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• Transcriptomic Profiling of an Anti-PD-L1 Treated Cohort of Newly Diagnosed GBM Patients

  Checkpoint inhibitor therapy has limited efficacy in glioblastoma patient outcomes. This study involves RNA sequencing (RNA-seq) of newly diagnosed GBM patients treated with concurrent atezolizumab, radiation therapy, and temozolomide. By analyzing RNA-seq data from 39 tumors, the study aims to explore tumor transcriptomic features, including immune-based transcriptomic programs and immune infiltration, to understand their influence on PD-L1 blockade treatment efficacy and to identify which patients may benefit more from such therapy.

  Study EGAS50000000784

• The National Institute of Neurological Disorders and Stroke (NINDS) Stroke Genetics Network (SiGN)

  The NINDS Stroke Genetics Network (SiGN) is a large international collaboration designed to detect genetic variants that predispose to subtypes of ischemic stroke. The study implements a genome wide association study (GWAS) methodology with all stroke cases undergoing phenotypic and stroke-subtype classification using the same web-based Causative Classification of Stroke (CCS) system, with data entered by trained and certified adjudicators at participating Research Centers (GRC's). SiGN includes ischemic stroke cases from 24 GRC's, 13 from the US and 11 from Europe. Each GRC has access to well-characterized ischemic stroke cases in which extensive phenotype data and high-quality DNA was available. Genome-wide data was available for many cases and for those without, new genome-wide genotyping, including exome chip genotyping of rare variants, was done through the Center for Inherited Diseases Research (CIDR). To maximize power for subtype analyses, genotyping resources were allocated almost exclusively to cases. With few exceptions, controls were drawn from studies with publicly available genome-wide data.

  Study phs000615

• Genomics of enteropathy associated T cell lymphoma (EATL)

  Enteropathy-associated T cell lymphoma (EATL) is a lethal and the most common neoplastic complication of celiac disease. In this study, we applied whole exome sequencing in 69 EATL tumors to define the genetic landscape of EATLs. The most frequently mutated gene in EATL was SETD2 (32% of cases), with loss of function mutations comprising a large proportion (41%) of those mutations. The JAK-STAT pathway was the most frequently mutated signaling pathway, with mutations in STAT5B being the most common, followed by JAK1, JAK3, STAT3, and the negative regulator of the pathway, SOCS1. We also identified mutations in NRAS and KRAS, as well as TP53 and TERT. Interestingly, the two types of EATL had highly overlapping genetic alterations indicating shared mechanisms underlying their pathogenesis. Gene expression analysis of the two types of EATL identify robust differences in transcriptional profiles. We further modeled the effects of SETD2 loss in vivo by developing a T cell specific knockout mouse model. These mice manifested an expansion of γδ T cells that identify novel roles for SETD2 in T cell development and lymphomagenesis. Together, our data render the most comprehensive genetic portrait yet of this uncommon but lethal disease, and may inform future classification schemes.

  Study EGAS00001001954

• Combined targeting of BRD4-associated Promoter Activation and NFKB Immunomodulation in ARID1A-mutated Gastric Adenocarcinoma

  Gastric cancer (GC) a leading causes of cancer-related deaths worldwide, with ARID1A identified as the second most frequently mutated driver gene in GC. This study involves comprehensive genomic profiling of a Singaporean cohort of over 200 GC patients to characterize the mutational signatures associated with ARID1A inactivation across various molecular subtypes of GC. The findings highlight a potential therapeutic approach for ARID1A-mutated GCs, targeting both tumor-intrinsic mechanisms (BRD4-associated promoter activation) and extrinsic immunomodulatory pathways (NFKB signaling).

  Study EGAS00001006397

• Myelodysplastic Syndrome (MDS) in Humanized Mice

  This study was to develop a faithful pre-clinical MDS patient-derived xenotransplantation model in cytokine-humanized immunodeficient "MISTRG" mice. We performed targeted genome sequencing on bone marrow from patients with MDS or AML and from bone marrow of mice engrafted with the respective patient bone marrow. Cytokine-humanized immunodeficient mice faithfully replicate human MDS.

