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• RNA-Seq data of de novo assembly individual EGYPT

  This is the blood RNA-Seq read data used for expression analysis such as haplotypic expression (mapped against GRCh38).

  Dataset EGAD00001006036

• GWAS on covid-19 severity and susceptibility in the province of Bergamo, Italy

  This is a case-control GWAS that involved the voluntary recruitment of inhabitants of the Bergamo province via an online questionnaire. We collected detailed clinical data and verified all information through personal interviews. Cases (severe COVID-19; G1) and controls (mild or asymptomatic COVID-19, G2; non-infected, G3) were matched by age, sex and risk factors

  Study EGAS00001007310

• Identification of High-Risk PHF19 Expressing Cells in Myeloma Single-Cell Multiomics

  The aim of this study is to identify novel subsets of cells that are associated with progression and response to treatment. In this project, we study the tumor fraction from 49 myeloma patients across stages of progression. Samples were collected from 10 smoldering multiple myeloma (SMM), 22 newly diagnosed multiple myeloma (NDMM), and 17 relapsed refractory multiple myeloma (RRMM) patients. These samples were then sorted using magnetic-activated cell sorting (MACS) for CD138+ cells that represent the tumor fraction of each sample. The CD138+ fraction then underwent whole genome sequencing (WGS), where possible, and single-cell multiomics. Single-cell multiomics can now measure scRNA-seq and scATAC-seq simultaneously, which we use in this project. Using single-cell multiomics, we will study subclonal changes in gene expression, chromatin accessibility, and identify novel regulatory relationships within myeloma tumors. Furthermore, we will apply state of the art single-cell and single-cell multiomic techniques to better identify the more high-risk components of myeloma.

  Study phs003220

• Whole Genome Scan for Pancreatic Cancer Risk in the Pancreatic Cancer Cohort Consortium and Pancreatic Cancer Case-Control Consortium (PanScan)

  Within the framework of the NCI-sponsored Cohort Consortium, investigators from 12 prospective epidemiologic cohorts formed the Pancreatic Cancer Cohort Consortium in 2006. This study, also known as "PanScan", is funded by the National Cancer Institute (NCI) and involves conducting a genome-wide association study (GWAS) of common genetic variants to identify markers of susceptibility to pancreatic cancer. In 2007, the study was expanded to include 8 case-control studies. The study team includes scientists from the cohorts comprising the Consortium, the NCI and the Pancreatic Cancer Case Control Consortium (PanC4). PanScan I and II were conducted in 12 cohort studies and 8 case-control studies, leading to the discovery of four novel regions in the genome associated with risk for pancreatic adenocarcinoma. The third phase of PanScan (PanScan III) was conducted using recently identified incident pancreatic cancer cases drawn from fourteen cohorts from the cohort consortium, including nine prospective cohorts who participated in PanScan I, and five newly joined cohorts. The nine cohort studies that participated in PanScan I and had new genotyping of cases in PanScan III include ATBC, CPS-II, EPIC, HPFS, NHS, PHS, PLCO, SMWHS, and WHI; the five newly joined cohort studies include the Agricultural Health Study (AHS), the Multiethnic Cohort Study (MEC), the Melbourne Collaborative Cohort Study (MCCS), the Vitamins and Lifestyle Study (VITAL), and Selenium and Vitamin E Cancer Prevention Trial (SELECT). In addition to the cases from cohorts, we also included cases from the Gastrointestinal Cancer Clinic of Dana-Farber Cancer Institute Study (DFCI-GCC); from the University Hospital in Heidelberg, Germany, which is part of a larger European clinical case-control study (PANDoRA); and from clinic-based cases from eastern Spain (PANKRAS-II). The dbGaP datasets available include all subjects previously made available from PanScan I and II, plus 1,582 new incident pancreatic cancer cases of European descent from prospective cohorts, case-control studies or case series (genotyped as part of PanScan III). Also included are 61 pancreatic cancer cases and 67 control subjects from PanScan I as well as 173 pancreatic cancer cases from PanScan III of Asian ancestry from the Shanghai Men's and Women's Health Study (Supplemental Table 10, Wolpin et al. (Nat Genet, 2014)). The control population used in the analysis for the Wolpin et al. manuscript included cancer-free individuals from the prospective cohorts that contributed pancreatic cancer cases to PanScan III and controls from the Spanish Bladder Cancer SBC/EPICURO study that were previously genotyped using the OmniExpress, Omni 1M or Omni 2.5M SNP arrays. The data from these control subjects were posted to dbGaP under the GWAS in which they were initially genotyped and will not be made available in duplicate under this dbGaP study.The summary statistics for PanScan I-III were generated as detailed in Wolpin BM. et al., Genome-wide association study identifies multiple susceptibility loci for pancreatic cancer, Nature Genetics 2014; 46(9):994-1000 (https://www.nature.com/articles/ng.3052), and Klein, A. et al., Genome-wide meta-analysis identifies five new susceptibility loci for pancreatic cancer, Nature Communications, 2018;9(1):556 (https://www.nature.com/articles/s41467-018-02942-5). The dataset includes results from an association study of 5,117 individuals diagnosed with pancreatic ductal adenocarcinoma (PDAC) and 8,845 control individuals, or a total of 13,962 subjects of European ancestry (as compared to the genotype and phenotype information under this project that includes 9,437 individuals (PanScan I and II PDAC case and control individuals and PanScan III PDAC cases only). This is due to the fact that PanScan III “borrowed” GWAS data from control individuals genotyped separately from the PanScan GWAS project and are therefore not included as raw genotypes in phs000206.v5.p3. Association analysis was performed separately for PanScan I-II and PanScan III, followed by a meta-analysis of the two datasets. Results were filtered based on a minor allele frequency (MAF) < 0.01, an imputation INFO score < 0.3 and a heterogeneity P-value < 1x10-10 leaving a total of 9,758,390 variants. Columns in the summary statistics dataset are as follows: ID: variant rsIDChr: chromosome numberPosition: position in the chromosome, genome build GRCh37/hg19MarkerName: variant identifierAllele1: reference alleleAllele2: alternative alleleFreq1: allele frequency for allele2FreqSE: standard error of the allele frequencyMinFreq: the minimal allele frequency across studiesMaxFreq: the max allele frequency across studiesEffect: effect size for allele2StdErr: standard errorP-value: meta-analysis p-valueDirection: summary of effect direction for each studyHetISq: I^2 statistic which measures heterogeneity on scale of 0-100%HetChiSq: chi-squared statistic in simple test of heterogeneityHetDf: degrees of freedom for heterogeneity statisticHetPVal: P-value for heterogeneity statistic

  Study phs000206

• CIP: Obesity-Diabetes Familial Risk, Viva La Familia Study

  The VIVA LA FAMILIA Study was designed to identify genetic variants influencing childhood obesity and its comorbidities in the Hispanic population. Family recruitment and phenotyping were conducted in 2000-2005 in Houston, TX. All enrolled children (n=1030) and parents gave written informed consent or assent. The protocol was approved by the Institutional Review Boards for Human Subject Research for Baylor College of Medicine and Affiliated Hospitals and for Texas Biomedical Research Institute. The VIVA LA FAMILIA study design and methodology have been described in detail (Butte NF, 2006). Each family was ascertained on an obese proband, defined as a BMI > 95th percentile, between the ages 4-19 y. The cross-sectional, longitudinal study design consisted of baseline measurements, with a one-year. GWAS was performed using the Illumina HumanOmni1 v1.0 BeadChips on 815 children from 263 Hispanic families and HumanOmni 2.5-8v1 on an additional 43 children. Exome sequencing is being performed on 822 children using NimbleGen capture, followed by Illumina DNA sequencing. Butte NF, Cai G, Cole SA, Comuzzie AG. Viva la Familia Study: genetic and environmental contributions to childhood obesity and its comorbidities in Hispanic population. Am J Clin Nutr 2006;84(3):646-54. PMID: 16960181

  Study phs000616

• Single cell sequencing of breast cancer T cells reveals a tissue-resident memory subset associated with improved prognosis

  The quantity of tumor infiltrating lymphocytes (TILs) in breast cancer (BC) is a robust prognostic factor for improved patient survival particularly in triple negative and HER2-overexpressing BC subtypes. Whilst T cells are the predominant TIL population, the relationship between quantitative and qualitative differences in T cell subpopulations and patient prognosis remains unknown. We performed single-cell RNA sequencing (scRNA-seq) of 6311 T cells isolated from human BCs, and show for the first time that significant heterogeneity exists in the infiltrating T cell population. We demonstrated that high TIL BCs contained significant numbers of CD8+ T cells with features of tissue-resident memory T (TRM) cell differentiation and that these CD8+ TRM cells expressed high levels of immune checkpoint molecules and effector proteins. A CD8+ TRM gene signature developed from the scRNA-seq data was significantly associated with improved patient survival in early-stage triple negative breast cancer (TNBC) and provided better prognostication compared with CD8 expression alone. Our data suggests that CD8+ TRM contribute to BC immunosurveillance and are the key targets of modulation through immune checkpoint inhibition. Further understanding of the development, maintenance and regulation of TRM cells will be crucial for successful immunotherapeutic development in BC.

  Study EGAS00001002845

• Somatic_mutations_in_twin_breast_cancers

  The aim of this study is to investigate the somatic mutations in twins with BRCA1/2 negative breast cancer with no strong family history.

