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• Improving CLL Vγ9Vδ2-T cell fitness for cellular therapy by ex vivo activation and ibrutinib

  We studied whether Vγ9Vδ2-T cells can exploited as autologous effector lymphocytes in chronic lymphocytic leukemia (CLL). Healthy controls (HC) Vγ9Vδ2-T cells were activated by and had potent cytolytic activity against CLL cells, however CLL-derived Vγ9Vδ2-T cells proved dysfunctional with respect to effector cytokine production and cytotxicity. Dysfunction of Vγ9Vδ2-T cells was reversible upon activation with autologous monocyte-derived dendritic cells (mODCs). RNA sequencing confirmed that Vγ9Vδ2-T cells from CLL patients have a transcriptional profile that is distinct from HC Vγ9Vδ2-T cells prior to ex vivo expansion, although the profile after ex vivo expansion is similar between CLL and HC Vγ9Vδ2-T cells. Gene expression profiling implicated alterations in both synapse formation and exhaustion as conceivable contributors to compromised Vγ9Vδ2-T cell function in CLL patients. Taken together, CLL-mediated dysfunction of autologous Vγ9Vδ2-T cells is fully reversible, resulting in potent cytotoxicity towards CLL cells.

  Study EGAS00001003193

• Whole genome sequencing of Sinonasal hemangiopericytoma and patient derived cell line model

  Solitary fibrous tumor/Hemangiopericytoma (SFT/HPC) is a rare subtype of soft tissue sarcoma associated with NAB2-STAT6 gene fusions. This study established and characterized a novel SFT/HPC patient-derived cell line called SFT-S1 using whole genome sequencing.

  Study EGAS50000000025

• Multi-omics analysis of pediatric high-risk neuroblastoma

  Neuroblastoma is the most common extracranial solid malignancy among children originating from undifferentiated neural crest cells. Despite recent intensified treatment, high-risk patients still show a high mortality rate. To explore a new therapeutic strategy, we performed integrated analysis in 30 neuroblastoma cases.

  Study JGAS000246

• Resistance_to_MAPK_inhibitor_induces_internal_duplication_in_BRAF

  2 BRAFV600E cell lines that have been made resistance to 1. the BRAF inhibitor PLX4720 and 2. the combination therapy of dabrafenib and trametinib seem to have a internal duplication in the kinase domain. We would like to know if this is caused by a translocation.

  Study EGAS00001001304

• Pheno-seq profiles of single clonal tumor spheroids derived from a patient with colorectal cancer

  Pheno-seq is a new approach that integrates high-throughput imaging and transcriptomic profiling of clonal spheroids/organoids to dissect functional tumor cell heterogeneity in 3D cell culture systems. The method is based on the iCELL8 technology (TakaraBio) that uses barcoded nanowells and a micro-solenoid valve dispenser. The CRC_spheroid dataset contains demultiplexed RNA-sequencing profiles (FASTQ file format, NextSeq 500) of 95 clonal tumor spheroids derived from a patient with colorectal cancer.

  Dataset EGAD00001004131

• The genomic complexity of early T-cell progenitor acute lymphoblastic leukemia

  CREST The accurate identification of structural variations using whole-genome DNA sequencing data generated by next-generation sequencing technology is extremely difficult. To address this challenge, we have developed CREST, an algorithm that uses sequencing reads with partial alignments to the reference human genome (so-called soft-clipped reads) to directly map the breakpoints of somatic structural variations. We applied CREST to paired tumor/normal whole genome sequencing data from five cases of T-lineage acute lymphoblastic leukemia (T-ALL). A total of 110 somatic structural variants were identified, >80% of which were validated by genomic PCR and Sanger sequencing. The validated structural variants included 31 inter-chromosomal translocations, 19 intra-chromosomal translocations, one inversion, 22 deletions and 16 insertions. A comparison of the results generated with CREST to those obtained using the traditional paired-end discordant mapping methods demonstrate CREST to have a much higher sensitivity and specificity. In addition, application of CREST to publicly available whole-genome sequencing data from the human melanoma cancer cell line COLO-829 demonstrated the identification of 50 novel structural variations not detected using the standard methods, 20 of which were selected for validation with a 90% success rate. These data demonstrate that direct mapping of soft-clipped reads offers an improved method for detecting structural variants at the nucleotide level of resolution. T-ALL Early T-cell precursor acute lymphoblastic leukaemia (ETP ALL) is an aggressive malignancy of unknown genetic basis. We performed whole-genome sequencing of 12 ETP ALL cases and assessed the frequency of the identified somatic mutations in 94 T-cell acute lymphoblastic leukaemia cases. ETP ALL was characterized by activating mutations in genes regulating cytokine receptor and RAS signalling (67% of cases; NRAS, KRAS, FLT3, IL7R, JAK3, JAK1, SH2B3 and BRAF), inactivating lesions disrupting haematopoietic development (58%; GATA3, ETV6, RUNX1, IKZF1 and EP300) and histone-modifying genes (48%; EZH2, EED, SUZ12, SETD2 and EP300). We also identified new targets of recurrent mutation including DNM2, ECT2L and RELN. The mutational spectrum is similar to myeloid tumours, and moreover, the global transcriptional profile of ETP ALL was similar to that of normal and myeloid leukaemia haematopoietic stem cells. These findings suggest that addition of myeloid-directed therapies might improve the poor outcome of ETP ALL.

