genomic profiles of two medullary thyroid cancers and report the presence of a putative oncogenic BRAF fusion in one. Such alterations previously observed in other malignancies and known targets of available drugs, can benefit patients who currently have no therapy options.

  Study EGAS00001001473

• Clonal evolution in myeloma: the impact of maintenance lenalidomide and depth of response on the genetics and sub-clonal structure of relapsed disease in uniformly treated newly diagnosed patients

  The emergence of treatment resistant sub-clones is a key feature of relapse in multiple myeloma. Therapeutic attempts to extend remission and prevent relapse include the maximisation of response and use of maintenance therapy. We used whole exome sequencing to study the genetics of paired presentation and relapse samples from 56 newly diagnosed patients, following induction therapy, randomised to receive either lenalidomide maintenance or observation as part of the Myeloma XI trial. Patients included were considered high risk, relapsing within 30 months of maintenance randomisation. Patients achieving a complete response had predominantly branching evolutionary patterns leading to relapse, characterised by a greater mutational burden, an altered mutational profile, bi-allelic inactivation of tumour suppressor genes, and acquired structural aberrations. Conversely, in patients achieving a partial response the evolutionary features were predominantly stable with a similar mutational and structural profile. There were no significant differences between patients relapsing after maintenance lenalidomide vs observation. This study shows that the depth of response is a key determinant of the evolutionary patterns seen at relapse.

  Study EGAS00001003539

• Low and variable tumor reactivity of the intratumoral TCR repertoire in human cancers

  Infiltration of human cancers by T cells is generally interpreted as a sign of immune recognition, and there is a growing effort to reactivate dysfunctional T cells at such tumor sites. However, these efforts only have value if the intratumoral T cell receptor (TCR) repertoire of such cells is intrinsically tumor-reactive, and this has not been established in an unbiased manner for most human cancers. To address this issue, we analyzed the intrinsic tumor-reactivity of the intratumoral TCR repertoire of CD8+ T cells in ovarian and colorectal cancer – two tumor types for which T cell infiltrates form a positive prognostic marker. Data obtained demonstrate that a capacity to recognize autologous tumor is limited to approximately 10% of intratumoral CD8+ T cells. Furthermore, in two out of four patient samples tested, no tumor-reactive TCRs were identified, despite infiltration of their tumors by T cells. These data indicate that the intrinsic capacity of intratumoral T cells to recognize adjacent tumor tissue can be rare and variable, and suggest that clinical efforts to reactivate intratumoral T cells will benefit from approaches that simultaneously increase the quality of the intratumoral TCR repertoire.

  Study EGAS00001003119

• scRNA-seq of HSPC treated with gemcitabine and carbplatin

  The study used cryopreserved hematopoietic stem and progenitor cells (HSPCs) harvested from one patient with chronic myelogenous leukemia (CML). The cells were thawed and acclimatized for 48 hours in StemMACS HSC Expansion Media XF (Miltenyi Biotec) supplemented with StemMACS HSC Expansion Cocktail (Miltenyi Biotec) at 37°C in a humidified atmosphere containing 5% CO2. 4 samples of 2000000 HSPCs in 2 ml media each were then prepared and treated for 24 hours: carboplatin-high: 150 µg/ml carboplatin carboplatin-low: 18.75 µg/ml carboplatin gemcitabine: 25 ng/ml gemcitabine control: no drug Single-cells were subsequently extracted using the ddSEQ™ Single-Cell Isolator (Bio-Rad) and later sequenced using the SureCell™ Whole Transcriptome Analysis 3' Library Prep Kit (Illumina) on the NextSeq 500 System (Illumina) using the NextSeq 500/550 High Output Kit v2.5 150 Cycles (Illumina) all following the manufacturer's instructions. FASTQ-files were then processed following the ddSeeker (Romagnoli, D., et al., BMC Genomics 2018, doi:10.1186/s12864-018-5249-x) and Drop-seq (Macosko, E.Z., et al., Cell 2015, doi:10.1016/j.cell.2015.05.002) protocols for processing scRNA-seq data to yield the final digital gene expression for each cell.

