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• SUDC Registry and Research Collaborative

  The Sudden Unexplained Death in Childhood Registry and Research Collaborative (SUDCRRC), created at NYU Langone Health in 2014, connects academic investigators, forensic pathologists, and medical examiner and coroner partner offices to study sudden unexpected pediatric deaths, aged 1 month to 18 years, whose death is unexplained or unclear at the end of the public mandated investigation, including autopsy. Each case includes collection and analysis of all records (medical history from prenatal records throughout life, death scene investigation, autopsy/toxicology/ancillary death investigation reports including photographs and histology slides), biospecimens, and in-depth family interviews. Whole exome sequencing is performed on each deceased child and both biological parents. Additional studies are pursued when indicated by pathology review. Each case receives a multidisciplinary masked review process and parental written consent is obtained. The NYU institutional review board approved this study.

  Study phs003383

• Disease-Linked Regulatory DNA Variants and Homeostatic Transcription Factors in Epidermis

  The role of non-coding variants in polygenic skin disease and their connection to homeostatic transcription factors (TFs) in epidermis was investigated. Homeostatic TFs were identified by perturb-seq in differentiating keratinocytes, using either 10x or split-pool approaches to sequencing, with follow-up validation by siRNA and RNA-seq. TF binding events were profiled by population sampling Cleavage Under Targets & Release Using Nuclease (CUT&RUN), in which a random population of neonatal foreskin keratinocytes were assayed by CUT&RUN for homeostatic TFs under progenitor growth and differentiation conditions. Heterozygous alleles were identified from the TF binding data and examined for allele specific binding events (ASBs). ASBs were then compared with non-coding variants linked to skin disease. Variants with potentially pathogenic effects were identified. Promoters and high TF occupancy genomic regions were found to be "buffered" against variants causing ASBs.

  Study phs003977

• Childhood Cancer Data Initiative (CCDI): Molecular Characterization Initiative

  The National Cancer Institute's (NCI) Childhood Cancer Data Initiative (CCDI) focuses on the critical need to collect, analyze, and share data to address the burden of cancer in children, adolescents, and young adults (AYAs). The Molecular Characterization Initiative (MCI) will further the CCDI's goals by providing access to better diagnostic tests for pediatric and AYA patients. The molecular characterizations of solid tumors, soft tissue sarcomas, and rare diseases are performed in a CLIA-certified setting as results may be used to screen for and/or confirm clinical trial eligibility, direct treatment, or otherwise contribute to the conduct of the trial. The following molecular characterization assays were performed:Tumor/Normal Whole Exome sequencing Methylation arraysArcher fusion panel Deidentified clinical reportsNote: New data will be added periodically, please check the CCDI Hub Explore site for updates.

  Study phs002790

• Whole genome sequencing data from tumor and normal samples

  Whole genome sequencing FASTQ files from tumor and normal samples from 202 patients. All experiments reported in this article were performed in the Clinical Laboratory Improvement Amendments (CLIA)-certified and College of American Pathologists (CAP)-accredited laboratories at Personalis Inc., as guided by the Association for Molecular Pathology (AMP) and CAP’s joint recommendations52. Preferred input material consisting of FFPE slides (enabling H&E and macrodissection which is part of the standard NeXT Personal process) was not available for the majority (94%) of tumor samples. Most tumor samples (72%) were processed from FFPE curls, with the remaining processed from pre-extracted DNA and fresh frozen material. Where FFPE material on slide was available, tumor sections were macrodissected to increase tumor content, with a minimum allowable cellularity threshold of 20% determined by pathological review. The tumor cellularity threshold of 20% was chosen based on prior work demonstrating that no significant correlation is observed between tumor purity and assay limit of detection (LOD) at this threshold31. Genomic DNA was isolated from tumor and normal samples and WGS libraries prepared as previously described31. Genomic DNA was isolated from matched tumor and normal samples using the Qiagen AllPrep DNA/RNA FFPE Tissue Kit or the QIAamp DNA Mini Kit (QIAGEN, Germantown, MD, USA) using internally optimized workflows. WGS sequencing libraries were prepared with 120-500 ng of acoustically sheared genomic DNA (Covaris LLC, Woburn, MA, USA) using the KAPA HyperPrep Kit (Roche Sequencing Solutions, Pleasanton, CA, USA) and customized methods. Libraries were cleaned-up using AMPure XP beads and then quantified using the KAPA Library Quantification Kit (Roche Sequencing Solutions, Pleasanton, CA, USA), before being sequenced to 30X depth of coverage using a NovaSeq 6000 instrument (Illumina, San Diego, CA, USA).

  Dataset EGAD50000001909

• Dynamic Evolution of Fibroblasts Revealed by Single Cell RNA Sequencing of Human Pancreatic Cancer

  Understanding the constituents of the pancreatic ductal adenocarcinoma (PDAC) microenvironment may illuminate more efficacious targets for treating this aggressive malignancy. However, the compositional changes occurring in untreated and treated PDAC relative to both normal and inflamed pancreas have not been well characterized. To provide a more comprehensive understanding of the PDAC tumor microenvironment relative to the non-cancerous pancreas, we performed single-cell expression profiling (10X Genomics Chromium) on samples of upfront resectable PDAC, FOLFIRINOX-based treated PDAC, chronic pancreatitis, and normal pancreas specimens from 19 patients. Spatial gene expression profiling (10X Genomics Visium) was performed to gain additional insight into cell populations. Our analysis revealed that fibroblasts are central mediators of cell-cell communication in both inflamed and malignant settings and defined unique roles for these cell populations in different disease contexts.

  Study phs003751

• Establishment of xenogfafts and cultured cell lines from clinical samples

  The purpose of the present study was to clarify the presence or absence of alterations in the molecular properties of patient-derived xenografts (PDXs) with up to eight passages in endometrial carcinomas. Alterations in the proportion of immunohistochemically positive/negative cells for PAX8, estrogen receptor, PAX2, and PTEN were observed in established PDXs of endometrioid carcinomas and carcinosarcomas, whereas proportions of cells with AE1/AE3, TP53, ARID1A PMS2, and MSH6 were maintained. Variants of cancer-associated genes in PDX compared to those in the parental tumors were examined in two cases, a frameshift deletion in BRCA1 was observed in the parental tumor tissue, and additional genomic alterations were found in the PDXs of this case. Genomic and phenotypic alterations in endometrial carcinoma PDXs relative to the parental tumors were observed and were partly associated with endometrial cancer-specific characteristics in cellular differentiation and gene mutations.

