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• 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

• Cellular Dynamics Upon Immune Checkpoint Inhibition

  Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment, yet most patients experience limited or no clinical benefit. To elucidate the mechanisms of response and resistance, we analyzed single-cell RNA-sequencing data from 141 patients across multiple cancer types and ICI treatment modalities, with longitudinally paired samples. Using a robust, integration-free deep phenotyping framework, we annotated 876,410 cells into 80 granular states. We identified consistent compositional changes in 17 cell subtypes following ICI treatment, including enhanced adaptive immune responses and reduced interferon-responsive cells. Co-regulated cell communities within the tumor microenvironment (TME) highlighted coordinated interplay between immune and non-immune components. Importantly, we discovered two distinct patient groups with divergent TME dynamics post-treatment: responders showed expansion of naive lymphocytes, while non-responders exhibited increased immune-experienced/suppressive cells. This dichotomy offers a potential predictive biomarker for patient stratification. Our comprehensive analysis of TME dynamics during ICI treatment advances understanding of response mechanisms and personalized cancer immunotherapy.

  Study EGAS50000000459

• Disease specific alterations in the olfactory mucosa of patients with Alzheimer’s disease

  OOlfactory dysfunction manifests early in several neurodegenerative disorders. Olfaction is orchestrated by olfactory mucosal cells located in the upper nasal cavity. However, it is unclear how this tissue reflects key neurodegenerative features in Alzheimer’s disease. Here we report that Alzheimer´s disease olfactory mucosal cells secrete toxic amyloid-beta. We detail cell-type-specific gene expression patterns, unveiling 147 differentially expressed disease-associated genes compared to the cognitively healthy controls, and 5 distinct populations in globose basal cell -, myofibroblast-, and fibroblast/ stromal – like cells in vitro. Overall, coordinated alteration of RNA and protein metabolism, inflammatory processes and signal transduction were observed in multiple cell populations, suggesting a key role in pathophysiology. Our results demonstrate the potential of olfactory cell cultures in modelling Alzheimer´s disease. Moreover, for the first time we provide single cell data on olfactory mucosa in Alzheimer´s disease for investigating molecular and cellular mechanisms associated with the disease.

  Study EGAS00001006019

• Pediatric Patient-Derived-Xenograft development in MAPPYACTS – international pediatric cancer precision medicine trial in relapsed and refractory tumors

  Pediatric patients with recurrent and refractory cancers are in most need for new treatments. This study developed patient-derived-xenograft (PDX) models within the European MAPPYACTS cancer precision medicine trial (NCT02613962). To date, 131 PDX models were established following heterotopical and/or orthotopical implantation in immunocompromised mice: 76 sarcomas, 25 other solid tumors, 12 central nervous system tumors, 15 acute leukemias, and 3 lymphomas. PDX establishment rate was 43%. Histology, whole exome and RNA sequencing revealed a high concordance with the primary patient’s tumor profile, human leukocyte-antigen characteristics and specific metabolic pathway signatures. A detailed patient molecular characterization, including specific mutations prioritized in the clinical molecular tumor boards are provided. Ninety models were shared with the IMI2 ITCC Paediatric Preclinical Proof-of-concept Platform (IMI2 ITCC-P4) for further exploitation. This new PDX biobank of unique recurrent childhood cancers provides an essential support for basic and translational research and new treatments development in advanced pediatric malignancies.

  Study EGAS00001007327

• 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

• Environmental Arsenic and Diabetes Mellitus (Chihuahua Cohort)