  Study EGAS00001004381

• Monitoring of leukemia clones in B-cell acute lymphoblastic leukemia at diagnosis and during treatment by single-cell DNA amplicon sequencing

  Acute lymphoblastic leukemia (ALL) is characterized by the presence of chromosomal changes, including numerical changes, translocations and deletions, which are often associated with additional single nucleotide mutations. In this study we used single-cell targeted DNA sequencing to determine the clonal heterogeneity of B-cell ALL at diagnosis and during chemotherapy treatment. With a customly designed DNA amplicon library targeting the most common mutations (in 110 genes) present in ALL, we analyzed bone marrow samples and/or blood samples from 12 B-ALL cases at diagnosis. For 4 cases where we detected multiple mutational clones at diagnosis, we also studied blood samples during the first weeks of chemotherapy treatment. This study shows that B-ALL cases with either a ETV6-RUNX1 or a BCR-ABL1 fusion have a low mutational burden, while cases with PAX5 alterations or hyperdyploidy have multiple clones at diagnosis, often with mutations in the JAK-STAT signaling pathway and the RAS signaling pathway. As expected, it can be observed that these clones disappear during treatment of the leukemia with almost no mutated cells left after two weeks of treatment.

  Study EGAS00001005029

• Whole-Genome Sequencing of Salivary Gland Adenoid Cystic Carcinoma

  Adenoid cystic carcinomas (ACCs) of the salivary glands are challenging to understand, treat, and cure. To better understand the genetic alterations underlying the pathogenesis of these tumors, we performed comprehensive genome analyses of 25 fresh-frozen tumors, including whole genome sequencing, expression and pathway analyses. In addition to the well-described MYB-NFIB fusion which was found in 11 tumors (44%), we observed five different rearrangements involving the NFIB transcription factor gene in seven tumors (28%). Taken together, NFIB translocations occurred in 15 of 25 samples (60%, 95%CI=41–77%). In addition, mRNA expression analysis of 17 tumors revealed overexpression of NFIB in ACC tumors compared with normal tissues (p=0.002). There was no difference in NFIB mRNA expression in tumors with NFIB fusions compared to those without. We also report somatic mutations of genes involved in the axonal guidance and Rho family signaling pathways. Finally, we confirm previously described alterations in genes related to chromatin regulation and Notch signaling. Our findings suggest a separate role for NFIB in ACC oncogenesis and highlight important signaling pathways for future functional characterization and potential therapeutic targeting.

  Study EGAS00001002812

• Federated discovery and sharing of genomic data using Beacons

  The Beacon Project is a Global Alliance for Genomics & Health (GA4GH) initiative that enables genomic and clinical data sharing across federated networks. The project is working toward developing regulatory, ethics and security guidance to ensure proportionate safeguards for distribution of data according to the GA4GH-developed “Framework for Responsible Sharing of Genomic and Health-Related Data”. Within this Nature Biotechnology Correspondence a description of the Beacon protocol and how it can be used as a model for the federated discovery and sharing of genomic data is offered to the community. A Beacon is defined as a web-accessible service that can be queried for information about a specific allele. A user of a Beacon can pose queries of the form “Have you observed this nucleotide (e.g., C) at this genomic location (e.g., position 32,936,732 on chromosome 13)?” to which the Beacon responds with either “yes” or “no.” In this way, a Beacon allows allelic information of interest to be discovered by a remote searcher with no reference to a specific sample or patient, thereby mitigating privacy risks. The Beacon API (represented as a RESTful web application) provides a technical specification that a Beacon server must implement. The specification is open source and available online here. To simplify the process of lighting a Beacon, a free, open-source reference implementation of the latest specification has been developed. GA4GH is promoting different levels of data access (open, registered, and controlled) for convenience and for compatibility across its projects. Each so-called access tier has distinct visibility and requirements for authorization. For example, ‘open access’ Beacons are accessible to anonymous users of the internet, whereas ‘registered access’ Beacons are accessible to registered users (for example, bona fide researchers and clinicians) who have agreed to a set of conditions of data use. Many of the largest genomic archives, such as dbGaP, the European Genome-phenome Archive and the European Variation Archive, have provided access to variation data through Beacons for some or all of their datasets. Beacons can be interconnected through the Beacon Network, a directory and search engine for Beacons. Although individual Beacons answer the question “Have you observed this allele?”, the Beacon Network answers the question “Who has observed this allele?”. Beacons can be freely registered to the Beacon Network and can be searched independently or in aggregate with other connected Beacons.