  Study EGAS00001002379

• SMARCB1 loss activates patient-specific distal oncogenic enhancers in malignant rhabdoid tumors

  Malignant rhabdoid tumor (MRT) is a highly malignant and often lethal childhood cancer. MRTs are genetically defined by bi-allelic inactivating mutations in SMARCB1, a member of the BRG1/BRM-associated factors (BAF) chromatin remodeling complex. Mutations in BAF complex members are common in human cancer, yet their contribution to tumorigenesis remains in many cases poorly understood. Here, we studied derailed regulatory landscapes as a consequence of SMARCB1 loss in the context of MRT. Our multi-omics approach on patient-derived MRT organoids revealed a dramatic reshaping of the regulatory landscape upon SMARCB1 reconstitution. Chromosome conformation capture experiments subsequently revealed patient-specific looping of distal enhancer regions with the promoter of the MYC oncogene. This intertumoral heterogeneity in MYC enhancer utilization is also present in patient MRT tissues as shown by combined single-cell RNA-seq and ATAC-seq. We show that loss of SMARCB1 drives patient-specific epigenetic reprogramming underlying MRT tumorigenesis.

  Study EGAS00001007590

• Identification and Characterization of Skin-Resident Memory T cells in Patients with Melanoma-Associated Vitiligo

  Metastatic melanoma patients who develop melanoma-associated vitiligo, an autoimmune cutaneous side effect after receiving immunotherapy, have better overall survival than those who do not develop vitiligo. The objective of this study is to determine the tumor-specific memory T cell responses in the skin, tumor and blood of melanoma patients with vitiligo. Matched melanoma tumor, distant vitiligo-affected skin, and blood were collected and sorted for T cells to perform paralleled single-cell RNA sequencing (scRNA-seq) and single-cell TCR sequencing (scTCR-seq) on the day of tissue collection. The transcriptional analysis identified three resident memory T (TRM) cell subsets which were shared between tumors and vitiligo-affected skin. scRNA-seq identified CD8+ T-cell clonotypes in tumors that co-existed as TRM in skin and as effector memory T (TEM) cells in blood. This study revealed that long-term melanoma survivors maintained memory T cell responses as broadly-distributed TRM and TEM compartments. 

  Study phs002309

• Arriba: accurate and efficient detection of gene fusions from RNA-Seq (H021)

  The identification of gene fusions from RNA sequencing data is a routine task in cancer research and precision oncology. However, despite the availability of many computational tools, fusion detection remains challenging. Existing methods suffer from poor prediction accuracy and are computationally demanding. We developed Arriba, a novel fusion detection algorithm with high sensitivity and short runtime. When applied to a large collection of published pancreatic cancer samples (n=803), Arriba identified a variety of driver fusions, many of which affected druggable proteins, including ALK, BRAF, FGFR2, NRG1, NTRK1, NTRK3, RET, and ROS1. The fusions were significantly associated with KRAS wild-type tumors and involved proteins stimulating the MAPK signaling pathway, suggesting that they substitute for activating mutations in KRAS. In addition, we confirmed the transforming potential of two novel fusions, RRBP1-RAF1 and RASGRP1-ATP1A1, in cellular assays. These results demonstrate Arriba’s utility in both basic cancer research and clinical translation.

  Study EGAS00001003554

• Center for Common Disease Genomics (CCDG) - Cardiovascular: Emory 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 selected from Emory University Cardiovascular Biobank. 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. 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.

  Study phs001880

• Summary Statistics GWAS SSNS

  Column 1 rsid: SNP identifier;Column 2 chromosome: name of chromosome on which the SNP is located;Column 3: position: base pair position on the chromosome;Column 4 minor_test_allele: the base that constitutes the minor allele;Column 5 major_allele: the base that constitutes the major allele;Column 6 maf: the frequency of the minor allele, indicated as a fraction of 1;Column 7 allele_freq_cases: the minor allele frequency in cases;Column 8 allele_freq_controls: the minor allele frequency in controls;Column 9 regression_pvalue: the p-value for the difference in allele frequency between cases and controls;Column 10 odds_ratio: the odds ratio, as calculated using logistic regression under an additive model with adjustment for the first ten principal components of ancestry

  Dataset EGAD00010002316

• Summary Statistics GWAS SSNS

  Column 1 “rsid”: SNP identifier Column 2 “chromosome”: name of chromosome on which the SNP is located Column 3: “position”: base pair position on the chromosome Column 4 “minor_test_allele”: the base that constitutes the minor allele Column 5 “major_allele”: the base that constitutes the major allele Column 6 “maf”: the frequency of the minor allele, indicated as a fraction of 1 Column 7 “allele_freq_cases”: the minor allele frequency in cases Column 8 “allele_freq_controls”: the minor allele frequency in controls Column 9 “regression_pvalue”: the p-value for the difference in allele frequency between cases and controls Column 10 “odds_ratio”: the odds ratio, as calculated using logistic regression under an additive model with adjustment for the first ten principal components of ancestry

  Dataset EGAD00001008782

• Somatic_mutation_profiling_of_intestinal_crypts_from_IBD

  In this project we want to investigate the role that somatic mutations in intestinal stem cells play in IBD. We will use laser capture microdissection to ascertain epithelial cells from an individual crypts/vilus. We will extract DNA from these and use a new low-input material library prep methods to make accurate libraries for sequencing. In this pilot phase of the project we will perform 15X whole-genome sequencing of a small number of crypts biopsied from four patients. Biopsies have been taken from inflammed and noninflammed patches to compare mutation rates and mutational signatures. We will also test if crypts from inflammed patches of a single patient are clonal (either within a given inflammed patch or across inflammed patches). We will quantify the rate of cancer driver mutations in inflammed and non-inflammed crypts. 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 EGAS00001002896

• DERMATLAS__Porocarcinoma_WES

  Virtually no other tumour type is associated with so many different forms as skin cancer. Histologically, tumours of the skin may arise from epithelium, including epidermis, hair follicle, sebaceous or sweat gland, melanocytes, dermal-associated mesenchymal structures or tissue resident immune cells, making for a diversity of clinical presentations. Importantly, many skin tumour types have an extremely poor prognosis. Many skin tumour subtypes have never undergone molecular profiling, or if they have, targeted sequencing has been used and the number of cases analyzed has been so limited that deriving firm conclusions about the profile of driver genes, DNA mutational signatures and germline alleles has not been possible For 70 key skin tumour subtypes defined by the World Health Organization, that have not undergone extensive genetic analysis previoulsy, we propose to perform whole exome and transcriptome sequencing, from a range of body sites, to build a genomic atlas of dermatological tumours, including detailed maps of SNVs, copy number alterations, genome-wide methylation and expression profiles. The cases in this cohort are porocarcinomas.

  Study EGAS00001005720

• DERMATLAS__Poroma_WES

  Virtually no other tumour type is associated with so many different forms as skin cancer. Histologically, tumours of the skin may arise from epithelium, including epidermis, hair follicle, sebaceous or sweat gland, melanocytes, dermal-associated mesenchymal structures or tissue resident immune cells, making for a diversity of clinical presentations. Importantly, many skin tumour types have an extremely poor prognosis. Many skin tumour subtypes have never undergone molecular profiling, or if they have, targeted sequencing has been used and the number of cases analyzed has been so limited that deriving firm conclusions about the profile of driver genes, DNA mutational signatures and germline alleles has not been possible For 70 key skin tumour subtypes defined by the World Health Organization, that have not undergone extensive genetic analysis previoulsy, we propose to perform whole exome and transcriptome sequencing, from a range of body sites, to build a genomic atlas of dermatological tumours, including detailed maps of SNVs, copy number alterations, genome-wide methylation and expression profiles. The cases in this cohort are poromas.

  Study EGAS00001007705

• DERMATLAS__Hidradenoma_papilliferum_RNAseq

  Virtually no other tumour type is associated with so many different forms as skin cancer. Histologically, tumours of the skin may arise from epithelium, including epidermis, hair follicle, sebaceous or sweat gland, melanocytes, dermal-associated mesenchymal structures or tissue resident immune cells, making for a diversity of clinical presentations. Importantly, many skin tumour types have an extremely poor prognosis. Many skin tumour subtypes have never undergone molecular profiling, or if they have, targeted sequencing has been used and the number of cases analyzed has been so limited that deriving firm conclusions about the profile of driver genes, DNA mutational signatures and germline alleles has not been possible For 70 key skin tumour subtypes defined by the World Health Organization, that have not undergone extensive genetic analysis previoulsy, we propose to perform whole exome and transcriptome sequencing, from a range of body sites, to build a genomic atlas of dermatological tumours, including detailed maps of SNVs, copy number alterations, genome-wide methylation and expression profiles. The cases in this cohort are hidradenoma papilliferums.

  Study EGAS00001005715

• DERMATLAS__Leiomyosarcoma_RNAseq

  Virtually no other tumour type is associated with so many different forms as skin cancer. Histologically, tumours of the skin may arise from epithelium, including epidermis, hair follicle, sebaceous or sweat gland, melanocytes, dermal-associated mesenchymal structures or tissue resident immune cells, making for a diversity of clinical presentations. Importantly, many skin tumour types have an extremely poor prognosis. Many skin tumour subtypes have never undergone molecular profiling, or if they have, targeted sequencing has been used and the number of cases analyzed has been so limited that deriving firm conclusions about the profile of driver genes, DNA mutational signatures and germline alleles has not been possible For 70 key skin tumour subtypes defined by the World Health Organization, that have not undergone extensive genetic analysis previoulsy, we propose to perform whole exome and transcriptome sequencing, from a range of body sites, to build a genomic atlas of dermatological tumours, including detailed maps of SNVs, copy number alterations, genome-wide methylation and expression profiles. The cases in this cohort are leiomyosarcomas.

  Study EGAS00001007631

• DERMATLAS__Hidradenoma_papilliferum_WES

  Virtually no other tumour type is associated with so many different forms as skin cancer. Histologically, tumours of the skin may arise from epithelium, including epidermis, hair follicle, sebaceous or sweat gland, melanocytes, dermal-associated mesenchymal structures or tissue resident immune cells, making for a diversity of clinical presentations. Importantly, many skin tumour types have an extremely poor prognosis. Many skin tumour subtypes have never undergone molecular profiling, or if they have, targeted sequencing has been used and the number of cases analyzed has been so limited that deriving firm conclusions about the profile of driver genes, DNA mutational signatures and germline alleles has not been possible For 70 key skin tumour subtypes defined by the World Health Organization, that have not undergone extensive genetic analysis previoulsy, we propose to perform whole exome and transcriptome sequencing, from a range of body sites, to build a genomic atlas of dermatological tumours, including detailed maps of SNVs, copy number alterations, genome-wide methylation and expression profiles. The cases in this cohort are hidradenoma papilliferums.