  Study JGAS000585

• DEPArray-based sorting of pure carcinoma and stromal populations from formalin-fixed paraffin-embedded (FFPE) tissues followed by shallow whole genome sequencing

  To overcome the challenges of low DNA yields, degraded DNA by formalin fixation and diluted signal of genomic aberrations by non-carcinoma components in the heterogeneous FFPE samples, we isolated pure carcinoma and stromal cells using the DEPArray™ NxT system, a microchip-based digital sorter that allows isolation of pure, homogeneous subpopulations of cells from FFPE samples. We isolated pure carcinoma and stromal cell populations from 12 FFPE tissues, including tissues from 9 primary and metastatic breast cancer and 3 primary ovarian high-grade serous carcinomas. This was followed by downstream shallow whole genome sequencing (WGS) for copy number landscape profiling for 10 samples. Seven out of 10 samples (even some with low tumour content or of old age) produced good quality genomic data, detecting sCNA in all carcinoma population samples but not in the stromal populations.

  Study EGAS50000001328

• Multimodal epigenetic sequencing analysis of cell-free DNA identifies biomarkers for ALS diagnosis and progression

  The role of the circulating epigenome in ALS remains understudied. We aim to develop diagnostic and prognostic blood-based biomarkers for Amyotrophic Lateral Sclerosis (ALS) by profiling methylome signatures in circulating cell-free DNA (cfDNA) in 20 sporadic ALS cases, 10 C9orf72-associated ALS cases, 10 asymptomatic C9orf72 expansion carriers, and 21 healthy controls using targeted enzymatic methyl-sequencing (EM-seq) of ~4 million CpG loci. We detected numerous differentially methylated genes, including several implicated in ALS risk and pathobiology, and integrated multiple epigenetic features with our Multimodal Epigenetic Sequencing Analysis (MESA) algorithm, achieving an ROC AUC of 0.91 and detecting ~70% of ALS cases at ~100% specificity. Methylation at a subset of loci also correlated with clinical progression and cerebrospinal-fluid neurofilament levels, supporting the potential of cfDNA-based biomarkers for ALS diagnosis and monitoring.

  Study EGAS50000001267

• TenK10K Phase 1:  Single Cell

  Understanding the genetic basis of gene expression can shed light on the regulatory mechanisms underlying complex traits and diseases. Single-cell resolved measures of RNA levels and single-cell expression quantitative trait loci (sc-eQTLs) have revealed genetic regulation that drives sub-tissue cell states and types across diverse human tissues. Here, we describe the first phase of TenK10K, the largest- to-date dataset of matched whole-genome sequencing (WGS) and single-cell RNA-sequencing (scRNA-seq). We leverage scRNA-seq data from over 5 million cells across 28 immune cell types and matched WGS from 1,925 individuals. This provides power to detect associations between rare and low-frequency genetic variants that have largely been uncharacterised in their impact on cell-specific gene expression. We map the effects of both common and rare variants in a cell type specific manner using SAIGE-QTL.

  Study EGAS50000001653

• Long-read sequencing of saliva collected and stablized at room temperature in Oragene devices on the PacBio Revio

  Saliva collected in Oragene™ devices and extracted with Nanobind kits yields high‑molecular‑weight DNA suitable for PacBio HiFi whole‑genome sequencing, offering a convenient alternative to blood collection (“High-quality HMW DNA was obtained from all samples…”). Sequencing of paired saliva and blood samples on the Revio system produced comparable HiFi read lengths, yields, and 30–39× genome coverage. Methylation profiles were also highly similar, with minor differences attributable to small amounts of non‑human DNA present in saliva (“DNA extracted from saliva is typically ~75–95% human…”). Variant calling using PacBio WGS pipelines showed high concordance between saliva and blood from the same donor for both SNVs and structural variants. These results demonstrate that saliva enables reliable, high‑throughput HiFi sequencing workflows with performance equivalent to blood.

  Study EGAS50000001666

• Raw human sequencing data for “Characterization of intestinal immune responses in generalized human and murine lipodystrophy”

  This dataset contains raw FASTQ files generated from peripheral blood and intestinal biopsy samples collected for the study “Characterization of intestinal immune responses in generalized human and murine lipodystrophy.” Peripheral blood sequencing was performed on samples from three healthy donors as controls and from a patient with acquired generalized lipodystrophy and Crohn’s disease (AGLCD) at two distinct timepoints. Intestinal biopsy–derived immune cells were sequenced from three individuals with Crohn’s disease as disease controls, as well as from the AGLCD patient (single timepoint). The data include paired-end FASTQ files derived from single-cell RNA sequencing and T-cell receptor repertoire profiling, enabling analyses of immune composition, transcriptional states, and clonal T-cell expansion. All data are controlled-access human genomic datasets and require appropriate authorization for secondary use.

  Study EGAS50000001517

• Genetic landscape of pediatric Retinoblastoma

  Retinoblastoma is a pediatric cancer of the developing retina. All retinoblastomas are believed to initiate with biallelic inactivation of the RB1 gene. To identify subsequent genetic lesions in retinoblastoma, we performed whole genome sequencing of tumor and normal DNA of 4 children with retinoblastoma and one matched orthotopic xenograft. Both alleles of RB1 were inactivated in the tumor samples. 3 of the patients had sporadic retinoblastoma and one patient had inherited retinoblastoma. Overall, there were few single nucleotide changes in coding regions of the genome and some of the tumors had few chromosomal lesions. There were very few new genetic lesions in the xenograft compared to the primary tumor. These data suggest that the genome in retinoblastoma is more stable than previously believed and there are relatively few recurrent genetic lesions in known cancer pathways other than the RB1 pathway.

