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• Genomic profile of sporadic multiple meningiomas

  Molecular mechanisms underlying the formation of sporadic MMs and clonal formation etiology of these tumors are poorly understood. In this study, we worked on a cohort of patients with spatially separated MMs without prior radiation exposure or a family history who underwent surgical resection of at least two meningiomas. Unbiased, comprehensive next generation sequencing was performed and relevant clinical data was analyzed. We identified that both NF2-loss and non-NF2 driven MMs can form due to monoclonal expansion and those tumors can acquire inter-tumoral heterogeneity through branched evolution. Grade I and II meningiomas can occur in the same patient. Thus, the molecular make-up and clinical behavior of one tumor in MMs, cannot reliably lend insight into that of the others and suggests the clinical management strategy for MMs should be tailored individually.

  Study EGAS00001005700

• ALK_inhibitors_in_the_context_of_ALK_dependent_cancer_cell_lines

  Anaplastic lymphoma kinase (ALK) has recently been found to be a critical cancer gene in cases of lung cancer, neuroblastomas and lymphomas. ALK inhibitors have recently shown significant activity in lung cancer patients with tumours that harbour the EML4-ALK gene rearrangement, but already drug-resistance is emerging. We have taken a lung cancer cell line H3122 (with the EML4-ALK rearrangement) and generated clones resistant to a small molecule inhibitor of ALK by serial exposure to the drug over 8 weeks. We now wish to characterise at the exome level whether the acquisiton of resistance has been accompanied by the development of new mutations that we can take forward for further study as the potential mechansims underlying the resistance. We therefore propose to exome sequence the parental NCI-H3122 cell line as well as drug-resistant clones.

  Study EGAS00001000082

• 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

• 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

• Combination_therapies_for_personalized_cancer_medicine

  It is the ambition of the team formed by members of the Netherlands Cancer Institute (NKI) and the Cancer Genome Project at the Wellcome Trust Sanger Institute (WTSI) to unravel the genomic and phenotypic complexity of human cancers in order to identify optimal drug combinations for personalized cancer therapy. Our integrated approach will entail (i) deep sequencing of human tumours and cognate mouse tumours; (ii) drug screens in a 1000+ fully characterized tumour cell line panel; (iii) high-throughput in vitro and in vivo shRNA and cDNA drug resistance and enhancement screens; (iv) computational analysis of the acquired data, leading to significant response predictions; (v) rigorous validation of these predictions in genetically engineered mouse models and patient-derived xenografts. This integrated effort is expected to yield a number of combination therapies and companion-diagnostics biomarkers that will be further explored in our existing clinical trial networks.

  Study EGAS00001000655

• Network-based systems pharmacology identifies heterogeneity in LCK and BCL2 signaling and differential vulnerability of T-cell acute lymphoblastic leukemia to targeted therapy

  T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy, and novel therapeutics are much needed. Profiling patient leukemia’ drug sensitivities ex vivo, we discovered striking inter-patient variability in T-ALL response to a panel of targeted agents. Applying network-based systems pharmacology analyses, by integrating ex vivo pharmacotyping, bulk and single-cell RNA-seq, genomics, phospho-proteomics, and genome-wide CRISPR screening data, to examine signal circuitry, we identified the pharmacogenomic basis of T-ALL drug response and revealed a therapeutic vulnerability that is directly related to the developmental stage of leukemia cells. In conclusion, our results indicate that heterogeneity in the differentiation of T-ALL drives activation of key signaling pathways in this leukemia, providing unique opportunities for targeted therapy.