  Study EGAS00001005714

• DERMATLAS__Poroma_RNAseq

  Virtually no other tumour type is associated with so many different forms as skin cancer. Histologically, tumours of the skin may arise from epithelium, including epidermis, hair follicle, sebaceous or sweat gland, melanocytes, dermal-associated mesenchymal structures or tissue resident immune cells, making for a diversity of clinical presentations. Importantly, many skin tumour types have an extremely poor prognosis. Many skin tumour subtypes have never undergone molecular profiling, or if they have, targeted sequencing has been used and the number of cases analyzed has been so limited that deriving firm conclusions about the profile of driver genes, DNA mutational signatures and germline alleles has not been possible For 70 key skin tumour subtypes defined by the World Health Organization, that have not undergone extensive genetic analysis previoulsy, we propose to perform whole exome and transcriptome sequencing, from a range of body sites, to build a genomic atlas of dermatological tumours, including detailed maps of SNVs, copy number alterations, genome-wide methylation and expression profiles. The cases in this cohort are poromas.

  Study EGAS00001005759

• DERMATLAS__Leiomyosarcoma_WES

  irtually no other tumour type is associated with so many different forms as skin cancer. Histologically, tumours of the skin may arise from epithelium, including epidermis, hair follicle, sebaceous or sweat gland, melanocytes, dermal-associated mesenchymal structures or tissue resident immune cells, making for a diversity of clinical presentations. Importantly, many skin tumour types have an extremely poor prognosis. Many skin tumour subtypes have never undergone molecular profiling, or if they have, targeted sequencing has been used and the number of cases analyzed has been so limited that deriving firm conclusions about the profile of driver genes, DNA mutational signatures and germline alleles has not been possible For 70 key skin tumour subtypes defined by the World Health Organization, that have not undergone extensive genetic analysis previoulsy, we propose to perform whole exome and transcriptome sequencing, from a range of body sites, to build a genomic atlas of dermatological tumours, including detailed maps of SNVs, copy number alterations, genome-wide methylation and expression profiles. The cases in this cohort are leiomyosarcomas.

  Study EGAS00001007628

• DERMATLAS__Porocarcinoma_RNAseq

  Virtually no other tumour type is associated with so many different forms as skin cancer. Histologically, tumours of the skin may arise from epithelium, including epidermis, hair follicle, sebaceous or sweat gland, melanocytes, dermal-associated mesenchymal structures or tissue resident immune cells, making for a diversity of clinical presentations. Importantly, many skin tumour types have an extremely poor prognosis. Many skin tumour subtypes have never undergone molecular profiling, or if they have, targeted sequencing has been used and the number of cases analyzed has been so limited that deriving firm conclusions about the profile of driver genes, DNA mutational signatures and germline alleles has not been possible For 70 key skin tumour subtypes defined by the World Health Organization, that have not undergone extensive genetic analysis previoulsy, we propose to perform whole exome and transcriptome sequencing, from a range of body sites, to build a genomic atlas of dermatological tumours, including detailed maps of SNVs, copy number alterations, genome-wide methylation and expression profiles. The cases in this cohort are porocarcinomas.

  Study EGAS00001005721

• DERMATLAS__Tubular_adenoma

  IVirtually no other tumour type is associated with so many different forms as skin cancer. Histologically, tumours of the skin may arise from epithelium, including epidermis, hair follicle, sebaceous or sweat gland, melanocytes, dermal-associated mesenchymal structures or tissue resident immune cells, making for a diversity of clinical presentations. Importantly, many skin tumour types have an extremely poor prognosis. Many skin tumour subtypes have never undergone molecular profiling, or if they have, targeted sequencing has been used and the number of cases analyzed has been so limited that deriving firm conclusions about the profile of driver genes, DNA mutational signatures and germline alleles has not been possible For 70 key skin tumour subtypes defined by the World Health Organization, that have not undergone extensive genetic analysis previoulsy, we propose to perform whole exome and transcriptome sequencing, from a range of body sites, to build a genomic atlas of dermatological tumours, including detailed maps of SNVs, copy number alterations, genome-wide methylation and expression profiles. The cases in this cohort are tubular adenomas.

  Study EGAS00001006686

• DERMATLAS__Tubular_adenoma_RNAseq

  IVirtually no other tumour type is associated with so many different forms as skin cancer. Histologically, tumours of the skin may arise from epithelium, including epidermis, hair follicle, sebaceous or sweat gland, melanocytes, dermal-associated mesenchymal structures or tissue resident immune cells, making for a diversity of clinical presentations. Importantly, many skin tumour types have an extremely poor prognosis. Many skin tumour subtypes have never undergone molecular profiling, or if they have, targeted sequencing has been used and the number of cases analyzed has been so limited that deriving firm conclusions about the profile of driver genes, DNA mutational signatures and germline alleles has not been possible For 70 key skin tumour subtypes defined by the World Health Organization, that have not undergone extensive genetic analysis previoulsy, we propose to perform whole exome and transcriptome sequencing, from a range of body sites, to build a genomic atlas of dermatological tumours, including detailed maps of SNVs, copy number alterations, genome-wide methylation and expression profiles. The cases in this cohort are tubular adenomas.

  Study EGAS00001006685

• DERMATLAS__Leiomyoma_WES

  Virtually no other tumour type is associated with so many different forms as skin cancer. Histologically, tumours of the skin may arise from epithelium, including epidermis, hair follicle, sebaceous or sweat gland, melanocytes, dermal-associated mesenchymal structures or tissue resident immune cells, making for a diversity of clinical presentations. Importantly, many skin tumour types have an extremely poor prognosis. Many skin tumour subtypes have never undergone molecular profiling, or if they have, targeted sequencing has been used and the number of cases analyzed has been so limited that deriving firm conclusions about the profile of driver genes, DNA mutational signatures and germline alleles has not been possible For 70 key skin tumour subtypes defined by the World Health Organization, that have not undergone extensive genetic analysis previoulsy, we propose to perform whole exome and transcriptome sequencing, from a range of body sites, to build a genomic atlas of dermatological tumours, including detailed maps of SNVs, copy number alterations, genome-wide methylation and expression profiles. The cases in this cohort are leiomyomas.

  Study EGAS00001007629

• DERMATLAS__Leiomyoma_RNAseq

  Virtually no other tumour type is associated with so many different forms as skin cancer. Histologically, tumours of the skin may arise from epithelium, including epidermis, hair follicle, sebaceous or sweat gland, melanocytes, dermal-associated mesenchymal structures or tissue resident immune cells, making for a diversity of clinical presentations. Importantly, many skin tumour types have an extremely poor prognosis. Many skin tumour subtypes have never undergone molecular profiling, or if they have, targeted sequencing has been used and the number of cases analyzed has been so limited that deriving firm conclusions about the profile of driver genes, DNA mutational signatures and germline alleles has not been possible For 70 key skin tumour subtypes defined by the World Health Organization, that have not undergone extensive genetic analysis previoulsy, we propose to perform whole exome and transcriptome sequencing, from a range of body sites, to build a genomic atlas of dermatological tumours, including detailed maps of SNVs, copy number alterations, genome-wide methylation and expression profiles. The cases in this cohort are leiomyomas.

  Study EGAS00001007630

• Whole-exome ultra-high throughput sequencing in brain samples of suicide victims who had suffered from major depressive disorder and control subjects who had died from other causes

  We carried out whole-exome ultra-high throughput sequencing in brain samples of suicide victims who had suffered from major depressive disorder and control subjects who had died from other causes. This study aimed to reveal the selective accumulation of rare variants in the coding and the UTR sequences within the genes of suicide victims. We also analysed the potential effect of STR and CNV variations, as well as the infection of the brain with neurovirulent viruses in this behavioural disorder. As a result, we have identified several candidate genes, among others three calcium channel genes that may potentially contribute to completed suicide. We also explored the potential implication of the TGF-β signalling pathway in the pathogenesis of suicidal behaviour. To our best knowledge, this is the first study that uses whole-exome sequencing for the investigation of suicide.

  Study EGAS00001002818

• Whole-exome ultra-high throughput sequencing in brain samples of suicide victims who had suffered from major depressive disorder and control subjects who had died from other causes.

  We carried out whole-exome ultra-high throughput sequencing in brain samples of suicide victims who had suffered from major depressive disorder and control subjects who had died from other causes. This study aimed to reveal the selective accumulation of rare variants in the coding and the UTR sequences within the genes of suicide victims. We also analysed the potential effect of STR and CNV variations, as well as the infection of the brain with neurovirulent viruses in this behavioural disorder. As a result, we have identified several candidate genes, among others three calcium channel genes that may potentially contribute to completed suicide. We also explored the potential implication of the TGF-β signalling pathway in the pathogenesis of suicidal behaviour. To our best knowledge, this is the first study that uses whole-exome sequencing for the investigation of suicide.

  Study EGAS00001003081

• Reference Profiles of ExRNAs in Normal Human Pregnancy

  In this study, we did a comprehensive exRNA profiling of plasma and serum specimens from healthy pregnant women, sampled at different gestational time points, and including subjects with diverse geographical and ethnic backgrounds. This study also contains samples from male and female healthy donors to provide a baseline. The aim of this study is to identify miRNAs that can predict the gestation age and to build a miRNA profile across gestation using small RNA-seq data.