  Study EGAS00001000346

• Exome sequencing of samples taken at multipl time points to monitor therapy response in AML

  As part of our individualized systems medicine program, personalized treatment options are identified and administered to chemorefractory AML patients based on exome sequencing and ex-vivo drug sensitivity and resistance testing data. In this study, we developed this approach further to take into account clonal heterogeneity and analyzed responses of 13 AML patients to chemotherapy and six patients to targeted treatments by using exome and ultra-deep amplicon resequencing. The data submitted includes fastq files from exome sequencing of multiple time-point samples collected from the 13 patients. In this study we identified rare subclonal variants present at diagnosis or later relapse samples and developed a correlation-based method to compare subclonal responses in serial samples across multiple time-points. Significant subclone-specific responses were observed subsequent to chemotherapy and specifically to targeted therapy in five patients.

  Study EGAS00001001948

• Reconstructing the dispersals and adaptive history of Bantu-speaking populations in Africa and North America

  Bantu languages are spoken by ~310 million Africans, yet the genetic history of Bantu-speaking populations remains largely unexplored. We generated genomic data for 1,318 individuals from 35 populations in western central Africa, where Bantu languages originated. We found that early Bantu speakers first moved southward, through the equatorial rainforest, before spreading toward eastern and southern Africa. We also found that genetic adaptation of Bantu speakers was facilitated by admixture with autochthonous populations, particularly for the HLA and LCT loci. Finally, we identified a major contribution of western central African Bantu speakers to the ancestry of African Americans, whose genomes present no strong signals of natural selection. Together, these results highlight the contribution of Bantu-speaking peoples to the complex genetic history of Africans and African Americans.

  Study EGAS00001002078

• Genomic and transcriptional landscape of P2RY8-CRLF2-positive childhood acute lymphoblastic leukemia

  The mutational and transcriptional landscape of P2RY8-CRLF2-positive ALL was defined in 41 major clone fusion-positive cases including 19 matched diagnosis and relapse pairs by an integrated analysis of whole-exome and RNA sequencing. We detected a variety of frequently subclonal and highly unstable JAK/STAT but also RTK/Ras pathway activating mutations in 76% of cases at diagnosis and virtually all relapses. Unlike P2RAY8-CRLF2 that was lost in 32% of relapses, all other genomic deletions affecting lymphoid development and cell cycle remained stable. Only IKZF1 alterations predominated in relapsing cases and increased from initially 36 to 58% in matched cases. IKZF1¹s transcriptional signature revealed compromised stem cell features with signs of impaired lymphoid differentiation, enhanced focal adhesion, activated hypoxia pathway, deregulated cell cycle and increased drug resistance.

  Study EGAS00001001847

• An oncogenic enhancer-rearrangement causes concomitant deregulation of EVI1 and GATA2 in leukemia. Targeted resequencing of chromosomal regions centered on 3q21 and 3q26 in conjunction with RNA-Seq from Acute Myeloid Leukemia patients.

  Chromosomal rearrangements without gene-fusions have been implicated in leukemogenesis by causing deregulation of proto-oncogenes via relocation of cryptic regulatory DNA elements. AML with inv(3)/t(3;3) is associated with aberrant expression of the stem-cell regulator EVI1. Applying functional genomics and genome-engineering, we demonstrate that both 3q-rearrangements reposition a distal GATA2 enhancer to ectopically activate EVI1 and simultaneously confer GATA2 functional haploinsufficiency, previously identified as the cause of sporadic familial AML/MDS and MonoMac/Emberger syndromes. Genomic excision of the ectopic enhancer restored EVI1 silencing and led to growth inhibition and differentiation of AML cells, which could be replicated by pharmacologic BET-inhibition. Our data show that structural rearrangements involving chromosomal repositioning of enhancers can cause deregulation of two unrelated distal genes, with cancer as the outcome.

  Study EGAS00001000669

• TRACERx: TRAcking non-small cell lung Cancer Evolution through therapy (Rx). Pilot Study. Multi-region sequencing of early-stage NSCLCs.

  Deciphering the complexity of non-small cell lung cancer (NSCLC) evolutionary histories may elucidate the basis for its dismal outcome. We performed multi-region sequencing of early-stage NSCLCs. Spatial dissection revealed branched tumor evolution, with driver mutations occurring before and after subclonal diversification. Intra-tumor heterogeneity in DNA copy number alterations, translocations and endogenous APOBEC mutational processes demonstrates that NSCLC may follow multiple distinct evolutionary trajectories simultaneously. In smokers, despite maintained carcinogen exposure, temporal dissection reveals a relative decrease in smoking-related mutations during tumor progression, accompanied by an increase in APOBEC-related mutations. In the tumors from ex-smokers, genome-doubling occurred before subclonal diversification, suggesting prolonged latency before clinical detection. Multi-region sequencing demonstrates the relentless and heterogeneous nature of genomic instability processes in early-stage NSCLCs.

  Study EGAS00001000809

• Tracing the origins of relapse in AML to stem cells

  In acute myeloid leukemia (AML), most patients relapse despite achieving remission. While relapse-specific mutations are sometimes detected at low frequency within bulk diagnosis samples, the cell type giving rise to relapse is unknown. Through combined genetic and functional analysis of purified subpopulations and xenografts from paired diagnosis/relapse samples, we identified two major patterns of relapse arising from therapy-resistant cells already present at diagnosis. In some cases relapse originated from rare leukemia stem cells with a primitive immunophenotype, while in other instances relapse developed from larger subclones of immunophenotypically-committed cells that retained strong stemness transcriptional signatures. The identification of distinct patterns of relapse should lead to improved methods for disease management and monitoring in AML. Moreover, the shared functional and transcriptional stemness properties that underlie both cellular origins of relapse underscore the importance of developing new therapeutic approaches that target stemness to prevent relapse.