  Study phs000340

• RNA sequencing data from glioblastoma primary cell lines treated with indisulam

  This study aimed to develop NovumRNA, a bioinformatics pipeline designed to predict non-canonical tumor-specific antigens (ncTSAs) from human tumor RNA-sequencing data, potentially broadening the target pool for cancer neo-epitope-based immunotherapies. The splicing-modulating drug indisulam was investigated for its potential to induce aberrant transcriptomes, potentially increasing ncTSAs, subsequently predicted by NovumRNA. Four glioblastoma primary cell lines were derived from patient Cavitron Ultrasonic Aspirator (CUSA) material, cultured as neurospheres, and treated with indisulam or vehicle control. RNA was extracted at 6 and 16 hours post-treatment and sequenced using the NovaSeq platform. The resulting RNA-seq data was analyzed with NovumRNA, using healthy brain GTEx samples as controls, to identify and validate ncTSAs induced by indisulam treatment. NovumRNA is available at: https://github.com/ComputationalBiomedicineGroup/NovumRNA.

  Study EGAS50000000680

• Most HCCs in Taiwan show the mutational signature of aristolochic acid

  Plants in the genus Aristolochia contain the mutagen aristolochic acid (AA) and have been widely used in traditional medicines and for weight loss. AA binds covalently to genomic DNA and induces a highly distinctive mutational signature. While AA involvement in urinary-tract cancers in Taiwan is known, the possible role of AA in hepatocellular carcinomas (HCCs) in Taiwan has not been examined. Here, we whole-exome sequenced 98 unselected HCCs from Taiwan and analyzed the mutational signatures for evidence of AA mutagenesis. Remarkably, more than 78% of HCCs showed strong evidence of AA mutagenesis, often associated with high mutation burdens. Non-synonymous mutations in genes known to be HCC driver genes were detected. Importantly, we elucidated the potential of immunotherapy in this cohort of liver cancer patients.

  Study EGAS00001002301

• Mechanisms of Therapy Driven Clonal Evolution in Oncogenic RAS Mutant Relapsed Acute Lymphoblastic Leukemia

  Although multi-agent combination chemotherapy is curative in a significant fraction of childhood acute lymphoblastic leukemia (ALL) patients, 20% of cases relapse and most die due to chemo-refractory disease. Here we used whole-exome and whole-genome sequencing to analyze the mutational landscape and pattern of clonal evolution at relapse in pediatric ALL cases. These analyses showed that ALL relapses originate from a common ancestral precursor clone of the diagnosis and relapsed populations and frequently harbor mutations implicated in chemotherapy resistance. RAS-MAPK pathway activating mutations in NRAS, KRAS and PTPN11 were present in 24/55 (44%) cases in our series. Notably, while some cases showed emergence of RAS mutant clones at relapse, in others, RAS mutant clones present at diagnosis were replaced by RAS wild type populations. Mechanistically, functional dissection of mouse and human wild type Kras and mutant Kras (Kras G12D) isogenic leukemia cells demonstrated induction of methotrexate resistance, but also improved response to vincristine, in mutant Kras- expressing lymphoblasts. These results identify chemotherapy driven selection as a central mechanism of leukemia clonal evolution and pave the road for the development of tailored personalized therapies for the treatment of relapsed ALL.