  The Chihuahua Cohort was established as part of a larger NIEHS-funded project that used laboratory models (tissue culture and mice) and human subjects to examine the association between exposure to arsenic and diabetes, including identification of mechanisms underlying this association. All procedures involving human subjects were approved by institutional review boards at the University of North Carolina at Chapel Hill and Cinvestav-IPN (Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Mexico City, Mexico). All participants provided signed informed consent. A total of 1,160 adults (≥ 18 years old) with a minimum 5-year uninterrupted residency in the Chihuahua study area were recruited between 2008 and 2012. Samples of drinking water were obtained from the participants' households. Data on residency, occupation, drinking-water sources and use, smoking, alcohol consumption, and medical history were recorded by a study questionnaire. Spot urine and fasting venous blood were collected during medical examination that included an oral glucose tolerance test (OGTT) with blood drawn 2 hr after a 75-g glucose dose. Plasma from both fasting and 2-hr blood samples was collected. Body mass index (BMI) of each participant was calculated from body weight and height. BMI cutoffs of ≥ 25.0, ≥ 30, and < 18.5 kg/m2 were used to define overweight, obese, and underweight individuals, respectively. Participants' waist circumference was also measured. Blood pressure was assessed using a manual sphygmomanometer. Three measurements were taken at intervals of at least 1 min, with a 5-min rest before obtaining the first reading; the mean of the last two measurements was used. The concentrations of arsenic in drinking water and arsenic species in urine were measured by hydride generation-atomic absorption spectrometry. The limit of detection for As in water as well as for As species in urine was 0.01 µg As/L. Creatinine concentration in urine was determined using an established colorimetric assay. DNA was isolated from blood for genotyping analysis.The following measures were taken: glucose concentration in fasting blood (FBG) and in blood collected 2 hours into OGTT (2HBG); concentrations of triglycerides, HDL and total cholesterol (TC) in fasting plasma; and LDL was calculated using the Friedewald equation. Diabetes was classified by FPG ≥ 126 mg/dL, 2HPG ≥ 200 mg/dL, or self-reported diabetes diagnosis or medication use (WHO/International Diabetes Federation 2006). Prediabetes was defined as the absence of diabetes with FPG ≥ 110 mg/ dL or 2HPG ≥ 140 mg/dL. Elevated fasting levels of each lipid were defined as plasma TG ≥ 150 mg/dL, TC ≥ 200 mg/dL, and LDL ≥ 130 mg/dL. Fasting HDL < 40 mg/dL in men and < 50 mg/dL in women were designated as low. Hypertension was defined by systolic blood pressure (SBP) > 140 mm Hg, diastolic blood pressure (DBP) > 90 mmHg, or self-reported use of anti-hypertensive medication. Genotyping analysis, which will be available in version 2 of this study, was carried out in a subset of ~600 subjects with focus on enzymes involved in the metabolism of arsenic, including AS3MT, GSTs.All data collected during the medical exams or generated by the above-described chemical and biochemical analysis of water, urine and blood/plasma, as well as results of the genotyping analysis are included in dbGaP. Data generated by metabolomics and epigenetic analyses in small subsets of the Chihuahua cohort are not included, but are available in published articles.

  Study phs002139

• PCR-free shallow whole genome sequencing for chromosomal copy number detection from plasma of cancer patients is an efficient alternative to the conventional PCR-based approach

  Somatic copy number alterations (SCNAs) can be detected in tumor cell-free DNA (cfDNA) by shallow whole genome sequencing (sWGS). Polymerase chain reaction (PCR) is typically included in library preparations, but a PCR-free method could be an effective alternative for research and diagnostics. Peripheral blood samples (n=22) were collected in EDTA-containing tubes from non-small cell lung cancer patients (n=10) and healthy donors (n=12). PCR and PCR-free library preparations underwent sWGS and the following metrics were compared: mapping quality, proportion of duplicate reads, genome coverage, sequencing read length and copy number profiles. The PCR-free method was further evaluated on archived plasma samples (n=33) of varying pre-analytical quality collected in EDTA or lithium heparin tubes. Archived samples were from acute myeloid leukaemia (n=15) and B-cell lymphoma (n=18) patients. The percentage of unique reads was significantly higher for the 22 samples analysed by PCR-free (95.7%) compared to PCR (84%). PCR-free libraries from 33 archived samples produced data of a comparable quality, with 95.4% unique reads. All other evaluated metrics were highly comparable for PCR and PCR-free library preparations. We conclude that SCNA detection can be performed by PCR-free sWGS on cfDNA from cancer patients and is feasible for diagnostic and archival plasma collected in EDTA- or lithium heparin-containing tubes. Our results pave the way for an automated cfDNA workflow for cancer plasma samples.