  Study EGAS00001002225

• Genome-wide DNA methylation profiles by MeDIP-seq of cord blood cells and cord blood mononuclear cells obtained from twins conceived through in vitro fertilization and naturally conceived controls

  The study included 47 newborn twins conceived though in vitro fertilisation (IVF) and 60 non-IVF-conceived twins from the Peri/postnatal Epigenetic Twins Study (PETS). Cord blood was collected at birth and used to process mononuclear cells. Whole blood cells (WBCs) from cord blood of 98 twins (40 IVF and 58 non-IVF) and cord blood mononuclear cells (CBMCs) of 82 twins (35 IVF and 47 non-IVF) were subjected to DNA methylation profiling. Methylated DNA immunoprecipitation followed by deep sequencing (MeDIP-seq) was applied to generate genome-wide DNA methylation profiles in a total of 180 samples. Single-end reads were mapped onto hg19 using BWA. Methylation levels were quantified using MEDIPS and used to identify IVF-associated differentially methylated regions.

  Study EGAS00001002248

• Therapeutic Targeting of Ependymoma as Informed by Oncogenic Enhancer Profiling

  Genomic sequencing has driven precision-based oncology therapy; however, genetic drivers remain unknown or non-targetable for many malignancies, demanding alternative approaches to identify therapeutic leads. Ependymomas are chemotherapy-resistant brain tumours, which, despite genomic sequencing, lack effective molecular targets. Here, we mapped active chromatin landscapes in 42 primary ependymomas in two non-overlapping primary ependymoma cohorts. Enhancer regions revealed novel oncogenes, molecular targets, and pathways, which when subjected to small molecule inhibitor or shRNA treatment, increased survival and slowed proliferation in mouse and neurosphere patient-derived models of ependymomas. This study represents one of the largest enhancer mapping study of any cancer type to date, and provides a framework for target and drug discovery for other cancers recalcitrant to therapeutic development because of their lack of known genetic drivers.

  Study EGAS00001002696

• Transcriptome sequencing of Gingivo-buccal Cancer : ICGC-India Project_YR03

  Transcriptome Sequencing of Gingivo-buccal Cancer: ICGC-India ProjectAs a part of the ICGC, India has undertaken genomic studies on gingivobuccal cancer of the oral cavity, which is the most prevalent form of cancer among men in India. There are various known environmental (life-style) correlates of this cancer, the most important of which are tobacco chewing and HPV infection. Transcriptome sequencing of paired RNA samples – isolated from the tumor and adjacent normal tissues of 12 patients – have been performed. Detailed clinical characterization of the patients, collection of data on demographic and environmental exposures, and isolation of DNA samples from adjacent normal and tumor tissues collected from each patient are being done at the Advanced Centre for Research, Treatment and Education on Cancer, Mumbai. Sequencing is being performed at the National Institute of Biomedical Genomics, Kalyani.

  Study EGAS00001002851

• Whole genome characterisation of lung cancer organoids and tissue

  Organoids are self-organizing 3D structures grown from stem cells that recapitulate essential aspects of organ structure and function. Here we describe a method to establish long-term expanding human airway organoids from broncho-alveolar biopsies or lavage material. The pseudostratified airway organoid epithelium consists of basal cells, functional multi-ciliated cells, mucus-producing goblet cells, and CC10-secreting club cells. Airway organoids derived from cystic fibrosis (CF) patients allow assessment of CFTR function in an organoid swelling assay. Organoid culture conditions also allow gene editing as well as the derivation of various types of lung cancer organoids. Respiratory syncytial virus (RSV) infection recapitulated central disease features and dramatically increases organoid cell motility, found to be driven by the non-structural viral NS2 protein. We conclude that human airway organoids represent versatile models for the in vitro study of hereditary, malignant, and infectious pulmonary disease.

  Study EGAS00001002899

• Study the differences at the trascriptome level between iNKT and T cells

  Chimeric antigen receptor anti-CD19 (CAR19)-T cell immunotherapy-induced clinical remissions in CD19+ B cell lymphomas are often short-lived. We tested whether CAR19-engineering of the CD1d-restricted invariant NKT (iNKT) cells would result in enhanced anti-lymphoma activity. CAR19-iNKT cells co-operatively activated by CD1d- and CAR19-CD19-dependent interactions are more effective than CAR19-T cells against CD1d-expressing lymphomas in vitro and in vivo. The swifter in vivo anti-lymphoma activity of CAR19-iNKT cells and their enhanced ability to eradicate brain lymphomas underpinned an improved tumor-free and overall survival. CD1d transcriptional de-repression by all-trans retinoic acid results in further enhanced cytotoxicity of CAR19-iNKT cells against CD19+ chronic lymphocytic leukemia cells. Thus, iNKT cells are a highly efficient platform for CAR-based immunotherapy of lymphomas and possibly other CD1d-expressing cancers.

  Study EGAS00001003176

• Comparison_of_transcriptional_response_of_induced_pluripotent_stem__iPS__cell_derived_and_monocyte_derived_macrophages_to_bacterial_lipopolysaccharide_stimulation

  In the first part of this project, we will differentiate IPS cells from 5 human donors into macrophages, and extract RNA from unstimulated and LPS stimulated macrophages to perform RNA sequencing. We will also extract RNA before and after stimulation in blood- derived macrophages from 5 additional, unrelated healthy samples. In the second part of the project, RNA-seq data will be analysed to compare LPS response of these two macrophage populations. In summary, we will perform 75bp PE RNA-seq on 20 samples (10 pre and post stimulus), on the HiSeq 2500 platform. Samples will be multiplexed at 5 samples / lane, so we will require 4 flow cells in total.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 EGAS00001000563

• Spatial and temporal diversity in genomic instability processes define early stage lung cancer evolution.

  Deciphering the complexity of non-small cell lung cancer (NSCLC) evolutionary histories may elucidate the basis for its dismal outcome. We performed multi-region sequencing on 25 regions from seven early-stage NSCLCs. Spatial dissection revealed branched tumor evolution, with driver mutations occurring before and after subclonal diversification. Intra-tumor heterogeneity in DNA copy number alterations, translocations and endogenous APOBEC mutational processes, demonstrates that NSCLC may follow multiple distinct evolutionary trajectories simultaneously. In smokers, despite maintained carcinogen exposure, temporal dissection reveals a proportional decrease in smoking-related mutations during tumor progression, accompanied by an increase in APOBEC-related mutations. We observed genome-doubling events early in tumor development of ex-smokers, suggesting prolonged latency periods before clinical detection. Multi-region sequencing demonstrates the relentless and heterogeneous nature of genomic instability processes in early-stage NSCLCs.