  Study phs001778

• Identifying and Reducing Disparities in Patient-Reported Outcomes Among African American Prostate Cancer Survivors

  This research study aimed to identify disparities in prostate cancer symptom burden and their contributors among African American, Hispanic, and non-Hispanic White prostate cancer survivors. We collected patient-reported outcomes data, focusing on various aspects of the survivors' health and well-being, clinical data, demographics data, and germline genomic data.

  Study phs003745

• Whole Genome Sequencing of CRLF2/IL7RA transduced cells

  There are two samples, 42 (control) and 49 To test the role of activated CRLF2/IL7RA in leukemia initiation we expressed CRLF2 together with IL7RA in human CB hematopoietic progenitors. Human CRLF2 and wild type and/or activated mutant form of human IL7RA (IL7RAwt/ins) were cloned into a lentiviral vector with a bi-cistronic cassette under the expression control of an Eμ-B29 promoter/enhancer to augment expression in B-cell precursors. Backbone vector expressing GFP (BB). Whole genome sequencing Leukemic (49) and BB transduced (42) corresponding CB cells were collected from transplanted mice. Sequencing libraries were prepared from these samples

  Dataset EGAD00001005456

• Targeted Germline Sequencing of the Leeds Melanoma Cohort

  In this project we performed targeted sequencing of known and suspected melanoma susceptibility genes in a cohort of melanoma patients and matched controls. Our aim was to identify variants that predispose to melanoma development. The melanoma cases used in this study were population ascertained.

  Dataset EGAD00001007520

• MATISSE Whole-exome sequencing data

  Sample availability: WES was performed on 41 available baseline tumor and blood samples (22 CCRs/MPRs, 5 PPRs, 14 CRN/NPRs). Tumor DNA was extracted from formalin-fixed paraffin-embedded (FFPE) primary tumor and lymph node metastasis sections containing at least 10% viable tumor cells present in the sample. A pathologist (LS) scored the tumor percentage and indicated the most tumor-dense region on a hematoxylin and eosin (H&E) stain slide for subsequent DNA isolation. According to the manufacturer's protocol, five to 10 FFPE slides (10 µm) were used for DNA isolation using the AllPrep DNA FFPE isolation kit (Qiagen, 80234) and the QIAcube. Germline DNA was isolated from baseline PBMCs using the AllPrep DNA / RNA / miRNA Universal isolation kit (Qiagen, 80224) and the QIAcube, according to the manufacturer’s protocol. Genetic Diagnostics and Sequencing Services (CeGaT) performed whole-exome sequencing sequencing in Germany. Data processing: Demultiplexing of the sequencing reads was performed with Illumina bcl2fastq (v2.20). Adapters of the reads were trimmed with Skewer (v0.2.2), without quality trimming. Sequencing reads were aligned with BWA (v0.7.17) to the human reference genome GRCh38 (Ensemble, v105). Duplicated reads were marked using Picard (v2.25.0) MarkDuplicates, after which quality scores were recalibrated using GATK4 (4.2.2.0) BaseRecalibrator. FastQC (v0.12.1), MultiQC (v1.14), Mosdepth (v0.3.3) and NGScheckmate (v1.0.1) were used for assessing data quality, on FASTQ files and intermediate processing steps.

  Dataset EGAD50000001469

• Exome sequencing to identify predisposition to Wilms tumour

  To identify new Wilms tumor predisposition genes, we performed whole-exome paired-end sequencing of lymphocyte DNA from 12 affected individuals from six unrelated, non-syndromic Wilms tumor families in which known causes had been excluded.We prepared DNA libraries from 1.5 mg blood-derived genomic DNA using the Paired-End DNA Sample Preparation Kit (Ilumina). DNAwas fragmented using Covaris technology and the libraries were prepared without gel size selection. We performed target enrichment using the TruSeq Exome Enrichment Kit (Illumina) by targeting 62 mb of the human genome. The captured DNA libraries were PCR amplified using the supplied paired-end PCR primers.Sequencing was performed with an Illumina HiSeq2000 generating 2?101 bp reads.