  Study phs003182

• HELIUS cohort

  The gut microbiota composition is unique to every individual but is shaped by common factors including diet, lifestyle, medication use, early-life determinants, living environment or genetics. Most of these factors may be influenced by ethnicity. This study explored variations in fecal microbiota composition in 6048 individuals with different ethnic backgrounds living in the same geographical area (Amsterdam, the Netherlands). The HELIUS data are owned by the Amsterdam University Medical Centers, location AMC in Amsterdam, The Netherlands. To allow sharing of microbiome data collected in HELIUS with (inter)national researchers, 16s rRNA sequence analysis has been stored at the European genome-phenome archive (EGA; accession code EGAD00001004106). This requires that access needs to be granted, also because the HELIUS data are stored with relevant phenotypical variables. Access is granted to all researchers affiliated with an internationally recognized research institution who request to use the HELIUS data within the EGA context, after having signed the data transfer agreement. Any researcher can request the data by submitting a proposal to the HELIUS Executive Board as outlined at http://www.heliusstudy.nl/en/researchers/collaboration, by email: heliuscoordinator at amsterdamumc dot nl. The HELIUS Executive Board will check proposals if they do not conflict with ethical approvals and informed consent forms of the HELIUS study.

  Study EGAS00001002969

• Mechanisms on relapse after allogeneic hematopoietic cell transplantation in CMML

  Disease relapse is a major cause of treatment failure after allogeneic hematopoietic cell transplantation (HCT), and mechanisms on relapse still remain to be elucidated. We experienced a patient with chronic myelomonocytic leukemia (CMML) who underwent haploidentical HCT from his daughter and developed relapse. To understand the mechanisms on relapse after HCT, we analyze blood samples at HCT and at relapse.

  Study JGAS000317

• Genetic landscape of pediatric Adrenocortical Tumor

  Paediatric adrenocortical carcinoma is a rare malignancy with poor prognosis. Here we analyse 37 adrenocortical tumours (ACTs) by whole-genome, whole-exome and/or transcriptome sequencing. Collectively, these findings demonstrate the nature, timing and potential prognostic significance of key genetic alterations in paediatric ACT and outline a hypothetical model of paediatric adrenocortical tumorigenesis.

  Study EGAS00001000257

• Exome sequence data for germline, primary tumor, and relapse tumor of a transformed non-Hodgkins lymphoma patient with unexpected long-time remission

  The patient was diagnosed with a transformed high-grade non-Hodgkin lymphoma stage III, and treated with conventional R-CHOP (Rituximab (R), Cyclophosphamide (C), Doxorubicin (H), Vincristine (O) and Prednisone (P)). Unfortunately, she suffered from severe toxicity but recovered during the following six months remission until a biopsy verified relapse. The patient refused second line combination chemotherapy, but accepted a 3 months palliation with R and Chlorambucil. Unexpectedly, she obtained continuous complete remission and is at present >9 years after primary diagnosis.Molecular studies and data evaluation by principal component analysis, mutation screening, and copy number variations of the primary and relapsed tumor, identified patterns of branched lymphoma evolution, most likely diverging from an unknown in situ follicular lymphoma.

  Study EGAS00001001973

• Genome-Wide Association of Native and Post Aspirin Platelet Function Phenotypes

  The goal of this study was to identify genetic variants in a genome-wide association study (GWAS) that are associated with previously obtained platelet function phenotypes measured in each individual under baseline conditions and following 2 weeks of low dose aspirin (ASA). During this study we performed a high density 1 million-SNP genome scan on subjects from GeneSTAR (representing 800 2-generational families with a family history of premature coronary artery disease, 60% white and 40% African American, N=3232). We identified genomic loci associated with quantitative platelet phenotypes prioritized for their biological interest, determined associations between genomic loci and baseline platelet phenotypes (primary phenotypes are platelet aggregation in platelet rich plasma induced by collagen, adenosine diphosphate (ADP), arachidonic acid (AA), and epinephrine (Epi), determined associations between genomic loci and post-ASA platelet phenotypes, ie, measures of ASA "resistance" (primary phenotypes are as above, plus urinary levels of the prostaglandin metabolite, 11-dehydro-thromboxane B2 ), and compared peaks of association between genomic loci and three common baseline platelet phenotypes (collagen-, epinephrine-, and ADP-induced aggregation in platelet rich plasma) with associations found for these same phenotypes in the Framingham Heart Study. We also determined whether any significant genotype-phenotype associations in the 1 million SNP genome scan could be localized to any specific genes or potential genes of interest using publicly available databases and further examined whether candidate genes previously associated with a specific platelet phenotype are located in a genomic region of interest as determined from the SNP genome scan. We conducted replications of our findings, and are presently involved in larger scale meta-analysis of findings for pre-aspirin and post-aspirin associations. The study population is constituted of full siblings (SIBS) (ages 35-78 years) identified from The Johns Hopkins Sibling Study, now called GeneSTAR, the spouses of the SIBS, and their adult offspring (>21 years of age). They include 3200 individuals from approximately 300 African American and 500 white extended families. "Spouse" refers to the other parent of any SIB offspring, independent of marital status. Sibship sizes among families range from 1 to 16 (excluding index cases). On average, each SIB has 2 potentially eligible offspring. A family for this study is defined by all of the full sibships and the total numbers of offspring that come from all SIBS, rather than just the nuclear family.

  Study phs000375

• Stromal-induced epithelial-mesenchymal transition induces drug resistance in acute lymphoblastic leukemia

  Bone marrow (BM) microenvironment-induced drug resistance in acute lymphoblastic leukemia (ALL) is thought to be mediated by intercellular interaction of leukemic cells with BM niches, but the mechanistic basis of resistance is poorly understood. Here, we genomic and functional analyses, we show that ALL-BM mesenchymal stromal cells (MSC) interactions encompass direct cell-cell adhesion via integrin α4β1, uni-directional secretion of soluble factors from MSC to ALL, and bidirectional transfer of cellular vesicles through tunneling nanotubes. We show that this crosstalk drives an epithelial-mesenchymal transition (EMT)-like program in ALL cells adhering to MSC, thereby triggering stem cell-like features including drug resistance and survival advantage. Moreover, single-cell RNA sequencing of cell line and primary ALL samples identified a hybrid cell state derived from B-ALL adhered to MSC, that exhibits both B-ALL and MSC gene signatures that are orchestrated by an EMT-like program. Multiple EMT-activating pathways including WNT/β-catenin, cytokine/STAT3, TGFβ, NOTCH1, and NF-κB-dependent signaling pathways are activated in MSC-adherent ALL cells; however, only the inhibition of either WNT/β-catenin or cytokine/STAT3 pathway could attenuate the survival and drug resistance of ALL cells adherent to MSC. Notably, we identified that this hybrid cell state exhibited elevated WNT/β-catenin-mediated transcriptional activity. Finally, we show that blocking of the interaction of β-catenin and CBP interaction abrogates the survival and drug resistance of ALL cells adhered to MSC, indicating that targeting of an EMT-like program is potential therapeutic regimen in targeting cell extrinsically acquired drug resistance in ALL.

  Study EGAS00001006120

• Chracterising cellur pathways underlying CD3/CD28 activation of human CD4+ cells

  We devised an approach to disentangle the TCR and CD28 pathways upon stimulation in naive and memory primary human CD4+ T cells (Tcons) in response to defined stimulatory signals. Isolated memory and naïve T cells were activated using anti-CD3, anti-CD28 or both in combination. As a control we cultured cells in the same conditions but without the stimuli. We carried Chipmentation using the H3K27ac antibody on 200,000 cross-linked cells. 1) 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 please see http://www.sanger.ac.uk/datasharing/ .

  Dataset EGAD00001006611

• CD36 defines CML cells less sensitive to imatinib

  Tyrosine kinase inhibitors (TKIs) are highly effective for treatment of chronic myeloid leukemia (CML), but very few patients are cured. Major drawbacks with TKIs are their low efficacy in eradicating the leukemic stem cells responsible for disease maintenance and relapse upon TKI cessation. Here, we performed RNA-sequencing of flow-sorted primitive (CD34+CD38low) and progenitor (CD34+CD38+) chronic phase CML cells and identified transcriptional upregulation of 32 cell surface molecules relative to corresponding normal bone marrow cells. Focusing on novel markers with increased expression on primitive CML cells, we confirmed upregulation of the scavenger receptor CD36 and the leptin receptor (LEPR) by flow cytometry. We also delineate a subpopulation of primitive CML cells expressing CD36 that is less sensitive to imatinib treatment. Using CD36 targeting antibodies, we show that the CD36 positive cells can be targeted and killed by antibody dependent cellular cytotoxicity (ADCC). In summary, CD36 defines a subpopulation of primitive CML cells with decreased imatinib sensitivity that can be effectively targeted by ADCC using an anti-CD36 antibody.

  Study EGAS00001002421

• TONIC-Trial-cfDNA-Project

  Cell-free DNA (cfDNA) is an emerging technology to predict and monitor response to cancer treatment, including immune checkpoint blockade (ICB). However, data on cfDNA dynamics during ICB in metastatic triple negative breast cancer (mTNBC) are limited. While most applications of cfDNA involve assays that focus on mutation detection, mTNBC and multiple other cancer types are driven by copy number alterations (CNAs). We evaluate cfDNA-based copy number profile abnormality (CPA) score as a potential biomarker for monitoring ICB response in mTNBC, analyzing data from 87 patients enrolled in stage 1 and stage 2 of the TONIC-trial. We find significant concordance between cfDNA-based and tissue-based CNA profiles. Additionally, responders show a decrease in CPA scores upon ICB at week 6 (3 cycles of nivolumab). These findings underscore the potential of cfDNA-based CNA dynamics as a non-invasive biomarker for ICB early response assessment in patients with mTNBC.