  Study EGAS00001000840

• Whole Genome Sequencing to track subclonal heterogeneity in 18 samples from 3 Chronic Lymphocytic Leukemia patients subjected to repeated cycles of therapy.

  This study took 18 samples from three patients with Chronic Lymphocytic Leukemia. The 3 CLL patients received multiple different treatments sequentially for a period of up to 7 years. Peripheral blood samples were taken at 5 specific time points during disease progression together with 1 matched buccal swab per patient. All the selected patients had unmutated IgVH status reflecting poor prognosis. However, none of the patients had complex genomic aberrations associated with aggressive disease. Peripheral blood samples and buccal smears were obtained from patients, who had given informed consent for sequential sample collection and analysis. Tumour samples were obtained before treatment, after treatment and at relapse and subjected to Ficoll separation. Lymphocyte cell purity was assessed by full blood count enumeration. Buccal smears were obtained and processed using Isohelix.

  Study EGAS00001000885

• G&T-seq: parallel sequencing of the genomes and transcriptomes of single cells

  The ability to simultaneously sequence the genome and transcriptome of the same single cell offersa powerful means to dissect functional genetic heterogeneity at the cellular level. Here we describeG&T-seq, a method for separating and sequencing genomic DNA and full-length mRNA from singlecells. By applying G&T-seq to over 220 single cells we reveal cellular properties that cannot beinferred from DNA or RNA sequencing alone, including associations between DNA copy numbervariation and gene expression dosage. We further demonstrate the detection of coding interchromosomalfusions and single nucleotide variants in both the genomes and transcriptomes ofindividual cells. G&T-seq enables the study of genotype-phenotype associations in single cells, andthe investigation of DNA cell lineage trees of healthy and diseased tissues with transcriptome inferredcell types and states.

  Study EGAS00001001204

• DNA methylation and somatic mutations converge on cell cycle and define similar evolutionary histories in brain tumors

  The evolutionary history of tumor cell populations can be reconstructed from patterns of genetic alterations. In contrast to the stability of genetic events, epigenetic states are reversible and sensitive to the microenvironment, prompting the question whether epigenetics can be similarly used to discover tumor phylogeny. We examined the spatial and temporal dynamics of DNA methylation in a cohort of low-grade gliomas and their patient-matched recurrences. Genes upregulated through promoter hypomethylation during malignant progression to high-grade glioblastoma were enriched in cell cycle function, evolving in parallel with genetic alterations that deregulate the G1/S cell cycle checkpoint. Moreover, phyloepigenetic relationships robustly recapitulated phylogenetic patterns inferred from somatic mutations. These findings highlight widespread co-dependency of genetic and epigenetic events throughout brain tumor evolution.

  Study EGAS00001001255

• BLUEPRINT DNA Methylation 450K data of mantle cell lymphoma

  We have applied an analytic strategy to decipher the DNA methylome of 86 mantle cell lymphomas (MCL) in light of the methylome of the entire B-cell lineage. In this way, we first identified two MCL subgroups that respectively carry epigenetic imprints of pre- and post-germinal center B cells. Secondly, we observed that pure tumor-specific changes are rare, as most (89-99%) DNA methylation alterations in MCL are within or in close proximity of those regions showing dynamic methylation in normal B cells. Several thousand of these differentially methylated regions in MCL show concurrent changes in enhancer-associated histone modifications, including a region located 650 Kb away from the MCL oncogene SOX11. At the clinical level, epigenetic and genetic changes co-evolve during MCL progression and the magnitude of epigenetic changes is associated with overall survival of the patients.

  Study EGAS00001001637

• Drugging the catalytically inactive state of RET kinase in RET-rearranged tumors.

  Oncogenic fusion events have been identified in a broad range of tumors. Among them, RET rearrangements represent distinct and potentially druggable targets that are recurrently found in lung adenocarcinomas. We provide further evidence that current anti-RET drugs may not be potent enough to induce durable responses in such tumors. We report that potent inhibitors, such as AD80 or ponatinib, that stably bind in the DFG-out conformation of RET may overcome these limitations and selectively kill RET-rearranged tumors. Using chemical genomics in conjunction with phosphoproteomic analyses in RET-rearranged cells, we identify the CCDC6-RETI788N mutation and drug-induced mitogen-activated protein kinase pathway reactivation as possible mechanisms by which tumors may escape the activity of RET inhibitors. Our data provide mechanistic insight into the druggability of RET kinase fusions that may be of help for the development of effective therapies targeting such tumors.

  Study EGAS00001002335

• Pilot study for Illumina TST170 NGS panel on cutaneous T cell lymphoma samples

  A number of genomic studies using next generation sequencing (NGS) techniques have attempted to understand the underlying genetic basis of cutaneous T-cell lymphoma and found alterations in genes that are involved in T-cell activation, NF-kB and JAK-signal transducer and activator of transcription (STAT) pathways. 8 diagnostic skin biopsy samples (2xplaque, 6xtumour) on FFPE blocks were selected from 8 MF patients (stage IB:n=1, IIB:n=6, IVA2:n=1). An H&E was performed in order to assess percentage of tumor cells, viable cells, necrosis and immune infiltration, to determine the number of slides required for NGS. Freshly cut unstained slides were manually macrodissected prior to DNA and RNA extraction. Targeted deep sequencing was performed using panel of 170 genes associated with common solid tumours (Illumina TruSight Tumour 170 NGS panel). VCF files generated via the Illumina’s Basespace platform.