  Study EGAS00001004692

• Neoadjuvant immunotherapy leads to pathological responses in MMR proficient and MMR deficient early stage colon cancers

  PD-1 plus CTLA-4 blockade is highly effective in advanced-stage, mismatch repair (MMR)-deficient (dMMR) colorectal cancers, yet not in MMR-proficient (pMMR) tumors. We postulated a higher efficacy of neoadjuvant immunotherapy in early-stage colon cancers. In the exploratory NICHE study (ClinicalTrials.gov: NCT03026140), patients with dMMR or pMMR tumors received a single dose of ipilimumab and two doses of nivolumab before surgery, the pMMR group with or without celecoxib. The primary objective was safety and feasibility; 40 patients with 21 dMMR and 20 pMMR tumors were treated, and 3 patients received nivolumab monotherapy in the safety run-in. Treatment was well tolerated and all patients underwent radical resections without delays, meeting the primary endpoint. Of the patients who received ipilimumab + nivolumab (20 dMMR and 15 pMMR tumors), 35 were evaluable for efficacy and translational endpoints. Pathological response was observed in 20/20 (100%; 95% exact confidence interval (CI): 86–100%) dMMR tumors, with 19 major pathological responses (MPRs, ≤10% residual viable tumor) and 12 pathological complete responses. In pMMR tumors, 4/15 (27%; 95% exact CI: 8–55%) showed pathological responses, with 3 MPRs and 1 partial response. CD8+PD-1+ T cell infiltration was predictive of response in pMMR tumors. These data indicate that neoadjuvant immunotherapy may have the potential to become the standard of care for a defined group of colon cancer patients when validated in larger studies with at least 3 years of disease-free survival data.

  Study EGAS00001004160

• Transcriptome profiling of megakaryocytes and platelets: application to GP9- and IKZF5-related thrombocytopenia

  Platelets are anucleate cells produced in the bone marrow and derived from large progenitor cells called megakaryocytes (MKs). Platelets receive RNA transcripts from their progenitorial MKs during thrombopoiesis. However, the correspondence between platelet and MK transcriptomes is poorly understood, particularly in the context of germline mutations that cause platelet formation defects or thrombocytopenia. We have studied the effects of two such mutations on MK and platelet transcriptomes. We generated immortalized MK cell line (imMKCL)-based models of Bernard-Soulier syndrome and IKZF5-related thrombocytopenia. MKs derived from imMKCLs with either a homozygous deletion of GP9 (GP9-/-) or a heterozygous Y121F variant in IKZF5 (IKZF5WT/Y121F) exhibited reduced proplatelet formation (reductions of 96% and 57%, respectively). Platelets from patients with either GP9-/- or IKZF5WT/Y121F genotypes had broad transcriptomic dysregulation, suggesting that (pro)platelet formation defects due to mutations in glycoprotein receptor and transcription factor genes such as GP9 and IKZF5 affect the trafficking of transcripts from MKs into platelets. RNA-seq data from MKs at four stages of differentiation revealed widespread but distinct changes in expression over time between the GP9-/- and the IKZF5WT/Y121F genotypes. Dysregulated genes in GP9-/- MKs were enriched for RNA metabolism and actin/tubulin folding pathways while those in IKZF5WT/Y121F MKs were enriched for cell cycle pathways. Most of these genes were also dysregulated in the platelets of patients with the corresponding diseases. Our results suggest that patients with inherited forms of thrombocytopenia present with a transcript trafficking defect during platelet formation.

  Study EGAS50000001276

• Harnessing the Electronic Health Record to Predict Risk of Cardiovascular Disease: Sangre Por Salud (SPS) Biobank GWAS Data

  These data are from subjects in the Sangre Por Salud (SPS) Biobank, a Latino population from the Southwest United States. Subjects were genotyped in 2 batches on the Illumina Multi-ethnic Global Array. Data from this study were used for testing a new cardiovascular risk score and evaluating polygenic risk scores. SPS biobank GWAS data is available on 3699 subjects.

  Study phs003553

• Expression-Based Subtypes Define Pathologic Response to Neoadjuvant Immune-Checkpoint Inhibitors in Muscle-Invasive Bladder Cancer

  Checkpoint immunotherapy (CPI) has increased survival for some patients with advanced stage bladder cancer (BCa). However, most patients do not respond. Here, we characterized the tumor and immune microenvironment in pre- and post-treatment tumors from the PURE01 neoadjuvant pembrolizumab immunotherapy trial, using a consolidative approach that combined transcriptional and genetic profiling with digital spatial profiling.

  Study EGAS00001005549

• Extensive patient-to-patient single nuclei transcriptome heterogeneity in pheochromocytomas and paragangliomas

  Pheochromocytomas (PC) and paragangliomas (PG) are rare neuroendocrine tumors of varied genetic makeup, associated with high cardiovascular morbidity and a variable risk of malignancy. We focused on PCPG tumors with germline SDHB and RET mutations, representing distinct prognostic groups with worse or better prognoses, respectively. We applied single-nuclei RNA sequencing (snRNA-seq) on tissue samples from 11 patients.