  Study EGAS50000001308

• Imaging: Hispanic Community Health Study/Study of Latinos (HCHS/SOL)

  The Hispanic Community Health Study/Study of Latinos (HCHS/SOL) is a multi-center epidemiologic study in Hispanic/Latino populations to determine the role of acculturation in the prevalence and development of disease, and to identify risk factors playing a protective or harmful role in Hispanics/Latinos. The study is sponsored by the National Heart, Lung, and Blood Institute (NHLBI) and six other institutes, centers, and offices of the National Institutes of Health (NIH). The goals of the HCHS/SOL include studying the prevalence and development of disease in Hispanics/Latinos, including the role of acculturation, and identifying disease risk factors that play protective or harmful roles in Hispanics/Latinos. A total of 16,415 persons of Cuban, Dominican, Mexican, Puerto Rican, Central American, and South American backgrounds were recruited through four Field Centers affiliated with San Diego State University, Northwestern University in Chicago, Albert Einstein College of Medicine in the Bronx area of New York, and the University of Miami. Seven additional academic centers serve as scientific and logistical support centers. Study participants aged 18-74 years took part in an extensive clinic exam and assessments to ascertain socio-demographic, cultural, environmental and biomedical characteristics. Annual follow-up interviews are conducted to determine a range of health outcomes.

  Study phs003963

• Circulating tumour DNA (ctDNA) data of High Grade Serous Ovarian Cancer Patients

  This study contains circulating tumour DNA (ctDNA) data derived from longitudinal plasma samples of High Grade Serous Ovarian Cancer (HGSC) patients belonging to the DECIDER study (NCT04846933). Ovarian cancer kills more than 40 000 women in Europe each year, and HGSC is the most common and most difficult to treat subtype of this disease. This study contains different sequencing datasets with samples from different stages during the treatment of the patients.

  Study EGAS50000000674

• Oral microbiome metagenomic sequencing - Human Phenotype Project (HPP)

  This study characterizes the oral microbiome of participants enrolled in the Weizmann Institute Human Phenotype Project (HPP), a longitudinal cohort study. Oral swab samples were collected and subjected to shallow whole-genome sequencing using the Gencove low-pass sequencing platform. Raw reads include residual human host sequences in addition to microbial sequences. The dataset comprises metagenomic FASTQ files from [N] participants. Data access is restricted in accordance with participant informed consent and Weizmann IRB approval

  Study EGAS50000001763

• Clonal_selection_after_gene_therapy_in_SCD___Duplex_sequencing

  This study includes the targeted duplex sequencing data relating to this study. A custom targeted panel was used including 29 AML-associated genes, and a set of mutations from driver-containing clones that were sequenced during the WGS tree-building phase of the study. Targeted sequencing is performed on each of 6 individuals included at the study at at least 3 time points per individual: one prior to gene therapy, and two post-therapy time points.

  Study EGAS00001007253

• Illumina GSA-MD v3 genotyping arrays for 183 samples

  Genotyping arrays for 183 samples from patients with a neuroendocrine tumor of the small intestine. All samples have been hybridized on Illumina GSA-MD v3 arrays with standard automated protocols. Reading of the chips was performed on Illumina iScan+ scanners and this file is the result of primary analysis done using Illumina GenomeStudio software. It contains data for 147 tumors, 2 adenomas, 1 lymph node, 19 mesenteric nodules, 6 liver metastasis and 8 normal ileum samples.

  Dataset EGAD50000000905

• A Phase I/II Trial of T Cell Receptor Gene Therapy Targeting HPV-16 E7 for HPV-Associated Cancers

  This is a phase I clinical trial testing the safety and efficacy of gene-engineered T cells expressing a T-cell receptor targeting an HLA-A*02:01-restricted epitope of HPV-16 E7 (E7 TCR T cells) in patients with metastatic HPV-16+ epithelial cancers. A total of 12 patients were treated. The maximum tested dose was tolerated. Side effects were most consistent with the expected toxicities of the lymphocyte-depleting conditioning regimen and high-dose aldesleukin. Six of the 12 patients demonstrated objective clinical responses. Translational studies of the infused T cell characteristics did not correlate strongly with clinical response. Genomic defects in the targeted peptide-HLA complex did demonstrate definitive mechanisms of resistance in some patients.

  Study phs002286

• Kidney_tumour_RNA

  This is a bulk DNA and RNA sequencing study of human renal tumours

  Study EGAS00001002487

• Clonal evolution in myeloma: the impact of maintenance lenalidomide and depth of response on the genetics and sub-clonal structure of relapsed disease in uniformly treated newly diagnosed patients

  The emergence of treatment resistant sub-clones is a key feature of relapse in multiple myeloma. Therapeutic attempts to extend remission and prevent relapse include the maximisation of response and use of maintenance therapy. We used whole exome sequencing to study the genetics of paired presentation and relapse samples from 56 newly diagnosed patients, following induction therapy, randomised to receive either lenalidomide maintenance or observation as part of the Myeloma XI trial. Patients included were considered high risk, relapsing within 30 months of maintenance randomisation. Patients achieving a complete response had predominantly branching evolutionary patterns leading to relapse, characterised by a greater mutational burden, an altered mutational profile, bi-allelic inactivation of tumour suppressor genes, and acquired structural aberrations. Conversely, in patients achieving a partial response the evolutionary features were predominantly stable with a similar mutational and structural profile. There were no significant differences between patients relapsing after maintenance lenalidomide vs observation. This study shows that the depth of response is a key determinant of the evolutionary patterns seen at relapse.

  Study EGAS00001003539

• Deep intronic homozygous variation in PSMC3 causes a syndromic neurosensory disorder combining deafness and cataract

  The association of congenital deafness and early-onset cataracts inherited as a recessive trait is a rare combination described in only a few syndromes with very few genes identified to date. We propose that the PSMC3 proteasome subunit dysfunction leads to a novel human syndrome that includes early-onset cataracts and deafness and suggest that Rpt5 plays a major role in inner ear and lens development.

  Study EGAS00001003942

• GENETIC HISTORY OF ITALY

  Recent scientific literature has highlighted the relevance of population genetic studies both for disease association-mapping in admixed populations and for understanding the history of human migrations. Deeper insight into the history of Italian population is critical for understanding the peopling of Europe. Because of its crucial position at the centre of the Mediterranean basin, the Italian peninsula has experienced a complex history of colonization and migration, whose genetic signatures are still present in contemporary Italians. In this study, we investigated genomic variation in the Italian population using 2.5 million single nucleotide polymorphisms (SNPs) in a sample of more than 300 unrelated Italian subjects with well-defined geographical origins. We combined several analytical approaches to interpret genome-wide data on 1,272 individuals from European, Middle Eastern, and North African populations. We detected three major ancestral components contributing different proportions across the Italian peninsula, and signatures of continuous gene flow within Italy, which has produced remarkable genetic variability among contemporary Italians. In addition, we have extracted novel details about the Italian population’s ancestry: we identified genetic signatures of major historical events in Europe and the Mediterranean basin from the Neolithic (e.g., peopling of Sardinia) to recent times (e.g., ‘barbarian invasion’ of Northern and Central Italy). These results are valuable for further genetic, epidemiological and forensic studies in Italy and in Europe.

  Study EGAS00001001458

• Sarcopenia related to Head and Neck squamous cell carcinomas: transcriptome modifications of muscle cells induced by distant malignant cells

  The biological mechanisms of sarcopenia are still very poorly understood, particularly in the case of Head and Neck Squamous Cell Carcinomas (HNSCC). However, there is good reason to believe that diffusible factors originating from tumor cells exert a distant deleterious effect on muscle cells. To test this hypothesis we implemented a dual approach based both on experiments carried out in vitro and on the study of muscle fragments from patients.

  Study EGAS50000000669

• Dual-mTOR inhibitor Rapalink-1 reduces prostate cancer patient-derived xenograft growth and alters tumor heterogeneity

  Bone metastasis is the leading cause of prostate cancer (PCa) mortality, frequently marking the progression to castration-resistant PCa. In this study, we compared the molecular pathways enriched in a set of bone metastasis from breast and prostate cancer from snap-frozen tissue. To further model PCa drug resistance mechanisms, we used two patient-derived xenografts (PDX) models of bone-metastatic PCa, BM18 and LAPC9.

  Study EGAS00001004431

• Assessment of genetic and epigenetic variation in human IPS cells

  In order to progress human induced pluripotent stem cells (hiPSCs) towards the clinic, several outstanding questions must be addressed. It is possible to reprogram different somatic cell types into hiPSCs but it is unlcear whether some cell types carry through fewer mutations through reprogramming (either due to mutations present in the primary cells, or mutations accumulated during reprogramming). Through in depth analysis of hiPSCs generated from different somatic cells, it will be possible to assess the variation in genetic stability of different cell types.

  Dataset EGAD00001000384

• Analysis of genes associated with autistic spectrum disorder, schizophrenia, and bipolar disorder.

  Autism spectrum disorders (ASD) represent a heterogeneous group of neurodevelopmental disorders with strong genetic predispositions. Although an increasing number of genetic variants have been implicated in the pathogenesis of ASD, little is known about the relationship between ASD-associated genetic variants and individual ASD traits. We performed case-control association study of 32 Japanese children with ASD (mainly with high-functioning autism) and 36 with typical development.

  Study JGAS000731

• Analysis of tumor periphery and center-specific mutations in renal cell carcinoma

  Renal cell carcinoma (RCC) is a genomically heterogeneous tumor. In the present project, the question whether intratumoral heterogeneity follows a zonal pattern indicating spatial niches was addressed. Whole exome sequencing of 16 paired samples from tumor periphery and center revealed a number of region-specific functional SNVs and Indels. Therefore, RCCs are not composed of evenly admixed tumor cells but show topological differences in their clonal composition.

