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• Multiomic characterization of clonotypic B cells

  DNA was purified using AMPure XP magnetic beads (Beckman Coulter [BC] Life Sciences, Indianapolis, IN) and its quality was evaluated in an Agilent 4200 Tapestation using the Genomic DNA ScreenTape system (Agilent, Santa Clara, CA). DNA was quantified using the Qubit System (Invitrogen). Extracted DNA from AL patients was fragmented to 200bp by a Covaris S220 ultrasonicator (Covaris, Woburn, MA) and used to generate and capture libraries following the manufacturer’s indications from Twist Bioscience’s Human Core Exome Enrichment Kit (Twist Bioscience). Extracted DNA from MM patients and HA was fragmented to an average size of 225 bp using a Covaris S220 ultrasonicator (Covaris, Woburn, MA) and subjected to DNA library construction using Chromium Genome Reagent Kit V2 for Exome Assays (10X Genomics). Target enrichment was performed with SureSelectXT Human All Exon V6 Capture Library (Agilent) or SureSelectXT2 Human All Exon V5+UTRs (Agilent), and sequence targets were captured and amplified in accordance with the manufacturer’s protocol. Final libraries were combined with standard Illumina sequencing primers and paired-end sequenced (150bp) on a HiSeq X platform (Illumina, CA) or in a NovaSeq 6000 (Illumina).

  Dataset EGAD50000002162

• scRNA dataset for 15 samples

  This dataset includes single cell (sc)RNA-seq of N=3 patient-derived xenograft (PDX) samples profiled at baseline (no drug treatment) and N=12 samples from one PDX profiled during the course of treatment (N=1 sample each for 4 treatment arms x 3 timepoints). The dataset includes bam files that have been purged of reads mapping to cells where a majority of the reads from that cell mapped to the mouse genome. All scRNA-seq data were generated using the Chromium Next GEM Single Cell 5' Reagent Kits v2 (Dual Index) from 10X Genomics.

  Dataset EGAD50000001424

• Blueprint: A human variation panel of genetic influences on epigenomes and transcriptomes in three immune cell types, (ChIP-Seq for CD14-positive, CD16-negative classical monocyte, on genome GRCh37)

  ChIP-Seq data for 172 CD14-positive, CD16-negative classical monocyte sample(s). 572 run(s), 345 experiment(s), 340 analysis(s) on human genome GRCh37. Analysis documentation available at http://ftp.ebi.ac.uk/pub/databases/blueprint/blueprint_Epivar/protocols/README_chipseq_analysis_ebi_20160816

  Dataset EGAD00001002672

• MutWP5: CRUK Mutographs of Cancer: Breast: Cancer Mastectomy (Targeted) (2020-01-29)

  Sequencing of LCM-derived microbiopsies from 30 women who mastectomies due to Breast Cancer. Goal to assess the mutational burden, spectrum, and clonal dynamics within the tissue. Targeted data will be used as a driver and clonality screen, highly clonal or driver-containing samples will subsequently be sent for whole-genome sequencing. Results from this portion of the study will be compared to women who had cosmetic breast reduction surgeries and those with germline BRCA 1/2 mutations. . This dataset contains all the data available for this study on 2020-01-29.

  Dataset EGAD00001005923

• Blueprint: A human variation panel of genetic influences on epigenomes and transcriptomes in three immune cell types, (ChIP-Seq for CD4-positive, alpha-beta T cell, on genome GRCh37)

  ChIP-Seq data for 154 CD4-positive, alpha-beta T cell sample(s). 355 run(s), 265 experiment(s), 250 analysis(s) on human genome GRCh37. Analysis documentation available at http://ftp.ebi.ac.uk/pub/databases/blueprint/blueprint_Epivar/protocols/README_chipseq_analysis_ebi_20160816

  Dataset EGAD00001002673

• Genetic regulation of RNA splicing in human pancreatic islets

  Here we provide access to newly generated RNA-seq data for 101 human islet samples used to map genetic effects on gene expression and alternative splicing (eQTLs and sQTLs) in a total of 399 human islets. We also make publicly available genotyping array data for 128 human islets, including the fraction of 101 human islet samples with existing RNA-seq data.

  Dataset EGAD00001009102

• MutWP5: CRUK Mutographs of Cancer: Breast: BRCA Carriers (Targeted) (2020-01-29)

  Sequencing of LCM-derived microbiopsies from 20 women who underwent risk-reducing reduction mastectomies due to germline BRCA1/2. Goal to assess the mutational burden, spectrum, and clonal dynamics within the tissue. Targeted data will be used as a driver and clonality screen, highly clonal or driver-containing samples will subsequently be sent for whole-genome sequencing. Results from this portion of the study will be compared to women who had cosmetic breast reduction surgeries and those with cancer. . This dataset contains all the data available for this study on 2020-01-29.

