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• Mutational_burden_in_skin_following_UV_treatment_WGS

  We wish to assess the changes in mutational burden in patients under going UV treatment for psoriasis. Using duplex sequencing we will assess mutational burden in traditionally sun exposed (arm) and non-sun exposed (buttock) skin epidermis both pre and post UV treatment.

  Study EGAS00001007682

• GWAS data (Illumina 2.5 M SNPs) in Cuban cohorts of dengue disease

  We will have 274 individuals typed for the Illumina Human Omni 2.5 chip. The individuals are from two locations in Cuba (Havana and Guantanamo) and from four phenotype classes (asymptomatic, control dengue fever and dengue hemorrhagic fever).

  Study EGAS00001002276

• Chromatin accessibility analysis of TFEB overexpression in LT-HSC

  Long-term hematopoietic stem cells (LT-HSC) were sorted from human cord blood and cultured overnight before transduction with lentivirus overexpressing GP91 (CTRL) or TFEB. Six days later, BFP+ transduced cells were sorted for DNA extraction, library preparation and sequencing

  Study EGAS00001004971

• Mutational_burden_in_oesophagus__nanoseq_

  We wish to accurately assess mutational burden and signature from patients of different ages using clonal oesophageal epithelium and duplex-seq. We will also attempt to look for differences between smokers and non-smokers and individuals with different levels of alcohol consumption.

  Study EGAS00001007695

• Integrated genetic and epigenetic analysis of myxofibrosarcoma

  Myxofibrosarcoma (MFS) is a common histological subtype of adult soft tissue sarcoma characterized by an infiltrative growth pattern and a high propensity for local recurrence. We underwent whole exome sequencing, RNA sequencing, and methylation analysis of MFS.

  Study EGAS00001002889

• Parallel Detections of Somatic Gene Mutations in Surgically Resected Tumor tissues and Matched Plasma Specimens in Early-Stages of Primary Breast Cancer

  We developed two panel successively, contain 68 and 136 genes respectively. Combination with ultrasound or mammography, it could be used for breast cancer early detection and avoided unnecessary surgery or other invasive detection.

  Study EGAS00001003075

• HCA_Heart_Disease_BHF_DZHK_RNA_

  Cell Atlas of the diseased human heart. 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 EGAS00001004566

• Single cell RNA sequencing of lung adenocarcinoma.

  We performed single cell RNA sequencing (scRNA-seq) for 208,506 cells derived from 58 lung adenocarcinomas from 44 patients, which covers primary tumour, lymph node and brain metastases, and pleural effusion in addition to normal lung tissues and lymph nodes.

  Study EGAS00001003681

• Isotype_resolved_sequencing_of_B_cell_receptor_in_measles_virus_infection

  Isotype-resolved sequencing of B cell receptor in measles virus infection 1) 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 please see http://www.sanger.ac.uk/datasharing/

  Study EGAS00001002635

• Transcriptome_analysis_of_LCM_samples_

  We aim to set up a RNA pipeline for LCM samples to study transcriptome landscape of tumor and normal tissues. RNA was extracted from Lazer capture micro-dissection tissues and cDNA libraries were prepared with SMARTseq2 protocol. Libraries are pooled to be sequenced.

  Study EGAS00001003862

• Molecular profiling of DLBCL patients treated in the PETAL trial

  Using whole-exome sequencing and shallow whole genome sequencing for simultaneous screening of mutations, copy number alterations, and translocations, 5 biology-based risk profiles could be reproduced in an independent cohort of DLBCL patients, from the PETAL trial.

  Study EGAS00001005828

• STRATAA_RNAseq

  Transcriptome signatures of acute typhoid infection 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 EGAS00001003967

• Molecular and clinical effects of selective TYK2 inhibition with deucravacitinib in psoriasis

  Investigate changes in IL-23/Th17- and type I interferon-pathway biomarkers and gene responses, and measures of selectivity for TYK2 over Janus kinases (JAKs) 1–3, in patients with moderate to severe psoriasis receiving deucravacitinib.

  Study EGAS00001005875

• Airway Dysbiosis Accelerates Lung Function Decline in Chronic Obstructive Pulmonary Disease

  This repository contains human sample derived microbiome full-length 16S rRNA sequencing data for sputum samples in COPD patients. The project goal is to understand the association of the lung microbiome with accelerated lung function decline in COPD patients.

  Study EGAS00001006444

• Transcriptomic analysis of MYC overexpression in LT-HSC.

  Long-term hematopoietic stem cells (LT-HSC) were sorted from human cord blood and cultured overnight before transduction with lentiviral vectors (empty E CTRL or MYC). Six days after transduction, BFP+ transduced cells were sorted for RNA extraction and sequencing

  Study EGAS00001004970

• Mutational_burden_in_skin_following_UV_treatment_Nanoseq

  We wish to assess the changes in mutational burden in patients under going UV treatment for psoriasis. Using duplex sequencing we will assess mutational burden in traditionally sun exposed (arm) and non-sun exposed (buttock) skin epidermis both pre and post UV treatment.

  Study EGAS00001007681

• RNA seq before and after cold pressor test

  The cold pressor test (CPT) is a widely used pain provocation test to investigate both pain tolerance and cardiovascular responses. Twenty-two females were phenotypically assessed before and after a CPT, and blood samples were taken for RNA-sequencing.

  Study EGAS00001006690

• Exome_sequencing_of_UK_Birth_Cohorts___Born_in_Bradford

  We propose to exome sequence birth cohorts with near complete population coverage (thus addressing the ascertainment biases of previous studies), which have detailed longitudinal cognitive and educational data on parents and children, and for which genotyping chip data are readily available.

  Study EGAS00001006978

• Exome_sequencing_of_UK_Birth_Cohorts___Millennium_Cohort_Study

  We propose to exome sequence birth cohorts with near complete population coverage (thus addressing the ascertainment biases of previous studies), which have detailed longitudinal cognitive and educational data on parents and children, and for which genotyping chip data are readily available.

  Study EGAS00001007789

• FASTQ files for Recommendations to mitigate FFPE-associated problems in NGS

  42 NGS libraries of a 13y/o FFPE sample, a tissue-and-patient-matched FF sample, and a GIAB sample (NA12878). In technical replicates (untreated DNA, treated DNA, two different library types, at least library duplicates for each case). Illumina NextSeq, HiSeq and NovaSeq paired-end sequencing.

  Dataset EGAD00001008399

• DETECT-A NGS Data Batch 3

  This batch is a subset of the full DETECT-A dataset, containing 29294 fastq files generated from 3653 subjects. All sequencing was conducted using Illumina HiSeq 4000 and Illumina MiSeq platforms. Note that the division into batches follows no specific criteria and that the sequencing data for each subject has multiple files which may span multiple datasets. Thus, for a comprehensive analysis, it is recommended to request access to all datasets that comprise this study.

  Dataset EGAD00001008597

• A95632D

  Whole genome sequencing for single cells for library A95632D 644 samples; filetype=bam

  Dataset EGAD00001008222

• A95635B

  Whole genome sequencing for single cells for library A95635B 593 samples; filetype=bam

  Dataset EGAD00001008223

• DETECT-A NGS Data Batch 2

  This batch is a subset of the full DETECT-A dataset, containing 498 fastq files generated from 71 subjects. All sequencing was conducted using Illumina HiSeq 4000 and Illumina MiSeq platforms. Note that the division into batches follows no specific criteria and that the sequencing data for each subject has multiple files which may span multiple datasets. Thus, for a comprehensive analysis, it is recommended to request access to all datasets that comprise this study.