  Blog federated-discovery-using-beacons

• FASTQ files of total RNA-Seq data of POPS control samples

  Placental biopsies (n = 64 female placentas, n = 67 male placentas) were selected from healthy pregnancies from the POPs cohort. These patients had no evidence of hypertension at booking and during pregnancy, did not experience pre-eclampsia, Hemolysis, Elevated Liver enzymes, and Low Platelets (HELLP) syndrome, gestational diabetes, or diabetes mellitus type I or type II and other obstetric complications. They delivered live babies with a birth weight percentile in the normal range (20-80th percentile), with no evidence of slowing in fetal growth trajectory. Chorionic villi from the corresponding placentas (free from decidua, visible infarction, calcification, hematoma, or damage) were collected and processed within 30 minutes of separation from the uterus. After repeated washes in chilled phosphate buffered saline, the samples were placed in RNA later (Applied Biosystems) and stored at -80°C. Total placental RNA was extracted using mirVana Isolation Kit (Ambion). For each placenta, approximately 5 mg of tissue were homogenized in the Lysis/Binding solution for 20 sec at 6 m/s using a bead beater (FastPrep24) and Lysing Matrix D Tubes (MP Biomedicals). The samples were then spun at 13,000 rpm for 5 min at 4°C and the supernatants recovered. Afterwards, the manufacturer's instructions were followed. Immediately after the RNA extraction, placental RNA samples were DNase-treated using DNA-free DNA Removal Kit (Ambion), aliquoted, and stored in -80°C. Quantity and quality of the RNA samples were assessed using the Agilent 2100 Bioanalyzer, the Agilent RNA 6000 Nano Kit (Agilent Technologies), and Qubit fluorometer. Libraries were prepared starting with 300-500 ng of good quality total RNA (RIN ≥7.5) using the TruSeq Stranded Total RNA Library Prep Kit with Ribo-Zero Human/Mouse/Rat (Illumina), according to the manufacturer's instructions. The kit contains 96 uniquely indexed adapter combinations in order to allow pooling of multiple samples prior to sequencing. After determining their size (with the Agilent 2100 Bioanalyzer and the Agilent High Sensitivity DNA Kit by Agilent Technologies) and concentration (by qPCR with the KAPA Illumina ABI Prism Library Quantification Kit, Kapa Biosystems), libraries have been pooled and sequenced (single-end, 125 bp) using a Single End V4 Cluster Kit and an Illumina HiSeq2500 or HiSeq4000 instrument.

  Dataset EGAD00001003457

• Genetic analysis of HLA and immune escape genes in Diffuse Large B-cell Lymphoma

  Fifty percent of diffuse large B-cell lymphoma (DLBCL) cases lack cell-surface expression of the class-I major histocompatibility complex (MHC-I), thereby escaping immune recognition by cytotoxic T cells. In order to comprehensively identify the mechanisms involved in MHC-I loss, we first performed immunophenotypic analysis of both MHC class-I and -II in 657 cases across the spectrum of B-NHL, revealing that loss of MHC-I, but not MHC-II, is preferentially restricted to DLBCL. We then used whole exome and targeted deep-sequencing to examine genes involved in MHC-I expression in 74 DLBCL samples representative of MHC-I positive and negative cases. We show here that somatic biallelic or monoallelic inactivation of B2M and/or HLA-I is present in 80.9% (34/42) of MHC-I negative tumors. Furthermore, 68.8% (22/32) of MHC-I positive DLBCLs also harbored monoallelic HLA-I genetic alterations (MHC-I positivemono) that lead to allelic imbalance, suggesting allele-specific inactivation. Both MHC-I negative and MHC-I positivemono cases showed a significantly higher mutational burden as well as a higher number of inferred neo-antigens, suggesting co-selection of HLA-I loss and sustained neo-antigen production. Interestingly, the analysis of > 500.000 individuals in two databases revealed homozygosity of germline HLA-I genes in 26-38% of DLBCL patients, a frequency significantly higher than that observed in any other cancer type. In mice, germinal-center B cells lacking HLA-I expression did not progress to lymphoma and were counterselected in the context of oncogene-driven lymphomagenesis, suggesting that additional events are needed to license immune evasion. These results suggest a multi-step process of HLA-I loss including both germ-line and somatic events in DLBCL development, and have direct implications for the pathogenesis and immunotherapeutic targeting of this disease.