  Study EGAS00001004700

• Investigate the evolutionary trajectories during invasiveness acquisition in early lung adenocarcinoma

  The evolutionary trajectories of early lung adenocarcinoma (LUAD) have not been fully elucidated. We hypothesize that genomic analysis between pre-invasive and invasive components will facilitate the description of LUAD evolutionary patterns. We micro-dissect malignant pulmonary nodules (MPNs) into paired pre-invasive and invasive components for panel-genomic sequencing and recognize three evolutionary trajectories. Evolutionary mode 1 (EM1) demonstrates none of the common driver events between paired components, but another two modes, EM2A and EM2B, exhibit critical private alterations restricted to pre-invasive and invasive components, respectively. When ancestral clones harbor EGFR mutations, truncal mutation abundance significantly decrease after the acquisition of invasiveness, which may be associated with the intratumoral accumulation of infiltrated B cells. Harboring EGFR mutations is critical to the selective pressure and further impacts the prognosis. Our findings extend the understanding of evolutionary trajectories during invasiveness acquisition in early LUAD.

  Study EGAS00001004754

• 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

• Exome sequencing data from two myelosarcomas

  Isolated myeloid sarcoma (MS, i.e. acute myeloid leukemia without detectable bone marrow infiltration) is rare and most patients subsequently develop overt AML. We prospectively performed whole exome sequencing of uterine MS, concomitant morphologically normal bone marrow (BM) and subsequently developing AML from two women. Both patients harbored preleukemic clones in the morphologically normal BM, including DNMT3A mutations. In addition, recurrent mutations were identified in the NFE2 gene, a gene not previously associated with AML or isolated MS. Retrospective studies of further MS samples, twelve with and four without preceding or concomitant bone marrow AML, revealed NFE2 mutations in two additional cases, both with isolated MS and prior myeloid malignancies. We conclude that DNMT3A mutated preleukemia may predispose for the frequent bone marrow relapses following isolated MS and that recurrent NFE2 mutations may have a role in the development of isolated MS.

  Study EGAS00001002562

• CRLF2_sequencing_project_

  I hope to gain insight into novel genetic aberrations present in these patients that will highlightimportant pathways that are involved in this subtype of leukaemia. It would be interesting to see ifthe mutations and pathways that are activated are consistent between the patients, or differencesare observed dependent upon whether the patient has the translocation or the PAR1 deletion. Ofnote is the high association with either numerical gains of chromosome X or numerical/structuralabnormalities of chromosome 21 (Down syndrome, iAMP21) in patients with CRLF2 deregulation. Ihope to find abnormalities linking chromosomes X and 21 to CRLF2 deregulation in BCP‐ALL. Byincluding the three patients that are normal for CRLF2, but have consistent genetic abnormalitiesfound in the experimental cohort, I expect to find genetic differences between these two groupsthat will help us to identify novel molecular targets specific to CRLF2 deregulation.

  Study EGAS00001000080

• 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

• Molecular Sub-grouping of CNS-PNET

  In our study we aimed to define CNS-PNET subgroups. We performed Expression, Genotyping and/or Immunohistochemistry on 142 samples from 20 worldwide centers. Using these techniques, we have identified three molecular subgroups with distinct expression and copy number patterns, as well as, unique clinical characteristics. Specifically, these molecular subgroups were distinguished by primitive neural (group 1), oligoneural (group 2), and mesenchymal lineage (group 3) gene-expression signatures with differential expression of cell-lineage markers LIN28 and OLIG2. Our report underscores the importance of concerted, collaborative efforts to study large retrospective cohorts of tumours and patients to accelerate biological and ultimately therapeutic studies of rare tumours. The outcome of such a collaboration allowed us to identify LIN28 and OLIG2 as promising diagnostic and prognostic molecular markers for CNS PNET that warrant further assessment in prospective clinical trials.

  Study EGAS00000000116

• 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

• Genomic Heterogeneity and the Small Renal Mass

  Tumor heterogeneity is believed to represent a barrier to pre-operative genomic characterization in kidney cancer. Previous studies of heterogeneity in clear cell renal cell carcinoma (ccRCC) evaluated only large and metastatic tumors. In small renal tumors in which multiple biopsies are not feasible, the extent of heterogeneity remains unknown. In this study, we evaluated how the extent of genomic heterogeneity in small and large ccRCC. A total of 23 small (<4cm ) and 24 large (>7cm ) ccRCC had 3 regions sampled for evaluation of copy number, clear-cell A/clear-cell B (ccA/ccB) classification, and cell cycle progression (CCP) score. Small tumors have less genomic complexity and significantly fewer subclonal events. Pre-treatment genomic characterization based on a single biopsy in small ccRCC can provide insight into biologic potential to make clinical decisions.