  Dataset EGAD00001008591

• Paired WGS data of 45 samples and 2 paired WES sample of RRMM (multiple myeloma)

  Here is mostly paired WGS data of RRMM, 45 samples (tumors and controls) in 86 runs. This data was produced by using Illumina TruSeq Nano DNA and NovaSeq6000 or HiSeq X Ten for sequencing. One tumor/control pair is WES data using Agilent SureSelect V5+UTRs and NovaSeq6000 for sequencing.

  Dataset EGAD00001009682

• RNA-seq from time-course experiment treating cells for 72h

  RNA sequencing from MSTO-211H cell line cultures treated for 72h with vehicle solution, palbociclib 250nM, or abemaciclib 250nM (N = 3, each). RNA-seq prepared using TruSeq Stranded mRNA libraries and sequenced with Illumina HiSeq 4000. Data is in raw fastq format, paired end. Some samples have been split in two lanes, with a final count of 24 fastq files.

  Dataset EGAD00001007737

• Neuroblastoma WGS samples used for detection of seismic amplification

  Paired-end WGS data of 27 neuroblastoma patient samples (10 obtained at diagnosis, 6 at relapse and 11 matched blood samples as controls) used for detection of complex "seismic" amplification. Mean coverage is 24-55x per sample. The remaining patient samples of the dataset can be found under accession number EGAS00001001308.

  Dataset EGAD00001007807

• Diseased heart analysis: RNA Adult (2025-10-14)

  Samples for this project are taken from adult human hearts which have been preserved using 2 different methods (cold static storage on ice, and hypothermic perfusion). Samples have been acquired at various time points during post-preservation normothermic perfusion. The aim of the project is to assess the transcriptional changes caused by these differing methods of preservation. . This dataset contains all the data available for this study on 2025-10-14.

  Dataset EGAD00001015738

• RNAseq of primary mesothelioma cell lines

  Mesothelioma is an aggressive cancer associated with previous exposure to asbestos and dismal prognosis. Since a pemetrexed/cisplatin combination was introduced for treatment of mesothelioma, no new first- or second-line therapies have been discovered. Thus, to better understand what drives mesothelioma carcinogenesis and to identify potential targets for therapy, in this project we aim at performing RNAseq analysis of a panel of mesothelioma cells lines.

  Dataset EGAD00001010924

• RNAseq of primary mesothelioma cell lines

  Mesothelioma is an aggressive cancer associated with previous exposure to asbestos and dismal prognosis. Since a pemetrexed/cisplatin combination was introduced for treatment of mesothelioma, no new first- or second-line therapies have been discovered. Thus, to better understand what drives mesothelioma carcinogenesis and to identify potential targets for therapy, in this project we aim at performing RNAseq analysis of a panel of mesothelioma cells lines.

  Dataset EGAD00001009642

• DETECT-A NGS Data Batch 5

  This batch is a subset of the full DETECT-A dataset, containing 12740 fastq files generated from 3211 subjects. All sequencing was conducted using Illumina HiSeq 4000 and Illumina MiSeq platforms. Note that the division into batches follows no specific criteria and that the sequencing data for each subject has multiple files which may span multiple datasets. Thus, for a comprehensive analysis, it is recommended to request access to all datasets that comprise this study.

  Dataset EGAD00001015426

• A90679

  Whole genome sequencing for single cells for library A90679 1034 samples; filetype=bam

  Dataset EGAD00001008219

• DETECT-A NGS Data Batch 1

  This batch is a subset of the full DETECT-A dataset, containing 43963 fastq files generated from 3024 subjects. All sequencing was conducted using Illumina HiSeq 4000 and Illumina MiSeq platforms. Note that the division into batches follows no specific criteria and that the sequencing data for each subject has multiple files which may span multiple datasets. Thus, for a comprehensive analysis, it is recommended to request access to all datasets that comprise this study.

  Dataset EGAD00001008415

• Genomic Data for Integrative Profiling of T790M Negative EGFR Mutated NSCLC

  Contains WES and RNA-seq for the 59 patients with first- and second-generation EGFR TKI-resistant metastatic EGFR-mutated NSCLC.

  Dataset EGAD00001010272

• iPSC and iNeuron RNAseq, chip-seq and single cell CRISPR activation

  Dataset includes 1) RNAseq for Bob_Ngn2 cell differentiation from iPSC to iNeuron stage (time point 0, 24, 48 and 96 hours). 2) Bob_Ngn2 cell line chip-seq (H3K4me3, H3K4me1, H3K27me3, H3K9me3, H3K27ac, H3K36me3) for both iPSC and iNeuron stage with 3 replicates at each time point. 3) Single cell CRISPR activation experiment with 96 endogenous genes.

  Dataset EGAD00001010050

• scRNAseq of patients with chronic graft-versus-host-disease

  This dataset contains 10 samples from 9 patients with chronic graft-versus-host disease (GVHD). Each sample is analysed with Chromium V(D)J and 5' Gene Expression Platform v1.1 (10X Genomics). The raw data includes fastq files for Gene expression and fastq files for V(D)J Expression. The processed data have been deposited in the ArrayExpress database at EMBL-EBI (www.ebi.ac.uk/arrayexpress) under accession number E-MTAB-13419.

  Dataset EGAD00001012121

• DETECT-A NGS Data Batch 4

  This batch is a subset of the full DETECT-A dataset, containing 25210 fastq files generated from 3040 subjects. All sequencing was conducted using Illumina HiSeq 4000 and Illumina MiSeq platforms. Note that the division into batches follows no specific criteria and that the sequencing data for each subject has multiple files which may span multiple datasets. Thus, for a comprehensive analysis, it is recommended to request access to all datasets that comprise this study.

  Dataset EGAD00001015360

• DETECT-A NGS Data Batch 6

  This batch is a subset of the full DETECT-A dataset, containing 9 fastq files generated from 8 subjects. All sequencing was conducted using Illumina HiSeq 4000 and Illumina MiSeq platforms. Note that the division into batches follows no specific criteria and that the sequencing data for each subject has multiple files which may span multiple datasets. Thus, for a comprehensive analysis, it is recommended to request access to all datasets that comprise this study.

  Dataset EGAD00001015458

• BLUEPRINT release January 2015, Bisulfite-Seq for CD4-positive, alpha-beta T cell

  Bisulfite-Seq data for 3 CD4-positive, alpha-beta T cell sample(s). 61 run(s), 3 experiment(s), 3 alignment(s). Part of BLUEPRINT release January 2015. Analysis documentation available at http://ftp.ebi.ac.uk/pub/databases/blueprint/releases/20140811/homo_sapiens/README_bisulphite_analysis_CNAG_20140811

  Dataset EGAD00001001157

• BLUEPRINT release August 2015, Bisulfite-Seq for conventional dendritic cell, on genome GRCh38

  Bisulfite-Seq data for 2 conventional dendritic cell sample(s). 30 run(s), 2 experiment(s), 2 alignment(s) on human genome GRCh38. Part of BLUEPRINT release August 2015. Analysis documentation available at http://ftp.ebi.ac.uk/pub/databases/blueprint/releases/20150820/homo_sapiens/README_bisulphite_analysis_CNAG_20150820

  Dataset EGAD00001001497

• BLUEPRINT release August 2015, Bisulfite-Seq for mature eosinophil, on genome GRCh38

  Bisulfite-Seq data for 1 mature eosinophil sample(s). 15 run(s), 1 experiment(s), 1 alignment(s) on human genome GRCh38. Part of BLUEPRINT release August 2015. Analysis documentation available at http://ftp.ebi.ac.uk/pub/databases/blueprint/releases/20150820/homo_sapiens/README_bisulphite_analysis_CNAG_20150820