  Study EGAS00001002567

• Transcriptional_Consequences_of_Copy_Number_Changes_MY_HDBR_200531

  Every normal human cell has two copies of each non-sex chromosome. The gain or loss of an extra copy underlies many health conditions, including developmental syndromes and cancer. Ultimately, it is the patterns of genes that are turned on and off that determines which proteins a cell produces and its biological function. Despite the importance of changes in chromosome number (known as aneuploidy or copy number changes), little is known about how these changes impact patterns of gene expression. This project will aim to fill this gap by creating an atlas of patterns of gene expression in cells from developmental tissues with aberrant numbers of chromosomes. These gene expression profiles will then be compared to the patterns of expression in the same cells with two copies of each chromosome, directly measuring the precise, cell specific, consequences of copy number change on gene expression.

  Study EGAS00001005100

• Genomic DNA of tumor tissues, adjacent normal tissues, and peripheral blood were extracted using QIAamp DNA mini Kit (QIAGEN, cat. #51306)

  Although genomic instability, epigenetic abnormality, and gene expression dysregulation are hallmarks of colorectal cancer, these features have not been simultaneously analyzed at single cell resolution. Using optimized single cell multiomics sequencing together with multiregional sampling of the primary tumor, lymphatic and distant metastases, we provide insights beyond intratumoral heterogeneity. Genome wide DNA methylation levels were relatively consistent within a single genetic sublineage. The genome-wide DNA demethylation patterns of cancer cells were consistent in all 10 sequenced patients. The cancer cells’ DNA demethylation degrees clearly correlated with the densities of the heterochromatin-associated histone modification H3K9me3 of normal tissue, and those of repetitive element Long Interspersed Nuclear Element 1. Our work demonstrates the feasibility of reconstructing genetic lineages, and tracing their epigenomic and transcriptomic dynamics with single cell multiomics sequencing.

  Study EGAS00001003242

• Splicing patterns in SF3B1 mutated uveal melanoma generate shared immunogenic tumor-specific neo-epitopes

  Disruption of splicing patterns due to mutations of genes coding splicing factors in tumors represents a potential source of tumor neo-antigens, which would be both public (shared between patients) and tumor-specific (not expressed in normal tissues). In this study, we show that mutations of the splicing factor SF3B1 in uveal melanoma (UM) generate such immunogenic neo-antigens. Memory CD8+ T cells specific for these neo-antigens are preferentially found in 20% of UM patients bearing SF3B1 mutated tumors. Single cell analyses of neo-epitope specific T cells from the blood identified large clonal T cell expansions, with distinct effector transcription patterns. Some of these expanded TCRs are also present in the corresponding tumors. CD8+ T cell clones specific for the neo-epitopes specifically recognize and kill SF3B1-mutated tumor cells, supporting the use of this new family of neo-antigens as therapeutic targets.

  Study EGAS00001005226

• Combination_Immune_Checkpoint_Inhibition_in_Australian_Rare_Cancers_WES

  Combination immune checkpoint inhibition (ICI) with anti-CTLA-4 and anti-PD-1 blockade has demonstrated significant clinical activity across tumour types. Rare cancer patients have limited treatment options due to the scarcity of studies of novel treatment options, so they are often offered chemotherapies untested in their disease. ONJ2016-001/CA209-538 is a prospective, multicentre clinical trial of combination ICI (ipilimumab and nivolumab) in patients with advanced rare cancers, including biliary tract, adrenocortical, rare gynaecological and neuroendocrine cancers (https://clinicaltrials.gov/ct2/show/NCT02923934). The primary endpoint is clinical benefit rate (complete response + partial response + stable disease >3 months) by RECIST 1.1. This study involves generation and analysis of pre-treatment formalin fixed paraffin embedded (FFPE) tumour DNA sequencing data, paired with germline DNA sequencing data, to potentially identify genomic biomarkers that may associate with clinical benefit or other clinical efficacy / toxicity metrics.

  Study EGAS00001005709

• Vento_Placental_Cell_Atlas

  The Human Cell Atlas initiative is an ambitious global research effort which aims to describe every cell in the human body across all developmental stages to generate a reference map to accelerate progress in science and medicine particularly relating to human development and disease. The initiative is led by investigators based at the Wellcome Sanger Institute and the Broad Institute of MIT and Harvard and funding support from the Wellcome and NIH. This specific project will assess human development. We aim to interrogate the cellular composition and molecular regulators underpinning development and maturation through single cell RNA-sequencing/spatial transcriptomics and computational algorithms to predict cellular developmental trajectories and cell-cell interactions. We will subsequent validate these findings in situ using allied imaging technologies e.g. immunohistochemistry and RNAscope and in vitro culture of human intestinal organoids (HIOs).

  Study EGAS00001004187

• Analysis of IDHwt-glioblastoma samples from paired primary and recurrent tumor samples

  IDHwt-glioblastomas rapidly recur after initial treatment. To study genetic evolution in glioblastoma, we analyzed whole genomes of 21 pairs of primary and recurrent tumor samples using next generation sequencing. In addition we sequenced RNA from 16 tumor pairs and a panel of 50 glioma-associated genes in tumor pairs from 43 patients (including 14 of the 21 patients included in the WGS discovery set). Glioblastoma subtypes were determined using 450k/EPIC methylation arrays. This study was supported within the e:med program of the German Ministry of Education and Research (BMBF) by the collaborative research project ‘SYS-GLIO - Systems-based prediction of the biological and clinical behavior of gliomas’ (https://www.sys-med.de/de/demonstratoren/sys-glio/) This study is part of the Heidelberg Center for Personalized Oncology - HIPO-043

  Study EGAS00001003184

• Transcriptome sequencing of Gingivo-buccal Cancer : ICGC-India Project_Batch05

  Transcriptome Sequencing of Gingivo-buccal Cancer: ICGC-India ProjectAs a part of the ICGC, India has undertaken genomic studies on gingivobuccal cancer of the oral cavity, which is the most prevalent form of cancer among men in India. There are various known environmental (life-style) correlates of this cancer, the most important of which are tobacco chewing and HPV infection. Transcriptome sequencing of paired RNA samples – isolated from the tumor and adjacent normal tissues of 28 patients – have been performed. Detailed clinical characterization of the patients, collection of data on demographic and environmental exposures, and isolation of DNA samples from adjacent normal and tumor tissues collected from each patient are being done at the Advanced Centre for Research, Treatment and Education on Cancer, Mumbai. Sequencing is being performed at the National Institute of Biomedical Genomics, Kalyani.

