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• AfricanNeo WGS aDNA Dataset

  This dataset includes WGS data of 12 ancient individuals (97–688 years BP) from Zambia and South Africa, presented in Fortes-Lima et al. Nature 2023. Further details like C14-dates and archaeological descriptions were reported elsewhere (Meyer et al. Azania 2021; Steyn et al. African Archaeological Review 2022).

  Dataset EGAD00001011320

• Sequencing Data of Leukemic Samples

  Sequencing data of leukemic samples included in study. Including WES, WGS and targeted sequencing files from patients at diagnosis, remission and at relapse. The dataset includes samples from 52 pediatric patients, totaling 311 samples.

  Dataset EGAD00001015662

• CBP has opposing functions during cerebellar development and is a targetable tumor suppressor at late stages of medulloblastoma initiation

  CBP has opposing functions during cerebellar development and is a targetable tumor suppressor at late stages of medulloblastoma initiation

  Dataset EGAD00001001461

• GIS-LUNGTCR1-2016_VAL-FASTQ

  This dataset contains FASTQ files of targeted Amplicon deep-sequencing data, for validation of the mutations found in WES. There are 16 patients and 95 samples in total, including 16 controls and 79 tumors. 140 fastq in total, multiple runs for some of the samples. Please refer to the sample-ID from filename for merging.

  Dataset EGAD00001001981

• eQTL summary statistics

  This dataset contains the eQTL summary statistics (nominal pass, significant eQTLs, best associated variant per gene). eQTL mapping was performed with fastQTL. This dataset was generated as part of the following study: Panousis et al (2019). Combined genetic and transcriptome analysis of patients with SLE: Distinct, targetable signatures for susceptibility and severity.

  Dataset EGAD00001005041

• PFA ependymoma study -WGS data

  WGS bam file for the 18 samples used in Michealraj et al. Cell 2020. The dataset includes PFA ependymoma tissue, derived line and blood samples of 6 patients WGS data were aligned with BWA to the hg38 human reference genome (igenome) and further processed according to the GATK best practice pipeline.

  Dataset EGAD00001006045

• Single-Nuclei RNA-seq of healthy (post-mortem) and temporal lobe epilepsy (biopsy) subjects.

  To identify dysfunctional neuronal subtypes underlying seizure activity in the human brain, we have performed single-nucleus transcriptomics analysis of >110,000 neuronal transcriptomes derived from temporal cortex samples of multiple temporal lobe epilepsy and non-epileptic subjects.

  Dataset EGAD00001006575

• Gluten reactive and non-reactive T-cells from treated celiac disease patients on a gluten challenge sampled at day 6

  Gluten reactive T-cells from blood samples from patients undergoing a 3 day gluten challenge. Samples were collected on day 6. Both gluten reactive and non-gluten reactive T-cells were sequenced.

  Dataset EGAD00001006899

• Gene expression and Cancer

  Dac EGAC00001001727

• CHIP and LOY in AD

  Dac EGAC00001003606

• PRADO trial - Personalized response-directed surgery and adjuvant therapy after neoadjuvant ipilimumab plus nivolumab in stage III melanoma

  The dataset includes WES sequencing data on PRE- treatment biopsies of lymph node metastasis (n=79) The technology used for sequencing is llumina HiSeq. The PRADO trial tested a personalized response-directed treatment approach based on the pathologic response after neoadjuvant ipilimumab plus nivolumab in stage III melanoma patients. In patients achieving a major pathologic response, in their index lymph node (the largest lymph node metastasis at baseline), therapeutic lymph node dissection (TLND) and adjuvant therapy were omitted. Patients with partial response underwent TLND only, whereas patients with pathologic non-response underwent TLND and adjuvant systemic therapy ± synchronous radiotherapy.

  Dataset EGAD50000000393

• Metastatic Adrenocortical Carcinoma Displays Higher Mutation Rate and Tumor Heterogeneity than Primary Tumors

  We have analyzed 33 human metastatic adrenocortical tumors from 14 patients with advanced metastases and performed whole exome sequencing to identify novel signatures in these tumors. We observed tumor heterogeneity in these tumors coming from the same metastatic tissue site across different patients while the different metastatic tumor sites coming from the same patient are more homogenous in nature.

  Study phs001658

• Whole-genome variant calling of individuals from the study of allergic diseases in the Canary Islands

  Research study of genetic susceptibility and analyses of polygenic risk scores in allergic diseases. This dataset consists of variant data derived from whole-genome sequencing in reference samples from one of the parental populations (i.e., North Africans). The dataset consist of 15 VCF files (and corresponding index files) with a total of 1.58 million variants called using GATK v4 and following the Broad Variant Calling Best Practices, from a set of unrelated individuals sequenced in paired-read mode 2x150 bp using an Illumina HiSeq 4000 sequencer.

  Dataset EGAD50000000429

• Raw scRNA-seq data from B-lineage cells in the blood of celiac disease patients

  Raw scRNA-seq data from 355 IgA+ peripheral blood B-lineage cells of two untreated celiac disease patients. The data was generated with the Smart-seq2 protocol and sequenced on a NextSeq500 instrument (Illumina) with 75 bp paired-end reads in high-output mode. The dataset contains R1 and R2 reads for each single cell (fastq.gz files) for cells passing quality control based on number of detected genes, reads, mitochondrial genes, reads mapping to the reference transcriptome and a productively rearranged immunoglobulin heavy chain IgA isotype reconstructed by the computational tool BraCeR. Metadata for the cells is provided in a csv file.

  Dataset EGAD50000000340

• Methylation sequencing dataset for "Molecular counting enables accurate and precise quantification of methylated ctDNA"

  Methylation sequencing dataset for "Molecular counting enables accurate and precise quantification of methylated ctDNA." This dataset was created by running samples through Northstar Response, where bisulfite converted samples are amplified in a multiplex PCR targeting more than 500 genomic regions. Samples in this dataset include contrived samples made from 84 different tumors DNA, each mixed with their matched buffy coat DNA at varying ratios, as well as cfDNA and buffy coat DNA samples collected from 67 cancer patients undergoing treatment. All samples were sequenced on Illumina NextSeq 2000 with single end 100 cycle sequencing; files are in fastq.gz format.

  Dataset EGAD50000001015

• Transcriptome of memory B cells with autoproliferation in MS

  Transcriptional profile of resting/hi and autoproliferating/Dim memory B cells in Multiple sclerosis patients. In brief, non-proliferating (CFSEhi) and AP+ (CFSEdim) CD19+ CD27+ B cells from PBMCs of 5 natalizumab-treated female RRMS (NAT) patients were sorted following 7 days of autoproliferation. Transcriptome libraries were constructed from the same samples, except for one sample pair, which was excluded due to limited input material (5 donors as for Methylome, D1; D2, D3, D5, D6; samples from donor D4 unfortunately technically failed). SMARTer Total Stranded RNA-seq library construction with ribosomal depletion was performed and then sequenced on NovaSeq S4 lane.

  Dataset EGAD50000001270

• Single cell RNAseq and TCRseq data from tumor and blood samples from 4 patients with muscle invasive bladder cancer

  For this dataset we performed single cell RNAseq paired with single cell TCR-seq on tumor and blood samples from 4 patients. This dataset contains 4 tumor samples as well as 4 blood samples. Each sample is made up of 2 sets of paired fastq files. The first pair contains reads corresponding to RNA transcripts (_Transcripts in file name), while the second pair contain reads corresponding to TCRs (_VDJ in file name). Sequenced on the Illumina NovaSeq6000 platform in a paired-end run using an SP flow cell (v1.5, 300 cycles).

  Dataset EGAD50000001381

• Single cell RNA-seq of 24 samples from 13 individual human embryonic meninges of PCW 5.0-13.0 using 10X chromium technology

  A total of 24 samples of meninges from 13 normal human embryos of post-conceptional week (PCW) 5.0-13.0 were dissected and subject to 10Xgenomics chromium single cell RNA sequencing with the purpose of identifying cell types and gene expression programs for normal meninges development. All libraries were sequenced on an Illumina NovaSeq 6000 using S4 to a target sequencing depth of 100,000 reads/cell. Final data after processing with STARSolo 2.7.10a, using human genome GRCh38.p12 and transcript annotations from ENSEMBL release 93 from reference package GRCh38-3.0.0 as available from 10Xgenomics, consists of 24 BAM files.

  Dataset EGAD50000001434

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

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

  Dataset EGAD50000001550

• CLUSTER Consortium RNAseq PBMC Dataset of pre-methotrexate UK JIA patients cohort

  This is the RNAseq PBMC dataset (paired FASTQ files, n = 82 paired files) generated from pre-methotrexate treatment JIA patients cohort samples. Total PBMC were isolated from pre-treated blood of JIA patients and clinical metadata is also included in this dataset. Samples were sequenced on the NovaSeq6000 instrument (Illumina, San Diego, US) at 300pM, using a 100bp paired read run with corresponding 8bp dual sample index and 5bp or 8bp unique molecular index reads. Run data were demultiplexed and converted to FASTQ files using Illumina’s BCL Convert Software v3.75.

  Dataset EGAD50000001457

• Khoe-San genome Project (KSGP)

  The Khoe-San Genome Project (KSGP) includes whole genome data generated for 190 study participants from Southern Africa (Namibia and South Africa) representing people speaking a Namibian Khoe-San language (n=150, 12 groups) or regional non-Khoe-San groups (n=40), specifically defined here as Namibian Himba (n=10), South African Southern Bantu (n=12 and representing the Ubuntu Genome Project led by the University of Limpopo) or South African Coloured/European (n=18). Deep whole genome data has been generated for the purposes of cataloguing the extent of regional genetic diversity, creating population specific references and evolutionary trajectories, while creating a population-matched panel of normal (PoN) genetic diversity required for disease associated studies across the region.