  Dataset EGAD00001005920

• High-Coverage Whole-Exome Sequencing Identifies Candidate Genes for Suicide in Victims with Major Depressive Disorder

  In this study, we applied an Illumina HighSeq platform-based high-coverage WES technique, which, in addition to the exons, allows the determination of 5′- and 3′-UTRs, promoters to a certain length, along with off-target sequences, such as introns, intergenic regions and infecting viruses. Brains from suicide victims (n = 23; 15 males and eight female) who had suffered from major depressive disorder and from control participants (n = 21; 14 males and seven females) who had died from other causes were used for whole-exome sequencing. Alignment files in bam format were uploaded.

  Dataset EGAD00001004082

• Blueprint: A human variation panel of genetic influences on epigenomes and transcriptomes in three immune cell types, (RNA-Seq for CD14-positive, CD16-negative classical monocyte, on genome GRCh37)

  RNA-Seq data for 197 CD14-positive, CD16-negative classical monocyte sample(s). 197 run(s), 197 experiment(s), 197 analysis(s) on human genome GRCh37. Analysis documentation available at http://ftp.ebi.ac.uk/pub/databases/blueprint/blueprint_Epivar/protocols/README_rnaseq_analysis_sanger_20160816

  Dataset EGAD00001002674

• MutWP5: CRUK Mutographs of Cancer: Breast: BRCA Carriers (Exome) (2020-01-29)

  Sequencing of LCM-derived microbiopsies from 20 women who underwent risk-reducing reduction mastectomies due to germline BRCA1/2. Goal to assess the mutational burden, spectrum, and clonal dynamics within the tissue. Exome data will be used as a driver and clonality screen, highly clonal or driver-containing samples will subsequently be sent for whole-genome sequencing. Results from this portion of the study will be compared to women who had cosmetic breast reduction surgeries and those with cancer. . This dataset contains all the data available for this study on 2020-01-29.

  Dataset EGAD00001005921

• Blueprint: A human variation panel of genetic influences on epigenomes and transcriptomes in three immune cell types, (RNA-Seq for CD4-positive, alpha-beta T cell, on genome GRCh37)

  RNA-Seq data for 212 CD4-positive, alpha-beta T cell sample(s). 212 run(s), 212 experiment(s), 212 analysis(s) on human genome GRCh37. Analysis documentation available at http://ftp.ebi.ac.uk/pub/databases/blueprint/blueprint_Epivar/protocols/README_rnaseq_analysis_sanger_20160816

  Dataset EGAD00001002671

• Sequence analysis of colorectal serrated lesions

  Recent studies have shown that colorectal serrated lesions, which include sessile serrated adenomas (SSAs) and traditional serrated adenomas (TSAs), are precursors of colorectal cancer. However, the molecular mechanisms underlying the carcinogenesis, particularly in TSAs, remain largely uncharacterized. To clarify their molecular and clinicopathological characteristics, we performed mutation and methylation analyses of cancer-associated genes in 78 serrated lesions, including TSAs, SSAs and microvesicular hyperplastic polyps. Target exon sequence analysis was performed with 39 genes, including genes known to be frequently mutated in colorectal cancers and/or serrated lesions. We also used bisulfite pyrosequencing to assess the methylation status of various cancer-associated genes and marker genes of the CpG island methylator phenotype (CIMP). The prevalence of mutations in genes associated with Wnt signaling was significantly higher in TSAs than SSAs (65% vs. 28%, p < 0.01). Among those, RNF43 mutations were observed in 38% of TSAs and 17% of SSAs. In immunohistochemical studies of 39 serrated lesions, the prevalence of abnormal nuclear ?-catenin accumulation was significantly higher in TSAs (57%) than SSAs (8%) (P = 0.01). SMOC1 methylation was detected in 54% of TSAs but in no SSAs (p < 0.01). Additionally, SMOC1 methylation was more prevalent among TSAs with KRAS mutation (82%) than with BRAF mutation (38%, p = 0.03). Lesions with CIMP-high or RNF43 mutations were detected only in TSAs with BRAF mutation, suggesting two distinct carcinogenic pathways in TSAs. Mutations in genes associated with Wnt signaling play a greater role in the carcinogenesis of TSAs than SSAs.

  Study JGAS000217

• Single-cell gene expression data from CD8+ T cells from two Austrian COVID19 patients stimulated with wildtype and mutant SARS-Cov-2 peptides

  The data contains single-cell gene sequencing data (10x Genomics) from FACS-purified CD8 T lymphocytes from two Austrian patients. The cells were stimulated with one MHC class I peptides obtained from a common (wild type) variant and an emerging mutant variant of the SARS-Cov-2 virus. Then the samples were multiplexed using hashtag oligos. We provide the raw and aligned sequence data for: i. The single-cell experiments ii. The PCR-amplified samples for enrichment of the hashtag oligo multiplexing barcodes iii. The PCR-amplified samples for enrichment of the T Cell Receptor (TCR) VDJ region for immuno-profiling. The samples and libraries were processed and obtained in collaboration between St. Anna Children's Cancer Research Institute (CCRI), CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, and the Medical University of Vienna. The cell barcodes and processed data has been submitted to the GEO database with GEO accession GSE166651.