  Study EGAS00001006230

• GeoMx DSP of NGS mRNA expression in pre-treatment biopsies from patients with metastatic triple-negative breast cancer treated with PARP inhibitors.

  This dataset contains GeoMx digital spatial profiling (DSP) data from 12 FFPE pre-treatment biopsies of metastatic HR-altered breast cancer patients subsequently treated with PARP inhibitors (Olaparib or Talazoparib). Samples were collected from primary breast tumors (n=7) and metastatic sites including lymph nodes (n=2), bone (n=2), and brain (n=1). Tissue sections were stained for pan-cytokeratin (PANCK) to selectively profile tumor cells, with NGS-based transcriptome data generated for both PANCK+ and PANCK- regions. The dataset includes raw data files (176 fastq files) along with clinical annotations.

  Dataset EGAD50000001932

• T cell and Antibody Responses in Rituximab-Treated Lymphoma Patients After SARS-CoV-2 Vaccination

  This dataset contains T cell receptor (TCR) sequencing data from 51 RNA samples, each processed into three independent libraries (tot 153 FASTQ files). Sequencing was performed on an Illumina NextSeq 500 platform using the NextSeq 500/550 Mid Output Kit v2.5 (300 Cycles), generating paired-end FASTQ files with dual 10 bp barcodes and 5% PhiX as internal control. Libraries were quantified with the Qubit HS dsDNA kit and assessed for fragment size distribution using the Agilent Tapestation D1000 system before isochoric pooling to 4 nM and sequencing in two independent runs. The resulting dataset enables analysis of TCR β-chain CDR3 sequences for clonal expansion and diversity studies.

  Dataset EGAD50000001714

• M116 Microbiome data

  M116 stool was collected from 3 different days (3 biological replicates) and kept at -20ºC until DNA extraction (Biobanc IDIBGI and Goodgut®). Total genomic DNA was extracted from 150–200 mg of each stool sample after homogenisation using the DNeasy Powersoil Pro kit (Qiagen®) according to manufacturer’s instructions. Quality and quantity of DNA were evaluated using Qubit® BR kit on a Qubit®2.0 fluorimeter (ThermoFisher Scientific®) and on a Nanodrop ND-2000 UV-Vis spectrophotometer (ThermoFisher Scientific®). The v3-v4 region of the bacterial 16S rRNA gene was amplified and sequenced (paired-end 250-bp) following standard practices at external facilities (Novogene®) using previously described primers 515F. Files types included in this dataset are raw Fastq files.

  Dataset EGAD50000001288

• A single-cell atlas of the early COPD lung - Nanopore long-read

  Single cell atlas of the human airways from 10 patients suffering of early stage Chronic Obstructive Pulmonary Disease and 12 healthy age matched volunteers. This dataset was sequenced by 10X Genomics 3’ RNA-seq profiling. It is composed of more than 400 000 cells coming from 119 samples total. Sampling was performed by brushings and biopsies from the nose to the 6 th division of the airways. 14 samples were also sequenced using Nanopore long-read sequencing.

  Dataset EGAD50000001002

• ICARUS-LUNG01 dataset

  A total of 46 frozen tumor biopsies underwent WES analysis, while 41 blood samples were used as germline controls.Tumor samples qualified for whole exome sequencing (WES) if they contained ≥10% tumor cells. For bulk RNA-seq, 20 paired baseline and on-treatment frozen tumor biopsies were analyzed. Tumor samples qualified if they contained ≥30% tumor cells. For GeoMx spatial transcriptomic study we used 7 patients from the ICARUS LUNG01 trial focusing on tumour and immune cell compartments. We selected 7 paired baseline and on-treatment patient samples for analysis. We selected up to 4 regions of interest (ROI) per sample tissue. We identified tumour and immune cell areas of illumination (AOI) using CK and CD45 antibodies respectively

  Dataset EGAD50000001014

• Targeted panel somatic variant sequencing dataset for "Molecular counting enables accurate and precise quantification of methylated ctDNA"

  Targeted panel somatic variant sequencing dataset for "Molecular counting enables accurate and precise quantification of methylated ctDNA." This dataset was created by running 60 cfDNA samples from patients with metastatic cancer to the lung through a research-use, tumor-naive, targeted-panel assay for measuring somatic mutations across a panel of 80 genes. All samples were sequenced on Illumina NextSeq 2000 with 150x2 paired end sequencing; files are in fastq.gz format. For the original study, the variant allele fractions of these somatic mutations were compared with the Tumor Methylation Scores calculated from Northstar Response in the same samples.