  Dac EGAC50000000798

• 10X CD4 auto-antigens

  Ex vivo CD4 T-cells from 4 donors were stimulated with antigen-coupled beads to aCD3, ABD, EBNA1, ANO2 or CRYAB and the LiveCD3+CD4+CFSEdim cells were sorted by flow cytometry. Cells were labelled with barcoded antibodies to identify the original stimulus. All stimulations from each donor were pooled into four reactions, i.e. one reaction per donor. Libraries were assembled with the 10X Chromium Next GEM Single Cell 5’ Kit for TCR and transcriptome with feature barcodes. Dataset contains raw fastq reads as well as supplementary information needed to link fastq files to modality, i.e. gene-expression, protein or VDJ, and includes supplementary information to de-multiplex the reactions by stimulation condition.

  Dataset EGAD50000002201

• Archive growth Statistics

  EGA Statistics Bibliography Growth Community Archive Distribution Catalogue In this section, we expose the overall volume of data available to download and the different archived file types. EGA Archive growth in size and number of files The below figure represents the EGA archive growth in size (TB) and number of files. EGA Archive Growth per year lineChart('ega-archive-growth', 'https://stats.ega-archive.org/growth/archive', ['Volume (TB)'], ['T']) Archive files The below figure represents on a initial level, the percentage of archived files by data technology. The second level, acessible by clicking in the required extension, displays the number of files by extension archived in the ega archive. Please click over the extension to learn more about the files. EGA Archived Files barChart('ega-archived-files', 'https://stats.ega-archive.org/extensions', false ,'', true)

  Documentation about/statistics/archive

• WES Profiles from the CheckMate-577 Clinical Trial

  The dataset contains WES profiles of 396 patients from the CheckMate-577 (CA209-577) clinical trial whose ICF allows data deposition into a public repository. The Allprep DNA/RNA FFPE kit was used to simultaneously purify genomic DNA and total RNA from formalin-fixed, paraffin embedded (FFPE) tissue sections. DNA was analyzed by Whole Exome Sequencing using Swift Biosciences Accel-NGS 2S Hyb DNA Library Kit for library preparation and hybridization using Agilent SureSelect All Exon v6, followed by sequencing on the Illumina NovaSeq platform with a 100bp paired-end strategy and a target read depth of 100M per tumor sample. Fastq files are included.

  Dataset EGAD50000002395

• Deciphering the mutational landscape and the genome organization of LMS

  Leiomyosarcoma (LMS) are an uncommon group of malignant mesenchymal tumors composed of cells showing distinct smooth muscle differentiation. These tumors occur mainly in adults in any location of the body (soft-tissue, viscera or uterine). Soft-tissue LMS represent 10-15% of all soft-tissue sarcomas. The most frequent locations are the limbs followed by the retroperitoneum and uterine.

  Study EGAS00001001262

• Chracterising cellur pathways underlying CD3/CD28 activation of human CD4+ cells

  We devised an approach to disentangle the TCR and CD28 pathways upon stimulation in naive and memory primary human CD4+ T cells (Tcons) in response to defined stimulatory signals. Sorted Tcons were activated using a titration of anti-CD3 and anti-CD28 in combination as well as individually. As a control we cultured cells in the same conditions but without the stimuli. In total, we defined seven conditions from four individuals for sequencing. This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/ .

  Dataset EGAD00001006612

• Chracterising cellur pathways underlying CD3/CD28 activation of human CD4+ cells

  We devised an approach to disentangle the TCR and CD28 pathways upon stimulation in naive and memory primary human CD4+ T cells (Tcons) in response to defined stimulatory signals. Sorted Tcons were activated using a titration of anti-CD3 and anti-CD28 in combination as well as individually. As a control we cultured cells in the same conditions but without the stimuli. In total, we defined seven conditions from four individuals for sequencing. This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/.

  Dataset EGAD00001006610

• Spatial targeted gene sequencing of metastatic melanoma

  We performed deep targeted DNA sequencing for a panel of 265 cancer-related genes. This included subsampling 35 different regions of a metastatic melanoma biopsy that was treated with anti-PD-1 inhibitor. Samples with cancer cell purity greater than 80% based on pathologic assessment were used for cancer gene panel DNA sequencing. Mean sequencing coverage was 861x and paired-end reads in FASTQ format were generated by the Illumina pipeline and aligned to the reference human genome hg19 build using the Burrows-Wheeler Alignment Tool (BWA, v0.7.5) with default settings. Aligned reads were further processed using GATK with best practices for removing duplicates, indel removal and recalibration.

  Dataset EGAD00001005821

• Characterization of arrested B-lymphoid differentiation and leukemic cell states in ETV6-RUNX1-positive pediatric leukemia

  RNA was extracted from eight diagnostic ETV6-RUNX1 positive acute lymphoblastic leukemia samples collected in PAXgene blood RNA tubes using PAXgene Blood RNA kit (cat #762174, Qiagen GmbH, Hilden, Germany), following the version 2 instructions for manual purification. Samples were processed with Globin-Zero Gold rRNA Removal Kit (Illumina) and directional libraries were prepared using NEBNext Ultra Directional RNA Library Prep kit (New England Biolabs). The library preparation and paired end (150 bp) sequencing were performed by Novogene (HK) Company Limited (Hong Kong, China) using Illumina Novaseq 6000 aiming at 70 million read pairs per sample.

  Dataset EGAD00001006406

• 3q-capture DNA sequencing of atypical 3q26 cases

  3q-capture DNA sequencing was performed as we described previously 13. In summary, genomic DNA was fragmented using the Covaris shearing device (Covaris), and sample libraries were assembled following the TruSeq DNA Sample Preparation Guide (Illumina). After ligation of adapters and an amplification step, target sequences of chromosomal regions 3q21.1-q26.2 were captured using custom in-solution oligonucleotide baits (Nimblegen SeqCap EZ Choice XL). The design of target sequences was based on the human genome assembly hg19: chr3q21.1:126036241-130672290 - chr3q26.2:157712147-175694147. Amplified captured sample libraries were paired-end sequenced (2x100 bp) on the HiSeq 2500 platform (Illumina) and aligned against the hg19 reference genome using the Burrows-Wheeler Aligner (BWA)25

  Dataset EGAD00001006123

• Tam-Seq of HGSOC samples for fixative comparison study

  Targeted amplicon sequencing of samples as part of the study "Methanol-based fixation is superior to buffered formalin for next-generation sequencing of DNA from clinical cancer samples. The amplicon panel consists of 48 amplicons in TP53, PTEN, EGFR, PIK3CA, KRAS and BRAF genes as described previously [Forshew, STM 2012]. All libraries were pooled and quantify using DNA 1000 kit on Agilent 2100 Bioanalyzer and KAPA SYBR FAST ABI Prism qPCR Kit (KAPA Biosystems) on 7900HT Fast Real-Time PCR System (Applied Biosystems) according to the supplier's recommendations. Reads were aligned using bwa-mem v0.7.12-r1039 to the 1000 genomes version of human genome build GRCh37, retaining duplicate reads.

  Dataset EGAD00001001937

• SCLC study George et al. - WGS data set

  Whole genome sequencing was performed with DNA extracted from fresh-frozen tumor and normal material. Short insert DNA libraries were prepared with the TruSeq DNA PCRfree sample preparation kit (Illumina) for paired-end sequencing at a minimum read length of 2x100bp. Human DNA libraries were sequenced to an average coverage of minimum 30x for both tumor and matched normal. Murine DNA libraries of tumor and matched normal were both sequenced to a coverage of 25x.

  Dataset EGAD00001001273

• Transcriptomic profiling of RIRCD patient skeletal muscle, comparing muscle during affected phase to healthy control, and affected patient with and without additional EARS2 mutations.

  Illumina Nextseq total RNA sequencing profiles of skeletal muscle biopsies of 5 affected patients (F3/2M, F4/1F, F5/1M, F2/2F, F2/1M) compared to 6 control (Control040500, Control3509, Control3934, Control3949, Control4994, Control5106) and comparing 3 patients with additional EARS2 mutations (F2/2F, F2/1M, F5/1M) to 2 patients without (F3/2M, F4/1F). Illumina MiSeq total RNA sequencing profiles of skeletal muscle biopsies from patient F3/1M during affected disease phase (4 replicates: F3-1M_Affected_1, F3-1M_Affected_2, F3-1M_Affected_3, F3-1M_Affected_4) compared to recovered phase (F3-1M_Recovered_1, F3-1M_Recovered_2, F3-1M_Recovered_3, F3-1M_Recovered_4).

  Dataset EGAD00001006381

• The Causes of Clonal Blood Cell Disorders Study - SCOR_Custom (2018-04-19)

  We took a bone marrow aspirate and peripheral blood samples from a healthy patient aged around 60, and use flow cytometry to isolate 100 HSCs, 50 MEPs, and 50 GMPs. We grew these up into colonies, then whole genome sequenced each colony. Somatic mutations act as a unique barcode for each clone. We have designed a panel for targeted resequencing of the mutations that we find. We are now looking for these mutations in the peripheral blood, to see the dynamics of how HSCs contribute to the peripheral blood in health. This dataset contains all the data available for this study on 2018-04-19.