  Dataset EGAD00001006995

• Kibbutzim Family study

  The Kibbutzim Family Study (KFS) aimed to investigate the environmental and genetic determinants of cardiometabolic traits (phenotype is LDL-C)

  Dataset EGAD00010001551

• Whole genome sequencing in prime-edited human organoids

  We performed whole genome sequencing to detect possible off-target mutations induced by prime editing. Liver organoids, derived from a healthy control, were transfected with either control (GFP) plasmids or prime editing plasmids (GFP+PE2+pegRNA+nickRNA) to induce a 6-bp deletion in CTNNB1. One control and two prime-edited organoid lines were clonally expanded from single cells. High-throughput sequencing was performed on the complete genomic DNA isolated from these clonal lines, as well as the starting culture (bulk). After correction for germline mutations in the starting culture, new mutations in the control and prime-edited lines were compared. The same approach was followed in small intestinal organoids, derived from a patient with disease-causing 3-bp deletion in DGAT1. In these small intestinal organoids, prime editing was used to insert the 3 missing nucleotides. Two corrected clones were compared to one control clone.

  Dataset EGAD00001006352

• Cancer-independent, second somatic NF1 mutation of normal tissues in neurofibromatosis type 1

  Cancer predisposition syndromes mediated by recessive cancer genes generate tumours via somatic variants (second hits) in the unaffected allele. Second hits may or may not be sufficient for neoplastic transformation. Here, we performed whole genome and exome sequencing on 479 tissue biopsies from a child with neurofibromatosis type 1, a multi-system cancer-predisposing syndrome mediated by constitutive monoallelic NF1 inactivation. We identified multiple independent NF1 driver variants in histologically normal tissues, but not in 610 biopsies from two non-predisposed children. We corroborated this finding using targeted duplex sequencing, including a further nine adults with the same syndrome. Overall, truncating NF1 mutations were under positive selection in normal tissues from individuals with neurofibromatosis type 1. We demonstrate that normal tissues in neurofibromatosis type 1 commonly harbour second hits in NF1, the extent and pattern of which may underpin the syndrome's cancer phenotype.

  Dataset EGAD00001015398

• 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

• HipSci RNA sequencing for embryonic stem cell control lines

  The HipSci project brings together diverse constituents in genomics, proteomics, cell biology and clinical genetics to create a UK national iPS cell resource and use it to carry out cellular genetic studies. In this sub-study we perform RNA sequencing on commercially available embryonic stem cell lines as control samples against which to compare HipSci's iPS cell lines.

  Study EGAS00001001727

• Tumor gene expression profiles for the study "TGF-β attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells"

  RNA was extracted from formalin-fixed and paraffin embedded tumors of a large cohort of bladder cancer patients before treatment with anti-PD-L1. RNA was sequenced using a capture based approach (exome capture, RNA access).

  Dataset EGAD00001003977

• Whole-exome sequencing of glioblastomas with long-term relapse interval

  Whole-exome sequencing data (Agilent SureSelectXT Human All Exon V7). Retrospective study of matched pairs of initial and post-therapeutic GBM cases treated with temozolomide+radiotherapy with a recurrence period greater than one year. Matched normal, initial and post-therapeutic samples for 27 patients and 1 patient (GBM046) with a matched normal and two post-therapeutic samples.

  Dataset EGAD00001008568

• Genetic background for cardio vascular disorders in the general Finnish population

  Low coverage (4-6x) sequencing on samples from population cohorts (Finrisk, Health2000) will be done at Wellcome Trust Sanger Institute (WTSI) using Illumina HiSeq sequencing technology. We will produce 100bp paired end reads. Variants will be called using the 1000 Genomes Project pipeline. The samples have been selected from a national representative set of approximately 30,300 samples and comprises 500 individuals of each gender in the extreme tail of high density lipoprotein (HDL) concentrations. Included individuals were between 25 and 65 years of age. Individuals with a diagnosis of diabetes or BMI&gt;30 were excluded from the study.

  Dataset EGAD00001001251

• A Tumour Organoid Biobank for Mapping Cancer Cell Vulnerabilities - TGS

  Targeted gene sequencing data from cancer patient-derived organoids and their matched tumour tissue samples. Part of a study to include genomic and transcriptomic sequencing data, along with CRISPR screening data from cancer patient-derived organoids and matched tumour tissues. Some organoids were developed as part of the Human Cancer Models Initiative (HCMI) in collaboration with Cancer Research UK (CRUK). The study includes organoids derived from colorectal, oesophageal, ovarian, pancreatic, and stomach cancer samples.