  Dataset EGAD00001001507

• BLUEPRINT release August 2015, Bisulfite-Seq for regulatory T cell, on genome GRCh38

  Bisulfite-Seq data for 1 regulatory T cell sample(s). 15 run(s), 1 experiment(s), 1 alignment(s) on human genome GRCh38. Part of BLUEPRINT release August 2015. Analysis documentation available at http://ftp.ebi.ac.uk/pub/databases/blueprint/releases/20150820/homo_sapiens/README_bisulphite_analysis_CNAG_20150820

  Dataset EGAD00001001564

• BLUEPRINT release August 2015, Bisulfite-Seq for monocytes - T=0days, on genome GRCh38

  Bisulfite-Seq data for 1 monocytes - T=0days sample(s). 15 run(s), 1 experiment(s), 1 alignment(s) on human genome GRCh38. Part of BLUEPRINT release August 2015. Analysis documentation available at http://ftp.ebi.ac.uk/pub/databases/blueprint/releases/20150820/homo_sapiens/README_bisulphite_analysis_CNAG_20150820

  Dataset EGAD00001001565

• BLUEPRINT release August 2016, Bisulfite-Seq for monocyte - RPMI_LPS_T=24hrs, on genome GRCh38

  Bisulfite-Seq data for 1 monocyte - RPMI_LPS_T=24hrs sample(s). 22 run(s), 2 experiment(s), 2 analysis(s) on human genome GRCh38. Part of BLUEPRINT release August 2016. Analysis documentation available at http://ftp.ebi.ac.uk/pub/databases/blueprint/releases/20160816/homo_sapiens/README_bisulphite_analysis_CNAG_20160816

  Dataset EGAD00001002302

• BLUEPRINT release August 2016, Bisulfite-Seq for monocyte - RPMI_BG_T=1hr, on genome GRCh38

  Bisulfite-Seq data for 1 monocyte - RPMI_BG_T=1hr sample(s). 14 run(s), 1 experiment(s), 2 analysis(s) on human genome GRCh38. Part of BLUEPRINT release August 2016. Analysis documentation available at http://ftp.ebi.ac.uk/pub/databases/blueprint/releases/20160816/homo_sapiens/README_bisulphite_analysis_CNAG_20160816

  Dataset EGAD00001002327

• BLUEPRINT release August 2016, Bisulfite-Seq for naive B cell, on genome GRCh38

  Bisulfite-Seq data for 3 naive B cell sample(s). 39 run(s), 3 experiment(s), 6 analysis(s) on human genome GRCh38. Part of BLUEPRINT release August 2016. Analysis documentation available at http://ftp.ebi.ac.uk/pub/databases/blueprint/releases/20160816/homo_sapiens/README_bisulphite_analysis_CNAG_20160816

  Dataset EGAD00001002361

• Multi-Region WES of Metastatic Colorectal Cancer

  In order to reconstruct the evolutionary history of metastatic colorectal cancer, we performed whole-exome sequencing of 12 metastatic colorectal cancer patients for whom the primary tumor and matched distant metastases to the brain (n=10) and liver (n=2). For 8 of the 12 patients, multiple regions (n=3-7) of the primary tumor and distant metastases were sequenced.

  Dataset EGAD00001004896

• Keratinocyte CRISPR screens (2019-08-14)

  Immortalised HaCaT keratinocytes were transduced with Cas9 and the CRISPR-KO v1.1 genome-wide gRNA library. The gRNA library was prepared from genomic DNA isolated 14 days post library transduction. gRNA representation will be compared to the original CRISPR-KO v1.1 library to reveal genes essential for HaCaT survival and growth. . This dataset contains all the data available for this study on 2019-08-14.

  Dataset EGAD00001005252

• WNT7B-reporter organoids sorted

  Transcriptomic data from pancreatic ductal adenocarcinoma (PDAC) organoids to investigate the role of WNT7B. This dataset includes: - Bulk mRNA sequencing of WNT7B-reporter pancreatic ductal adenocarcinoma (PDAC) organoids sorted for cells displaying low, medium and high expression of the reporter

  Study EGAS50000001543

• Improved Sezary cell detection and novel insights into immunophenotypic and molecular heterogeneity in Sézary syndrome

  We performed a prospective investigation in Sézary syndrome by the application of a standardized multiparameter flow cytometry, FACS-cell sorting, and RNA-sequencing for an in-depth immunophenotypic and transcriptional profiling of Sézary cells.

  Study EGAS00001005229

• Center for Common Disease Genomics [CCDG] - Neuropsychiatric: SPARK Simons Foundation Powering Autism Research for Knowledge

  In this study, we address the enormous challenges common complex diseases pose for genomic analysis and the enormous opportunities surmounting them offers for advancing healthcare. The common genetic disorders proposed for study here are believed to have extreme locus heterogeneity, requiring the analysis of large numbers of samples to comprehensively identify the genomic variants underlying them. We propose that a combination of deep population studies and joint analysis of SNPs, indels, and structural variants, both in coding and noncoding regions, will provide the next level of understanding of common genetic disorders. Whole genome sequencing (WGS) will be critical to this next-generation approach to the genomics of complex disease. WGS will need to be accompanied by the technical ability to generate and handle very large data sets, a particular focus and strength of New York Genome Center (NYGC). WGS will also need to be accompanied by new statistical tools and algorithms, which will be developed by the strong core group committed to this proposal.An overarching goal of this proposal, one that capitalizes on the power of WGS, is to identify disease-associated variants at the individual nucleotide level. In many cases, pathogenic mutations fall in noncoding regions of the genome, which can only be fruitfully explored with WGS. A major effort was put into building new computational strategies to functionally annotate noncoding transcribed sequences, and to build new datasets to enable such strategies, opening new frontiers of understanding of disease-related regulatory variants.

  Study phs002511

• National Heart Lung and Blood Institute Exome sequencing in SCID

  Analysis of the molecular etiologies of severe combined immunodeficiency (SCID) has led to important insights into the control of immune cell development. Most cases of SCID result from either X-linked or autosomal recessive inheritance of mutations in a known causative gene. However, in some cases, the molecular etiology remains unclear. To identify the cause of SCID in a patient known to lack the protein tyrosine phosphatase CD45, we utilized single nucleotide polymorphisms (SNP) arrays and whole exome sequencing. The patient's mother was heterozygous for an inactivating mutation in CD45, while the paternal alleles lacked mutations. The patient exhibited a single CD45 mutation identical to the maternal allele. Patient SNP array analysis revealed no change in copy number but loss of heterozygosity for the entire length of chromosome 1 (Chr1), indicating that disease was caused by uniparental disomy (UPD) with isodisomy of the entire maternal Chr1 bearing the CD45 mutation. Non-lymphoid blood cells and other mesoderm and ectoderm-derived tissues retained UPD of the entire maternal Chr1 in this patient who had undergone successful bone marrow transplantation. Exome sequencing revealed mutations in 7 additional genes bearing nonsynonymous SNPs predicted to have deleterious effects. These findings represent the first reported case of SCID caused by UPD and suggest UPD should be considered in SCID and other recessive disorders, especially when the patient appears homozygous for an abnormal gene found in only one parent. Evaluation for alterations in other genes affected by UPD should also be considered in such cases.