  Study EGAS00001005054

• Spatiotemporal immune atlas of the first clinical-grade gene-edited pig-to-human kidney xenotransplant

  Pig-to-human xenotransplantation is rapidly approaching the clinical arena; however, it is unclear which immunomodulatory regimens will effectively control human immune responses to pig xenografts. We transplanted a gene-edited pig kidney into a brain-dead human recipient on pharmacologic immunosuppression and studied the human immune response to the xenograft using spatial transcriptomics and single-cell RNA sequencing. Human immune cells were uncommon in the porcine kidney cortex early after xenotransplantation and consisted of primarily myeloid cells. Both the porcine resident macrophages and human infiltrating macrophages expressed genes consistent with an alternatively activated, anti-inflammatory phenotype. No significant infiltration of human B or T cells into the porcine kidney xenograft was detected. Altogether, these findings provide proof of concept that conventional pharmacologic immunosuppression is sufficient to restrict infiltration of human immune cells into the xenograft early after compatible pig-to-human kidney xenotransplantation.

  Dataset EGAD50000000359

• Single cell RNA sequencing of mononuclear cells from synovial fluid of patients with rheumatoid arthritis

  Mononuclear cells were collected from synovial fluid of anti-citrullinated positive antibodies (ACPA)-positive rheumatoid arthritis patients (n=8) and ACPA-negative RA patients (n=8). Global cell types (i.e., no enrichment) were obtained from these cryopreserved synovial fluid mononuclear cells (SFMC) samples and immediately fixed and processed using the GEM-X Flex Gene Expression Reagent Kits (10x Genomics) according to protocol. Following Gel Bead-in Emulsion (GEM) generation, samples were processed using the standard manufacturer’s protocol. Once sequencing libraries passed standard quality control metrics, libraries were sequenced on an Illumina NextSeq2000 P4 100 cycle reagent kit with the following read structure: R1: 28, R2: 90, I1: 10, I2: 10. Libraries were sequenced to obtain a read depth greater than 10,000 reads/cell for gene-expression (GEX). FASTQ files are made available. More detailed information can be obtained in Argyriou A. et al, Annals of the Rheumatic Disease, 2025.

  Dataset EGAD50000001801

• Microbiome

  16S-sequencing: All stool samples were processed according to the standards of the Flemish Gut Flora Project (Falony et al., 2016). All samples were processed together and sequenced in as a single batch (dual index run DI23R22) which included positive controls (PC, identical stool sample), negative controls (PCR-mix) and ‘blanks’ or negative controls of the extraction (no sample). In addition, a Runella strain (RS) was included to check for potential cross-contamination, as this strain is not present in human samples. The V4 region of the 16S rRNA gene was amplified with the primer pair 515F and 806R (GTGYCAGCMGCCGCGGTAA and GGACTACNVGGGTWTCTAAT, resp.), modified to contain a barcode sequence between each primer and the Illumina adaptor sequences to produce dual- barcoded libraries (Tito et al., 2019). Sequencing was performed on the Illumina MiSeq. Sequences were processed using the LotuS (Hildebrand et al., 2014) and DADA2 pipeline (Callahan et al., 2016) using RDP 16 as the reference taxonomy.

  Dataset EGAD50000002027

• 16S-based fecal microbiota composition

  The dataset reports the 16S rRNA gene sequencing of the fecal microbiota of donors from the Milieu Intérieur Cohort. The Milieu Intérieur cohort includes a total of 1,000 healthy individuals of western European ancestry, recruited in France as part of the Milieu Intérieur project. To assess their fecal microbiota composition, 16S rRNA profiles were generated from stool samples of 863 of the 1,000 donors. Human stool samples were produced at home no more than 24 hours before the scheduled medical visit and collected in a double-lined sealable bag maintaining strict anaerobic conditions. Upon reception at the clinical site, the fresh stool samples were aliquoted and stored immediately at -80°C. DNA was extracted from stool and barcoding PCR was carried out using indexed primers targeting the V3-V5 region of the 16S rRNA gene. Equal volumes of normalized PCR reaction were pooled and thoroughly mixed. The amplicon libraries were sequenced on Illumina MiSeq.