  Dataset EGAD00001015468

• Genetic Epidemiology of Lung Cancer Consortium GWAS of Familial Lung Cancer

  Familial lung cancer cases were collected by the Genetic Epidemiology of Lung Cancer Consortium (GELCC) recruitment sites: University of Cincinnati, Karmanos Cancer Institute at Wayne State University, Louisiana State University Health Sciences Center-New Orleans, Mayo Clinic, and Medical College of Ohio. Familial cases for this study came from three sources: 1) one case each from families (at least 3 affected lung cancer cases in the family) included in the linkage analysis; 2) one case from linkage-eligible families (at least 3 affected lung cancer cases in the family) but where there were insufficient biospecimens available to make them informative for linkage analysis; and 3) one case from families not eligible for the linkage study with a family history of at least one first or second degree relative affected with lung cancer. Unrelated controls were selected from 1) among the spouses of family members, thus matching on socio-economic status (SES) and ethnicity (typically) of the cases or 2) from case-control studies of lung cancer conducted in the same location in which the linkage families were collected and matched on age, sex, and race. All cases and controls self-reported as European American. Biospecimens used for normal DNA extraction included blood, saliva or mouthwash. Some samples underwent whole genome amplication.

  Study phs000629

• RNA-seq study of human long-term and short-term hematopoietic stem cells from umblical cord blood with lentiviral overexpression of S1PR3

  To investigate the molecular and biological pathways altered by S1PR3OE in human hematopoietic stem cells (HSC), we performed RNA-sequencing (RNA-seq) of LT- and ST-HSC 3 days after transduction with control or S1PR3 overexpression (OE) lentiviral vectors. LT-HSC and ST-HSC from 3 pool of CB lin- were FACS-purified, cells were prestimulated for 4 hours and transduced with lentiviral vectors. At day 3, 2000-5300 BFP+ cells were FACS-purified for RNA isolation with a PicoPure kit. We were able to isolate only 1600-1800 BFP+ cells from LT-HSC control samples as opposed to 4000-5400 BFP+ cells from S1PR3OE samples. Thus, we pooled all control BFP+ LT-HSC cells into one sample for RNA-seq analysis. BFP- LT-HSC from control vector transduction were purified from CB1 as an additional LT-HSC control. Nextera libraries generated from 10 ng RNA from 5 LT-HSC samples (2 controls, 3 S1PR3OE) and 6 ST-HSC samples (3 controls, 3 S1PR3OE) were subjected to 125 bp, paired-end RNA-sequencing on the Illumina HiSeq 2500 with an average of 50 million reads/sample at the Center for Applied Genomics, Sick Kids Hospital.

  Study EGAS00001004798

• TNBC ctDNA Targeted Panel

  Circulating tumour DNA (ctDNA) detection in liquid biopsy is an emerging alternative to tissue biopsy, but its utility in treatment response monitoring and prognosis in triple negative breast cancer (TNBC) remains to be well understood. In this study, we determined the presence of early stage TNBC ctDNA detectable actionable mutations with a clinically validated hotspot treatment indication panel. Sequencing of plasma DNA from 130 TNBC patients collected within 7 months of primary treatment completion revealed that 7.7% had detectable residual disease with a hotspot panel. Among neoadjuvant treated patients, we observed a trend where patients with incomplete pathologic response and positive ctDNA within 7 months of treatment completion were at risk of reduced progression free survival. We propose that a high risk subset of early TNBC patients treated in NAT protocols may be identifiable by combining tissue response and sensitive ctDNA detection.

  Study EGAS00001006937

• Genomic gain of EBV's LMP-1 in NKTCL

  The study found a high recurrence of genomic gain of LMP1 locus within EBV-associated NKTCL. The pilot data set and extended dataset of 77 WGS NKTCLs found 18/77 tumoral genomes to harbour genomic gain of LMP-1 locus within the EBV viral genomes within NKTCL tumoral sequencing data. The study also found 1/10 NKTCL cell lines to be positive for LMP-1 locus gain within EBV genomes too. This dataset includes solely the confirmatory WGS data of LMP-1 gain from NKYS cell lines using Oxford Nanopore long-read sequencing technology.

  Study EGAS50000000260

• Illumina ExomeChip genotyping data from the Cretan Greek isolate collection HELIC MANOLIS

  Isolated populations can empower the identification of rare variation associated with complex traits through next generation association studies. Here we have genotyped individuals from a Greek population isolate on the Illumina HumanExome Beadchip. The HELIC (Hellenic Isolated Cohorts) MANOLIS (Minoan Isolates) collection focuses on Anogia and surrounding Mylopotamos villages. Recruitment of this population-based sample was primarily carried out at the village medical centres. All individuals were older than 17 years and had to have at least one parent from the Mylopotamos area. www.helic.org **The data may not be used for population genetics analyses.**

  Study EGAS00001000630

• PAS Pedigrees: Identification of novel genetic variants contributing to cardiovascular disease in pedigrees with premature atherosclerosis.