  Study phs000479

• Genetic Markers of Lipids in Indians: A Validation Study of Most Relevant Findings of Genome-Wide Association Studies

  We aimed to validate the GWAS loci (identified in European populations) related to serum lipid levels (total cholesterol, triglycerides, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and very low-density lipoprotein cholesterol (VLDL-C)) in the Indian population originally recruited to examine the 20-year trend of cardiometabolic risk factors in rural and urban areas around National Capital region in India. Isolated DNA was processed for genotyping of 12 established GWAS variants using multiplex Sequenom Mass ARRAY technology. We examined the association of these genetic variants with different lipid levels and found association of eight variants for lipid levels. We also derived weighted genetic risk scores (wGRAS) using the validated variants. The wGRS for triglycerides and VLDL-C was derived based on four associated variants (rs174546 at FADS1, rs17482753 at LPL, rs2293889 at TRPS1, rs4148005 at ABCA8, rs4420638 at APOC1) which was associated with 36.31 mg/dL elevated triglycerides and VLDL-C (β=0.95, SE=0.16, pTRPS1 and rs4147536 at ADH1B) was associated with 40.62 mg/dL higher total cholesterol (β=1.01, SE=0.23, pTRPS1, rs4147536 at ADH1B, rs4420638 at APOC1 and rs660240 at CELSR2). The wGRS derived from five associated variants (rs174546 and FADS1, rs17482753 at LPL, rs4148005 at ABCA8, rs4420638 at APOC1 and rs7832643 at PLEC) was associated with 10.64 mg/dL lower HDL-C (β= -0.87, SE =0.14, pThe phenotypic and genotypic data will be made available on the dbGaP portal for access.

  Study phs003469

• ILyAD (Indolent Lymphoma And vitamin D)

  Indolent non-Hodgkin lymphomas are incurable diseases, and require intermittent and often morbid and expensive therapy during their prolonged natural history. Lower intensity and better-tolerated, cost-effective treatment strategies are needed for these patients. Low vitamin D levels at diagnosis of indolent lymphomas are strongly associated with inferior outcomes to treatment. Standard therapy for low tumor burden, indolent lymphoma includes a single agent monoclonal antibody (rituximab). In our double-blind, placebo-controlled, randomized trial we evaluated if vitamin D supplementation with 2000IU oral cholecalciferol daily for three years improved the progression-free survival of patients with indolent lymphoma treated with single agent rituximab. Stratification factors for randomization included histology and Follicular Lymphoma International Prognostic Index (FL-IPI) prognostic score. The primary endpoint of the trial was progression-free survival over three years; secondary endpoints included response at 13 weeks, and overall survival. Eligible participants were adults with biopsy proven follicular lymphoma (grades 1-3a), small lymphocytic lymphoma, marginal zone lymphoma and mucosal-associated lymphoid tissue with no prior anti-lymphoma systemic therapy. Participants had Ann Arbor stage II or greater, measurable disease defined by Lugano criteria. Participants with osteoporosis requiring prescription treatment, symptomatic primary hyperthyroidism, hypercalcemia, creatinine greater than 1.5 times the upper limit of normal or a history of calcium-related kidney stones were excluded. Germline DNA was isolated from saliva samples obtained from participants at baseline. Whole exome sequencing was performed and SNPs were analyzed using the Agilent SureSelectXT Human All Exon V6 +UTR array. SNP data from 185 participants are available through dbGaP.

  Study phs003503

• Multiple Myeloma Clinical Targeted Sequencing of Patient Samples

  Purpose: Molecular diagnostics for the risk stratification of patients with multiple myeloma (MM) have languished in the area of cytogenetics and fluorescence in situ hybidization (FISH). However, here we present the case for next generation sequencing of MM patient samples to not only identify high-risk markers, but also mutations and deletions relating to immunomodulatory drugs (IMiDs), and more importantly to guide the sequencing of immunotherapy regimens in response to intrinsic antigen escape as a means of treatment resistance and relapse. Experimental design: CD138+ cell selected samples (n=134) from bone marrow aspirates from patients with multiple myeloma were sequenced using a targeted panel in a clinical diagnostics laboratory. Data were analyzed for high-risk markers, treatment-related resistance mechanisms, and precision medicine targets to guide the future treatment of patients in the clinic. Results: High-risk markers including t(4;14), t(14;16), t(14;20), gain or amplification 1q, deletion of CDKN2C, and deletion or mutation of TP53 were identified in 15% of newly diagnosed myeloma patient samples. At relapse, alterations in the cereblon degradation pathway were found in 24.3% of IMiD treated patients. Deletions of 4p (CD38) were also enriched in patients who received anti-CD38 treatment (P=0.03) which were mostly monoallelic. Deletions and mutations were detected in TNFRSF17 encoding BCMA in patients treated with anti-BCMA regimens, and the information was used to change the treatment of the patients. Conclusions: Targeted sequencing of multiple myeloma patient diagnostic samples can be used for risk stratification, and also to monitor and adjust treatments as resistance mechanisms evolve.

  Study phs003908

• Nanopore sequencing of blood, saliva, buccal mucosa samples of patients with inherited retinal disorders

  X-linked genetic disorders typically affect females less severely than males due to the presence of a second X chromosome not carrying the deleterious variant. However, the phenotypic expression in females is highly variable, which may be explained by an allelic skew in X chromosome inactivation. Accurate measurement of X inactivation skew is crucial to understand and predict disease phenotype in carrier females, with prediction especially relevant for degenerative conditions. We propose a novel approach using nanopore sequencing to quantify skewed X inactivation accurately. By phasing sequence variants and methylation patterns, this single assay reveals the disease variant, X inactivation skew, its directionality, and is applicable to all patients and X-linked variants. Enrichment of X-chromosome reads through adaptive sampling enhances cost-efficiency. Our study includes a cohort of 16 X-linked variant carrier females affected by two X-linked inherited retinal diseases: choroideremia and RPGR-associated retinitis pigmentosa. As retinal DNA cannot be readily obtained, we instead determine the skew from peripheral samples (blood, saliva and buccal mucosa), and correlate it to phenotypic outcomes. This revealed a strong correlation between X inactivation skew and disease presentation, confirming the value in performing this assay and its potential as a way to prioritise patients for early intervention, such as gene therapy currently in clinical trials for these conditions. Our method of assessing skewed X inactivation is applicable to all long-read genomic datasets, providing insights into disease risk and severity and aiding in the development of individualised strategies for X-linked variant carrier females.

  Study EGAS50000000440

• Coding and regulatory somatic profiling of triple-negative breast cancer in Sub-Saharan African patients

  The burden of triple-negative breast cancer (TNBC) may be shaped by genetic factors, particularly inherited and somatic mutation profiles. However, data on this topic remain limited, especially for the African continent, where a higher TNBC incidence is observed. In the age of precision medicine, cataloguing TNBC diversity in African patients becomes imperative. We performed whole exome sequencing, including untranslated regions, on 30 samples from Angola and Cape Verde, which allowed to ascertain on potential regulatory mutations in TNBC for the first time. A high somatic burden was observed for the African cohort, with 86% of variants being so far unreported. Recurring to predictive functional algorithms, 17% of the somatic single nucleotide variants were predicted to be deleterious at the protein level, and 20% overlapped with candidate cis-regulatory elements controlling gene expression. Several of these somatic functionally-impactful mutations and copy number variation (mainly in 1q, 8q, 6 and 10p) occur in known BC- and all cancer-driver genes, enriched for several cancer mechanisms, including response to radiation and related DNA repair mechanisms. TP53 is the top of these known BC-driver genes, but our results identified possible novel TNBC driver genes that may play a main role in the African context, as TTN, CEACAM7, DEFB132, COPZ2 and GAS1. These findings emphasize the need to expand cancer omics screenings across the African continent, the region of the globe with highest genomic diversity, accelerating the discovery of new somatic mutations and cancer-related pathways.