  Study EGAS00001000904

• ScRNA-seq of human kidney immune cells of patients with ANCA-associated glomerulonephritis, Lupus Nephritis against a healthy nephrectomy control

  ANCA-associated glomerulonephritis (AGN) associates with a high risk of end-stage kidneydisease. The role of kidney immune cells in local inflammation remains unclear. This study investigates kidney immune cell diversity and function. Kidney tissue from AGN patients (n=5) and a lupus nephritis (LN) patient (n=1) were aquired during a biopsy procedure for a clinical indication. Needle-core biopsies were obtained for histopathological examination, and an additional pass was performed to retrieve kidney tissue for scRNA-seq. Healthy kidney tissue (n=1) was obtained from a kidney that was surgically removed do tue due to a (non-invasive) papillary urothelial carcinoma. Immediately after collection, kidney tissue was processed into a single-cell suspension and sorted using a 4-color flow cytometry panel to isolate living, CD45+immune cells. To aid in the multi-omic characterization, surface markers and T and B cell repertoires were sequenced in 2 samples (1 AGN patient and the nephrectomy control). These samples were incubated with an oligo-antibody TotalSeq-C cocktail containing 130 unique cell surface antigens.

  Dataset EGAD50000000229

• Mitochondrial DNA sequencing in samples of Huntington’s disease patients

  Mitochondrial dysfunction is found in the brain and peripheral tissues of Huntington’s disease (HD) patients, which connects many pathological features of HD. In this project, we conducted a large-scale study of mtDNA variations with a sensitive mtDNA-targeted sequencing method called STAMP, at a median coverage of 4000-fold, in lymphoblast and blood samples of HD patients. mtDNA sequence variations and copy numbers were compared between samples from HD patients and healthy control individuals, and were assessed in relation to HD stages, and changes of HD phenotypes in longitudinal samples.

  Study EGAS00001004092

• Single-cell study of 14 childhood medulloblastoma patients

  Medulloblastoma intra-tumoural genetic heterogeneity and clonal evolution, and their role in disease pathogenesis and clinical behaviour, are poorly understood. We used single-cell whole-genome sequencing (sc-WGS) to reconstruct the natural history and temporal evolution of 14 medulloblastomas, representing its major clinico-molecular sub-classes. We identified wholly-clonal tumours which displayed single-clone expansion (i.e. linear evolution); all were observed in favourable-outcome sub-classes (i.e. MBWNT and infant MBSHH). In contrast, remaining tumours harboured sub-clonal structures which displayed punctuated or gradual trajectories; highest-risk sub-classes, typically characterised by MYC-amplification (MBGroup3) or TP53-mutation (MBSHH), and linked to genomic instability and LCA pathology, were most clonally-diverse. Clinically-adopted biomarkers were typically early-clonal/initiating events, representing exploitable targets for early-disease detection; in analyses of spatially-distinct tumour regions, a single biopsy was sufficient to assess their status. sc-WGS revealed events not previously appreciated in bulk tumour analysis, which arose later and/or sub-clonally and more commonly displayed spatial diversity; their clinical significance and role in disease evolution post-diagnosis now require establishment. In summary, our findings reveal diverse modes of tumour initiation and clonal evolution in the major medulloblastoma sub-classes, highlighting their pathogenic relevance and clinical potential.

  Dataset EGAD00001009057

• OICR: Molecular Pathological Epidemiology of Colorectal Cancer

  Colorectal cancer, the second most commonly diagnosed cancer, is a biologically heterogeneous disease. To characterize the molecular attributes of colorectal tumors, we conducted targeted sequencing at the Ontario Cancer Research Institution (OICR) of tumor and matched normal DNA samples from 2,542 colorectal cancer cases in the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO) [phs001078] and the Colon Cancer Family Registry (CCFR). These consortia are based on cohort and population-based case-control studies.