  Study EGAS00001002919

• MuTHER_adipose_tissue_small_RNA_expression

  We investigate the naturally occurring variation of small RNA expression in conjunction with genetic and gene expression variation. We shall assess the variation in subabdominal fat tissue small RNA levels in 168 unrelated MuTHER individuals. Using gene expression data from the same samples, we can survey how much the small RNA expression contributes to the variance in gene expression profiles. We can also take advantage of the high density genotyping data on these samples to identify genetic associations of small RNA expression levels, and the downstream effect of the genetic variants in small RNA sequence. Previous small RNA sequencing efforts have also extended the repertoire of small RNAs, and we hope to potentially find additional small RNAs active in adipose tissue biology. Altogether, the project should provide an exciting view into small RNA biology in humans, and lead to development of new methodology for analysis of molecular phenotype data.

  Study EGAS00001000212

• A proteogenomic atlas of the human neural retina

  The human neural retina is enriched for alternative splicing, and it is estimated that more than 10% of variants associated with inherited retinal diseases (IRDs) alter splicing. Previous research mainly used short-read RNA-sequencing techniques to investigate retina-specific splicing and splicing factors. However, this technique provides limited information about transcript isoforms. To gain a deeper understanding of the human neural retina and its isoforms, we generated a proteogenomic atlas that combines PacBio long-read RNA-sequencing data with mass-spectrometry and whole-genome sequencing data from three healthy human neural retina samples. About one third of the nearly 60,000 transcript isoforms were novel, and ten novel peptides that confirmed novel isoforms were detected. This study highlights the importance of studying tissue-specific transcriptomes in greater detail to better understand tissue-specific regulation and to identify disease-causing variants.

  Study EGAS50000000070

• Clonally heritable gene expression imparts a layer of diversity within cell types

  Cell types can be classified according to shared patterns of transcription. Non-genetic variability among individual cells of the same type has been ascribed to stochastic transcriptional bursting and transient cell states. Using high coverage single cell RNA profiling, we asked whether long-term, heritable differences in gene expression can impart diversity within cells of the same type. Studying clonal human lymphocytes and mouse brain cells, we uncovered a vast diversity of heritable gene expression patterns among different clones of cells of the same type in vivo. We combined chromatin accessibility and RNA profiling on different lymphocyte clones to reveal thousands of regulatory regions exhibiting interclonal variation which could be directly linked to interclonal variation in gene expression. Our findings identify a source of cellular diversity, which may have important implications for how cellular populations are shaped by selective processes in development, aging and disease.

  Study EGAS50000000161

• Evolutionary Trajectories of Small Cell Lung Cancer under Therapy

  Small cell lung cancer (SCLC) is one of the deadliest human cancers with a five-years survival rate of less than 7%. The standard of care for extensive-stage SCLC consists of systemic treatment with platinum and etoposide, recently combined with PD-L1 immune checkpoint inhibitors (ICI). SCLC patients show high sensitivity to platinum-based chemotherapy, followed by rapid recurrence, which distinguishes SCLC from most human cancers. Unfortunately, second-line treatment with other chemotherapeutics or immunotherapy is only marginally effective, and patients ultimately succumb to their disease. We performed whole exome sequencing, whole genome sequencing and transcriptome sequencing of multiple tumor regions from 65 patients with SCLC. We determined tumor phylogenies at diagnosis and throughout chemotherapy and immunotherapy by multi-region sequencing of 160 tumors from 65 patients, to thus decipher the evolutionary processes underlying the remarkable sensitivity of small cell lung cancer (SCLC) to chemotherapy.