  Study EGAS50000001013

• Analysis of mutational and proteomic heterogeneity of gastric cancer to monitor post-treatment tumor burden using circulating tumor DNA

  It remains unclear whether complete spectrum of tumor heterogeneity is reflected in circulating tumor DNA (ctDNA). Here, we performed multi-regional target sequencing of primary tumors from 10 patients who underwent surgical resection for gastric cancer. A total of 126 non-synonymous mutations were identified from 30 samples from 10 tumors. Of these, 16 (12.7%) were likely mutations that occurred early in tumor development (i.e., present in all three regions) and were designated founder mutations. Among those validated with highly sensitive digital PCR (dPCR), 93% of non-founder mutations were found in all three regions. Variant allele frequencies (VAFs) of founder mutations were significantly higher than those of non-founder mutations. Phylogenetic analysis demonstrated that five of eight tumors (62.5%, excluding two hypermutator) had at least one identifiable truncal/founder mutation. These findings led us to prioritize founder mutations for ctDNA detection with individually-designed primer/probe sets for dPCR. Marked proteomic diversity was present across the tumor regions both within and between patients independent of mutational status. In preoperative plasma, the average ctDNA VAF of founder mutations was significantly higher than that of non-founder mutations (p = 0.039). Our present data demonstrated that high VAF mutations in the tumor likely represent founder or truncal mutations. However, mutation patterns alone appear insufficient to predict protein heterogeneity. These results suggest that, in practice, mutations having high VAF identified without multi-regional sequencing may be useful for ctDNA monitoring but are inadequate to fully predict proteomic heterogeneity of the tumor.

  Study JGAS000231

• Genome-Wide Association Study of aspirin-induced PUD in a UK cohort

  Aspirin is a widely prescribed non-steroidal anti-inflammatory drug used as an effective analgesic and at low doses as anti-platelet drug for the prevention of cardiovascular diseases. However, aspirin is associated with a significant incidence of upper gastrointestinal (GI) complications, notably peptic ulceration. This study aims to identify genetic risk factors associated with the pathogenesis of aspirin-induced upper GI ulceration.A cohort of 248 patients with aspirin-induced, endoscopiclly confirmed GI ulceration and 491 controls (ulcer, without aspirin or aspirin without ulcer) were genotyped for 1.524,956 SNPs using the Illumina Omni 2.5 SNP array. A replication cohort (206 NSAID-induced ulcer cases [of which 87 were aspirin] and 309 controls) was subsequently genotyped for identified SNP association signals using Sequenom iPLEX Massarry. Logistic regression analysis of identified two SNP signal with suggestive association with aspirin-induced GI ulceration. A SNP within the EYA1 locus (rs12678747) was found to be associated with aspirin GI ulceration in both the discovery cohort (p=3.79x10-7, OR=2.06 ([1.55-2.73]) and, to a lesser extent, in the replication cohort (p=.0005, OR=1.71[1.17-2.50]. Combined analysis of both cohorts yielded a genome wide significant association (p=1.46x10-8). The rs12678747 genotype was found to be associated with significantly higher EYA1 transcript in ulcer biopsy tissue (p<0.05).Data suggest that EYA1 may represent a risk locus for aspirin-induced GI ulceration. Though it is thought that EYA1 may play a key role in mediating cell death/ survival

  Study EGAS00001002052

• Microsatellite data show recent demographic expansions in sedentary but not in nomadic human populations in Africa and Eurasia.

  The transition from hunting and gathering to plant and animal domestication was one of the most important cultural and technological revolutions in human history. According to archeologists and paleoanthropologists, this transition triggered major demographic expansions. However, few genetic studies have found traces of Neolithic expansions in the current repartition of genetic polymorphism, pointing rather toward Paleolithic expansions. Here, we used microsatellite autosomal data to investigate the past demographic history of 87 African and Eurasian human populations with contrasted lifestyles (nomadic hunter-gatherers, semi-nomadic herders and sedentary farmers). Likely due to the combination of a higher mutation rate and the possibility to analyze several loci as independent replicates of the coalescent process, the analysis of microsatellite data allowed us to infer more recent expansions than previous genetic studies, potentially resulting from the Neolithic transition. Despite the variability in their location and environment, we found consistent expansions for all sedentary farmers, while we inferred constant population sizes for all hunter-gatherers and most herders, which could result from constraints linked to a nomadic or semi-nomadic lifestyle and/or competition for land between herders and farmers. As an exception, we inferred expansions for Central Asian herders. This might be linked with the arid environment of this area, which may have been more favorable to nomadic herders than to sedentary farmers. Alternatively, current Central Asian herders may descent from populations who have first experienced a transition from hunter-gathering to sedentary agropastoralism, and then a second transition to nomadic herding.

  Study EGAS00001000652

• Quantification of chromosomal copy number aberrations by shallow whole-genome sequencing

  Detection of DNA copy number aberrations by shallow whole-genome sequencing (WGS) faces many challenges including lack of completion and errors in the human reference genome, repetitive sequences, polymorphisms, variable sample quality, and biases in the sequencing procedures.Formalin-fixed paraffin-embedded (FFPE) archival material, the analysis of which is important for studies of cancer, presents particular analytical difficulties due to degradation of the DNA and frequent lack of matched reference samples. We present a robust, cost-effective WGS method for DNA copy number analysis that addresses these challenges more successfully than currently available procedures. In practice very useful profiles can be obtained with 0.1 fold genome coverage. We improve on previous methods by; first, implementing a combined correction for sequence mappability and GC content, and second, applying this procedure to sequence data from the 1000 Genomes Project in order to develop a blacklist of problematic genome regions. A small subset of these blacklisted regions were previously identified by ENCODE, but the vast majority are novel unappreciated problematic regions. Our procedures are implemented in a pipeline called QDNAseq. We have analyzed over 1,000 samples, most of which were obtained from the fixed tissue archives of over 25 institutions.We demonstrate that for most samples our sequencing and analysis procedures yield genome profiles with noise levels near the statistical limit imposed by read counting. The described procedures also provide better correction of artifacts introduced by low DNA quality than prior approaches, and better copy number data than high-resolution microarrays at substantially lower cost.

  Study EGAS00001000642

• Prediction of pigmentation phenotypes by SNP typing in a Northern German population

  Human pigmentation traits are of great interest to many research areas, from ancient DNA analysis to forensic science. We aimed to develop a gene-based predictive model for pigmentation phenotypes in a realistic target population for forensic case work from Northern Germany. Our aim was to determine whether better prediction accuracy can be achieved, or fewer genetic markers may suffice, than in previously studied, genetically more heterogeneous populations. We investigated the association between eye, hair and skin colour, and 12 candidate single nucleotide polymorphisms (SNPs) from six genes. Our study comprised two samples of 300 and 100 individuals from Northern Germany who were carefully characterized with regard to pigmentation phenotypes. The first sample was used to select trait-associated SNPs whereas the second sample served to estimate odds ratios (ORs) and to quantify the predictive capability of the respective SNP genotypes. SNP rs12913832 in HERC2 was found to be strongly associated with blue eye colour (OR=15.6, p<1.2•10-4) and to yield reasonable predictive power (90% sensitivity, 63% specificity). SNP associations with hair and skin colour were weaker and genotypes less predictive. A comparison to two recently published sets of markers to predict eye and hair colour revealed that the consideration of additional SNPs with weak to moderate effect increases the predictive power in Northern Germans for eye colour, but not for hair colour. In addition, fine phenotyping and differentiation of hair colour (light / dark and red tint / no red tint) were found to increase the number of significant genotype-phenotype associations.