  The heritability of CVD has been estimated to be between 40 and 55%. Due to the low MAF, PAS-causing mutations cannot be identified by indirect genotyping because their presence cannot be inferred from common haplotypes, as has been done successfully to uncover common risk variants by GWAS. It has been shown by Ng et al that the causative gene for rare syndromes can be unequivocally identified by sequencing the exomes of only four cases and eight controls. We expect exome sequencing to result in a high number of mutations and non-causitive coding variants.

  Study EGAS00001000052

• Illumina Human OmniExpress genotyping data from the Cretan Greek isolate collection HELIC MANOLIS

  Isolated populations can empower the identification of rare variation associated with complex traits through next generation association studies. Here we have genotyped individuals from a Greek population isolate on the Illumina Human OmniExpress BeadChip array. The HELIC (Hellenic Isolated Cohorts) MANOLIS (Minoan Isolates) collection focuses on Anogia and surrounding Mylopotamos villages. Recruitment of this population-based sample was primarily carried out at the village medical centres. All individuals were older than 17 years and had to have at least one parent from the Mylopotamos area. www.helic.org **The data may not be used for population genetics analyses**

  Study EGAS00001000687

• Targeted myeloid panel DNA-Sequencing Mutations Matrix Validation Cohort

  Profiling of co-mutations was done by targeted resequencing using the TruSight Myeloid assay (Illumina, Chesterford, UK) covering 54 genes recurrently mutated in AML: BCOR, BCORL1, CDKN2A, CEBPA, CUX1, DNMT3A, ETV6, EZH2, IKZF1, KDM6A, PHF6, RAD21, RUNX1, STAG2, ZRSR2, ABL1, ASXL1, ATRX, BRAF, CALR, CBL, CBLB, CBLC, CDKN2A, CSF3R, FBXW7, FLT3, GATA1, GATA2, GNAS, HRAS, IDH1, IDH2, JAK2, JAK3, KIT, KRAS, MLL, MPL, MYD88, NOTCH1, NPM1, NRAS, PDGFRA, PTEN, PTPN11, SETBP1, SF3B1, SMC1A, SMC3, SRSF2, TET2, TP53, U2AF1 and WT1. For each reaction, 50 ng of genomic DNA was used. Library preparation was done as recommended by the manufacturer (TruSight Myeloid Sequencing Panel Reference Guide 15054779 v02, Illumina). Samples were sequenced paired-end (150 bp PE) on NextSeq- (Illumina) or (300 bp PE) MiSeq-NGS platforms, with a median coverage of 3076 reads (range 824–30565). Sequence data alignment of demultiplexed FastQ files, variant calling and filtering was done using the Sequence Pilot software package (JSI medical systems GmbH, Ettenheim, Germany) with default settings and a 5% variant allele frequency (VAF) mutation calling cut-off. Human genome build HG19 was used as reference genome for mapping algorithms.

  Dataset EGAD00001008506

• Paired-end Whole Exome-seq analysis of GBM, additional patient.

  Dataset contains one paired-end Whole Exome sequencing sample. One normal blood sample is also included.

  Dataset EGAD00001011989

• TOTHER3 dataset

  This dataset contains the FASTQ and BAM files for TOTHER3 study. Targeted DNA-Seq experiment were realized with 49 samples. Since this data was obtained with a panel of genes protected by Intellectual Property (IP), these files only contain information to validate the results published and, in consequence, sensible data had to be specifically removed.

  Dataset EGAD50000000562

• McGill EMC Community projects Release 7 for cell line "SaOS-2"

  Complete reference epigenome (as defined by IHEC) of a SaOS-2 cell line with osteosarcoma.

  Dataset EGAD00001007678

• Long read sequencing of 5 Intellectual Disability (ID) trios with PacBio Sequel. Dataset of samples: T2P, T2F and T2M

  5 trios were whole genome sequenced with PacBio Sequel to a depth of 15X (Trios 1-4) or 40X (Trio 5). For each trio the child was affected with severe ID, and the parents were unaffected. Dataset consists of Trio 2 samples: T2P, T2F and T2M

  Dataset EGAD00001006050

• Patient-Specific Factors Influence Somatic Variation Patterns in Von Hippel-Lindau Disease Renal Tumors

  Patients affected with von Hippel-Lindau disease are at risk of developing multiple independent clear cell renal carcinomas. This study performed whole genome sequencing on 40 tumors from 6 VHL patients to compare somatic variation patterns within and between patients. Although tumors from the same patient showed many differences, within-patient patterns were discernible. Single-nucleotide substitution type rates were significantly different between patients and showed biases in trinucleotide mutation context. We also observed biases in chromosome copy number aberrations. These results show that genetic background and/or environment can influence the types of mutations that occur.