  Study EGAS50000000169

• The Emirati T2T-level Pangenome: A complete Diploid Graph of 58 Genomes

  This study presents a comprehensive Emirati telomere-to-telomere level (T2T) pangenome, constructed from 116 haplotype-resolved assemblies generated from 58 individuals, including 28 trio-based and 30 single-sample assemblies. The assemblies exhibit high contiguity (median 150 Mb) and high consensus accuracy (median QV 59), with 71.9% of chromosomes reaching T2T-level scaffold status. The resulting pangenome graph captures both globally shared and regionally enriched genetic variation, including sequences in complex regions that are inaccessible to less complete assemblies. Comparisons indicate diversity levels comparable to those of the Human Pangenome Reference Consortium, while highlighting unique Emirati genomic features. This reference forms a key resource for human pangenomics and precision medicine in the UAE. This work provides a foundational resource to improve variant discovery and genome annotation, contributing vital diversity data to global pangenomics efforts and enabling precision medicine in the region.

  Study EGAS50000001232

• 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

• "Distinct immunometabolic signatures in circulating immune cells define disease outcome in acute-on-chronic liver failure"

  We performed single-cell transcriptomics of PBMC’s from healthy (n= 3), acute decompensated (AD) (n= 3) and Acute-on-chronic liver failure (ACLF) patients. Lay Summary: Acute-on-chronic liver failure (ACLF) develops in cirrhotic patients and is characterized by an hyper-inflammatory immune state driving multiple organ failure(s). As a paradox, circulating immune cells also show transcription and metabolic evidence of exhaustion, explaining why these patients are often susceptible to secondary infections. We characterized at a transcriptional level all circulating immune cells of ACLF patiens, and specifically unraveled a distinct recovery and non-recovery ACLF signature within the monocyte population. Moreover, these changes were closely linked to metabolic differences within these cells. The described alterations allowed for a robust prediction of recovery and non-recovery of patients at admission to the hospital.

  Study EGAS50000000391

• 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

• Acquisition_of_additional_mutations_drives_accelerated_progression_of_NPM1_positive_CMML_to_AML_

  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/We performed exome sequencing on serial samples from a patient with CMML who progressed to AML. The exome sequencing suggests that NPM1, TET2 and DNMT3a mutations were present in the dominant clone in the CMML sample and that NRAS is a new subclonal mutation in the AML sample. Diagnostic data shows the presence of a FLT3-ITD mutation in the AML sample, which is likely to have driven progression. Here we are performing re-sequencing of the putative driver and some passenger mutations which appear to be in the same clone to validate these mutations and to verify the relative quantification of these abnormalities .

  Study EGAS00001000619

• Identification and characterization of tertiary lymphoid structures in brain metastases

  Brain metastases (BrM) are the most common cancers in the brain. We performed transcriptome-wide gene expression profiling combined with spatial immune cell profiling to characterize the tumor immune microenvironment in BrM from different primary tumors. We found that BrM from lung carcinoma and malignant melanoma showed overall higher immune cell infiltration as compared to BrM from breast carcinoma. RNA sequencing-based immune cell deconvolution revealed gene expression signatures indicative of tertiary lymphoid structures (TLS) in subsets of BrM from lung cancer and melanoma. This finding was corroborated by multiplex immunofluorescence staining of immune cells in BrM tissue sections. Detection of TLS signatures was associated with prolonged survival after BrM diagnosis in lung cancer patients. Our findings highlight the cellular diversity of the tumor immune microenvironment in BrM of different cancer types and suggest a role of TLS formation for BrM patient outcome.

  Study EGAS50000000563

• Longitudinal single-cell transcriptomic study in patient-derived xenografts of pediatric T-ALL

  In this study, we conducted single cell full length total RNA sequencing (VASA-seq) on 13 matched pediatric T-ALL PDX samples at initial diagnosis and relapse, along with 5 non-relapsing PDX samples collected at initial diagnosis. We identified a subpopulation of T-ALL cells with stem-like cell features that expands substantially at relapse indicating resistance to first-line therapy. Chemotherapy resistance was further validated through functional testing: Two samples were subjected to in-vitro drug testing, treated with Cytarabine for three days, followed by single-cell transcriptomic analysis using 10x Genomics. Additionally, in-vivo drug testing was conducted on one sample, involving re-engraftment into mice and treatment with a combination of Vincristine, Doxorubicin, and Dexamethasone. Single-cell transcriptomic analysis using 10x Genomics was performed after 0, 15 and 30 days of treatment.