  Study EGAS00001001174

• Analysis of recent shared ancestry in a familial cohort identifies coding and noncoding autism spectrum disorder variants

  Autism spectrum disorder (ASD) is a collection of neurodevelopmental disorders characterized by deficits in social communication and restricted, repetitive patterns of behavior or interests. ASD is highly heritable, but genetically and phenotypically heterogeneous, reducing the power to identify causative genes. We performed whole genome sequencing (WGS) in an ASD cohort of 68 individuals from 22 families enriched for recent shared ancestry. We identified an average of 3.07 million variants per genome, of which an average of 112,512 were rare. We mapped runs of homozygosity (ROHs) in affected individuals and found an average genomic homozygosity of 9.65%, consistent with expectations for multiple generations of consanguineous unions. We identified potentially pathogenic rare exonic or splice site variants in 12 known (including KMT2C, SCN1A, SPTBN1, SYNE1, ZNF292) and 12 candidate (including CHD5, GRB10, PPP1R13B) ASD genes. Furthermore, we annotated noncoding variants in ROHs with brain-specific regulatory elements and identified putative disease-causing variants within brain-specific promoters and enhancers for 5 known ASD and neurodevelopmental disease genes (ACTG1, AUTS2, CTNND2, CNTNAP4, SPTBN4). We also identified copy number variants in two known ASD and neurodevelopmental disease loci in two affected individuals. In total we identified potentially etiological variants in known ASD or neurodevelopmental disease genes for ~61% (14/23) of affected individuals. We combined WGS with homozygosity mapping and regulatory element annotations to identify candidate ASD variants. Our analyses add to the growing number of ASD genes and variants and emphasize the importance of leveraging recent shared ancestry to map disease variants in complex neurodevelopmental disorders.

  Study EGAS00001006058

• OMKar

  The whole genome karyotype refers to the sequence of large chromosomal segments that make up an individuals genotype. karyotype analysis, which includes descriptions of aneuploidies and other rearrangements is crucial for understanding genetic risk factors, for diagnosis, treatment decisions, and genetic counseling linked to constitutional disorders. The current karyotyping standard is based on microscopic examination of chromosomes, a complex process that requires high expertise and offers Mb scale resolution. Optical Genome Mapping (OGM) technology can identify large DNA lesions in a cost-effective manner. In this paper, we developed OMKar, a method that uses OGM data to create a virtual karyotype. OMKar processes Structural (SV) and Copy Number (CN) Variants as inputs and encodes them into a compact breakpoint graph. It recomputes copy numbers using Integer Linear Programming to maintain CN balance and then identifies constrained Eulerian paths representing entire donor chromosomes. In tests using 38 whole genome simulations of constitutional disorders, OMKar reconstructed the karyotype with 88% precision and 95% recall on SV concordance and 95% Jaccard score on CN concordance. We applied OMKar to 50 prenatal, 41 postnatal, and 63 parental samples from ten different sites. OMKar reconstructed the correct karyotype in 144 out of 154 samples, covering 25 of 25 aneuploidies, 32 of 32 balanced translocations, and 72 of 82 unbalanced variations. Detected constitutional disorders included Cri-du-chat, Wolf-Hirschhorn, Prader-Willi deletions, Down, and Turner syndromes. Importantly, it identified a plausible genetic mechanism for five cases of constitutional disorder that were not detected by other technologies. Together, these results demonstrate the robustness of OMKar for OGM-based karyotyping.

  Study EGAS00001008245

• Sequencing-based counting and size profiling of plasma Epstein-Barr virus DNA enhance population screening of nasopharyngeal carcinoma.

  Circulating tumor-derived DNA testing for cancer screening has recently been demonstrated in a prospective study on identification of nasopharyngeal carcinoma (NPC) among 20,174 asymptomatic individuals. Plasma EBV DNA, a marker for NPC, was detected using real-time PCR. While plasma EBV DNA was persistently detectable in 97.1% of the NPCs identified, ∼5% of the general population had transiently detectable plasma EBV DNA. We hypothesized that EBV DNA in plasma of subjects with or without NPC may have different molecular characteristics. We performed target-capture sequencing of plasma EBV DNA and identified differences in the abundance and size profiles of EBV DNA molecules within plasma of NPC and non-NPC subjects. NPC patients had significantly higher amounts of plasma EBV DNA, which showed longer fragment lengths. Cutoff values were established from an exploratory dataset and tested in a validation sample set. Adopting an algorithm that required a sample to concurrently pass cutoffs for EBV DNA counting and size measurements, NPCs were detected at a positive predictive value (PPV) of 19.6%. This represented superior performance compared with the PPV of 11.0% in the prospective screening study, which required participants with an initially detectable plasma EBV DNA result to be retested within 4 weeks. The observed differences in the molecular nature of EBV DNA molecules in plasma of subjects with or without NPC were successfully translated into a sequencing-based test that had a high PPV for NPC screening and achievable through single time-point testing.

  Study EGAS00001002707

• Open_Targets_020_Epigenomes_of_Cell_Lines

  There is currently a drive to establish cell based assay systems of greater human biological and disease relevance through the use of well characterised transformed cell lines, primary cells and complex cellular models (e.g. co-culture, 3D models). However, although the field is gaining valuable experience in running more non-standard & complex cell assays for target validation and compound pharmacology studies, there is the lack of a systematic approach to determine if this expansion in cell assay models is reflected in increased human biological and disease relevance. The increasing wealth of publically available transcriptomic, and epigenome (ENCODE and Epigenome Roadmap) data represents an ideal reference mechanism for determining the relationship between cell types used for target & compound studies to primary human cells and tissues from both healthy volunteers & patients. The CTTV020 epigenomes of cell line project aims to generate epigenetic and transcriptomic profiles of cell lines and compare these with existing and newly generated reference data sets from human tissue and cell types. The aim is to identify assay systems which will provide greater confidence in translating target biology and compound pharmacology to patients. Multiple cell types commonly used within research have been grouped according to biology. Examples include erythroid, lung epithelial, hepatocyte cell types and immortalised models of monocyte / macrophage biology. 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 EGAS00001003136

• The Dutch Microbiome Project: Defining the (un)healthy gut microbiome

  The Dutch Microbiome Project (DMP) data includes raw data generated by shotgun metagenomic sequencing of faecal samples of 8,208 Dutch individuals, processed microbiome data analysed using Biobakery2 tools (including taxonomy, pathway, virulence factors and antibiotic resistance gene profiles), and basic phenotypes (age and sex, BMI). Data is made available in two randomly assigned batches to facilitate the data access and maintenance. Access to this dataset requires a minimal access procedure (data access form at https://forms.gle/eHeBdXJMXbVvCJRc8 or email request to the data access committee (DAC) of this study, listed at DAC EGAC00001001996, https://ega-archive.org/dacs/EGAC00001001996). This access procedure is to ensure that the data is being requested for research/scientific purposes only and thus complies with the informed consent signed by Lifelines participants, which specifies that the collected data will not be used for commercial purposes. Submitted data access forms will be evaluated by the DAC and Lifelines, and a response to requests will be given within two weeks. For requests from verified academic parties, access will be given without further delay. For requests from commercial parties, Lifelines will perform a pre-DPIA (Data Privacy Impact Assessment) to assess the risks of the proposed processing of personal data (e.g. purpose, storage, access, archiving, etc.) with respect to the GDPR (EU privacy laws) subject rights. Based on the outcome of the pre-DPIA, Lifelines will decide whether sharing data with the commercial entity is allowed and/or whether additional measures have to be taken.