  Dataset EGAD00001004087

• RNAseq on 20 samples of multiple myeloma patients and 3 normal plasma cells.

  RNAseq was performed using 200 ng of total RNA by GATC Biotech. Directional libraries were performed after mRNA selection by polyA selection using UTP method. RNA-seq libraries were sequenced on HiSeq2500 Illumina machine using 100bp paired-end reads. Reads alignment was performed using the STAR aligner (version 2.4.0f1) and human genome hg19 as reference.

  Study EGAS00001004347

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

  COG-N-519 primary neuroblastoma cells were innoculated by subcutaneous injection into NSG mice. When tumours reached a size of 100-200mm3 miRNAs conjugated to nanoparticles were injected intratumourally every 2 days for 1 week. 24 hr after the last injection, snap frozen tumour tissue was harvested for RNA extraction and RNA-seq analysis.

  Study EGAS00001005581

• Deciphering RBP - alternative splicing networks in ALS iPSC-MN: NOVA1 gain and loss of function systems

  We produced NOVA1 and EGFP over-expression RNA-seq datasets in three healthy control individuals using lentivirus-mediated gene transfer to model NOVA1 gain of function. Additionally, we produced a NOVA1 loss of function RNA-seq dataset by generating iPSC-MN with NOVA1 knock out produced by CRISPR/Cas9 in the CV-B iPSC line.

  Study EGAS00001005881

• Finding structural variation and functional consequences from the primary leukemia cells (CLL) at the single-cell level

  In this study, we aimed to identify somatic structural variation of chronic lymphocytic leukemia (CLL) at the single-cell level and investigate its direct consequence on the nucleosome occupancy using scNOVA approach. For this purpose, we performed strand-specific single-cell sequencing of primary leukemia samples from 63-year-old female patient.

  Study EGAS00001004925

• Targeted DNA sequencing

  Targeted DNA sequencing of high-grade serous ovarian cancer (HGSC) tumour and normal samples from 15 patients with homologous recombination deficiencies. The dataset includes fastq files from 243 HGSC tumours (15 primary, 3 relapse, 225 end-stage) and 15 normals from 15 HGSC patients. Following target hybrid capture of 63 genes involved in DNA repair and response to treatment with an Agilent SureSelect XT panel, sequencing libraries were generated using the SureSelect XT Low Input Target Enrichment System (Agilent) as per the manufacturer's protocol. Libraries were sequenced on an Illumina NextSeq 500 at the Peter MacCallum Cancer Centre (Melbourne, Australia).

  Dataset EGAD00001009747

• Somatic mutations predict an aggressive phenotype in meningioma but do not drive grade progression

  A subset of meningiomas progress in histopathological grade and drivers of progression are poorly understood. We aimed to identify somatic mutations and copy number alterations (CNAs) associated with grade progression in a unique matched tumour dataset. This dataset consists of DNA sequencing from 10 individuals with meningiomas, where the meningiomas have underdone grade progression. 50 meningiomas were sequenced from the 10 individuals using the hybrid capture-based TruSight Oncology 500 (TSO500) Library Preparation Kit, and 13 of those meningiomas were also sequenced using Agilent SureSelect Clinical Research Exome V2. BAM files for the sequencing data are included in the dataset.

  Dataset EGAD00001009391

• Whole genome sequencing of acute erythroid erythroid leukemia

  Briefly, twenty paired tumor and germline DNAs were extracted from patients’ BM and from buccal mucosa, respectively. Samples were subjected to massively parallel sequencing using the HiSeq 2000, HiSeq2500, HiSeq X Ten, and/or NovaSeq 6000 according to the manufacturer’s instructions. Sequencing reads were aligned to NCBI Human Reference Genome Build 37 (hg19) by Burrows−Wheeler Aligner, version 0.7.10, with default parameters (http://bio-bwa.sourceforge.net/). PCR duplicates were eliminated using Picard tools version 1.39 (GATK).

  Dataset EGAD00001008357

• Single cell sequencing of human normal luminal cells

  The dataset includes 12 paired FASTQ files (6 samples) with single cell transcriptome sequencing data of normal breast luminal cells from ducts and TDLUs derived from reduction mammoplasties from three patients. Chromium Single Cell 3’ Reagent Kit v2 or v3 (10x Genomics) were used for processing of cells, whereafter sequencing was performed using the Illumina® NextSeq500/550 High Output Kit v2. Cell Ranger was used for generating FASTQ files and files from different lanes were concatenated prior to uploading the data to EGA. "R1" files include the feature barcodes and UMIs, while "R2" files include the reads.

  Dataset EGAD00001008499

• Whole genome and RNA-sequencing in T-cell acute lymphoblastic leukemia

  Dataset includes whole genome and transcriptomic sequencing data from five T-cell acute lymphoblastic leukemia (T-ALL) patients. Whole genome sequencing has performed from both diagnostic (T-ALL sample) and control (remission sample) samples. RNA-sequencing has performed from diagnostic samples. Samples has been taken from the bone marrow or peripheral blood.

  Dataset EGAD00001008658

• Spinocerebellar ataxia 15 (SCA15) derived iPSC WGS

  A collection of four induced pluripotent stem cell models (iPSC) derived from patients diagnosed with Spinocerebellar ataxia 15 (SCA15) . Spinocerebellar ataxia 15 (SCA15) is a neurological condition characterised by progressive gait and limb ataxia as well as abnormalities in eye movement and difficulties with balance, speech and swallowing (Synofzik et al., 2011). Whole Genome Sequencing was performed to confirm the presence of a heterozygous deletions in the inositol 1,4,5-triphosphate receptor gene (ITPR1), characteristic of the disease. Cell models names: HPSI0216i-vieg_5 or Vieg_5 (WTSIi472-A), HPSI0216i-vieg_3 or Vieg_3 (WTSIi472-B), HPSI0216i-dacv_6 or Dacv_6 (WTSIi554-A), HPSI0216i-boho_3 or Boho_3 (WTSIi502-A). All iPSC models are available via ECACC-Culture Collections.

  Dataset EGAD00001009851

• WGS data for HGSC patient derived organoids and matching tumor and normal samples (Wennerberg)

  Sequencing data of 10 high-grade serous carcinoma (HGSC) patients (58 samples including blood derived normal samples as germline controls, fresh frozen tissue samples as tissue controls and organoids) sequenced with HiSeq X Ten / BGISEQ-500 / MGISEQ-2000.

  Dataset EGAD00001010019

• Single-cell RNA sequencing of breast cancer lung metastasis and adjacent normal tissue

  This dataset contains single-cell RNA sequencing data from two samples: L1 (breast cancer metastasis to lung) and N3 (adjacent normal lung tissue) from a female patient. The samples were processed using 10X Chromium 3' technology and sequenced on Illumina NextSeq 500. This data supports the study "Endocrine therapy reprogramming of breast cancer facilitates metastatic escape via upregulation of P-Rex1/Rac1 signalling" which investigates how endocrine therapy reprograms breast cancer cells, leading to upregulation of P-Rex1/Rac1 signalling pathways that facilitate metastatic escape. The single-cell analysis reveals cellular reprogramming mechanisms in endocrine therapy-resistant breast cancer cells that form metastases in the lung.

  Dataset EGAD00001015769

• Bulk RNA-seq dataset of Single cell RNA sequencing reveals induced bifurcated differentiation after RUNX1::RUNX1T1 depletion in patient-derived leukemic blasts

  In this study, we demonstrate that primary AML cells harboring the chromosomal translocation t(8;21) are critically dependent on the corresponding fusion gene, RUNX1::RUNX1T1, to suppress differentiation and maintain stemness. Silencing RUNX1::RUNX1T1 expression using siRNA-loaded lipid nanoparticles induces significant changes in chromatin accessibility, redirecting the leukemia-associated transcriptional network towards a myeloid differentiation program. Single-cell analyses reveal that this transcriptional reprogramming is associated with the depletion of immature stem and progenitor-like cell populations, accompanied by an expansion of granulocytic and eosinophilic/mast cell-like populations with impaired self-renewal capacity.

  Dataset EGAD00001015508

• 76 cancer and normal whole genomes from eleven SI-NET patients

  This dataset comprises of 76 cancer and normal whole genomes obtained from 11 SI-NET patients, in the form of two fastq files (forward and reverse reads) for each genome containing sequences generated by Illumina NovaSeq 6000 system.

  Dataset EGAD00001006161

• Oncogenic cooperation between the TCF7-SPI1 fusion and NRAS(G12D) requires β-catenin activity to drive T-cell acute lymphoblastic leukemia.

  In this study we investigate the role of TCF7-SPI1 fusions, more specifically in cooperation with RAS mutations. We make use of patients samples. This study contains paired-end RNA sequencing of the patients, Oxford Nanopore Technologies (ONT) sequencing, single cell RNA sequencing and RNA sequencing of treatment with inhibitors of these samples.

  Study EGAS00001005097

• HCA_Thymus_Disease_DiGeorge_Transplant_RNA

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

  Study EGAS00001004025

• SNP array analysis of spondylocostal dysostosis patient iPSCs and gene edited isogenic controls

  This study, "SNP Array Analysis of Gene Edited SDV Patient iPSCs" is part of a larger study where we applied our recently established experimental in vitro model system of the human segmentation clock, for the analysis of human segmentation defects of the vertebrae (SDV) including spondylocostal dysostosis (SCD). To this end we generated patient-derived iPSC lines, identified putative disease-causing mutations and corrected these mutations using CRISPR/Cas9-based genome editing technology. We identified in the patient-sample originally obtained from the NIGMS Human Genetic Cell Repository at the Coriell Institute for Medical Research (#: GM13539) heterozygous compound mutations in MESP2. These mutations were corrected accordingly and the resulting clones were genotyped by SNP array analysis.