  Study EGAS00001003285

• Forty-Five patient-derived xenografts capture the clinical and biological heterogeneity of Wilms tumor

  The lack of model systems has limited the preclinical testing of novel therapies for Wilms tumor (WT) patients who have poor outcomes. Herein, we established 45 heterotopic WT patient-derived xenografts (WTPDX) in CB17 scid-/- mice that capture the biological heterogeneity of Wilms tumor (WT). These WTPDX include 6 from patients with diffuse anaplasia, 9 from patients who later experienced disease relapse, and 13 from patients with bilateral disease. Early passage WTPDX showed enrichment of blastemal gene expression. Favorable histology WTPDX were chemosensitive, whereas unfavorable histology WTPDX were resistant to conventional chemotherapy with vincristine, actinomycin-D, and doxorubicin given singly or in combination. This WTPDX library is a unique scientific resource that retains the spectrum of biological heterogeneity present in WT and provides an essential tool to test novel targeted therapies in the era of precision medicine.

  Study EGAS00001003361

• Short and long-read sequencing of Brugada syndrome samples

  Genome-wide association studies (GWAS) are instrumental in identifying loci with an impact on human traits and disease. Typically, however, most GWAS information is considered redundant as it is based on neighboring single-nucleotide variants (SNVs) in strong linkage disequilibrium (LD). In this context, besides the most significant hit (lead SNV) in every trait- or disease-associated locus, the rest of GWAS hits are often marginally reported, examined, or exploited. To interrogate the value of integrating the information provided by the full set of GWAS hits and fine-mapping haplotypes containing these SNVs, here we focused on a locus repeatedly associated with traits of the cardiac electrical conduction system and arrhythmia (SCN5A-SCN10A). We found that the same SNV can exhibit differing associations depending on haplotype. Thus, these analyses provide corroborative evidence that assuming redundancy among neighboring GWAS hits has the risk of missing critical disease-risk associations.

  Study EGAS00001004927

• Genomic profiling of localized (lFL) and systemic follicular lymphoma (sFL) reveals novel insights into FL pathogenesis

  At diagnosis, the majority of FL presents with symptomatic disease in advanced/systemic stages of FL (sFL). In contrast only around 10 to 15% of cFL are diagnosed in localized stages (lFL). The biological knowledge is mainly based on data derived from global sFL analysis and only small cohorts of lFL were characterized intensively so far. It is well-known that the hallmark BCL2 translocation is less frequently observed in lFL. Furthermore, lFL differs from sFL concerning their gene expression and their N-glycosylation profiles. In consequence, comprehensive global analysis with CNA profiling and whole exome sequencing was performed in a large cohort of lFL. Additionally, the mutational profile as well as the CNA landscape of lFL and sFL, as well as for BCL2 translocation-positive and -negative was compared.

  Study EGAS00001006927

• Tracking the evolution of esophageal squamous cell carcinoma under dynamic immune selection by multi-omics sequencing

  Intratumoral heterogeneity (ITH) has been linked to decreased efficacy of clinical treatments. However, although genomic ITH has been characterized in genetic, transcriptomic and epigenetic alterations are hallmarks of esophageal squamous cell carcinoma (ESCC), the extent to which these are heterogeneous in ESCC has not been explored in a unified framework. Further, the extent to which tumor-infiltrated T lymphocytes (TILs) are directed against cancer cells, but how the immune infiltration acts as a selective force to shape the clonal evolution of ESCC is unclear. In this study, we perform multi-omic sequencing on 186 samples from 36 primary ESCC patients. Through multi-omics analyses, it is discovered that genomic, epigenomic, and transcriptomic ITH are underpinned by ongoing chromosomal instability. Based on the RNA-seq data, we observe diverse levels of immune infiltrate across different tumor sites from the same tumor. We reveal genetic mechanisms of neoantigen evasion under distinct selection pressure from the diverse immune microenvironment. Overall, our work offers an avenue of dissecting the complex contribution of the multi-omics level to the ITH in ESCC and thereby enhances the development of clinical therapy.

  Dataset EGAD00001009482

• Genomic profiling of subcutaneous patient derived xenograft models of solid childhood cancer

  The pediatric cancer cohort in this study included 70 PDX models from 65 different individuals. This cohort included a total of 16 different pediatric solid tumor subtypes, including fourteen Wilms tumors, thirteen hepatoblastomas, thirteen osteosarcomas, ten germ cell tumors, four neuroblastomas, three clear cell sarcomas, two adrenal cortical carcinomas, two leydig cell tumors, two medulloblastomas, one embryonal rhabdomyosarcoma (ERMS), one Ewing sarcoma, one pleomorphic sarcoma, one adenocarcinoma, one glioblastoma, one mesothelioma and one ovarian tumor. Notably, we have five samples with multiple PDX models from same patient, including two cases with duplicates (564 and 564-Dup, 1796 and 1796-Dup), one case with two different metastasis (560-SM, 560-LM), one case with two blocks from same tumor (1939 and 1939-Dup), and one case with different primary tumor from same patient (2264 and 1932). We have a total of 353 sequencing data, including 82 RNA sequencing data (RNA-seq), 138 whole-exome sequencing (WES) and 135 low-pass whole-genome sequencing (WGS). For RNA-seq data, we have 61 PDXs and 21 PTs; for WES, we have 67 PDXs, 30 PTs and 40 matched normal germlines; for WGS, we have 64 PDXs, 30 PTs and 40 matched normal germlines. Of which, 19 PT-PDX paired RNA-seq, 28 paired PT-PDX paired WES and WGS were included.