  Study EGAS00001005027

• Open_Targets_020_Epigenomes_of_Cell_Lines

  There is currently a drive to establish cell based assay systems of greater human biological and disease relevance through the use of well characterised transformed cell lines, primary cells and complex cellular models (e.g. co-culture, 3D models). However, although the field is gaining valuable experience in running more non-standard & complex cell assays for target validation and compound pharmacology studies, there is the lack of a systematic approach to determine if this expansion in cell assay models is reflected in increased human biological and disease relevance. The increasing wealth of publically available transcriptomic, and epigenome (ENCODE and Epigenome Roadmap) data represents an ideal reference mechanism for determining the relationship between cell types used for target & compound studies to primary human cells and tissues from both healthy volunteers & patients. The CTTV020 epigenomes of cell line project aims to generate epigenetic and transcriptomic profiles of cell lines and compare these with existing and newly generated reference data sets from human tissue and cell types. The aim is to identify assay systems which will provide greater confidence in translating target biology and compound pharmacology to patients. Multiple cell types commonly used within research have been grouped according to biology. Examples include erythroid, lung epithelial, hepatocyte cell types and immortalised models of monocyte / macrophage biology. 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 EGAS00001003137

• Open_Targets_020_Epigenomes_of_Cell_Lines

  There is currently a drive to establish cell based assay systems of greater human biological and disease relevance through the use of well characterised transformed cell lines, primary cells and complex cellular models (e.g. co-culture, 3D models). However, although the field is gaining valuable experience in running more non-standard & complex cell assays for target validation and compound pharmacology studies, there is the lack of a systematic approach to determine if this expansion in cell assay models is reflected in increased human biological and disease relevance. The increasing wealth of publically available transcriptomic, and epigenome (ENCODE and Epigenome Roadmap) data represents an ideal reference mechanism for determining the relationship between cell types used for target & compound studies to primary human cells and tissues from both healthy volunteers & patients. The CTTV020 epigenomes of cell line project aims to generate epigenetic and transcriptomic profiles of cell lines and compare these with existing and newly generated reference data sets from human tissue and cell types. The aim is to identify assay systems which will provide greater confidence in translating target biology and compound pharmacology to patients. Multiple cell types commonly used within research have been grouped according to biology. Examples include erythroid, lung epithelial, hepatocyte cell types and immortalised models of monocyte / macrophage biology. 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 EGAS00001003139

• Healthy_ageing_thymus

  Single cell RNA sequencing of immune and non-immune cells from healthy ageing thymus Thymus is a primary lymphoid organ that creates an environment for the T lymphocyte precursors differentiation into the naive T cells, which involves TCR gene rearrangement, negative and positive selection. Despite thymus critical function for the recognition of the pathogens it starts to atrophy very early in life. Thymic Epithelial Space (TES), where thymocyte education occurs, starts to decline rapidly just after birth, while with the onset of puberty thymus is also progressively replaced with adipose tissue. This leads to a reduced naive T cell output,which decreases an organism's ability to recognize pathogens. In our lab, we have already collected and characterized cell type composition and gene regulatory networks of the fetal tand adult human thymus (Park et al, Science 2020). In the current project we plan to expand the number of paediatric and adult samples in the study with the aim to understand how the process of thymic involution happens. We will use single-cell transcriptomics to zoom on changes that occur in immune and non-immune cell types in different phases of thymic involution with the hope to understand which gene expression changes are causal for the thymic involution process and how naïve T cell production can be increased in elderly. 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 EGAS00001004311

• Robust methylation-based classification of brain tumours using nanopore sequencing

  Background: DNA methylation-based classification of cancer provides a comprehensive molecular approach to diagnose tumours. In fact, DNA methylation profiling of human brain tumours already profoundly impacts clinical neuro-oncology. However, current implementations using hybridization microarrays are time-consuming and costly. We recently reported on shallow nanopore whole-genome sequencing for rapid and cost-effective generation of genome-wide 5-methylcytosine profiles as input to supervised classification. Here, we demonstrate that this approach allows to discriminate a wide spectrum of primary brain tumours. Results: Using public reference data of 82 distinct tumour entities, we performed nanopore genome sequencing on N=382 tissue samples covering 46 brain tumour (sub)types. Using bootstrap sampling in a cohort of N = 56 cases, we find that a minimum set of 1,000 random CpG features is sufficient for high-confidence classification by ad hoc random forests. We implemented score recalibration as confidence measure for interpretation in a clinical context and empirically determined a platform-specific threshold in a randomly sampled discovery cohort (N = 185). Applying this cut-off to an independent validation series (N = 184) yielded 148 classifiable cases (sensitivity 80.4%) and demonstrated 100 % specificity. Cross-lab validation demonstrated robustness with concordant results across four laboratories in 10/11 (90.9%) cases. In a prospective benchmarking (N = 15), median time to results was 21.1 hours. Conclusions: In conclusion, nanopore sequencing allows robust and rapid methylation-based classification across the full spectrum of brain tumours. Platform-specific confidence scores facilitate clinical implementation for which prospective evaluation is warranted and ongoing.

  Study EGAS00001006540

• Treatment stratification and biomarker validation using patient-derived head and neck cancer organoids

  Background Organoids are three-dimensional structures that can be grown from patient-derived material including carcinomas. These in vitro models can be cryopreserved to generate “living” biobanks that reflect patient heterogeneity. Head and neck cancer (HNC) is a collective term used for tumors arising in the head and neck area, including squamous cell carcinomas (HNSCC) and adenocarcinoma of the salivary gland. Methods to culture patient-derived HNC organoids have previously been described. Methods Organoids were derived from resection or biopsy material of patients included between 2016 and 2022. Organoids were characterised with immunohistochemistry and whole exome sequencing (WES) and exposed to chemo-, radio- and targeted-therapies. CRISPR/Cas9-based gene editing was applied to validate proposed biomarkers. Results We have extended our previously published organoid biobank to a total of 110 organoid models, some of which were characterised by histology and WES. Organoids recapitulated both single nucleotide variants and copy number alterations as found in patient HNSCC samples. Organoid and patient response to radiotherapy (RT; primary (n=6) and adjuvant (n=15)) could be compared in 21 HNC cases. In the adjuvant RT group, organoids derived from patients that relapsed were more resistant to RT in vitro, showing potential for guiding treatment options in this subset of patients. Conclusion Taken together, these results indicate illustrate the potential of organoids as a diagnostic tool in personalised medicine for HNC and indicate the potential of this technology for biomarker discovery and validation within the context of relevant patient heterogeneity.

  Study EGAS00001007076

• Efficacy of nivolumab in pediatric cancers with high mutation burden and mismatch-repair deficiency

  Purpose: Checkpoint-inhibitors have limited efficacy for children with unselected solid and brain tumors. We report the first prospective pediatric trial (NCT02992964) using nivolumab exclusively for refractory non-hematological cancers harboring tumor mutation burden (TMB) ≥5 mutations/megabase (mut/Mb) and/or mismatch-repair deficiency (MMRD). Patients and methods: Twenty patients were screened, and ten ultimately included in the response cohort of whom nine had TMB >10mut/Mb (three initially eligible based on MMRD) and one patient had TMB between 5-10 mut/Mb. Results: Delayed immune responses contributed to best overall response of 50%, improving on initial objective responses (20%) and leading to 2-year overall survival (OS) of 50% (95% CI; 27, 93). Four children, including three with refractory malignant gliomas are in complete remission at a median follow-up of 37-months (range: 32.4-60), culminating in 2-year OS of 43% (95% CI; 18.2, 100). Biomarker analyses confirmed benefit in children with germline MMRD, microsatellite instability, higher activated and lower regulatory circulating T-cells. Stochastic mutation accumulation driven by underlying germline MMRD impacted the tumor microenvironment, contributing to delayed responses. No benefit was observed in the single patient with a MMR-proficient tumour and TMB 7.4 mut/Mb. Conclusions: Nivolumab resulted in durable responses and prolonged survival for the first time in a pediatric trial of refractory hypermutated cancers including malignant gliomas. Novel biomarkers identified here need to be translated rapidly to clinical care to identify children who can benefit from checkpoint-inhibitors, including for upfront management of their cancers.