  Study EGAS00001001784

• Extracorporeal Life Support Survival in a Pediatric Hematopoietic Cellular Transplant Recipient with Presumed Graft Versus Host Disease-Related Fulminant Myocarditis

  We report the case of a 15-year-old female with hypodiploid pre-B acute lymphoblastic leukemia status post allogeneic hematopoietic stem cell transplantation (HCT) from a matched unrelated male donor who presented on transplant day +75 with cardiac arrest due to ventricular fibrillation associated with fulminant myocarditis. Using conventional diagnostics, an exhaustive search for microbial pathogens in the heart biopsy as well as nasopharynx, blood, urine, and endotracheal aspirate was performed but did not uncover a candidate pathogen. The family consented to a research study for the use of unbiased next-generation genomic sequencing for pathogen identification in the myocardial biopsy. DNA sequencing was performed on 1.5 x 108 sequencing pairs and no microbial pathogens were identified. Interestingly, a significant component of Y-chromosomal human DNA was identified, suggesting infiltration of at least 10 donor leukocytes per host cell. This finding is grossly consistent with the lymphocyte:myocyte ratio in the biopsy according to visual inspection at 40x magnification. This case merits discussion due to (1) her survival after 17 days of veno-arterial extracorporeal life support (ECLS) and (2) the possibility of cardiotropic graft versus host disease (GVHD).

  Study phs001336

• Temptation Resistance Failures: Transdiagnostic Features and Influences

  Multiple forms of psychopathology involve problems with resisting temptations and urges. This study utilizes experience sampling (ES) methodology to assess temptation resistance across different classes of temptations and urges including both common everyday temptations and more disorder-specific temptation classes. The study tests the hypothesis that the broad ability to successfully resist temptations and urges across temptation classes is a common features of the externalizing superspectrum (factor) of psychopathology, particularly the disinhibition spectra as defined by the Hierarchical Taxonomy of Psychopathology (HiTOP). Additional associations are expected to arise between reduced temptation resistance success for specific temptation classes and narrower symptom domains associated with the externalizing and internalizing spectra (e.g., binge eating, and nonsuicidal self-harm among internalizing symptoms). The study further tests genetic and environmental influences on temptation strength and resistance ability with a focus on polygenic scores, adverse childhood experiences and childhood neighborhood deprivation variables that have previously been related to externalizing. To address these issues, we will study up to 1200 subjects (minimum 1000) selected with enrichment for psychopathology. Subjects will be recruited from a combination of ResearchMatch, and targeted contact with Reddit groups, and targeted social media/online advertisements, with targeted recruitment of at least 150 subjects who indicate problems with SUD, alcohol use disorder (AUD) or nicotine dependence, 70 who indicate problems with gambling or other impulse control problems, 70 subjects with criminal/legal problems, and 70 subjects based on binge eating episodes 70 with self-injurious behavior, and 70 with obsessive-compulsive disorder. Subjects will complete the (Externalizing Spectrum Inventory-BF and HiTOP-SR) to measure externalizing and internalizing spectra. Diagnoses in key categories will be confirmed with structured diagnostic interviews. Subjects also complete information on childhood adversity and geocoding is used to assess environment during development. The two-week ES regimen collects data on the strongest types of temptations and urges experienced by the subject, their subjective strength, the goal of the urge (pleasure/relief from negative feelings), the level of conflict with other goals, whether the person attempted to resist the temptation, the resistance strategy, and resistance success, to allow assessment of the extent to which differences in each of these facets (and calculated temptation resistance efficacy) are related to narrow or broad dimensions of psychopathology. Whole genome sequencing with .5x coverage and imputation will be performed to allow generation of polygenic scores for externalizing and addiction in order to test the hypothesis that externalizing polygenic scores are related to poor temptation resistance efficacy across temptation classes.

  Study phs004064

• Genomic Analysis of Paired Endometrial Cancer Primaries and Metastases

  Formation of metastases is the major cause of cancer related deaths. Recent studies have sequenced primary endometrial carcinomas yielding data for a single entity in the progression from the birth of a progenitor tumor cell to metastatic disease. However, the progression of these tumors to metastases has not been characterized. We performed whole-exome sequencing of 98 tumor biopsies including complex atypical hyperplasias, primary tumors and paired abdominopelvic metastases to survey the evolutionary landscape of endometrial cancer. We expanded and reanalyzed TCGA-data, identifying novel recurrent alterations in primary tumors, including mutations in the estrogen receptor cofactor NRIP1 in 12% of patients. We found that likely driver events tended to be shared by primary and metastatic tissue-samples, with notable exceptions such as ARID1A mutations. Phylogenetic analyses in cases with multiple metastases indicated these metastases typically arose from one lineage of the primary tumor. These data indicate extensive genetic heterogeneity within endometrial cancers and relative homogeneity across metastatic sites.

  Study phs001127

• Evolution of the African pygmy phenotype

  The evolutionary history of the human ‘pygmy’ phenotype (small body size), a characteristic of African and Southeast Asian rainforest hunter-gatherers, is largely unknown. Here we use a genome-wide admixture mapping analysis to identify 16 genomic regions that are significantly associated with the pygmy phenotype in the Batwa, a rainforest hunter-gatherer population from Uganda (East Central Africa). The identified genomic regions have multiple attributes that provide supporting evidence of genuine association with the pygmy phenotype, including enrichments for SNPs previously associated with stature variation in Europeans and for genes with growth hormone receptor and regulation functions. To test adaptive evolutionary hypotheses we computed the haplotype-based iHS statistic and the level of population differentiation (FST) between the Batwa and their agricultural neighbors, the Bakiga, for each SNP. Both |iHS| and FST values were significantly higher for SNPs within the Batwa pygmy phenotype-associated regions than the remainder of the genome, a signature of polygenic adaptation. In contrast, when we expanded our analysis to include Baka rainforest hunter-gatherers from Cameroon and Gabon (West Central Africa) and Nzebi and Nzime neighboring agriculturalists, we did not observe elevated |iHS| or FST values in these genomic regions. Together, these results suggest adaptive and at least partially convergent origins of the pygmy phenotype even within Africa, supporting the hypothesis that small body size confers a selective advantage for tropical rainforest hunter-gatherers but raising questions about the antiquity of this behavior.

  Study EGAS00001000908

• Understand Paratyphoid Disease - host responses to human challenge with S. Paratyphi A (2019-08-28)

  This project aims to evaluate the transcriptional response to disease measured in whole blood of participants who developed enteric fever after challenge and, importantly, those who were challenged but stayed well throughout the challenge period. This data will provide unique coverage of the transcriptome and will yield invaluable insight after integration with a wealth of clinical data collected during this trial. 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/ . This dataset contains all the data available for this study on 2019-08-28.

  Dataset EGAD00001005298

• Natural history of clonal haematopoiesis (2017-09-04)

  The incidence of acute myeloid leukemia (AML) increases with age and mortality exceeds 90% when diagnosed after age 60. Only 10-15% of cases evolve from a pre-existing myeloproliferative or myelodysplastic disorder; the remaining cases arise de novo without a detectable prodrome and are diagnosed upon development of bone marrow failure. Analysis of diagnostic blood samples has demonstrated that de novo AML is preceded by the accumulation of somatic mutations in pre-leukemic hematopoietic stem and progenitor cells (preL-HSPCs) that subsequently undergo clonal expansion. If individuals in this pre-leukemic phase could be identified, methods for determination of risk and monitoring for progression to overt AML could be developed. However recurrent AML mutations also accumulate during aging in healthy individuals who never develop AML, referred to as age related clonal hematopoiesis (ARCH). To distinguish individuals with preL-HSPCs at high risk of developing AML from those with ARCH, we undertook deep targeted sequencing of genes recurrently mutated in AML in blood samples from 133 individuals in the European Prospective Investigation into Cancer and Nutrition (EPIC) study taken on average 6 years before they developed AML (pre-AML group), together with 683 matched healthy individuals (Control group). Pre-AML cases displayed accelerated age-correlated accumulation of somatic mutations.The identity, number and variant allele frequency (VAF) of mutations differed between the two groups, and were incorporated into a computational model of AML risk prediction that accurately distinguished pre-AML cases from controls on average 7 years prior to AML development. Our findings provide proof of concept that early prediction of AML development is feasible in high-risk populations, paving the way for early disease detection, monitoring, and potentially prevention.

  Dataset EGAD00001003703

• Genentech Colon Cancer Screen

  Identifying and understanding changes in cancer genomes is essential for the development of targeted therapeutics. Here we analyse systematically more than 70 pairs of primary human colon tumours by applying next-generation sequencing to characterize their exomes, transcriptomes and copy-number alterations. We have identified 36,303 protein-altering somatic changes that include several new recurrent mutations in the Wnt pathway gene TCF7L2, chromatin-remodelling genes such as TET2 and TET3 and receptor tyrosine kinases including ERBB3. Our analysis for significantly mutated cancer genes identified 23 candidates, including the cell cycle checkpoint kinase ATM. Copy-number and RNA-seq data analysis identified amplifications and corresponding overexpression of IGF2 in a subset of colon tumours. Furthermore, using RNA-seq data we identified multiple fusion transcripts including recurrent gene fusions involving R-spondin family members RSPO2 and RSPO3 that together occur in 10% of colon tumours. The RSPO fusions were mutually exclusive with APC mutations, indicating that they probably have a role in the activation of Wnt signalling and tumorigenesis. Consistent with this we show that the RSPO fusion proteins were capable of potentiating Wnt signalling. The R-spondin gene fusions and several other gene mutations identified in this study provide new potential opportunities for therapeutic intervention in colon cancer.

  Study EGAS00001000288

• DAC for study CMMRD–associated high-grade glioma

  This Data Access Committee (DAC) is responsible for de-identified, summarized somatic variant call data derived from paired tumor–blood Whole-exome sequencing of human samples in a glioma research study. Access requests are approved without additional restrictions and are granted solely for health-related research purposes.