  Study phs001975

• Genomic Regions Associated with Susceptibility to Barrett's Esophagus and Esophageal Adenocarcinoma in African Americans: The Cross BETRNet Admixture Study

  Differences in rates of diseases between different populations with similar environments are presumed to be secondary to variability in population frequencies of disease causing alleles. Recently admixed populations such as African Americans (AAs) provide a natural opportunity to identify disease-causing variants by examining the ancestry of long chromosomal haplotypes. Admixture mapping approach can be successful in locating genes for diseases such as EAC whose rates varies markedly between the ancestral populations. This is a case only study with 54 African American cases and also on a subset of 28 cases with high genotyping quality. We seek to identify chromosome regions that have excess European ancestry and contrasting it to excess African ancestry.

  Study phs001454

• Exome Sequencing of Schizophrenia Cases and Controls in the South African Xhosa Population

  The goal of this international collaborative project is to identify genes responsible for Schizophrenia in the Xhosa population of South Africa. The vast majority of the genetic basis for Schizophrenia has yet to be explained. We hypothesize that genes and pathways important to Schizophrenia will harbor different, severe disease-causing mutations in different affected individuals. Given the genetic diversity of African populations, we expect to find genes for Schizophrenia that have not yet emerged from studies of other populations. This project will also foster the development of gene discovery research for neuropsychiatric disorders in Africa. Our approach will identify genes important for the disorder in populations worldwide. These genes will stimulate future efforts to develop more effective treatment and prevention strategies.

  Study phs000959

• Ultrasensitive Detection and Monitoring of Circulating Tumor DNA using Structural Variants in Early-Stage Breast Cancer

  Circulating tumor DNA (ctDNA) detection has an emerging role in the management of breast cancer, offering a non-invasive means to monitor disease status and detect recurrence. This study demonstrates that longitudinal monitoring of tumor-specific structural variants - frequent alterations observed across many tumor types including all subtypes of breast cancer derived from Whole Genome Sequencing data - allows for ctDNA detection in nearly all participants in this cohort with untreated early breast cancer prior to starting neoadjuvant therapy. On-treatment ctDNA monitoring enabled the early identification of patients at high risk of recurrence and ctDNA was detected prior to relapse in participants across all receptor subtypes. These findings demonstrate the clinical validity of this assay approach for ultrasensitive ctDNA monitoring.

  Study EGAS50000000799

• Whole genome sequencing of 50 trios, where the child is affected with ID, and the parents are unaffected

  50 trios were whole genome sequenced with Complete Genomics to a depth of 80x. Each trio the child was affected with severe ID, and the parents were unaffected. All trios were negative for array, targetted gene and whole exome screening.

  Study EGAS00001000769

• Small-molecule inhibitors in melanoma - Kenski / Kong - WES (2019-04-11)

  Small-molecule inhibitors targeting the most commonly activated pathway in melanoma, MAPK pathway (either alone or in combination) are already given to melanoma patients for few years, and initially reduce tumour burden dramatically, eventually melanomas become resistant and tumours progress while on treatment. Resistance to this treatment occurs by acquisition of additional mutations or other alterations that affect the mitogen-activated protein kinase (MAPK) pathway by either direct or indirect signalling. Many resistance mechanisms somehow lead to reactivation of extracellular signal-regulated kinase (ERK), thereby restoring signalling of the oncogenic BRAF/MEK/ERK pathway. In addition, PI3K pathway activation contributes to resistance to BRAF inhibition. Less frequent but equally important to the phenomenon of targeted drug resistance is the observation that B15-20% of BRAF mutant melanoma patients fail to respond to BRAF inhibition already early on treatment, owing to intrinsic resistance. These patients have little therapeutic options, unless immunotherapy can be given. To better understand the resistance mechanisms in MAPK inhibitor-treated melanoma patients and melanoma biology, our lab generated a big panel of MAPK inhibitor resistant melanoma cell lines by continuous drug exposure. The understanding of the genetic landscape and gene expression as well as cross resistance to other treatment regimens, and other aspects of melanoma biology such as phenotype switch, will allow us to better exploit new therapeutic strategies for melanoma patients. . This dataset contains all the data available for this study on 2019-04-11.

  Dataset EGAD00001004952

• RNA-seq of cultured human hematopoietic stem and progenitor cells from umblical cord blood in cytokine-rich ex vivo culture conditions following sphingolipid modulation

  To elucidate the biological pathways altered by sphingolipid modulation with N-(4-hydroxyphenyl) retinamide (4HPR) treatment in human HSPC that may contribute to the restraint in proliferation while promoting persistence of HSC self-renewal as well as determine the mechanism of synergy in enhancement of HSC self-renewal with CB CD34+ agonists UM171 and StemRegenin 1 (SR1), we performed RNA-sequencing (RNA-Seq) of 3 pools of lin-CB cells following 2 or 4 days with DMSO, 4HPR, UM171+SR1 or 3-Factor (4HPR+UM171+SR1). We identified modulation of sphingolipid metabolism regulates self-renewal through activating coordinated stress pathways that coalesce on endoplasmic reticulum stress and autophagy programs.

  Study EGAS00001003756

• Single-cell profiling of the leukemic and non-leukemic immune cell compartments in CD8+ T-cell Large Granular Lymphocytic Leukemia

  We performed a detailed and precise characterisation of the clonally expanded leukemic cells in CD8+ T cell Large Granular Lymphocytic Leukemia (T-LGLL). By combining scRNA+TCRαβ-seq with bulk RNA sequencing data we showed evidence of a strong antigen-driven immune response that shapes the entire immune cell repertoire in T-LGLL. Our study highlights how the whole immune cell repertoire including the hyperexpanded CD8+ T-LGLL cells, the non-leukemic CD8+ cells, CD4+ cells, and monocytes contribute to the CD8+ T-LGLL disease phenotype. Please note that this submission contains the fastq files while the processed count matrices can be found in ArrayExpress by the accession E-MTAB-11170.

  Study EGAS00001005297

• minION fastq files of 10 different tumor samples from the Master program (H021)

  Nanopore RNA Sequencing was done for 10 tumor samples. Direct cDNA sequencing was performed using the SQK-DCS109 kit (Oxford Nanopore Technologies). For analysis of a single sample on a MinION flow cell (version R9.4.1), 5 μg RNA was used as input. For multiplexing on a MinION flow cell, 2.5 μg RNA per sample was used as input, and the native barcoding expansion kit EXP-NBD104 was employed in conjunction with SQK-DCS109. After reverse transcription with Maxima H Minus Reverse Transcriptase (Thermo Scientific), second-strand synthesis was performed using the 2x LongAmp Taq Master Mix (New England Biolabs). The resulting double-stranded cDNA was subjected to end-repair and dA-tailing using the NEBNext Ultra End Repair/dA-Tailing Module (New England Biolabs). For multiplexed libraries, this step was followed by barcode ligation and library pooling. Next, libraries were quantified with a Qubit Fluorometer 3.0 (Life Technologies). Finally, sequencing adapters were added to the library preparations and ligated with Blunt/TA Ligase Master Mix (New England Biolabs), followed by further quality control using a Qubit. Samples ACC1 and ACC2 were analyzed on individual MinION flow cells, while the remaining eight samples were sequenced as multiplexed libraries on two MinION flow cells by pooling four samples for each run. Five ACC samples were also analyzed individually on Flongle flow cells

  Dataset EGAD00001008970

• Common Variant GWAS, Genetics & Epidemiology of Colorectal Cancer Consortium (GECCO)

  Genetics & Epidemiology of Colorectal Cancer Consortium (GECCO) is a collaborative effort which aims to accelerate the discovery of colorectal cancer-related variants by discovering, replicating and fine-mapping Genome Wide Association Study (GWAS) findings, conducting a meta-analysis of GWAS data, and investigating how genetic variants are modified by environmental risk factors. The coordinating center for this consortium is based at the Fred Hutchinson Cancer Research Center (Principal investigator: Ulrike Peters). The GECCO Consortium is utilized in the following dbGaP individual studies. To view genotypes, and derived variables collected in these individual studies, please click on the following individual studies below or in the "Sub-studies" box located on the right hand side of this top-level study page phs001078 GECCO Consortium. phs000965 VITAL phs001056 DALS phs001077 WHI Colorectal Cancer phs001092 PMH CCFR phs001094 PLCO phs001104 ASTERISK phs001113 DACHS phs001114 HPFS phs001128 PHS phs001129 NHS phs001170 Colo2and3 phs001171MEC Colorectal Cancer

  Study phs001078

• Zostavax vaccination-induced changes in the T cell receptor repertoire to varicella zoster virus

  Diversity and size of the antigen-specific T cell receptor (TCR) repertoire are two critical determinants for successful control of chronic infection. Varicella zoster virus (VZV) that establishes latency during childhood is able to escape control mechanisms, in particular with increasing age. We examined the TCR diversity of VZV-specific CD4 T cells in individuals older than 50 years by studying three identical twin pairs and three unrelated individuals before and after vaccination with live attenuated VZV. While all individuals had a small number of dominant T cell clones, the breadth of the VZV-specific repertoire differed markedly among different individuals. A genetic influence was seen for the sharing of individual TCR sequences from antigen-specific cells, but not for repertoire richness or the selection of clonal dominance. VZV vaccination favored the expansion of infrequent VZV-specific TCRs including those from naïve T cells while leaving dominant T cell clones mostly unaffected.