  Study phs001072

• Non-canonical NF-κB signaling skews B cells away from germinal center to low-affinity effector fate

  The non-canonical (NC) NF-κB pathway is a central regulator of B-cell development and survival, yet its role during B-cell mediated adaptive responses remains uncharted. Here, we uncover an unanticipated regulatory function for NC NF-κB in shaping humoral immunity. High-resolution mapping of NC NF-kB status in B cells from human lymphoid tissues revealed low activity in germinal center B-cells (GCB) than effector subsets, suggesting a selective attenuation. Consistently, mice model harboring B-cells with enforced NC NF-κB activation revealed near- complete loss of GCB and high-affinity antibodies, following vaccination. GCB loss was not driven by intrinsic defects in formation or expansion, but by an immune-niche dysregulation marked by regulatory T-cell expansion. Mechanistically, NC NF-κB activation promoted B-cell- derived IL-10, and blocking this axis normalize the niche and rescue GCB. Concurrently, NC NF- κB signaling boosted low-affinity antibody responses by transcriptionally priming follicular B- cells for plasmacytic differentiation. Together, these findings position NC NF-κB as a tunable rheostat linking B-cell signaling to immune-niche control and humoral immunity.

  Study EGAS50000001646

• Targeting EGFR in NF1 Mutant Melanoma

  Our study focused on melanoma patients with driver mutations in the neurofibromin 1 (NF1) tumor suppressor gene, a subset of melanoma patients that have not benefitted from recent treatment advances. We have leveraged patient-derived short-term cultures (STCs) and multiomics approaches to identify molecular features that could be developed into therapies for NF1 mutant melanoma patients. Our studies revealed that the epidermal growth factor receptor (EGFR) is highly expressed and active in NF1 mutant melanoma cells, and that genetic or pharmacological EGFR inhibition impaired tumor cell proliferation, survival, and cell growth in patient-derived NF1 mutant but not NF1 wild-type melanoma models.

  Study phs003906

• Multi-modal spatial characterization of tumor-immune microenvironments in diffuse large B-cell lymphoma

  We have leveraged spatial transcriptomics together with proteomic and genomic analysis to investigate the spatial immunology and pathobiology of DLBCL. We define distinct cellular niches that differ in frequency across tumors, related to both Epstein-Barr virus (EBV) infection status and the anatomical site of the tumor, and show that residence within different cellular niches is associated with divergent functional states of T-cells and tumor B-cells due to different patterns of cell-cell communication. This provides a framework for understanding stereotyped patterns of spatial organization in DLBCL and immunological interactions associated with heterogeneity in immune cell infiltration and function across patients.

  Study EGAS50000001146

• Center for Common Disease Genomics (CCDG) - Cardiovascular: Cleveland Clinic Cohort

  The National Human Genome Research Institute (NHGRI) has funded the Centers for Common Disease Genomics (CCDG), a collaborative large-scale genome sequencing effort to comprehensively identify rare risk and protective variants contributing to common disease phenotypes and to better understand the general principles of genomic architecture underlying common, complex inherited diseases. This study contains variant calls derived from the whole genome sequence data of an early-onset coronary artery disease case-control cohort collected by the Cleveland Clinic. Case status was assigned based on the presence of myocardial infarction, coronary artery stenosis greater than 70% in at least one coronary artery, and/or revascularization (coronary angioplasty with or without stent placement or coronary artery bypass grafting) at an early age. For these samples, "early age" is defined as men 60 years of age or younger and women 70 years of age or younger.

  Study phs001871

• Single Cell Analysis of Healthy and Diseased Temporomandibular Joint Synovial Fluid

  Temporomandibular joint disorders (TMJDs) are a set of complex, poorly understood painful conditions that negatively affect many children and adults in the US. In this study, we establish a protocol to utilize irrigation fluid from TMJ arthrocentesis to perform single-cell RNA sequencing on cells contained in TMJ synovial fluid. Our results should help investigators better understand these conditions and identify novel therapeutic options.

  Study phs003645

• A new subgroup of hepatocellular adenomas with sonic hedgehog pathway activation

  Hepatocellular adenomas (HCA) are benign liver tumors divided in molecular subtypes characterized by mutations inactivating HNF1A, activating β-catenin or the IL-6/JAK/STAT inflammatory pathway. Molecular analyses of 533 HCA developed in 411 patients identified a new tumor subgroup with Sonic Hedgehog pathway activation due to focal deletions creating INHBE promoter/GLI1 fusions.