  Study EGAS50000000582

• 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

• Cell-type, allelic and genetic signatures in the human pancreatic beta cell transcriptome

  Pancreatic beta cells within the islets of Langerhans are centrally involved in the pathogenesis of both type 1 and type 2 diabetes. Describing the differentiated state of the human beta cell has been hampered so far by technical (low resolution microarrays) and biological limitations (whole islet preparations rather than isolated beta cells). We circumvent these by deep RNA sequencing of purified beta cells from 11 individuals, presenting here the first characterization of the human beta cell transcriptome. Additionally, we perform the first comparison of gene expression profiles between beta cells, whole islets (N=7) and beta cell depleted islet preparations (N=5), revealing thus beta cell specific expression signatures. Finally, we combine this with whole-genome sequencing data for 7 of our donors, describing here the first set of genetic variants controlling inter-individual variability in beta cell gene expression.

  Study EGAS00001000442

• CRLF2_sequencing_project_Exomes

  I hope to gain insight into novel genetic aberrations present in these patients that will highlight important pathways that are involved in this subtype of leukaemia. It would be interesting to see if the mutations and pathways that are activated are consistent between the patients, or differences are observed dependent upon whether the patient has the translocation or the PAR1 deletion. Of note is the high association with either numerical gains of chromosome X or numerical/structural abnormalities of chromosome 21 (Down syndrome, iAMP21) in patients with CRLF2 deregulation. I hope to find abnormalities linking chromosomes X and 21 to CRLF2 deregulation in BCP‐ALL. By including the three patients that are normal for CRLF2, but have consistent genetic abnormalities found in the experimental cohort, I expect to find genetic differences between these two groups that will help us to identify novel molecular targets specific to CRLF2 deregulation.

  Study EGAS00001000081

• Capture Hi-C identifies the chromatin interactome of colorectal cancer risk loci

  Multiple regulatory elements distant to their targets on the linear genome can influence the expression of a single gene through chromatin looping. Chromosome conformation capture implemented in Hi-C allows for genome-wide agnostic characterization of chromatin contacts. However, detection of functional enhancer-promoter interactions is precluded by its effective resolution that is determined by both restriction fragmentation and sensitivity of the experiment. Here we have developed a capture Hi-C (cHi-C) approach to allow an agnostic characterisation of these physical interactions on a genome-wide scale. Single nucleotide polymorphisms associated with complex diseases often reside within regulatory elements and exert effects through long-range regulation of gene expression. Applying this cHi-C approach to 14 colorectal cancer risk loci has allowed us to identify key long-range chromatin interactions in cis and trans involving these loci.

  Study EGAS00001001085

• 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

• Papuan_Genotyping

  By array based genotyping of indigenous individuals from different areas of Papua New Guinea, this project aims to provide the most comprehensive overview thus far of population structure and history in this part of the world. Papuans represent a key component in the current understanding of human history outside of Africa. Additionally, PNG harbours enormous cultural and linguistic diversity. Genotyping of diverse individuals, combined with previously generated whole-genome sequencing data, will allow the study of general patterns of population structure, the degree of genetic differentiation between groups, the extent of external gene flow into PNG and the genetic relationships to Australian Aboriginals.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 EGAS00001001587

• multi-OMICs study of a pair of infant monozygotic twins with concordant B-cell ALL

  B-cell acute lymphoblastic leukemia (B-cell ALL) is the most common cancer in childhood. Studying identical twins with B-cell ALL provides a unique and tractable model for deciphering the developmental timing of pre- and post-natal mutations contributing to clonal evolution. To date, this has mainly focused on major cytogenetic subgroups of childhood B-cell ALL, including MLL fusions, ETV6-RUNX1, hyperdiploidy, and BCR-ABL1. However, formal demonstration of the prenatal origin and “backtracking” the natural history of the leukemia remains understudied in “B-other”/Normal Karyotype (NK) B-cell ALL. To characterize the genetic and the epigenetic landscape of this particular leukemia subtype, we performed whole genome DNA-, B-cell receptor (BCR)-, and DNA bisulfite-sequencing on a pair of 8-month-old monozygotic twins diagnosed with concordant “B-other”/NK B-cell ALL.