  Study phs001082

• GeneScreen, a Population Based, Targeted Genomic Screening Study

  The GeneScreen research study was based at the University of North Carolina (UNC) at Chapel Hill. It brought together researchers from different disciplines, including genetics, clinical medicine, bioethics, sociology, anthropology, psychology, and public health, to study the best ways to offer targeted genetic screening to the general adult population. DNA samples were collected from people who joined GeneScreen to look at a targeted panel of 17 genes. It tested for genetic differences (called mutations) that can cause one of 11 rare, but preventable or treatable conditions, including certain types of cancer and heart disease. Each condition has specific medical advice people can follow with their doctors to prevent or treat a serious health problem. The GeneScreen study was approved by the UNC Institutional Review Board and by the Kaiser Permanente Center for Health Research Institutional Review Board. GeneScreen is funded by the National Human Genome Research Institute of the National Institutes of Health.

  Study phs001817

• Fine Mapping of Eight Psoriasis Susceptibility Loci

  Psoriasis is a common immune-mediate disease identified through scaly patches of the skin. In this study we collected genotype information on 5,067 samples of European ancestry as a follow-up study of our initial GWAS (Nair et al. 2009). We designed an Illumina iSelect custom genotyping array with 2,269 tagging SNPs in the eight known psoriasis susceptibility regions (MHC, IL12B, IL23R, IL23A, TNFAIP3, IL13, RNF114, and TNIP1). The custom array also included 5,463 SNPs outside the eight known susceptibility regions, which were selected based on their association p-values in a meta-analysis of HapMap-imputed genotypes of two published GWAS-CASP (Nair et al. 2009) and (Ellinghaus et al. 2010). After quality control we analyzed 4,806 samples (2,699 cases and 2,107 controls). Please note: The accession number for this dbGaP study was incorrectly listed in the relevant publication (Das et al., 2015, Eur. J. Hum. Genet 23:844-853) as phs000019.v1.p1.

  Study phs001298

• A Genome-wide Association Study (GWAS) of Risk for Osteosarcoma

  This is a genome-wide association study (GWAS) of osteosarcoma, the most common primary bone malignancy. Osteosarcoma typically occurs in adolescents and young adults. It occurs at increased frequency in several inherited cancer predisposition syndromes but the genetic contribution to sporadic osteosarcoma is largely unexplored. The objective of this study was to identify genetic risk factors for osteosarcoma by conducting a genome-wide association study. We developed collaborations with multiple institutions in order to attain the necessary sample size required to discover novel loci in the genome associated with osteosarcoma using the GWAS approach. Genomic DNA (either blood or buccal in source) derived from osteosarcoma cases was obtained from each participating institution or research group. De-identified blood or buccal cell DNA samples from osteosarcoma cases were derived from existing biobanks at the collaborative institutions. Control subjects were derived from existing NCI cohorts and matched by gender and ethnicity.

  Study phs000734

• The Microbial Ecology of Bacterial Vaginosis: A Fine Scale Resolution Metagenomic Analysis

  Archived self-collected vaginal swabs were utilized from a pilot study of vaginal douching cessation (NIH/NIAID R03-AI061131). Thirty-nine non-pregnant, reproductive-age women who reported the use of vaginal douche products in the two months prior to screening were enrolled. Thirty-three of these successfully completed the 16-week longitudinal study. Participants self-collected vaginal swabs and smears twice weekly. We report sequences based on the analysis of 16S rRNA gene sequences amplified from whole genomic DNA isolated from the swabs. Bacterial vaginosis (BV) is defined by Gram's stain of vaginal fluid (Nugent's score =7). The large body of information generated will facilitate understanding of vaginal microbial community dynamics, the etiology of BV, and drive the development of better diagnostic tools for BV. Furthermore, it is hoped that the information will enable a more personalized treatment of BV and ultimately, prevent adverse sequelae associated with BV.

  Study phs000261

• BarcUVa-Seq (Biology of Colorectal Cancer Risk Enhancers)

  This study was designed to generate a cohort of normal colon mucosal biopsies from the "average risk" population. Its primary aims included the development of an RNA-seq dataset of normal colon mucosal biopsies across three colon regions (ascending, transverse and descending). Further, we aimed to provide plausible prioritization to genetic components of colorectal cancer risk by employing methods such as expression quantitative trait loci analysis. In doing so, we provide a novel reference dataset for the study of colon cancer risk in the healthy colon epithelium. RNA-seq was performed in batches on an Illumina HiSeq 2500 (batch 1-7) or NovaSeq 6000 (batch 8) on a total of 463 samples. Matched genotyping data was generated on the Illumina OncoArray BeadChip. Phasing was carried out using Minimac 3 and imputation was performed using The Haplotype Reference Consortium panel on the Michigan Imputation Server.Genotype and RNA-seq data will be made available in dbGaP.

  Study phs003338

• Functional Genomic Landscape of Acute Myeloid Leukemia

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

  Study phs001657

• Type I Interferon Exacerbates Mycobacterium Tuberculosis Induced Human Macrophage Death

  In this study, we tested whether type I interferons (IFN-I), namely IFN-alpha and IFN-beta, may promote Mycobacterium tuberculosis (Mtb) pathogenesis by exacerbating cell death of human monocyte-derived macrophages (MDM) infected with Mtb. We differentiated the MDM under two different published methods (see Document Method.pdf for Table 1 of Methods). To determine if MDM infected with Mtb upregulates IFN-I transcripts, signaling factors, or IFN-I stimulated genes (ISGs), the MDM were infected with Mtb or treated with an activator of stimulator of IFN genes (STING), diamidobenzimidazole (di-ABZI). STING activation acted as a positive control for IFN-I induction and ISG upregulation. Indeed, di-ABZI treated MDM differentiated under both methods upregulated ISGs 24 hpi. At 24 hour post treatment, MDM differentiated under one method, but not under another method, upregulated ISGs, such as ISG15, IFITM3, and CXCL10, upon Mtb infection. MDM differentiated under both methods upregulated ISGs upon di-ABZI treatment.

  Study phs003607

• Neoadjuvant nivolumab or nivolumab plus ipilimumab in early-stage triple negative breast cancer: phase 2 adaptive BELLINI trial. WES

  The adaptive BELLINI trial explored whether short combination ICI induces immune activation (primary endpoint: two-fold increase in CD8+ T cells or IFNG), providing rationale for neoadjuvant ICI without chemotherapy. In window of opportunity cohorts A (4 weeks anti-PD1) and B (4 weeks anti-PD1 + anti-CTLA4), we observed immune activation in 53% (8/15) and 60% (9/15) of patients, respectively. High tumor-infiltrating lymphocytes (TILs) correlated with response. Based on these data, we opened cohort C for patients with high TILs (≥50%) who received 6 weeks neoadjuvant anti-PD1 + anti-CTLA4 followed by surgery (primary endpoint: pathological complete response, pCR). 53% (8/15) of patients had major pathological response (< 10% viable tumor) at resection, with 33% (5/15) having pCR. All cohorts met Simon’s two-stage threshold for expansion to stage II. In conclusion, neoadjuvant immunotherapy without chemotherapy demonstrates potential efficacy and warrants further investigation in patients with early TNBC.

  Study EGAS50000000568

• Neoadjuvant nivolumab or nivolumab plus ipilimumab in early-stage triple negative breast cancer: phase 2 adaptive BELLINI trial. RNA-Seq

  The adaptive BELLINI trial explored whether short combination ICI induces immune activation (primary endpoint: two-fold increase in CD8+ T cells or IFNG), providing rationale for neoadjuvant ICI without chemotherapy. In window of opportunity cohorts A (4 weeks anti-PD1) and B (4 weeks anti-PD1 + anti-CTLA4), we observed immune activation in 53% (8/15) and 60% (9/15) of patients, respectively. High tumor-infiltrating lymphocytes (TILs) correlated with response. Based on these data, we opened cohort C for patients with high TILs (≥50%) who received 6 weeks neoadjuvant anti-PD1 + anti-CTLA4 followed by surgery (primary endpoint: pathological complete response, pCR). 53% (8/15) of patients had major pathological response (< 10% viable tumor) at resection, with 33% (5/15) having pCR. All cohorts met Simon’s two-stage threshold for expansion to stage II. In conclusion, neoadjuvant immunotherapy without chemotherapy demonstrates potential efficacy and warrants further investigation in patients with early TNBC.

  Study EGAS50000000567

• Role of Microglia Somatic Mutations in Neurodegenerative Diseases

  Somatic genetic heterogeneity resulting from post-zygotic DNA mutations is widespread in human tissues and can cause diseases, however few studies have investigated its role in neurodegenerative processes such as Alzheimer&#39;s Disease (AD). Here we report the selective enrichment of microglia clones carrying pathogenic variants, that are not present in neuronal, glia/stromal cells, or blood, from patients with AD in comparison to age-matched controls. Notably, microglia-specific AD-associated variants preferentially target the MAPK pathway, including recurrent CBL ring-domain mutations. These variants activate ERK and drive a microglia transcriptional program characterized by a strong neuro-inflammatory response, both in vitro and in patients. Although the natural history of AD-associated microglial clones is difficult to establish in human, microglial expression of a MAPK pathway activating variant was previously shown to cause neurodegeneration in mice, suggesting that AD-associated neuroinflammatory microglial clones may contribute to the neurodegenerative process in patients.