  Dac EGAC50000000855

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

  This dataset is an Emirati telomere-to-telomere (T2T) pangenome graph in GBZ format built from 116 haplotype-resolved assemblies spanning 58 individuals (28 trio-based and 30 single-sample assemblies). Assemblies were generated with long-read sequencing (PacBio HiFi and ONT ultra-long) with standard polishing, then integrated into a graph representation. The genomes show high contiguity (median ≈150 Mb) and high consensus accuracy (median QV 59). The resulting GBZ graph captures globally shared and Emirati-enriched variation, including sequence in complex regions, and serves as a population-matched reference for downstream variant discovery and annotation.

  Dataset EGAD50000001756

• Chromosomal copy number heterogeneity predicts survival rates across cancers

  Survival rates of cancer patients vary widely within and between malignancies. While genetic aberrations are at the root of all cancers, individual genomic features cannot explain these distinct disease outcomes. In contrast, intra-tumour heterogeneity (ITH) has the potential to elucidate pan-cancer survival rates and the biology that drives cancer prognosis1,2. Unfortunately, a comprehensive and effective framework to measure ITH across cancers is missing3. Here, we introduce a scalable measure of chromosomal copy number heterogeneity that predicts patient survival across cancers. We show that the level of ITH can be derived from a single-sample copy number profile. Using gene-expression data we demonstrate that ongoing chromosomal instability underlies the observed heterogeneity. Analysing 11,534 primary cancer samples from 35 different malignancies, we find that copy number heterogeneity can be accurately deduced and predicts cancer survival across tissues of origin and stages of disease. Our results provide a unifying molecular explanation for the different survival rates observed between cancer types.

  Study EGAS00001004702

• Raw RNA-seq data for clinical efficacy and biomarker analysis of neoadjuvant atezolizumab in operable urothelial carcinoma in the ABACUS trial

  ABACUS is a single arm phase 2 study that investigated 2 cycles of atezolizumab (1200mg Q3) prior to cystectomy in 95 patients with muscle invasive transitional cell cancer (T2-4N0M0). Pathological complete response (pCR) occurring in ≥20% of patients was the primary endpoint. Biomarker analysis on sequential tissue was a co-primary endpoint. This dataset includes the raw RNA-seq data.

  Dataset EGAD00001006205

• ATAC-seq of metastatic prostate tumors

  This dataset includes Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq) data, in FASTQ format, from 70 metastatic castration-resistant prostate cancer tumor samples from the SU2C/PCF West Coast Dream Team (WCDT) project. The sequencing data is paired-end, 150 bp sequencing data from an Illumina NovaSeq 6000 machine. ATAC-seq libraries were prepared following the protocol described in Buenrostro et al. Nature Methods. 2013 (PMID: 24097267) and Corces et al. Nature Methods. 2017 (PMID: 28846090).

  Dataset EGAD00001009654

• Developmental Mechanisms of Human Congenital Heart Disease in Subjects with 22q11.2 Deletion Syndrome (DiGeorge Syndrome/Velocardiofacial Syndrome)

  The study is designed to identify genetic modifiers of cardiovascular defects in subjects with 22q11.2 deletion syndrome (22q11.2DS), also known as DiGeorge syndrome or velo-cardio-facial syndrome. Affymetrix 6.0 arrays were processed on 1,480 subjects with known cardiovascular anomalies or with normal structures, all with 22q11.2DS. One sample is a duplicate so it was removed. There are 1,472 samples total of unrelated, de-identified, probands. Over 90% have the same sized 3 million base pair deletion flanked by low copy repeats (LCR22) A and D, while approximately 6% have nested A to B deletions. The rest have other nested deletions, that include a deletion in the vicinity of TBX1 (between LCR22 A and B). A subset of the data was used to identify copy number variations serving as modifiers. Some data were previously published by Dr. Emanuel's team at Children's Hospital of Philadelphia in PA, USA (PMID:26742502; PMID:4896312; PMID:25892112; PMID:4570279). The de-identified DNA data from unrelated subjects come from multiple research sites in the US and Europe as part of the International 22q11.2 Consortium and the International 22q11.2 Brain and Behavior Consortium.

  Study phs001339

• Acral Melanoma PDXs from the admixed Brazilian Population - Patient Derived Xenograft samples VCF files with somatic SNV and INDELs - Whole exome sequencing data

  Raw, flagged and annotated VCF files with somatic calls made with CavEMan and Pindel for Patient Derived Xenograft samples. Variant effect prediction was run with Ensembl VEP v103. 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 EGAD00001015749

• Accurate sample assignment in a multiplexed, ultra-sensitive, high-throughput sequencing assay for minimal residual disease

  High throughput sequencing (HTS) (next generation sequencing) of the rearranged immunoglobulin and T-cell receptor genes promises to be cheaper and more sensitive than current methods for monitoring minimal residual disease (MRD) in patients with acute lymphoblastic leukemia. However, adoption of new approaches by clinical laboratories requires careful evaluation of all potential sources of error and the development of strategies to ensure the highest accuracy. Timely and efficient clinical use of HTS platforms will depend on combining multiple samples (multiplexing) in each sequencing run. Here we examine immunoglobulin heavy chain gene HTS on the Illumina MiSeq platform for MRD (HTS-MRD). We identify errors associated with multiplexing that could potentially impact on the accuracy of MRD analysis. We optimise a strategy combining high purity, sequence-optimised oligonucleotides, dual-indexing and an error-aware demultiplexing approach to minimise errors and maximise sensitivity. We present a probability-based demultiplexing pipeline, Error-Aware Demultiplexer (EAD) - that is suitable for all MiSeq sequencing strategies and accurately assigns samples to the correct identifier without excessive loss of data. Finally using controls quantified by digital PCR, we show that HTS-MRD can accurately detect as few as 1 in 106 copies of specific leukemic MRD.

  Study EGAS00001001303

• CRC organoid RNA-seq data access committee

  This DAC is responsible for granting access to RNA-seq data (paired-end FASTQ files) from 10 patient-derived colorectal cancer organoid patients. The data was ad hoc generated as part of the development of NovumRNA, a non-canonical tumor-specific antigen prediction pipeline.

  Dac EGAC50000000406

• Neuroblastoma relapse trio series from the AMC

  The majority of neuroblastoma patients have tumors that initially respond to chemotherapy, but a large proportion of patients will experience therapy-resistant relapses. The molecular basis of this aggressive phenotype is unknown. Whole genome sequencing of 23 paired diagnostic and relapsed neuroblastomas showed clonal evolution from the diagnostic tumor with a median of 29 somatic mutations unique to the relapse sample. Eighteen of the 23 relapse tumors (78%) showed RAS-MAPK pathway mutations. Seven events were detected only in the relapse tumor while the others showed clonal enrichment. In neuroblastoma cell lines we also detected a high frequency of activating mutations in the RAS-MAPK pathway (11/18, 61%) and these lesions predicted for sensitivity to MEK inhibition in vitro and in vivo. Our findings provide a rationale for genetic characterization of relapse neuroblastoma and show that RAS-MAPK pathway mutations may function as a biomarker for new therapeutic approaches to refractory disease.

  Dataset EGAD00001001360

• HudsonAlpha Long Read Sequencing Data of Individuals with Rare Suspected Genetic Conditions

  The data included in this project were generated from several IRB projects focused on the identification of the underlying genetic cause of undiagnosed rare conditions in infants, children and adults enrolled across the southeastern United States. Long read genome sequencing was performed on DNA samples collected as part of an IRB-approved study and findings from this testing was returned to enrolled study participants and the clinical team providing care. Proband participants in these studies were enrolled in both inpatient (neonatal intensive care units) and outpatient settings. When possible, biological relatives (including both biological parents) were also enrolled to help clarify inheritance of variants identified. Sequencing and analysis for SouthSeq is conducted at the HudsonAlpha Institute for Biotechnology in Huntsville, Alabama (https://www.hudsonalpha.org/). Results of testing are disclosed to participants by genetic counselors or trained non-genetics providers who also facilitate sharing of results with the participants' medical care teams when appropriate. Further, participant families may choose to opt-into return of secondary findings identified in the proband, which focus on pathogenic and likely pathogenic variation identified within the current ACMG gene list.

  Study phs003537

• Whole exome sequencing and methylation profiling of uveal melanoma

  Uveal melanoma (UM) is the most common primary cancer of the eye and frequently leads to metastatic death. Metastatic risk can be stratified into low, intermediate and high based on the presence of mutually exclusive mutations in EIF1AX, SF3B1 and BAP1, respectively. The purpose of this study was to comprehensively profile the genetic aberrations in a set of primary uveal melanomas using whole exome sequencing, as well as DNA methylation profiling of selected samples, to improve understanding of its pathogenesis.

  Study phs001421

• The Incidence of Thromboembolic Events in Patients with Antibodies to Heparin-PF4 after Cardiac Bypass

  The purpose of this study is to determine how often heart surgery patients who receive heparin develop an immune response (heparin-induced thrombocytopenia) that leads to clots forming in different parts of the body. These clots usually occur in the legs (deep venous thrombosis or DVT) or lungs (pulmonary embolism or PE) or cause heart attacks (myocardial infarction or MI) and strokes.