  Study EGAS00001003651

• 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

• Integrative sequencing reveals alterations in untreated and castration resistant prostate cancer

  We report the integrative sequencing of genomic, transcriptomic and DNA methylation changes in 28 untreated (PC) and 13 castration resistant prostate cancers (CRPC). AR, TGF-β and WNT signaling pathways were altered in CRPCs. We identified two new fusion genes, TMPRSS2-SKIL and DOT1L-HES6. Fusion analysis in an independent cohort validated SKIL as a recurrent 3’ fusion partner and oncogene in prostate cancer. The HES6 fusion was found in an AR-negative CRPC, and HES6 overexpression in vitro led to androgen independent growth. A distinct DNA methylation signature was found for CRPC. Transcriptome assembly uncovered 128 previously unannotated prostate cancer associated transcripts, including the ERG regulated transcript TPCAT-10-36067 whose knockdown had a dramatic effect on the growth, invasiveness, and rate of apoptosis of prostate cancer cells.

  Study EGAS00001000526

• Glioblastoma initiating cells are sensitive to histone demethylase inhibition due to epigenetic deregulation

  Tumor-initiating cells are a subpopulation of cells that have self-renewal capacity to regenerate a tumor. Here, we identify stem cell-like chromatin features in human glioblastoma initiating cells (GICs) and link them to a loss of the repressive histone H3 lysine 9 trimethylation (H3K9me3) mark. Increasing H3K9me3 levels by histone demethylase inhibition led to cell death in GICs but not in their differentiated counterparts. The induction of apoptosis was accompanied by a loss of the activating H3 lysine 9 acetylation (H3K9ac) modification and accumulation of DNA damage and downregulation of DDR genes. Upon knockdown of histone demethylases KDM4C and KDM7A both differentiation and DNA damage was induced. Thus, the H3K9me3-H3K9ac equilibrium is crucial for GIC viability and represents a chromatin feature that can be exploited to specifically target this tumor subpopulation.

  Study EGAS00001003750

• 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

• Novel mutations in TOP2A in gliomas

  High grade gliomas (HGGs) are aggressive, primary brain tumors with poor clinical outcomes. To better understand glioma pathobiology and find potential therapeutic susceptibilities, we designed a custom- panel 664 cancer- and epigenetics-related genes and employed targeted next generation sequencing to study the genomic landscape of somatic and germline variants in 182 glioma samples of different malignancy grades. Besides known alterations in TP53, IDH1, ATRX, EGFR genes, we found several novel variants that can be potential drivers in gliomas. In four patients from the Polish glioma cohort, we identified a novel recurrent mutation in the TOP2A gene coding for Topoisomerase 2A in glioblastomas (GBM, WHO grade IV gliomas). The mutation results in a substitution of glutamic acid (E) 948 to glutamine (Q) of TOP2 A and we predicted this E948Q substitution may affect DNA binding and a TOP2A enzymatic activity.

  Study EGAS00001004556

• The endometrial transcription landscape of MRKH syndrome

  The Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome (OMIM 277000) is characterized by agenesis of the uterus and upper part of the vagina in females with normal ovarian function. While genetic causes have been identified for a small subset of patients and epigenetic mechanisms presumably contribute to the pathogenic unfolding, too, the etiology of the syndrome has remained largely enigmatic. A comprehensive understanding of gene activity in the context of the disease is crucial to identify etiological components and their potential interplay. So far, this understanding is lacking, primarily due to the scarcity of samples and suitable tissue. In order to close this gap, we profiled endometrial tissue of uterus rudiments in a large cohort of MRKH patients using RNA-seq and thereby provide a genome-wide view on the altered transcription landscape of the MRKH syndrome.