  Study phs002213

• Xenodiagnosis of Lyme Disease

  Ixodes scapularis ticks are an important vector for at least six tick-borne human pathogens, including the predominant North American Lyme disease spirochete Borrelia burgdorferi. The ability for these ticks to survive in nature is credited, in part, to their ability to feed on a variety of hosts without excessive activation of the proinflammatory branch of the vertebrate immune system. While the ability for nymphal ticks to feed on a variety of hosts has been well-documented, the host-parasite interactions between larval I. scapularis and different vertebrate hosts is relatively unexplored. In our clinical trial, patients with prior Lyme disease who had completed antibiotic therapy were exposed to 25-30 laboratory-reared larval ticks. Skin biopsies were taken before tick placement and/or after ticks were allowed to feed to repletion and we examined the effects on the transcriptional profile of human skin after the larval tick bites. We note pronounced evidence of inflammation in humans.

  Study phs003314

• Functional Variant rs9344 at 11q13.3 Regulates CCND1 Expression in Multiple Myeloma with t(11;14)

  Multiple myeloma (MM) is a plasma cell (PC) malignancy characterized by cytogenetic abnormalities, such as t(11;14)(q13;q32), resulting in CCND1 overexpression. The rs9344 G allele within CCND1 is the most significant susceptibility allele for t(11;14). We have found the G risk allele is enriched in both healthy individuals of African ancestry and African American individuals with MM. The overall aim of this study was to identify the mechanism behind why the G allele is enriched in t(11;14) MM. To reach this goal, we performed ATAC-seq from 100,000 CD138+ tumor cells from 26 patients with MM. In addition, we performed ChIP-seq using antibodies against H3K4me1, H3K27ac and H3K4me3 from 100,000 CD138+ tumor cells from 8 patients with MM. We used these data to evaluate whether the G allele of rs9344 is associated with elevated chromatin accessibility, H3K27ac and H3K4me3 in t(11;14) MM.

  Study phs003997

• International Cancer Proteogenome Consortium (ICPC): Proteogenomics of Early Stage Lung Adenocarcinoma in Taiwan

  Lung cancer in East Asia is characterized by a high percentage of never-smokers with early-onset adenocarcinoma, predominantly with EGFR mutations. To provide an insight into the molecular phenotype of this demographically distinct disease, we have performed a proteogenomics study on a prospectively collected cohort representing early stage lung adenocarcinoma in Taiwan. The distinct mutational profile revealed a high prevalence of the APOBEC mutational signature in early-onset females, implicating differential regulation of APOBEC enzymes and DNA damage pathways, as well as enrichment of mutational signatures congruent with environmental carcinogens over-represented in the genomic location of EGFR. We delineate the proteogenomic hallmarks of tumor progression and propose a proteomics-informed classification that resolves the EGFR mutation heterogeneity associated with survival within the early stages. Functional annotation of the molecular subtypes by protein network analysis highlights candidate biomarkers for patient stratification. Our integrative analysis reveals the molecular architecture of lung cancer in East Asia and enables the path for precision medicine.

  Study phs001954

• PD-1 antibody-bound progenitor-exhausted CD8+ T cells in lymph nodes boost PD-1-blockade anti-tumor immunity in gastrointestinal cancer

  While progenitor-exhausted T cells (Tpex) expressing TCF1 and PD-1 are crucial for the therapeutic effect of immune checkpoint inhibitors (ICIs; therapeutic anti-PD-1 antibodies), the dynamics of ICI-bound Tpex are not fully understood. In this study, we investigated ICI-bound T cells in detail using combined sequencing analysis at the single cell level. By analyzing samples from gastrointestinal cancer patients with or without ICI treatment, we found that Tpex were enriched in proximal lymph nodes (LNs) and proliferated at a high rate after ICI treatment. Importantly, ICI high-bound Tpex in LNs shared T-cell receptor clonotypes with intratumoral exhausted CD8+ T cells (Tex), suggesting their migration to tumor sites after ICI treatment. These findings indicate that ICIs initially target PD-1+CD8+ Tpex in LNs, prompting their proliferation. Subsequently, these cells migrate to tumors and differentiate into Tex, thereby exerting anti-tumor immunity.

  Study JGAS000720

• Single Cell RNA Transcriptomics of Mantle Cell Lymphoma Reveals the Presence of Treatment-Resistant Subclones at the Time of Diagnosis

  Mantle cell lymphoma is a chronically relapsing B cell neoplasm characterized by clonal heterogeneity. We implemented single cell RNA sequencing of paired tumor samples from four patients with an aggressive nodal MCL at diagnosis and after failure of standard immunochemotherapy. Clustering the cells based on the inferred CNVs showed small subclones present at diagnosis with a CNV profile similar to the major subclone at relapse. Comparison of these subclones to major subclones present at diagnosis revealed 119 upregulated pathways common for the four patient with an aggressive MCL, including NF-kappaB and PTEN signaling pathways. Additionally, we sequenced a patient with an indolent to blastoid MCL transformation with intestinal tissue involvement. In contrast to other compartments at relapse, the cells in the intestine showed strikingly different CNV profile and presence of new driver mutations including NOTCH1. In conclusion, our study demonstrates that scRNAseq can potentially detect therapy resistant subclones at diagnosis.

  Study EGAS50000000825

• Resequencing_candidate_genes_for_male_spermatogenic_impairment

  This study aims to identify novel candidate variants from human Y-chromosomal genes DAZ, BPY2 and CDY1 by resequencing the coding regions of these genes from male patients with spermatogenic impairment. The coding regions of the genes have been amplified by standard PCR, amplicon lengths range from 244 to 486 bp. A total of 61 amplicons were amplified for each of the 96 patients, totalling to approx. 25 kb per sample. Amplicons were quantified by gel electrophoresis and pooled in approx. equimolar concentrations per patient. For each of the 96 submitted samples, approx. 1 microgram of amplified DNA pool is provided in a total volume of 120 microlitres. The samples need to be indexed and libraries prepared for a PE250bp Illumina MiSeq run. This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/

  Study EGAS00001002157

• Comparing nodal versus bony metastatic spread using tumour phylogenies

  The role of lymph node metastases in distant prostate cancer dissemination and lethality is ill defined. Patients with metastases restricted to lymph nodes have a better prognosis than those with distant metastatic spread, suggesting the possibility of distinct aetiologies. To explore this, we traced patterns of cancer dissemination using tumour phylogenies inferred from genome-wide copy-number profiling of 48 samples across 3 patients with lymph node metastatic disease and 3 patients with osseous metastatic disease. Our results show that metastatic cells in regional lymph nodes originate from evolutionary advanced extra-prostatic tumour cells rather than less advanced central tumour cell populations. In contrast, osseous metastases do not exhibit such a constrained developmental lineage, arising from either intra or extra-prostatic tumour cell populations, at early and late stages in the evolution of the primary. Collectively, this comparison suggests that lymph node metastases may not be an intermediate developmental step for distant osseous metastases, but rather represent a distinct metastatic lineage.

  Study EGAS00001001801

• A Genomics-Based Classification of Human Lung Tumors

  We characterized genome alterations in 1255 clinically annotated lung tumors of all histological subgroups to identify genetically defined and clinically relevant subtypes. More than 55% of all cases had at least one oncogenic genome alteration potentially amenable to specific therapeutic intervention, including several personalized treatment approaches that are already in clinical evaluation. Marked differences in the pattern of genomic alterations existed between and within histological subtypes, thus challenging the original histomorphological diagnosis. Immunohistochemical studies confirmed many of these reassigned subtypes. The reassignment eliminated almost all cases of large cell carcinomas, some of which had therapeutically relevant alterations. Prospective testing of our genomics-based diagnostic algorithm in 5145 lung cancer patients enabled a genome-based diagnosis in 3863 (75%) patients, confirmed the feasibility of rational reassignments of large cell lung cancer, and led to improvement in overall survival in patients with EGFR-mutant or ALK-rearranged cancers. Thus, our findings provide support for broad implementation of genome-based diagnosis of lung cancer.

  Study EGAS00001000647

• Autozygosity_pilot_Born_in_Bradford

  The offspring of first cousin marriages have ~6% of their genome autozygous, i.e. homozygous identical by descent, or even more if there was further consanguinity in their ancestry. In the UK there are large populations with very high first cousin marriage rates of 20-50%. Sequencing the exomes of a sample of these individuals has the potential both to support genetic health programmes in these populations, and to provide genetic research information about rare loss of function mutations. This pilot study based on existing cohort samples from the Born In Bradford study will identify homozygous individuals for almost all variants down to an allele frequency around 1%, plus individuals carrying hundreds of new homozygous rare loss-of-function variants, and will support development of community relations and ethics for a wider study currently being designed. The data deposited in the EGA consist of low coverage whole exome sequencing on these samples.