  Study phs001107

• Mind the gap: the relevance of the genome reference to resolve rare and pathogenic inversions

  Chromosomal inversions (INV) are particularly challenging to detect due to their copy-number neutral state and association with repetitive regions. Inversions represent about 1/20 of all balanced structural chromosome aberrations and can lead to disease by gene disruption or altering regulatory regions of dosage sensitive genes in cis. Short-read genome sequencing (srGS) can only resolve ~70% of cytogenetically visible inversions referred to clinical diagnostic laboratories, likely due to breakpoints in repetitive regions. Here we study twelve inversions by srGS (n=3) or long read genome sequencing (lrGS) (n=9)

  Study EGAS50000000436

• ERBB2/HER2 alterations in ctDNA and metachronous tissues of patients with metastatic urothelial cancer - WGS

  Whole genome sequencing data related to the publication "ERBB2/HER2 alterations in ctDNA and metachronous tissues of patients with metastatic urothelial cancer." ERBB2 alterations, usually amplifications or activating mutations, are seen in up to 20% of urothelial carcinoma and can be targeted by monoclonal antibodies, small molecule inhibitors, and most recently, antibody-drug conjugates. Here, we perform targeted and whole-genome sequencing of cell-free DNA and archival FFPE of mUC with and without ERBB2 alterations to identify unique genomic and clinical features of ERBB2-altered cancers, accompanied by IHC, FISH, and detailed clinical outcomes.

  Study EGAS50000001082

• ERBB2/HER2 alterations in ctDNA and metachronous tissues of patients with metastatic urothelial cancer - Targeted

  Targeted sequencing data related to the publication titled "ERBB2/HER2 alterations in ctDNA and metachronous tissues of patients with metastatic urothelial cancer." ERBB2 alterations, usually amplifications or activating mutations, are seen in up to 20% of urothelial carcinoma and can be targeted by monoclonal antibodies, small molecule inhibitors, and most recently, antibody-drug conjugates. Here, we perform targeted and whole-genome sequencing of cell-free DNA and archival FFPE of mUC with and without ERBB2 alterations to identify unique genomic and clinical features of ERBB2-altered cancers, accompanied by IHC, FISH, and detailed clinical outcomes.

  Study EGAS50000001081

• Mutation signatures in melanocytic nevi reveal characteristics of defective DNA repair

  Nevi are common benign melanocytic neoplasms that can be found on any skin location and share many of the genomic hallmarks of melanoma. In our recent report involving whole-exome sequencing of acquired nevi (Stark et al., 2018), ultra-violet radiation (UVR) related somatic mutation signatures (“signature 7”) (Alexandrov et al., 2013) were frequently observed in all lesions that were located on sun-exposed sites. In the study presented herein, we sought to investigate whether an independent Spanish cohort (Valencia, Spain) of minimally sun exposed nevi had genomic features consistent with our previous findings.

  Study EGAS00001004274

• Transcriptome sequencing of intravenous leiomyomatosis and uterine myoma

  Up to now, there are two hypothesis about the pathogenesis of the relationship of intravenous leiomyomatosis and uterine myoma. One theory suggests that the IVL comes from the smooth muscle cell in the vessel wall.The other theory indicates that the IVL derives from the uterine myometrium. However, limited to the technology, few studies have been deeply explore the underlying relation. In this study, we employ the RNA sequencing to explore the molecule relationship between IVL and uterus myoma. In order to identify the molecule relationship between IVl and uterine myoma we conducted transcriptome sequencing and bioinformaitc analysis

  Study EGAS00001002504

• Response to tumor-infiltrating lymphocyte adoptive therapy is associated with preexisting CD8+ T-myeloid cell networks in melanoma

  Adoptive cell therapy (ACT) using ex vivo–expanded tumor-infiltrating lymphocytes (TILs) can eliminate or shrink metastatic melanoma, but its long-term efficacy remains limited to a fraction of patients. Using longitudinal samples from 13 patients with metastatic melanoma treated with TIL-ACT in a phase 1 clinical study, we interrogated cellular states within the tumor microenvironment (TME) and their interactions. We performed bulk and single-cell RNA sequencing, whole-exome sequencing, and spatial proteomic analyses in pre- and post-ACT tumor tissues, finding that ACT responders exhibited higher basal tumor cell–intrinsic immunogenicity and mutational burden. Compared with nonresponders, CD8+ TILs exhibited increased cytotoxicity, exhaustion, and costimulation, whereas myeloid cells had increased type I interferon signaling in responders. Cell-cell interaction prediction analyses corroborated by spatial neighborhood analyses revealed that responders had rich baseline intratumoral and stromal tumor–reactive T cell networks with activated myeloid populations. Successful TIL-ACT therapy further reprogrammed the myeloid compartment and increased TIL-myeloid networks. Our systematic target discovery study identifies potential T-myeloid cell network–based biomarkers that could improve patient selection and guide the design of ACT clinical trials.