  Study EGAS00001004601

• 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

• Genomic and transcriptomic determinants of therapy resistance and immune landscape evolution during anti-EGFR treatment in colorectal cancer

  Despite biomarker stratification, the anti-EGFR antibody cetuximab is only effective against a subgroup of colorectal cancers (CRC). This genomic and transcriptomic analysis of the cetuximab resistance landscape in 35 RAS wild-type CRCs identified associations of NF-1 and non-canonical RAS/RAF-aberrations with primary resistance and validated transcriptomic CRC-subtypes as non-genetic predictors of benefit. 64% of biopsies with acquired resistance harbored no genetic resistance drivers. Most of these had switched from a cetuximab-sensitive transcriptomic subtype pre-treatment to a fibroblast- and growth factor-rich subtype at progression. Fibroblast-supernatant conferred cetuximab resistance in vitro, confirming a major role for non-genetic resistance through stromal remodeling. Cetuximab treatment increased cytotoxic immune infiltrates and PDL1 and LAG3 immune-checkpoint expression, potentially providing opportunities to treat cetuximab-resistant CRCs with immunotherapy.

  Study EGAS00001003367

• single nuclei RNASeq of 5 regions of the human prenatal brain

  Data generated through single nuclei RNA sequencing on 5 regions of the brain (frontal cortex, ganglionic eminence, hippocampus, thalamus and cerebellum) from 3 fetuses (two of 14 and one of 15 post-conception weeks, all female). Tissue was acquired from the MRC-Wellcome Trust Human Developmental Biology Resource (HDBR) with ethical approval. snRNA-seq libraries were prepared from ∼10,000 nuclei from each sample using Chromium Single Cell 3ʹ (v3) reagents (10X Genomics). Quality control of libraries was performed using the Agilent 5200 Fragment Analyzer before sequencing on an Illumina NovaSeq 6000 to a depth of at least 865 million (median = 1.01 billion) read pairs per library. Raw sequencing data were converted into FASTQ files. For a full description of data generation, please see Cameron et al, Biological Psychiatry 2022, https://doi.org/10.1016/j.biopsych.2022.06.033.

  Study EGAS00001006537

• 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

• RNA stability controlled by m6A methylation contributes to X-to-autosome dosage compensation in mammals

  In mammals, X-chromosomal genes are expressed from a single copy since males (XY) possess a single X chromosome, while females (XX) undergo X inactivation. To compensate for this reduction in dosage compared to two active copies of autosomes, it has been proposed that genes from the active X chromosome exhibit dosage compensation. However, the existence and mechanism of X-to-autosome dosage compensation are still under debate. Here, we show that X-chromosomal transcripts are reduced in m6A modifications and more stable compared to their autosomal counterparts. Acute depletion of m6A selectively stabilises autosomal transcripts, resulting in perturbed dosage compensation in mouse embryonic stem cells. We propose that higher stability of X-chromosomal transcripts is directed by lower levels of m6A, indicating that mammalian dosage compensation is partly regulated by epitranscriptomic RNA modifications.

  Study EGAS00001007112

• Establishment and characterization of an Epstein-Barr virus-positive cell line from a non-keratinizing differentiated primary nasopharyngeal carcinoma

  Nasopharyngeal carcinoma (NPC), a cancer that is etiologically associated with the Epstein-Barr virus (EBV), is endemic in Southern China and Southeast Asia. The scarcity of representative NPC cell lines owing to the frequent loss of EBV episomes following prolonged propagation and compromised authenticity of previous models underscores the critical need for new EBV-positive NPC models. Herein, we describe the establishment of a new EBV-positive NPC cell line, designated NPC268 from a primary non-keratinizing, differentiated NPC tissue. NPC268 can undergo productive lytic reactivation of EBV and is highly tumorigenic in immunodeficient mice. Whole-genome sequencing (WGS) revealed close similarities with the tissue of origin, including large chromosomal rearrangements, while whole-genome bisulfite sequencing (WGBS) and RNA sequencing demonstrated a hypomethylated genome and enrichment in immune-related pathways, respectively.