  Study EGAS00001000462

• pancreatic ductal adenocarcinoma exomes in study: Pro-immunogenic Impact of MEK inhibition combined with an anti-CD40 immunostimulatory antibody

  This dataset contains 3 pairs of exomes, germline (from whole blood) and patient-derived xenograft (PDX), from human pancreatic durctal adenocarcinoma patients. The data is referred to in the publication: "Pro-immunogenic impact of MEK inhibition synergizes with agonist anti-CD40 immunostimulatory antibodies in tumor therapy" (Nature Communications, 2020) Abstract: Cancer types with lower mutational load and a non-permissive tumor microenvironment are intrinsically resistant to immune checkpoint blockade. While the combination of cytostatic drugs and immunostimulatory antibodies constitutes an attractive concept for overcoming this refractoriness, suppression of immune cell function by cytostatic drugs may limit therapeutic efficacy. Here we show that targeted inhibition of mitogen-activated protein kinase (MAPK) kinase (MEK) does not impair dendritic cell-mediated T-cell priming and activation. Accordingly, combining MEK inhibitors (MEKi) with agonist antibodies (Abs) targeting the immunostimulatory CD40 receptor resulted in potent synergistic anti-tumor efficacy. Detailed analysis of the mechanism of action of MEKi GDC-0623 by means of flow cytometric analysis of the tumor immune infiltrate and whole tumor transcriptomics showed that, in addition to its cytostatic impact on tumor cells, this drug exerts multiple pro-immunogenic effects, including the suppression of M2-type macrophages, myeloid derived suppressor cells and CD4+ T-regulatory cells. In addition, MEKi was found to induce tumor-cell intrinsic interferon signaling, which contributed to antigen presentation by tumor cells. Finally, the tumoridical impact of MEKi involves the activation of multiple pro-inflammatory pathways involved in immune cell effector function in the tumor microenvironment. Our data therefore indicate that the combination of MEK inhibition with agonist anti-CD40 Ab is a promising therapeutic concept, especially for the treatment of mutant Kras-driven tumors such as pancreatic ductal adenocarcinoma.

  Dataset EGAD00001005938

• Atypical teratoid/rhabdoid tumoroids reveal subgroup-specific drug vulnerabilities

  Atypical teratoid/rhabdoid tumors (ATRTs) represent a rare, but aggressive pediatric brain tumor entity. They are genetically defined by mutations in SWI/SNF chromatin remodeling complex members SMARCB1 or SMARCA4. ATRTs can be subdivided in different molecular subgroups based on their epigenetic profiles. Although recent studies suggest that the different subgroups have distinct clinical features, subgroup-specific treatment regimens have not been developed thus far. This is hampered by the lack of pre-clinical in vitro models representative of the different molecular subgroups. Here, we describe the establishment of ATRT tumoroid models from the ATRT-MYC and ATRT-SHH subgroups. We demonstrate that ATRT tumoroids retain subtype-specific epigenetic and gene expression profiles. High throughput drug screens on our ATRT tumoroids revealed distinct drug sensitivities between and within ATRT subgroups. Our ATRT tumoroids represent the first pediatric brain tumor organoid model, providing representative pre-clinical models allowing for the development of subtype-specific therapies.

  Study EGAS00001006422

• MGA-NUTM1 fusion in high grade spindle cell sarcoma

  NUT carcinoma (NC) with mesenchymal differentiation have rarely been described in the literature. In this report, we describe the characterization of two cases of high grade spindle cell sarcoma harboring a novel MGA-NUTM1 fusion. Whole genome sequencing identified the presence of complex rearrangements resulting in a MGA-NUTM1 fusion gene in the absence of other significant somatic mutations. The fusion protein was predicted to retain nearly the entire protein sequence of both MGA (exons 1-22) and NUTM1 (exons 3-8). In contrast to typical cases of NC, these cases were successfully treated with aggressive local control measures (surgery and radiation) and both patients remain alive without disease. These cases describe a new subtype of NUTM1-rearranged tumors warranting expansion of diagnostic testing to evaluate for the presence of MGA-NUTM1 or alternative NUTM1 gene fusions in the diagnostic workup of high grade spindle cell sarcomas or small round blue cell tumors of ambiguous lineage.

  Study EGAS00001003341

• A cycling, progenitor-like cell population at the root of atypical teratoid rhabdoid tumor subtype differentiation trajectories.

  Background: Atypical teratoid rhabdoid tumors (ATRTs), characterized by the loss of SMARCB1, are among the most lethal pediatric central nervous system (CNS) tumors. Three molecular subtypes have been identified, each defined by distinct molecular and clinical features. No subtype-specific treatments are available, highlighting the necessity to better understand inter- and intra-subtype heterogeneity. Methods: We generated a single-nucleus transcriptome atlas of ATRTs, validated by single-cell ATAC-seq and spatial transcriptomics, to study subtype-specific differentiation trajectories. Results: We identified brain progenitor-like expression profiles within unique subtype-specific differentiation lineages. A shared cycling, progenitor-like cell population, interspersed throughout tumors, was observed across all ATRT samples. Moreover, we demonstrate that subtype-specific differentiation trajectories can be induced pharmacologically in ATRT tumoroids directing tumor cells towards a non-proliferative, mature phenotype. Conclusions: Our study reveals that ATRT subtypes exhibit signaling trajectories mirroring normal fetal brain development, enabling the development of maturation therapies tailored towards ATRTs.

  Study EGAS00001008108

• Next_gen_seq_of_eye_cancers

  Retinoblastoma (RB), the commonest eye cancer in children was the first cancer for which a genetic cause was identified: the Rb1 gene is a tumour suppressor gene that is mutated in RB. The Rb1 gene defect alone does not predict the clinical outcome. We propose to study other possible mechanisms: 1. Stepwise further mutations occur in RB, increasing its carcinogenesis. We will sequence the whole genome in RB tissue, and relate the different genes expressed to the treatments used. 2. Extracellular matric proteins contribute to a tumour permissive environment for RB to continue to grow. This includes Samll Leucine Rich Proteoglycans (SLRP), a family of 15 secreted extracellular matrix proteins involved in eye development. 3. Cancer stem cells (CSC), a subpopulation of treatment resistant cells, drive RB tumours, and whether these stem cells can be manipulated for new therapies. The aim of this study is to assist finding targeted diagnostic techniques and treatments for RB.

  Study EGAS00001002309

• CTCF/cohesin-binding sites are frequently mutated in cancer

  Cohesin is present in almost all active enhancer regions, where it is associated with transcription factors. Cohesin frequently colocalizes with CTCF (CCCTC-binding factor), affecting genomic stability, expression and epigenetic homeostasis. Cohesin subunits are mutated in cancer, but CTCF/cohesin-binding sites (CBSs) in DNA have not been examined for mutations. Here we report frequent mutations at CBSs in cancers displaying a mutational signature where mutations in A•T base pairs predominate. Integration of whole-genome sequencing data from 213 colorectal cancer (CRC) samples and chromatin immunoprecipitation sequencing (ChIP-exo) data identified frequent point mutations at CBSs. In contrast, CRCs showing an ultramutator phenotype caused by defects in the exonuclease domain of DNA polymerase ɛ (POLE) displayed significantly fewer mutations at and adjacent to CBSs. Analysis of public data showed that multiple cancer types accumulate CBS mutations. CBSs are a major mutational hotspot in the noncoding cancer genome.

  Study EGAS00001003010

• Utility of ctDNA to support patient selection for early phase clinical trials: The TARGET Study

  Next generation sequencing (NGS) of circulating tumour DNA (ctDNA) supports blood-based genomic profiling but is not routinely implemented in the clinic. TARGET is a molecular profiling programme with the primary aim to match patients to early phase clinical trials based on analysis of both somatic mutations and copy number alterations (CNA) across a 641 cancer-associated gene panel in a single ctDNA assay. For the first 100 TARGET patients, ctDNA data showed good concordance with matched tumour and results were turned round within a clinically acceptable timeframe for Molecular Tumour Board (MTB) review. When applying a 2.5% Variant Allele Frequency (VAF) threshold actionable mutations were identified in 41/100 patients, with 11 of these patients going onto a matched therapy. These data support the application of ctDNA in an early phase trial setting where broad genomic profiling of contemporaneous tumour material enhances patient stratification to novel therapies and provides a practical template for bringing blood-based analyses to the clinic.

  Study EGAS00001003407

• Dynamics of neoantigen landscape during immunotherapy

  Immune checkpoint inhibitors have shown significant therapeutic responses against tumors containing increased mutation-associated neoantigen load. We have examined the evolving landscape of tumor neoantigens during the emergence of acquired resistance in non-small cell lung cancer patients after initial response to immune checkpoint blockade with anti-PD1 or anti-PD-1/anti-CTLA4 antibodies. Analyses of matched pretreatment and resistant tumors identified genomic changes resulting in loss of 7 to 18 putative mutation-associated neoantigens in resistant clones. Peptides generated from the eliminated neoantigens elicited clonal T cell expansion in autologous T cell cultures, suggesting that they generated functional immune responses. Neoantigen loss occurred through elimination of tumor subclones or through deletion of chromosomal regions containing truncal alterations and were associated with changes in T cell receptor clonality. These analyses provide insights into the dynamics of mutational landscapes during immune checkpoint blockade and have implications for development of immune therapies that target tumor neoantigens.

  Study EGAS00001002704

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

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

  Study EGAS00001005314

• Differential expression profile of gluten-specific T cells identified by single-cell RNA-seq

  Gluten-specific CD4+ T cells drive the pathogenesis of celiac disease and circulating gluten-specific T cells can be identified by staining with HLA-DQ:gluten tetramers. In this first single-cell RNA-seq study of tetramer-sorted T cells from untreated celiac disease patients blood, we found that gluten-specific T cells showed distinct transcriptomic profiles consistent with activated effector memory T cells that shared features with Th1 and follicular helper T cells. Compared to non-specific cells, gluten-specific T cells showed differential expression of several genes involved in T-cell receptor signaling, translational processes, apoptosis, fatty acid transport, and redox potentials. Many of the gluten-specific T cells studied shared T-cell receptor with each other, indicating that circulating gluten-specific T cells belong to a limited number of clones. Moreover, the transcriptional profiles of cells that shared the same clonal origin were transcriptionally more similar compared with between clonally unrelated gluten-specific cells.