  Study EGAS50000001217

• Scalable Whole-Exome Sequencing of Cell-Free DNA Reveals High Concordance with Metastatic Tumors

  We performed whole genome sequencing and whole-exome sequencing of cell-free DNA (cfDNA) and whole-exome sequencing of matched tumor biopsies and germline DNA from patients with metastatic cancer. Using ichorCNA, a software tool that quantifies tumor content in ultra-low pass whole genome sequencing (~0.1x) of cfDNA without prior genomic characterization of the tumor, we show genome-wide concordance between cfDNA and tumor biopsies and detectability of high tumor fractions (&gt;0.1) in the cfDNA of many patients with metastatic cancer. We then established that whole-exome sequencing of cfDNA can enable comprehensive profiling of tumors from blood, with high tumor-content cfDNA samples demonstrating concordance of clonal somatic mutations, copy number alterations, mutational signatures, and neoantigens with matched tumor biopsies. This study introduces a new method to identify patients that could be eligible for tumor profiling from cfDNA and sheds light on the concordance between metastatic tissue and blood biopsies.

  Study phs001417

• Functional Dynamics of the Elderly Gut Microbiome During Probiotic Consumption

  A mechanistic understanding of the health benefits conferred by consumption of probiotic bacteria has been limited by our knowledge of the resident gut microbiota and its interaction with the host. We used fecal samples from a study of twelve healthy individuals aged 65-80 to characterize the structure and functional dynamics of the gut microbiota associated with consumption of the single-organism probiotic, Lactobacillus rhamnosus GG ATCC 53103 (LGG). Samples were collected prior to probiotic consumption (day 0), on day 28 immediately after consuming 10^10 CFU of LGG twice daily for 28 days and day 56, one month after stopping LGG consumption. Our integrative approach incorporated bacterial 16S rRNA gene sequencing, whole-community expression profiling using RNA-seq, and metagenomic sequencing. We highlight the value of combinatorial &#39;omics methods and concomitant high-resolution informatics to probe the role that probiotics may play on the structure and function of the resident microbiota.

  Study phs000896

• Divergence between high metastatic tumor burden and low circulating tumor DNA concentration in metastasized breast cancer

  Circulating tumor DNA (ctDNA) was reported to represent a highly sensitive biomarker of metastatic cancer disease directly reflecting tumor burden and dynamics. Here we investigated the role of ctDNA in patients with metastatic breast cancer. In an index patient with more than 100,000 circulating tumor cells (CTCs) in serial blood analyses, whole genome, exome, or targeted deep sequencing of the primary tumor, metastases, and 551 CTCs were consistent with a genetically homogeneous cancer. However, the allele fractions (AFs) of ctDNA were only 2-3% in each analysis, which did neither reflect the tumor burden nor the dynamics of this progressive disease by far. Indeed, plasma analyses of 71 further patients demonstrated highly variable AFs of mutant fragments, which frequently did not correspond to the tumor burden. These results provide insights into mechanisms involved in CTC and ctDNA release into the circulation and have important implications for diagnostic tests based on liquid biopsies.

  Study EGAS00001000625

• Whole exome sequencing of long-term, never relapse exceptional responders of trastuzumab-treated HER2+ metastatic breast cancer

  Trastuzumab has significantly improved the overall survival of patients with HER2+ metastatic breast cancer (MBC). However, outcomes can vary, with patients progressing within 1-year of treatment or exceptional cases of complete response to trastuzumab for ≥ 10 years. Identification of the underlying genomic aberrations of “exceptional responders (ExRs)” compared to “rapid non-responders (NR)” increases our understanding of the mechanisms involved in MBC progression and identification of biomarkers of trastuzumab response and resistance. Whole exome sequencing was performed on six ExRs compared to five NR. The overall fraction of genome copy number alteration (CNA) burden was higher in NR patients (P=0.07), while more significantly pronounced in copy number gains (P=0.03) in NR compared to ExRs. Delineation of the distribution of CNA burden across the genome identified a greater degree of CNA burden in NR within chr8 (P=0.02) and in chr17 (P=0.06) and conferred a statistically significant benefit in overall survival.