  Study phs002050

• 65 prostate cancer cases WGS and transcriptome sequencing project

  We obtained whole-genome and transcriptome sequencing of tumor-benign pairs from 65 Asian prostate cancer (PCa) patients. Taken together with the TCGA PCa cohort, our integration analysis provides the first comprehensive mutational landscape of PCas across major ethnics worldwide and reveals potential novel role of frequent altered chromatin remodeler genes in PCas without androgen receptor (AR) alteration and complex rearrangements derived from Chromoplexy. In addition, we identified 5 putative tumor suppressor genes (TSGs) chains including one on chromosome 13q with novel findings of PCDH9 (deletions in 15/65 tumors) which was implicated in aggressive progression of prostate cancer. Finally, the integrative pathway and co-expression network analysis followed by the functional study indicated the frequent altered genes, particularly focal amplifications of PLXNA1 (11/65), in semaphoring signaling of axon guidance pathway may interact with PI3K/AKT and AR signaling and also contribute to the aggressiveness and progression of prostate cancer.

  Study EGAS00001000888

• Barcoding reveals complex clonal dynamics of de novo transformed human mammary cells

  Most human breast cancers have already diversified genomically when they first become clinically evident, by which time extensive heterogeneous histopathologies, transcriptomes and growth patterns are also apparent. Accordingly, important initial events and the cellular context in which they occur have been difficult to characterize. Using DNA barcoding, we now demonstrate the high efficiency with which both purified basal and luminal cells isolated directly from normal adult human mammary tissue can be rapidly transformed by a single oncogene (KRASG12D) resulting in the production within 8 weeks in vivo of serially transplantable, polyclonal, invasive ductal carcinomas that are phenotypically heterogeneous and transcriptionally distinct from the initial cells transduced. Barcoding also revealed a consistent dramatic change in the clonal content of passaged tumours. This system thus provides a powerful new platform for examining early events in the genesis, evolution and treatment response of malignant human mammary cells generated using defined mutations.

  Study EGAS00001001310

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

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

  Study EGAS00001005948

• Multiregion Whole Exome sequencing of pHGG and DIPG

  The failure to develop effective therapies for paediatric glioblastoma (pGBM) and diffuse intrinsic pontine glioma (DIPG) is in part due to their intrinsic heterogeneity. Analysis of 142 sequenced cases revealed multiple tumour subclones, spatially and temporally co-existing in a stable manner as observed by multiple sampling strategies. This dataset provides multi region sequencing of high grade gliomas and diffuse intrinsic pontine gliomas from 15 patients. DNA was extracted from FFPE sections in 2-13 regions of each tumour and sequenced with Agilent SureSelect whole exome sequencing. Germline DNA was also sequenced in 14 cases. Data was aligned to hg19 with bwa and is provided as 79 separate BAM files.

  Dataset EGAD00001004114

• Copy number profiling using PlasmaSeq

  In order to establish copy number profiles from the various samples we prepared libraries and subjected them to whole-genome sequencing at a shallow sequencing depth (0.1x)

  Dataset EGAD00001000761

• WGS analysis of Japanese liver cancer

  Liver cancer is prevalent worldwide, mainly associated with virus infection, and its underlying etiology and genomic structure are heterogeneous. Here we provide a whole-genome landscape of somatic alterations in 300 Japanese liver cancers. Our comprehensive analysis elucidated point mutations in non-coding regions, structural variants (SVs), and virus integrations, in addition to coding mutations, and demonstrated new mutational signatures related with liver carcinogenesis, novel recurrently mutated coding and non-coding regions such as lincRNA NEAT1/MALAT1, promoters, CTCF binding sites, and regulatory regions. SV analysis found a significant association with replication timing, and revealed that known cancer genes (CDKN2A, CCND1, APC, and TERT) and new cancer genes (ASH1L, NCOR1, MACROD2) were recurrently affected by SVs, leading to altered expression of nearby genes. These results emphasize the value of whole genome sequencing analysis to discover cancer driver mutations and to understand comprehensive molecular profiles of liver cancer, especially for SVs and non-coding mutations.