  Study EGAS00001005517

• Lenalidomide Resistance in del(5q) Myelodysplastic Syndrome Follows Loss of RUNX1/TP53-mediated Megakaryocytic Differentiation

  Interstitial deletion of the long arm of chromosome 5 (del(5q)) is the commonest structural genomic variant in myelodysplastic syndromes (MDS). Lenalidomide (LEN) is the treatment of choice for patients with del(5q) MDS, but half of the responding patients become resistant within two years. TP53 mutations are detected in ~20% of patients who become resistant to LEN. Our data show that patients who become resistant to LEN harbor either TP53 or RUNX1 mutations or loss of RUNX1 expression. Here we show that LEN-induced degradation of IKZF1 permits a RUNX1/GATA2 complex to drive megakaryocytic differentiation and consequent del(5q) MDS progenitor cell death via CRBN-mediated CSNK1A1 degradation. Overexpression of GATA2 is able to restore LEN sensitivity in the context of RUNX1 or TP53 mutations by enhancing LEN-induced megakaryocytic differentiation. Screening for TP53 and RUNX1 mutations or downregulation should identify patients resistant to LEN, and strategies to activate GATA2 may resensitize del(5q) MDS cells to LEN

  Study EGAS00001004113

• RNA-seq from human embryonic tissues (additional samples 2018)

  How the genome activates or silences transcriptional programmes governs organ formation. Little is known about this in human post-implantation embryos undermining our ability to benchmark the fidelity of in vitro stem cell differentiation or cell programming, or interpret noncoding variation as potential causes of disease. Here, by studying histone modification we identified genome-wide open chromatin states and active repression across thirteen tissues during human organogenesis. We integrated the data with transcription to build the first view of how promoter states from nearly 20,000 genes differentially regulate alternative organ fates, arguing against bivalency during human organogenesis. The data illustrate tissue-specific as well as complex patterns of enhancer activity functional in zebrafish and impute master transcription factors. Overlaying 739 noncoding de novo mutations in patients allowed phenotypic correlation of developmental disorders to unanticipated target genes. Taken together, the data provide a comprehensive genomic framework for understanding normal and abnormal human development.

  Study EGAS00001003738

• Colorectal adenomas, NKI-AvL TGO series Stool-Proteomics

  Colorectal cancer (CRC) develops from normal epithelium, through a benign precursor lesion called adenoma, by accumulation of genetic alterations affecting oncogenes and tumour suppressor genes. About 5% of colorectal adenomas are estimated to progress to CRC. However, it is important to identify which adenomas actually are at high-risk of progression, because these should serve as intermediate endpoints for e.g. CRC screening programs. In clinical practice, adenomas with a size of ≥10 mm, villous component and/or high-grade dysplasia, called advanced adenomas, are considered high-risk, although this classification lacks solid evidence. Specific DNA copy number changes are associated with adenoma-to-carcinoma progression.For this tissue dataset, we applied low-pass whole genome sequencing to 98 non-advanced and advanced adenomas. These adenomas were classified as lesions with low-risk or high-risk of progression, according to the presence of specific DNA copy number changes (Carvalho et al, CancerPrevRes, 2018).

  Study EGAS00001002953

• Immune profiling reveals enrichment of distinct immune signatures in high-risk oral potentially malignant disorders

  Oral epithelial dysplasia (OED) associates with an increased risk of oral squamous cell carcinoma (OSCC). Changes in the immune landscape of OED that accompany transformation remain understudied. We evaluated gene co-expression in benign lesions (fibroepithelial polyps; FEP), high-risk OED (mod-sev OED) and early stage OSCC. We demonstrate that transcripts indicating immune responses are enriched in high-risk OED. In particular, immune signatures representing high lymphocyte infiltration and cytotoxic responses are prominent, indicating active immunosurveillance. Expression of immune checkpoint molecules was enriched in high-risk OED and further increased in early stage OSCC. Seventy percent of high-risk OED displayed a T cell-inflamed phenotype histology suggesting that they might be responsive to anti-PD-1 immunoprevention. Other immunoprevention strategies are required for the 30% of high-risk OED are not immune-enriched. Overall, our data point the way for new approaches to non-surgical management of OED.

  Study EGAS00001005520

• CCL22 chemokine mutations drive natural killer cell lymphoproliferative disease by biasing GPCR signaling

  Chronic lymphoproliferative disorder of natural killer cells (CLPD-NK) is characterized by clonal expansion of NK cells of incompletely understood genomic basis. Here, we report somatic mutations in the chemokine gene CCL22 as the hallmark of a distinct subset of CLPD-NK. CCL22 mutations were enriched at highly conserved residues, were mutually exclusive of STAT3 mutations, and were associated with gene expression similar to normal CD16dim/CD56bright NK cells. Mechanistically, the mutations resulted in ligand-biased chemokine receptor signaling, with decreased internalization of the G-protein-coupled receptor for CCL22, CCR4, via impaired β-arrestin recruitment. This resulted in increased cell chemotaxis in vitro, bidirectional crosstalk with the hematopoietic microenvironment, and enhanced NK cell proliferation in vivo in transgenic human IL-15 mice. Somatic CCL22 mutations illustrate a novel mechanism of tumor formation in which gain-of-function chemokine mutations promote tumorigenesis by biased G-protein-coupled receptor signaling and dysregulation of microenvironmental crosstalk.

  Study EGAS00001006009

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

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

  Study EGAS00001005948

• Loss of Epigenetic Barrier is Required for Enhancer Hijacking-Mediated Oncogenic Transcription

  Structural variants (SVs) involving enhancer hijacking can disrupt chromatin topologies to cause oncogene activation in cancer genomes, yet the molecular determinants for the transcriptional output of enhancer hijacking remain largely unknown. We developed a multimodal approach to integrate genome sequencing, chromosome conformation, and sequence-based deep learning for quantitative analysis of transcriptional effects and structural reorganization imposed by SVs in leukemic genomes. We identified candidate pathogenic SVs including recurrent t(5;14) translocations that cause the hijacking of BCL11B enhancers for oncogenic activation of TLX3-dependent transcriptional programs. By engineering patient-associated t(5;14) in isogenic leukemia cells, we uncovered an uncharacterized mechanism whereby DNA methylation serves as an epigenetic barrier to enhancer hijacking and loss of epigenetic barrier is a molecular determinant for the transcriptional output of pathogenic SVs. Hence, leveraging the epigenetic barriers of SV-mediated oncogenic programs may provide new opportunities to reprogram gene regulation as epigenetic therapies in human disease.

  Study EGAS00001006140

• Exome & MiSeq sequencing of individuals with Huntington's disease

  The age at onset of motor symptoms in Huntington's disease (HD) is driven by HTT CAG repeat length but modified by other genes. In this study, we used exome sequencing of 683 patients with HD with extremes of onset or phenotype relative to CAG length to identify rare variants associated with clinical effect. We discovered damaging coding variants in candidate modifier genes identified in previous genome-wide association studies associated with altered HD onset or severity. Variants in FAN1 clustered in its DNA-binding and nuclease domains and were associated predominantly with earlier-onset HD. Nuclease activities of purified variants in vitro correlated with residual age at motor onset of HD. Mutating endogenous FAN1 to a nuclease-inactive form in an induced pluripotent stem cell model of HD led to rates of CAG expansion similar to those observed with complete FAN1 knockout. Together, these data implicate FAN1 nuclease activity in slowing somatic repeat expansion and hence onset of HD.

  Study EGAS00001006383

• The landscape of chromothripsis across adult cancer types

  Chromothripsis is a recently identified mutational phenomenon, by which a presumably single catastrophic event generates extensive genomic rearrangements of one or a few chromosome(s). Considered as an early event in tumour development, this form of genome instability plays a prominent role in tumour onset. Chromothripsis prevalence might have been underestimated when using low-resolution methods, and pan-cancer studies based on sequencing are rare. We analysed chromothripsis in 28 tumour types covering all major adult cancers (634 tumours, 316 whole-genome and 318 whole-exome sequences). We show that chromothripsis affects a substantial proportion of human cancers, with a prevalence of 49% across all cases. Chromothripsis generates entity-specific genomic alterations driving tumour development, including clinically relevant druggable fusions. Chromothripsis is linked with specific telomere patterns and univocal mutational signatures in distinct tumour entities. Longitudinal analysis of chromothriptic patterns in 24 matched tumour pairs reveals novel insights in the clonal evolution of tumours with chromothripsis. (H021)

  Study EGAS00001004250

• Neuroblastoma heterogeneity

  Neuroblastoma is a pediatric solid tumor characterized by strong clinical heterogeneity. Although certain complex genomic alterations, such as extrachromosomal DNA amplifications (ecDNA), are associated with adverse outcomes and have been recurrently detected in neuroblastomas, the mutational processes involved in their generation remain largely unclear. By examining the topography of complex rearrangements along with mutational signatures derived from all variant classes, we identify previously unrecognized co-occurring mutational footprints, which we termed mutational scenarios. We demonstrate that clinical neuroblastoma heterogeneity is linked to differences in the processes driving these mutational scenarios. Whereas high-risk MYCN-amplified neuroblastoma genomes were characterized by signs of replication slippage and stress, homologous recombination-associated signatures defined high-risk non-MYCN-amplified patients. Non-high-risk neuroblastomas, on the other hand, were marked by footprints of chromosome missegregation and TOP1 mutational activity. This analysis provides a systematic perspective on the repertoire of mutational patterns that contribute to clinical neuroblastoma heterogeneity.

  Study EGAS00001007016