  Study EGAS00001004486

• Latency and interval therapy affect the evolution in metastatic colorectal cancer

  While comparison of primary tumor and metastases has highlighted genomic heterogeneity in colorectal cancer (CRC), previous studies have focused on a single metastatic site or limited genomic testing. Combining data from whole exome and ultra-deep targeted sequencing, we explored possible evolutionary trajectories beyond the status of these mutations, particularly among patient-matched metastatic tumors. Our findings confirm the persistence of known clinically-relevant mutations (e.g. those of RAS family of oncogenes) in CRC primary and metastases, yet reveal that latency and interval systemic therapy affect the course of evolutionary events within metastatic lesions. Specifically, our analysis of patient-matched primary and multiple metastatic lesions, developed over time, showed a similar genetic composition for liver metastatic tumors, which were 21-months apart. This genetic makeup was different from those identified in lung metastases developed before manifestation of the second liver metastasis. These results underscore the role of dormancy in the evolutionary path of metastatic CRC.

  Study EGAS00001003646

• Familial adult myoclonic epilepsy in Sri Lankan and Indian families

  Familial adult myoclonic epilepsy 1 (FAME1), first recognised in Japanese families, was recently shown to be caused by a TTTCA repeat insertion in intron 4 of SAMD12 on chromosome 8. We performed whole genome sequencing on two families with FAME, one of Sri Lankan origin and the other of Indian origin, and identified a TTTCA repeat insertion in SAMD12 in both families. Haplotype analysis revealed that both families shared the same core ancestral haplotype reported in Japanese and Chinese families with FAME1. Mutation dating, based on the length of shared haplotypes, estimated the age of the ancestral haplotype to be approximately 670 generations, or 17,000 years old. Our data extend the geographic range of this repeat expansion to Southern Asia and potentially implicate an even broader regional distribution given the age of the variant. This finding suggests patients of Asian ancestry with suspected FAME should be screened for the SAMD12 TTTCA expansion.

  Study EGAS00001004012

• Massively parallel single-cell B-cell receptor sequencing enables rapid discovery of diverse antigen-reactive antibodies

  Using high-throughput single-cell B-cell receptor sequencing (scBCR-seq) we obtained accurately paired full-length heavy- and light-chain variable regions from thousands of individual B cells in a massively parallel fashion. We sequenced more than 250,000 B cells from rat, mouse and human repertoires to characterize their lineages and expansion. In addition, we immunized rats with chicken ovalbumin and profiled antigen-reactive B cells from lymph nodes of immunized animals. The scBCR-seq data recovered 81% (n = 56/69) of B-cell lineages identified from hybridomas generated from the same set of B cells that were subjected to scBCR-seq. Importantly, scBCR-seq identified an additional 710 candidate lineages that were not recovered as hybridomas. We synthesized, expressed and tested 93 clones from the identified lineages and found that 99% (n = 92/93) of the clones were antigen-reactive. Our results establish scBCR-seq as a powerful tool for antibody discovery.

  Study EGAS00001003663

• scRNA-seq of LN and lymphoma stroma

  The activities of non-haematopoietic cells (NHCs), including mesenchymal stromal cells and endothelial cells, in lymphomas, reportedly underlie lymphomagenesis. However, understanding of lymphoma NHCs has been hampered by unexplained NHC heterogeneity, even in normal human lymph nodes (LNs). Here, we constructed a single-cell transcriptome atlas of &gt;100,000 NHCs collected from 27 human samples, including LNs and various nodal lymphomas, revealing 30 distinct subclusters, including some that were previously unrecognized. Notably, this atlas was highly useful for comparative analysis with lymphoma NHCs, which revealed an unanticipated landscape of subcluster-specific changes in gene expression and interaction with malignant cells in follicular lymphoma NHCs, facilitating our understanding of stromal remodelling in lymphoma and potentially suggesting novel biomarkers. Our study largely updates NHC taxonomy in human LNs and pertains to analysis of disease status, providing a rich resource and deeper insights into LN and lymphoma biology and offering to advance lymphoma management and therapy.

  Study EGAS00001005732

• Chemotherapy induces canalization of cell state in childhood B-cell precursor acute lymphoblastic leukemia

  Comparison of intratumor genetic heterogeneity in cancer at diagnosis and relapse suggests that chemotherapy induces bottleneck selection of subclonal genotypes. However, evolutionary events subsequent to chemotherapy could also explain changes in clonal dominance seen at relapse. We therefore investigated the mechanisms of selection in childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL) during induction chemotherapy where maximal cytoreduction occurs. To distinguish stochastic versus deterministic events, individual leukemias were transplanted into multiple xenografts and chemotherapy administered. Analyses of the immediate post-treatment leukemic residuum at single-cell resolution revealed that chemotherapy has little impact on genetic heterogeneity. Rather, it acts on extensive, previously unappreciated, transcriptional and epigenetic heterogeneity in BCP-ALL, dramatically reducing the spectrum of cell states represented, leaving a genetically polyclonal but phenotypically uniform population, with hallmark signatures relating to developmental stage, cell cycle and metabolism. Hence, canalization of the cell state accounts for a significant component of bottleneck selection during induction chemotherapy.

  Study EGAS00001004407