  Study EGAS00001007172

• ATAC-Seq of healthy and IBD blood samples

  PBMCs from blood samples of 9 age- and gender-matched healthy subjects and 25 IBD patients were isolated through a Ficoll density gradient and used to isolate live CD4 T cells through a magnetic cell isolation kit (Miltenyi Biotec). Twelve thousand live CD4 T cells were then used to prepare ATAC-Seq libraries. Briefly, crude nuclei of live CD4+ T cells were treated with Tagment DNA buffer and Tagment DNA Enzyme (Nextera DNA Library Prep Kit, Illumina), and then the DNA was purified by MinElute PCR Purification Kit (Qiagen). Transposed DNA fragments were amplified using specific adapters followed by purification with MinElute PCR Purification Kit (Qiagen). Fragments from 240-360pb were selected in the PippinHT system (Sage Science). The quality of the library and its DNA concentration were assessed by Bioanalyzer instruments (Agilent Technologies) and ultimately submitted for sequencing using Illumina HiSeq 2500 sequencer, V4 chemistry.

  Study EGAS00001007343

• Detecting and quantifying clonal selection in somatic mosaicism

  In this study, we introduce a scalable method to identify clonal selection in an individual tissue, agnostic of the underlying mutations. To study clonal selection in the haematopoietic system, we performed whole genome sequencing on bone marrow CD34+ haematopoietic stem and progenitor cells from 22 non-leukemic individuals, 30-89 years of age. We performed 90x whole genome sequencing for all samples and re-sequenced 19 samples with sufficient DNA to a total target coverage of 270x. Whole genome sequencing of hair follicle DNA from the same individuals was used as germline control. In addition, we sequenced unseparated bone marrow mononuclear cells, CD3-CD34- bone marrow mononuclear cells, and peripheral blood granulocytes from 14 samples. Samples were collected from individuals undergoing hip replacement surgery as part of the Mechanisms of Age-Related Clonal Haematopoiesis (MARCH) Study (REC Ref: 17/YH/0382).

  Study EGAS00001007558

• Colorectal Microenvironment Spatial Mapping

  In colorectal cancer (CRC), interactions between tumor and immune cells within the tumor microenvironment are critical drivers of tumorigenesis, immune evasion, prognosis, and therapeutic response. Therefore, a deeper understanding of the spatial organization of cancer and immune cells within the CRC microenvironment is urgently needed. In this study, we aimed to characterize distinct cell populations and patterns of spatial gene expression associated with CRC tumorigenesis and immune infiltration. Spatial transcriptomics (ST) was performed on CRC and adjacent normal tissues to investigate the patterns of gene expression. Integrative ST data and publicly available single-cell RNA sequencing (scRNA-seq) data analysis tools were used for data integration, dimension reduction, clustering, and differential expression analysis. This study identified novel immunosuppressive cell populations and immune regulatory factors in CRC. Further functional validation of these findings will be essential to assess their potential as therapeutic targets.

  Study EGAS00001008254

• Genetic origins of the Kiritimati population from central-eastern Micronesia

  The migration of Austronesian-speaking populations through Oceania has intrigued researchers for decades. The Kiribati islands, situated along the boundaries of Micronesia and Polynesia, provide a crucial link in this migration. We analyzed the genome-wide data of the Kiritimati population of Kiribati to uncover their genetic origins and connections with other Oceanian groups. Our study reveals that the Kiritimati population primarily exhibits Remote Oceanian-related ancestry associated with ancient Lapita and present-day Polynesian populations. In addition, our identity-by-descent analysis identifies populations from Philippines as their closest relatives in Island Southeast Asia. The genetic links between Kiritimati, ancient Lapita, and modern Polynesians underscore the shared ancestry and continuous gene flow across these regions. This genetic continuity and ongoing links are supported by linguistic and cultural evidence, illustrating a complex history of migration and admixture in Oceania.

  Study EGAS00001008060

• 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