  Study EGAS00001007393

• shallow WGS and deep targeted panel on ctDNA in rhabdomyosarcomas

  The genomic spectrum of rhabdomyosarcoma (RMS) progression from primary to relapse is not fully understood. In this study we investigate 35 patients with relapsed RMS from two contributing institutions, 18 fusion-positive (FP-RMS) and 17 fusion-negative RMS (FN-RMS). Targeted DNA or whole exome sequencing (WES) was used to detect alterations in paired primary/relapsed samples. In 10 cases, circulating tumor DNA (ctDNA) from multiple timepoints through clinical care and progression was analyzed for feasibility of liquid biopsy in monitoring treatment response/relapse. ctDNA alterations were evaluated using a targeted custom RMS panel (36 genes) at high coverage for single nucleotide variation and fusion detection, and a shallow whole genome sequencing for copy number variation. FP-RMS had a stable genome with relapse, with the most common secondary alterations : CDKN2A/B, MYCN and CDK4 alterations, being already present at diagnosis and impacting overall survival. FP-RMS lacking major secondary events at baseline acquired recurrent MYCN and AKT1 alterations. FN-RMS acquired a higher number of new alterations, most commonly SMARCA2 missense mutations. ctDNA analyses detected pathognomonic variants in all RMS patients at diagnosis, regardless of FP/FN or type of alterations, while at relapse selected alterations were confirmed in 86% of FP-RMS and 100% FN-RMS. Moreover, a higher number of fusion reads was detected with increased disease burden and at relapse in patients following a fatal outcome. These results underscore patterns of tumor progression within a relatively stable genomic landscape and provide rationale for using liquid biopsy to monitor treatment response.

  Study EGAS00001007399

• Whole-Genome Sequencing in Multiplex Epilepsy Families

  Epilepsy is one of the most common neurologic disorders, affecting approximately 4% of individuals at some time in their lives. More than 30% of people with epilepsy continue to have seizures despite treatment, and improved approaches to treatment and prevention are sorely needed. In the search for new strategies to reduce the burden of disease, the discovery of specific genes that influence risk offers a novel opportunity to clarify pathogenic mechanisms, identify susceptible individuals prior to seizure onset, and treat and prevent seizures in people at risk. Despite clear evidence of the importance of genetics in susceptibility to epilepsy, only limited progress has been made in identifying the specific genes that influence risk. One of the greatest challenges for genetic research on this disorder is its extreme clinical and genetic heterogeneity. Although epilepsy is broadly defined by recurrent unprovoked seizures, it is so variable in its clinical manifestations, natural history, and treatment response that most epileptologists view it as a collection of different syndromes ("epilepsies") with distinct etiologies. The genetic effects on susceptibility are also likely to be extremely variable, ranging from rare variants with high penetrance (some of which produce Mendelian patterns of inheritance) to common variants with low penetrance. Recent findings strongly suggest that rare gene variants play a major role in the genetic architecture of the epilepsies. The purpose of this study was to discover new genetic risk factors for epilepsy. The primary approach was to use whole-genome sequencing to interrogate classes of genetic variants, including very rare variants, in multiplex families. Our main hypothesis was that, in at least some proportion of these families, a single variant would explain all instances of epilepsy. Variants identified within the families could then be tested for cosegregation within the family and also validated by seeing enrichment in sporadic epilepsy cases. Furthermore, understanding the impact of rare variation in epilepsy also has the potential to provide insight into the genetic architecture of other complex human diseases. Our analysis focused on families containing multiple individuals with non-acquired (idiopathic or unknown cause) epilepsy under the hypothesis that these would be enriched for genetic control. The families studied had been previously collected and phenotyped in detail, and contain an average of 3.8 individuals per family with a range of different types of epilepsy. We selected one or two affected individuals from each family for sequencing. This work has generated NGS data on 60 samples from 29 multiplex epilepsy families. We have established that, under a monogenic model of inheritance, sequencing pairs of distantly related relatives is an effective method for reducing the number of candidate variants. Critically, we have found that no single variant can explain a large proportion of these epilepsy families. This work emphasizes that identifying causal variants among the many genetic candidates found in this work will require very large sample sizes and gene-based analyses.

  Study phs000690

• Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud university medical center

  Dac EGAC00001003193

• DAC for genomic data obtained within the Micrometastasis (Oslo1) project from Oslo, Norway

  Dac EGAC00001000558

• DAC for Transcriptome analysis in very preterm infants with chronic lung disease after birth

  Dac EGAC00001000698

• DAC for Cardiac Translatomes of 80 Human Samples (65 DCM cases 15 controls)

  Dac EGAC00001001040

• Control iPSC lines with clinically annotated genetic variants for versatile multi-lineage differentiation Committee

  Dac EGAC00001001226

• Genomics to select patients with metastatic breast cancer for targeted therapy DAC

  Dac EGAC00001002293

• Data Access Committee for the project: Epic arrays from human OB and their mimics

  Dac EGAC00001002482

• The Data Access Committee for Human Olfactory Mucosa Cells (DAC_HOM) at UEF

  Dac EGAC00001002527

• The EMC-NICHE DAC considers appeals for hematopoietic/niche-related data sets.

  Dac EGAC00001001897

• RNA-Seq data for AEL paper

  Dataset EGAD00001003412

• Whole exome data for AEL paper

  Dataset EGAD00001003413

• Mesothelima_OSCHP_Files

  Oncoscan CHP files for the Mesothelemia Project

  Dataset EGAD00010001540

• Translational Gastroenterology Unit, University of Oxford Data Access Committee for the EPIC-CD study

  Dac EGAC00001003481

• Cyr61-MAC DAC

  DAC for access to dataset on Cyr61-MAC and HUVEC

  Dac EGAC50000000355

• Data access committee for datasets generated by the Tampere University Computational Biology research group

  Dac EGAC50000000177

• A genome-wide association study for nasopharyngeal carcinoma in Hong Kong population

  Study EGAS00001006102

• Exploration of neuroblastoma xenograft models for tumor extracellular RNA profiling in murine blood plasma

  Study EGAS00001007295

• DAC_For_MPN

  This is the DAC for the MPN data set from Milena Kalmer.

  Dac EGAC50000000531

• DAC PRECISE Bennstein

  Data access control for datasets submitted by SysMed - PRECISE

  Dac EGAC50000000476

• Cancer Alliance Exome

  Exome sequencing for individualized cancer interpretation

  Dataset EGAD00001006236

• Exome

  Exome Seq for Study EGAS00001001844

  Dataset EGAD00001002159

• GEN_COVID_phenotype_lab

  Lab values for GEN_COVID cohort.

  Dataset EGAD00001007837

• SPGRX_phenotype_basic

  Basic phenotypes for SPGRX cohort.

  Dataset EGAD00001007848

• Transcriptome sequencing in monozygotic twins discordant for Mayer-Rokitansky-Küster-Hauser syndrome

  Study EGAS00001006370

• INMUNGEN_CoV2_phenotype_lab

  Lab values for INMUNGEN_CoV2 cohort.

  Dataset EGAD00001007847