  Dataset EGAD00001009863

• ctDNA monitoring using patient-specific sequencing and integration of variant reads - Breast cohort

  Circulating tumor-derived DNA (ctDNA) can be used to monitor cancer dynamics noninvasively. Detection of ctDNA can be challenging in patients with low-volume or residual disease, where plasma contains very few tumor-derived DNA fragments. We show that sensitivity for ctDNA detection in plasma can be improved by analyzing hundreds to thousands of mutations that are first identified by tumor genotyping. We describe the INtegration of VAriant Reads (INVAR) pipeline, which combines custom error-suppression methods and signal-enrichment approaches based on biological features of ctDNA. With this approach, the detection limit in each sample can be estimated independently based on the number of informative reads sequenced across multiple patient-specific loci. We applied INVAR to custom hybrid-capture sequencing data from 176 plasma samples from 105 patients with melanoma, lung, renal, glioma, and breast cancer across both early and advanced disease. By integrating signal across a median of >105 informative reads, ctDNA was routinely quantified to 1 mutant molecule per 100,000, and in some cases with high tumor mutation burden and/or plasma input material, to individual parts per million. This resulted in median Area Under the Curve (AUC) values of 0.98 in advanced cancers, and 0.80 in early stage and challenging settings for ctDNA detection. We generalized this method to whole-exome and whole-genome sequencing, showing that the INVAR may be applied without requiring personalized sequencing panels, so long as a tumor mutation list is available. As tumor sequencing becomes increasingly performed, such methods for personalized cancer monitoring may enhance the sensitivity of cancer liquid biopsies.

  Dataset EGAD00001006293

• Diverse mutational landscapes in human lymphocytes

  A lymphocyte suffers many threats to its genome, including programmed mutation during differentiation, antigen-driven proliferation and residency in diverse microenvironments. After developing protocols for single-cell lymphocyte expansions, we sequenced whole genomes from 717 normal naive and memory B and T lymphocytes and hematopoietic stem cells. All lymphocyte subsets carried more point mutations and structural variants than haematopoietic stem cells – the extra mutations were mostly acquired during differentiation, with burdens higher in memory than naive lymphocytes, although T cells also had a higher rate of mutation accumulation throughout life. Off-target effects of immunological diversification accounted for most of the additional differentiation-associated mutations in lymphocytes. Memory B cells acquired, on average, 18 off-target mutations genome-wide for every one on-target IGV mutation during the germinal centre reaction. Structural variation was 16-fold higher in lymphocytes than stem cells, with ~15% of deletions being attributable to off-target RAG activity. Mutational processes associated with ultraviolet light exposure and other sporadic mutational processes generated hundreds to thousands of mutations in some memory lymphocytes. The mutation burden and signatures of normal B lymphocytes were broadly comparable to those seen in many B-cell cancers, suggesting that malignant transformation of lymphocytes arises from the same mutational processes active across normal ontogeny. The mutational landscape of normal lymphocytes chronicles the off-target effects of programmed genome engineering during immunological diversification and the consequences of differentiation, proliferation and residency in diverse microenvironments.

  Dataset EGAD00001008107

• A DNA methylation atlas of normal human cell types

  A DNA methylation atlas of normal human cell types. The atlas includes 205 whole-genome bisulfite sequencing (WGBS) samples, from 39 sorted cell types. The samples were paired-end sequenced with 30x coverage.

  Dataset EGAD00001009789

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

  Whole genome 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 EGAD00001015469

• Single cell multi-omic study of H3-K27M mutant diffuse midline glioma across age and location

  Histone 3 lysine27-to-methionine (H3-K27M) mutations most frequently occur in childhood diffuse midline gliomas (DMGs) of the pons, but are also increasingly recognized in adult DMGs. Their potential heterogeneity at different ages and midline locations are vastly understudied. Here, through dissecting the single-cell transcriptomic, epigenomic and spatial architectures of a comprehensive cohort of patient H3-K27M DMGs, we delineate how age and anatomical location shape glioma cell-intrinsic and -extrinsic features in light of the shared driver mutation. We conducted multi-omic profiling of 50 H3-K27M mutant patient tumors. We performed deep full-length Smart-seq2 fresh single-cell (n=18) or frozen single-nucleus (n=25) RNA-sequencing (sc/snRNA-seq) of 43 tumors). We additionally analyzed the open chromatin profiles of 8 tumors utilizing the single-cell/nucleus assay for transposase-accessible chromatin using sequencing (snATAC-seq)

  Study EGAS00001006994

• Whole-genome sequencing across 449 samples spanning 47 ethnolinguistic groups provides insights into genetic diversity in Nigeria

  African populations have been drastically underrepresented in genomics research and failure to capture the genetic diversity across the numerous ethnolinguistic groups (ELGs) found in the continent has hindered the equity of precision medicine initiatives globally. Here, we describe the whole-genome sequencing of 449 Nigerian individuals across 47 unique self-reported ELGs. Population structure analysis reveals genetic differentiation amongst our ELGs, consistent with previous findings. From the 36 million SNPs and indels discovered in our dataset, we provide a high-level catalog of both novel and medically-relevant variation present across the ELGs. These results emphasize the value of this resource for genomics research, with added granularity by representing multiple ELGs from Nigeria. Our results also underscore the potential of using these cohorts with larger sample sizes to improve our understanding of human ancestry and health in Africa.

  Study EGAS00001007036

• Effects of busulfan, fludarabine and clofarabine treatment on human small intestinal organoids generated from healthy donors

  The intestine is vulnerable to chemotherapy-induced toxicity due to its high epithelial proliferative rate, making gut toxicity an off-target effect in several cancer treatments, including conditioning regimens for allogeneic hematopoietic cell transplantation (HSCT). In HSCT, intestinal damage is an important factor in the development of Graft-versus-Host Disease (GVHD), an immune complication in which donor immune cells attack the recipient's tissues. Here, we developed a novel human intestinal organoid-based 3D model system to study the effects of chemotherapy-induced intestinal epithelial damage at the RNA level. We show that chemotherapy conditioning specifically reprograms the intestinal epithelial transcriptome after treatment with either busulfan (3.5μM), fludarabine (15μM) or clofarabine (0.5μM) for 24h. This knowledge can potentially enable us to understand which changes undergo in healthy tissues upon conditioning and how those are related with immune activation typical in GVHD.

  Study EGAS00001007550