  Study JGAS000151

• Timing chromosomal amplification events using patterns of somatic mutations in high hyperdiploid acute lymphoblastic leukemia

  This dataset included samples with high hyperdiploid acute lymphoblastic leukemia (ALL) collected from the Division of Clinical Genetics, Lund University, Sweden. All samples were subjected to whole genome sequencing using the Illumina HiSeqX platform. Paired-end sequencing (2x150bp) was done to ~60x coverage for diagnostic samples and ~30x coverage for remission samples. The paired-end reads were aligned to the human reference genome GRCh37 (https://www.ncbi.nlm.nih.gov/assembly/GCF_000001405.25/) by the Burrows-Wheeler Aligner tool (version 0.7.17). Duplicate reads marking and local realignment were performed by GATK (version 4.0.11.0).

  Study EGAS00001007052

• Integrative understanding of human immune system by functional genomics and development of intervention strategies for the prevention of autoimmune diseases

  To elucidate the regulation of gene expression in immune cell subsets and its contribution to autoimmune diseases, Whole blood and various immune cell subsets from 119 Systemic Lupus Erythematosus (SLE), 65 Dermatomyositis & Polymyositis, 67 Systemic Sclerosis, 19 Mixed Connective Tissue Disease, 18 Sjogren's syndrome, 24 Rheumatoid Arthritis, 23 Behcet's disease, 18 Adult Onset Still���s Disease, 25 ANCA-associated Vasculitis, 16 Takayasu���s Arteritis and 141 healthy controls (C) were collected (Naive_CD4, Mem_CD4, Fr._I_nTreg, Fr._II_eTreg, Fr._III_T, Th1, Th2, Th17, Tfh, NK, Naive_CD8, Mem_CD8, EM_CD8, CM_CD8, TEMRA_CD8, Naive_B, USM_B, SM_B, DN_B, Plasmablast, CL_Mono (or CD16n_Mono), CD16p_Mono, Int_Mono, NC_Mono, mDC, pDC, LDG, Neu). Whole genome sequencing was performed with whole blood samples. RNA-seq was performed with each immune cell subset samples. After filtering and normalization of the gene expression data, eQTL analysis was performed in each immune cell type. 15 immune cell subsets ATAC-seq was also performed in 8 SLE and HCs, each.

  Study JGAS000220

• Cell type mapping of inflammatory muscle diseases highlights selective myofiber vulnerability in inclusion body myositis

  Inclusion body myositis (IBM) is the most prevalent inflammatory muscle disease in older adults with no effective therapy available. In contrast to other inflammatory myopathies like subacute immune-mediated necrotizing myopathy (IMNM), IBM follows a chronic disease course with both inflammatory and degenerative features of pathology. Moreover, causal factors and molecular drivers of IBM progression are largely unknown. Therefore, we paired single-nucleus RNA sequencing with spatial transcriptomics from patient muscle biopsies to map cell type-specific drivers underlying IBM pathogenesis compared to IMNM muscles and non-inflammatory skeletal muscle samples. In IBM muscles, we observed a selective loss of type 2 myonuclei paralleled by increased levels of cytotoxic T and cDC1 cells. IBM myofibers were either characterized by upregulation of cell stress markers featuring GADD45A and NORAD, or protein degradation markers including RNF7 associated with p62 aggregates. GADD45A upregulation was preferentially seen in type 2A myofibers associated with severe tissue inflammation. We also noted IBM-specific upregulation of ACHE encoding acetylcholinesterase, which can be regulated by NORAD activity and result in functional denervation of myofibers. Our results provide promising insights into possible mechanisms of myofiber degeneration in IBM and suggest a selective type 2 fiber vulnerability linked to genomic stress and denervation pathways.