  Dataset EGAD50000001016

• RNA-Seq of human longitudinal whole blood samples from PCR-positive and PCR-negative adults following controlled inoculation with Influenza A H3N2 virus.

  Understanding of the transcriptomic profile of individuals in early influenza infection is limited. To investigate this, longitudinal whole-blood samples (n=178) were taken from adult participants following controlled inoculation with Influenza A H3N2 virus (sampling at baseline (0) and days 1, 2, 3, 7, 10 and 14 post-challenge). Most participants became influenza PCR-positive; a minority remained PCR-negative. Total RNA was extracted from PAXgene tubes before undergoing globin and rRNA depletion. DNA libraries were constructed using the NEBNext® Ultra™ II Directional RNA Library Prep Kit for Illumina. All samples were then sequenced using Illumina NovaSeq 6000.

  Dataset EGAD50000000956

• ATAC sequencing raw data files of human Treg cell subsets

  Assay for Transposase-Accessible Chromatin using sequencing (ATAC) sequencing of human CD38+, HLA-DR+, CD38+ HLA-DR+, and CD38- HLA-DR- regulatory T (Treg) cell subsets sorted from peripheral blood pooled from 4 healthy donors. After isolation and purification of Treg cell subsets with flow cytometry, samples were frozen and transferred to Active Motif for ATAC sequencing. The dataset contains one raw sequencing file (fastq) of accesible regions for each of the above-mentioned Treg cell subsets.

  Dataset EGAD50000000664

• Paired-end RNA-Seq Dataset of 72 Brain Organoid Samples: Sequencing and Gene Expression Analysis

  72 fastq sequencing files of 72 brain-organoid paired-end sequenced samples (R1/R2). RNA sequencing libraries were prepared using the NEBNext Ultra II RNA Library Prep Kit for Illumina following the manufacturer’s instructions (New England Biolabs, USA). mRNAs were first enriched with Oligo(dT) beads. The samples were sequenced using a 2x150 Pair-End configuration (ver. 1.5) on an Illumina NovaSeq 6000 The raw sequence reads were aligned to the human reference genome GRCh38 using the STAR aligner (Dobin et al., 2013). Gene expression levels were quantified using the FeatureCounts tool (Liao et al., 2014) (file: "All_Counts_final.xlsx") For more information, see "Study Description"

  Dataset EGAD50000000935

• HiDEF-seq single-molecule sequencing of single-strand mismatches and damage

  Our study sought to resolve, with single-molecule fidelity, the mismatches and damage events that precede DNA mutations. Using a novel single-molecule, long-read sequencing method (HiDEF-seq) we detect base substitutions when present in either one or both DNA strands. We also detect cytosine deamination, a common type of DNA damage, with single-molecule fidelity. This study profiled 134 samples from diverse tissues, including from individuals with cancer predisposition syndromes. These samples revealed single-strand mismatch and damage signatures. Since double-strand DNA mutations are only the endpoint of the mutation process, our approach enables new studies of how mutations arise in a variety of contexts, especially in cancer and aging.

  Dataset EGAD50000000460

• Targeted long-read snIso-Seq of the human brain in neurodegenerative diseases

  Nuclei were extracted from postmortem human brain, and cDNA libraries were generated using the 10X Genomics 3' v3.1 kit. Prior to fragmentation, 75% of the library was reserved for long-read sequencing. This unfragmented library was used for target enrichment with a custom 50 gene probe panel from Twist Biosciences. The resulting amplified cDNA libraries were sequenced on a Sequel II. The files provided have undergone CCS generation, and we recommend following the guidelines in https://isoseq.how/ for further analysis starting with removal of primers using lima. The primer sequences that should be supplied are the Read 1 and TSO primers from the 10X Genomics kit.

  Dataset EGAD50000000179

• EGAD00010000628

  The TEENAGE study target population comprised adolescent students aged 13 to 15 years attending the first three classes of public secondary schools located in the wider Athens area of Attica.

  Dataset EGAD00010000628

• MPN mutation order followup

  To evaluate the presence of mutations in frequently mutated genes in MPN by performing targeted resequencing of a selected gene panel comprising of 111 genes across 40 samples with MPN.

  Dataset EGAD00001000848