  Study EGAS00001002091

• WGBS files for PCGP NBL_MYCN_ATRX

  WGBS files for PCGP NBL_MYCN_ATRX paper titled "MYCN Amplification and ATRX Mutations are Incompatible in Neuroblastoma"

  Dataset EGAD00001004559

• singel cell RNAseq dataset for the study "Composition and functional status of T and NK cells in Extramedullary myeloma tumor microenvironment""

  Dataset contains all newly generated single cell RNAseq data generated for the study. It includes 5 EMM soft tissue samples, 5 EMM bone marrow samples (EMM_BM) and 6 RRMM BM samples without EMM (RRMM_BM). Samples that are sequenced twice are marked by _1 or _2 in the sample name. The sample name mentioned corresponds to the sample name used in the publication. The rest of the EMM single cell RNAseq samples mentioned int the publication, EMM_03_1, EMM_11, EMM_14_1, EMM_14_2, EMM_16, and EMM_15_1 are already uploaded in EGA archive – dataset id EGAD50000000053.

  Dataset EGAD50000001511

• Single-cell omics data for COVID-19 patients

  Single-cell RNA-seq, single-cell ATAC-seq, and genotypes used in the analysis for the study "Altered and allele-specific open chromatin landscape reveal epigenetic and genetic regulators of innate immunity in COVID-19". The RNA-seq and ATAC-seq are raw data in FASTQ format while the genotypes are in the VCF format which was filtered and imputed (more details are available in the main text of the study).

  Dataset EGAD00001009331

• Whole genome, exome and transcriptome analysis to guide individualized cancer interpretation

  Study Design: The Cancer Alliance study was a collaboration of nine academic medical institutions in the New York city area and led by the New York Genome Center. Tumor-normal paired samples were submitted by the institutions for whole genome, whole exome and transcriptome sequencing and bioinformatics analysis at New York Genome Center. Relevant clinical histories were also collected. Raw sequence files were available to all collaborators. Variant call files were analyzed both manually by interpreters at NYGC and by IBM Watson Genome Analytics. This study was approved by a central institutional review board (IRB), Biomedical Research Alliance of New York, and by local IRBs, including Stony Brook University and Northwell Health. The study was supported in part by a grant from the IBM corporation (IBM Watson Health) to the New York Genome Center, New York Genome Center philanthropic funds and Rockefeller University grant # UL1TR000043 from the National Center for Advancing Translational Sciences (NCATS), and the National Institutes of Health (NIH) Clinical and Translational Science Award (CTSA) program. The principal investigator Robert B. Darnell MD, PhD., is a Howard Hughes Medical Institute Investigator. Results: Pending Publication of Analysis of Study Conclusions: Pending Publication of Analysis of Study

  Study EGAS00001004013

• Combinatorial CRISPR screen identifies fitness effects of paralogues FAM50A and FAM50B

  Genetic redundancy has evolved as a way for human cells to survive the loss of genes that are single copy and essential in other organisms, but also allows tumours to survive despite having highly rearranged genomes. In this study we CRISPR screen 1,191 gene pairs, including paralogues and known and predicted synthetic lethal interactions to identify 105 gene combinations whose co-disruption results in a loss of cellular fitness. 27 pairs influence fitness across multiple cell lines including the paralogues FAM50A/FAM50B, two genes of unknown function. Silencing of FAM50B occurs across a range of tumour types and in this context disruption of FAM50A reduces cellular fitness whilst promoting micronucleus formation and extensive perturbation of transcriptional programmes. This dataset includes CRISPR screening of cancer cell lines, RNA sequencing studies of cancer cell lines and also data from the sequencing of tumour xenografts collected from mice.

  Dataset EGAD00001006648

• Genotyping microarray data of molecular tumorboard patients in the context of the HRD-manuscript published in IJC

  Intensity files (.idat) derived from the Infinium CytoSNP-850K BeadChip microarray (Illumina) were used to analzye a possible Homologous-Recombination-Repair Deficiency (Molecular Rationale for a PARP-Inhibitor therapy) of n= 39 tumor patients (each n= 39 .idat files of the green and red chanel respectively) presented in the Molecular Tumorboard at the University Hospital Erlangen. Using these files a Genomic Instability Score was bioinformatically deducted (R-based scripts, e.g. ASCAT, scarHRD) based upon the presence of three parameteres "Loss of Heterozygosity, LOH", "Large Scale Transitions, LST" and "Telomeric Allelic Imbalances, TAIs". The associated manuscript is published in International Journal of Cancer, IJC.