  Study EGAS50000000310

• African American Multiple Myeloma GWAS

  The case set is from a case-control study designed to identify common genetic risk factors for multiple myeloma in African Americans, the population with the highest risk for this cancer. We conducted two GWAS and combined each of these with convenience controls consisting of unaffected African American participants in cohorts with existing GWAS data. We then conducted a meta-analysis of the two sets. Cases were persons of African ancestry with smoldering or active multiple myeloma identified at participating oncology clinics or through SEER registries, as part of the African American Multiple Myeloma Study (AAMMS) diagnosed from Jan 1, 1988 through July 31, 2016. The majority of the samples were collected from incident and prevalent cases diagnosed since Jan 1, 2008 (80.9%), with a minority obtained from biobanks from cases diagnosed prior to 2008 (19.1%). Additional samples were obtained from the Multiethnic Cohort (USC and University of Hawaii) (n=40), the University of California at San Francisco Multiple Myeloma Study (n=27), and from the Multiple Myeloma Research Consortium for secondary analysis (samples originally provided to MMRC by 8 additional sites (n=84)). We have identified the phenotype (smoldering myeloma, plasma cell multiple myeloma, or myeloma not otherwise specified (myeloma NOS) when myeloma phenotype was not known), sex and age at diagnosis in this data set. The initial GWAS set consisted of 1308 (1,305 passed QC) cases with DNA samples, with a GWAS performed on the Illumina Human Core. Controls consisted of 7,078 unaffected African American subjects who were participants in the African American Prostate and Breast Consortium, with existing GWAS data from the Illumina1M Duo BeadChip. The second GWAS set consisted of 529 African American multiple myeloma patients with samples (406 from University of Arkansas, results not contained in this dataset because NCI funds were not used for the collection and genotyping) with GWAS data resulting from the Illumina Mega-BeadChip v1.1. Controls were 2,390 unaffected African American participants in the Multiethnic Cohort with existing GWAS data from the same array. After QC and removal of duplicates within sets, sex mismatches, and removal of plasmacytoma cases (ICD-0 code 9731), this deposited data set contains the typed GWAS data for the Illumina Human Core (set 1) (n=1298), and for the MegaBead Chip v1.1 (set 2) (n=123), with the University of Arkansas samples removed, for a total of 1,421 case genotypes. Note that 13 samples that overlap set 1 and set 2 were included.

  Study phs001632

• Transcriptome profiling of megakaryocytes and platelets: application to GP9- and IKZF5-related thrombocytopenia

  Platelets are anucleate cells produced in the bone marrow and derived from large progenitor cells called megakaryocytes (MKs). Platelets receive RNA transcripts from their progenitorial MKs during thrombopoiesis. However, the correspondence between platelet and MK transcriptomes is poorly understood, particularly in the context of germline mutations that cause platelet formation defects or thrombocytopenia. We have studied the effects of two such mutations on MK and platelet transcriptomes. We generated immortalized MK cell line (imMKCL)-based models of Bernard-Soulier syndrome and IKZF5-related thrombocytopenia. MKs derived from imMKCLs with either a homozygous deletion of GP9 (GP9-/-) or a heterozygous Y121F variant in IKZF5 (IKZF5WT/Y121F) exhibited reduced proplatelet formation (reductions of 96% and 57%, respectively). Platelets from patients with either GP9-/- or IKZF5WT/Y121F genotypes had broad transcriptomic dysregulation, suggesting that (pro)platelet formation defects due to mutations in glycoprotein receptor and transcription factor genes such as GP9 and IKZF5 affect the trafficking of transcripts from MKs into platelets. RNA-seq data from MKs at four stages of differentiation revealed widespread but distinct changes in expression over time between the GP9-/- and the IKZF5WT/Y121F genotypes. Dysregulated genes in GP9-/- MKs were enriched for RNA metabolism and actin/tubulin folding pathways while those in IKZF5WT/Y121F MKs were enriched for cell cycle pathways. Most of these genes were also dysregulated in the platelets of patients with the corresponding diseases. Our results suggest that patients with inherited forms of thrombocytopenia present with a transcript trafficking defect during platelet formation.

  Study EGAS50000001276