  Dataset EGAD00001004979

• Transcriptome Analysis of Malignant Peripheral Nerve Sheath Tumor-like Melanoma

  Malignant peripheral nerve sheath tumor (MPNST)-like melanoma is a rare malignancy with overlapping characteristics of both neural sarcoma and melanoma. The genomics of MPNST-like melanoma have not been previously described. In this study, we performed whole transcriptome sequencing analysis in 8 samples from 6 patients diagnosed with MPNST-like melanoma. In correlation with deletion ofxa0SERPINB4xa0in all our samples, there was noxa0SERPINB4xa0mRNA expression in our cohort, suggesting a potential tumor-suppressor role of SERPINB4 in MPNST-like melanomas.xa0HRAS, a gene uncommonly mutated in cutaneous melanomas, was mutated in 2 patients, but with no increased mRNA expression.xa0BRAFxa0mRNA expression, resultant from an atypicalxa0BRAFxa0mutation, was increased in association with an inactivatingxa0NF1xa0mutation. Our data demonstrate the role of alternative mechanisms of RAS pathway activation in MPNST-like melanomas and suggest the potential role of other molecular pathways in its carcinogenesis.

  Dataset EGAD00001007000

• Genetics of gene expression in human macrophage response to Salmonella

  Understanding how cells sense and respond to their environment, and how these responses are modulated by genetic variation, are fundamental biological problems, particularly for understanding how pathogenic organisms invade and manipulate the cells of the human immune system. Macrophages recognize and respond to many important human pathogens including HIV-1, Mycobacteria tuberculosis and Salmonella. This study will focus on the cellular response of human macrophages to Salmonella infection and how this response is modulated by the genetic bacground of the individual as well as additional pro-inflammatory stimulus (interferon-gamma priming). We will acquire 100 human induced pluripotent stem cell lines from the HipSci project, differentiate the cells in vitro into macrophages and expose them to four environmental conditions: (i) no stimulation, (ii) interferon-gamma (18h), (iii) Salmonella typhimurium SL1344 (5h), (iv) interferon-gamma (18h) + Salmonella (5h).Subsequently, we will isolate RNA from the samples for sequencing.

  Dataset EGAD00001003204

• Atypical teratoid/rhabdoid tumors (ATRT) are comprised of three epigenetic subgroups with distinct enhancer landscapes

  Atypical teratoid/rhabdoid tumor (ATRT) is one of the most common brain tumors in infants and young children. Although the prognosis of ATRT patients is poor, some patients respond very well to current treatments, suggesting inter-tumor molecular heterogeneity. To investigate this further, we genetically and epigenetically analyzed a large cohort of ATRTs (n = 170). Three distinct molecular subgroups of ATRTs, associated with differences in demographics, tumor location and type of SMARCB1 alterations, were identified using DNA-methylation or gene expression analyses. Whole genome DNA- and RNA-sequencing found no other recurrent mutations explaining the differences between subgroups. However, whole genome bisulfite-sequencing and H3K27Ac ChIP-sequencing of primary tumors revealed clear differences in methylation patterns and enhancer landscapes, leading to the identification of subgroup-specific regulatory networks.

  Dataset EGAD00001001444

• Subclonal diversification of primary breast cancer

  Cancers are ecosystems of genetically related clones, competing across space and time for limited resources. To understand the clonal structure of primary breast cancer, we applied genome and targeted sequencing to 295 samples from 49 patients’ tumors. The extent of subclonal diversification varied considerably among patients and encompassed many spatial patterns, including local growth, intraductal dissemination and clonal intermixture. Landmarks of disease progression, such as acquiring invasive or metastatic potential, arose within detectable subclones of antecedent lesions, suggesting that subclonal mutations could be relevant if actionable. No defined temporal order of mutation was evident, with the commonest genes, including PIK3CA, TP53, BRCA2, PTEN and MYC, mutated early in some, late in others, often exhibiting parallel evolution across subclones. Signatures of homologous recombination deficiency correlated with response to neoadjuvant chemotherapy. Thus, the interplay of mutation, growth and competition drives clonal structures of breast cancer that are complex, variable across patients and clinically relevant.

  Dataset EGAD00001000965