  Dataset EGAD00010002736

• Acral Melanoma PDXs from the admixed Brazilian Population - Tumour and unfiltered PDX sample CRAM files - RNAseq

  Patient Derived Xenograft RNAseq sample CRAM files mapped to build GRCh38. Acral melanoma (AM) is an aggressive melanoma subtype with limited therapeutic options and poor outcomes. In non-European descent and admixed populations, like in Latin America, it can account for a significant proportion of cutaneous melanoma cases. Here, we performed comprehensive genomic and functional profiling of AM from a uniquely diverse Brazilian cohort. Whole-exome and transcriptome sequencing was performed on both tumours and patient-derived xenograft (PDX) samples. The PDX were obtained from a comprehensive collection of patient-derived xenograft (AM-PDX) models that we established which faithfully retained the histopathological and genomic features of the original tumours.

  Dataset EGAD00001015742

• International Genetics of Parkinson Disease Progression (IGPP) Consortium: EPIPARK and HBS2 Cohorts

  EPIPARK and HBS2 cohorts were analyzed as part of the International Genetics of Parkinson Disease Progression (IGPP) Consortium. EPIPARK is a population-based cohort to study non-motor symptoms in parkinsonism in the city of Lübeck, Germany led by Drs. Meike Kasten and Christine Klein. HBS2 is a recently enrolled subset of participants in the Harvard Biomarkers Study led by Dr. Clemens Scherzer (www.bwhparkinsoncenter.org/biobank) of 89 participants with a diagnosis of Parkinson Disease (PD). Genotyping with Illumina Infinium Multi-Ethnic Genotyping Arrays (MEGA chip) was performed by Dr. Scherzer, Harvard Medical School and Brigham and Women’s Hospital. 179 participants with a diagnosis of PD from EPIPARK and 89 participants with a diagnosis of PD from HBS2 met Q/C criteria were analyzed.

  Study phs002328

• Resistance to Checkpoint Blockade Therapy Through Inactivation of Antigen Presentation

  Although immune checkpoint blockade (CPB) leads to prolonged responses in 15-40% of patients with metastatic melanoma, treatment refractory disease and progression after initial response remain major causes of mortality. While predictors of response have been reported, the common mechanisms of both primary and acquired resistance are poorly understood. To identify mechanisms of resistance and examine the evolving landscape in response to CPB, we performed whole exome sequencing (WES), immunohistochemistry (IHC), and RNA-sequencing (RNAseq) of longitudinal tumor biopsies from 17 metastatic melanoma patients treated with various CPB therapies. We found no significant changes in both mutational and neoantigen loads over time between responders and nonresponders. However, we identified abnormalities in one gene, beta-2-microglobulin (B2M), an essential component of MHC Class I antigen presentation, that were present in samples during disease progression but not regression. In total, we identified B2M aberrations in 29.4% of patients, including multiple early frameshift mutations, loss of heterozygosity (LOH) overlapping B2M, and absence of tumor-specific B2M protein expression. Additional defects in the antigen presentation and IFNγ pathways were identified but were not restricted to progressing lesions in our cohort. In two independent cohorts of 105 and 38 melanoma patients treated with ipilimumab (anti-CTLA4) and pembrolizumab (anti-PD1) respectively, we found that B2M LOH was enriched 3-fold in nonresponders (~30%) vs. responders (~10%) and associated with poorer overall survival (log-rank p=0.01, p=0.006). Loss of both copies of B2M was found only in nonresponders. We also found evidence for association of LOH overlapping IFNGR1 with poorer overall survival exclusively in the anti-PD1 cohort. Thus, B2M loss is likely a common mechanism of primary and acquired resistance to therapies targeting CTLA4 or PD-1.

  Study phs001427

• A whole genome analysis of single fetal human stem cells from the liver and the intestine

  Mutations of embryonic and fetal origin have the potential to affect a large proportion of adult cells and may alter cancer predisposition or lead to genetic disease syndromes. We have recently shown that human adult-stem cells progressively acquire approximately 40 novel tissue-specific mutations per year throughout postnatal life. Prenatal mutation rates are as yet unknown. Here we determined genome-wide mutation patterns of single stem cells in human development by sequencing of clonally expanded intestinal and liver organoid cultures of 2nd trimester human foetuses. Our results show that mutation rates in fetal stem cells are significantly higher than in adult stem cells.

  Study EGAS00001002886