  Study phs000606

• Genome-wide DNA methylation sequencing identifies epigenetic perturbations in the upper airways under long-term exposure to moderate levels of ambient air pollution

  While the link between exposure to high levels of ambient particulate matter (PM) and increased incidences of respiratory and cardiovascular diseases is widely recognized, recent epidemiological studies have shown that low PM concentrations are equally associated with adverse health effects. As DNA methylation is one of the main mechanisms by which cells regulate and stabilize gene expression, changes in the methylome could constitute early indicators of dysregulated signaling pathways. So far, little is known about PM-associated DNA methylation changes in the upper airways, the first point of contact between airborne pollutants and the human body. Here, we focused on cells of the upper respiratory tract and assessed their genome-wide DNA methylation pattern to explore exposure-associated early regulatory changes. Using a mobile epidemiological laboratory, nasal lavage samples were collected from a cohort of 60 adults that lived in districts with records of low (Simmerath) or moderate (Stuttgart) PM10 levels in Germany. PM10 concentrations were verified by particle measurements on the days of the sample collection and genome-wide DNA methylation was determined by enzymatic methyl sequencing at single-base resolution. We identified 231 differentially methylated regions (DMRs) between moderately and lowly PM10 exposed individuals. A high proportion of DMRs overlapped with regulatory elements, and DMR target genes were involved in pathways regulating cellular redox homeostasis and immune response. In addition, we found distinct changes in DNA methylation of the HOXA gene cluster whose methylation levels have previously been linked to air pollution exposure but also to carcinogenesis in several instances. The findings of this study suggest that regulatory changes in upper airway cells occur at PM10 levels below current European thresholds, some of which may be involved in the development of air pollution-related diseases.

  Study EGAS00001007374

• Prematurity and Respiratory Outcome Program: Clinical Research Center Study of Functional and Lymphocytic Markers of Respiratory Morbidity in Hyperoxic Preemies

  Approximately 550,000 babies born prematurely each year in the United States suffer from birth at a time in development when the respiratory tract and immune system would normally be protected and maintained in a naïve state. This project is a component of the NIH Prematurity and Respiratory Outcomes Program (PROP) whose goals are the identification of disease mechanisms and biomarkers to stratify premature infants, at the time of discharge, for their risk of subsequent pulmonary morbidity. This Clinical Research Center (CRC) project will investigate prematurity-dependent alterations in cellular innate and adaptive immune systems resulting in increased susceptibility to respiratory infections and environmental irritants, and leading to respiratory morbidity in the first year of life. Prior studies have established developmental (maturity) and disease-related changes in circulating and pulmonary lymphocyte populations, but a comprehensive assessment of their relationship to disease risk/outcome has not been undertaken. We hypothesize that cellular and molecular immuno-maturity is altered due to intrinsic and extrinsic factors presented by premature birth in such a way as to reduce resistance to viral infections and to promote cytotoxic damage to the lung. We will evaluate immunologic maturity by comprehensively phenotyping lymphocyte populations in peripheral blood sampled at premature delivery, at the time of discharge from the hospital and at twelve months corrected age. The lymphocytic phenotype will be analyzed particularly in the context of gestational age and maternal-fetal stressors capable of modulating oxidative stress (oxygen exposure, infection and environmental tobacco smoke exposure). Additionally, we will assess changes in the molecular phenotype of isolated CD8 lymphocytes, a cell type preferentially recruited to the lungs of premature infants and capable of contributing to disease pathogenesis, by genome-wide expression profiling, in order to uncover novel disease pathways and define a gene expression signature associated with disease risk. We propose to build a statistical model, using cellular and molecular phenotypes and additional clinical variables, for stratifying risk of lung morbidity within the first year of life. Finally, we will assess the development of the gut microbiome in the preterm subjects to correlate with the observation of development of the adaptive immune system.

  Study phs001297

• Prader-Willi Syndrome and Early-onset Morbid Obesity Natural History Protocol

  This observational study will involve the comprehensive assessment of the medical, behavioral and nutritional history and the clinical features of individuals with Prader-Willi syndrome and individuals with features of PWS-like/EMO. A blood sample will be obtained from the participants in order to create a DNA and RNA repository. In those PWS participants with a known deletion a blood sample will be collected for DNA in order to perform array comparative genome hybridization (aCGH) microarray or Methylation-Specific Multiplex Ligation-dependent Probe Amplification (MS-MLPA) studies to characterize the extent of the deletion. DNA samples will be sent to the Consortium Center at Baylor College of Medicine for the performance of the aCGH studies and to either Dr. Driscoll or Dr. Butler lab for MS-MLPA analysis. No drugs or treatments will be administered through this protocol. Our goal is to enroll as many participants as possible over a 8 year period. Currently we have enrolled 297 total subjects of which 265 have PWS and 32 EMO. Our original goal was to have enrolled over the first 5 years a clinical database of 200 individuals with PWS and 100 with EMO. We have exceeded expectations in PWS enrollment, but have fallen short in the enrollment of individuals with EMO. Therefore, we would like to reset our goals. We now propose to have an enrollment goal of 400 total subjects of which 350 will have PWS and 50 will have EMO. Eligible participants will be initially enrolled in the natural history study from the 4 clinic sites currently involved with PWS (University of Florida, Kansas University Medical Center, Vanderbilt University and University of California at Irvine). Participants assessed will serve to provide a background of information and a willing cohort for future interventional studies. All participants will have had standard genetic testing at a commercial laboratory prior to entry into the study. The PWS participants will be classified into one of the 3 main molecular classes (deletion, UPD and ID). The EMO participants will have had laboratory testing ruling out PWS and chromosomal aneuploidy (e.g., trisomy 21, Klinefelter syndrome, etc.). Going forward we feel it is important that all newly recruited EMO subjects have an aCGH as part of their evaluation so we can identify those with discrete deletions, duplications or copy number variants (CNV) and compare them to those without aCGH abnormalities. The participants will be assessed annually (0-3 years of age) or biennially (> 3 years) in the Clinical Research Center (or equivalent facility) using standardized protocol including photographs for documentation purposes to compare the evolution of the clinical phenotype.

  Study phs000575

• IMMUcan Upstream SCCHN3 cohort

  The goal of IMMUcan is to understand how the immune system interacts with tumors and how therapeutic interventions influence this interaction. This cohort includes patients from the UPSTREAM trial, with squamous cell carcinoma of the head and neck (SCCHN) cancer which has spread (metastatic) or the tumour has come back after previous treatment (recurrent). Comprehensive profiling data are integrated with longitudinally collected clinical information. Cellular profiling of the same tumor samples was performed using multiplex immunofluorescence imaging, imaging mass cytometry, and H&E staining.

  Study EGAS50000001505

• Whole Genome Sequencing of HER2-Positive Metastatic Extramammary Paget’s Disease: A Case Report

  Extramammary Paget’s disease (EMPD) is a rare cancer that occurs within the epithelium of the skin. Whole genome sequencing of the tumor and matched blood was performed. Whole genome sequencing revealed the underlying copy number variation landscape in HER2-positive metastatic EMPD. The presence of alternative signalling pathways and genetic variants suggests potential interactions with HER2 signalling, which possibly contributed to the HER2 overexpression and observed response to HER2-directed therapy combined with other agents in a comprehensive treatment regimen.

  Study EGAS50000000243

• Risk and modifying factors in Frontotemporal Dementia

  Understanding the molecular mechanisms underlying frontotemporal dementia (FTD) is essential for the development of successful therapies. Here, we present Phase 1 of a multi-omics, multi-model data resource for FTD research which will allows in-depth molecular research into these mechanisms. We have integrated and analysed data from the frontal lobe of FTD patients with mutations in MAPT, GRN and C9orf72 and detected common and distinct dysregulated cellular pathways. Our results highlight that excitatory neurons are the most vulnerable neuronal cell type and that vascular aberrations are a common hallmark in FTD. Via integration of multi-omics data, we detected several transcription factors and pathways which regulate the strong neuroinflammation observed in FTD-GRN. Finally, using small RNA-seq data and verification experiments in cellular models, we identified several up-regulated miRNAs that inhibit cellular trafficking pathways in FTD and lead to microglial activation. In this work we shed light on novel mechanistic and pathophysiological hallmarks of FTD. In addition, we believe that this comprehensive, multi-omics data resource will further mechanistic FTD research by the community.

  Study EGAS00001004895

• A Whole Genome Association Search for Type 2 Diabetes Genes in African Americans

  Over 2.8 million African Americans have type 2 diabetes mellitus (T2DM). This represents approximately 13% of the African American population and a significant proportion of the 21 million Americans living with diabetes. On average, an African American individual is twice as likely to have T2DM as a European American peer. Our research group has been actively involved in the study of African American diabetes genetics for over 15 years. We hypothesize that genes contributing to the development of T2DM in African Americans exist and can be located using modern molecular genetic methods. With the exception of TCF7L2(Transcription factor 7-like 2) evidence to date suggests variants that contribute T2DM risk in European-derived populations are not significant contributors to African American T2DM risk. We have performed a SNP-based Whole Genome Association (WGA) analysis on the Affymetrix 6.0 in a case control population of over 1000 African American T2DM cases and over 1000 non-diabetic controls. The DNAs have been collected from participants using uniform criteria from North Carolina and neighboring states. Genotype data will be subjected to extensive genetic analysis with the goal of defining a priority list of SNPs for genotyping in independent populations for confirmation and further detailed analysis.

  Study phs000140

• International Consortium on the Genetics of Systemic Lupus Erythematosus (SLEGEN)

  The genetic makeup of an individual strongly influences the risk of developing systemic lupus erythematosus (SLE). The identification of genes that predispose an individual to SLE will lead to earlier and better diagnosis, better treatments, and possibly prevention. To this end, the International Consortium on the Genetics of Systemic Lupus Erythematosus (SLEGEN) was formed in 2005 and is composed of lupus researchers who agreed to pool their knowledge and resources to search for genes that predispose to lupus. Eight laboratories contributed DNA samples for genotyping at the Broad Institute and association with SLE was performed by the Data Coordinating Center (Wake Forest University), as part of a four stage study design. Stages one and two of this design were graciously funded by the Alliance for Lupus Research (www.lupusresearch.org). In this stage of the study, approximately 767 SLE patients (cases) were compared to approximately 383 non-SLE patients (controls) for differences among the Illumina HumanHap300. The affected individuals are all females of European decent. 82% of the cases are the index case from multiplex pedigrees for SLE and the remaining 18% have self-reported first degree relatives with SLE. A detailed summary of the methods and results can be found in the manuscript in Nature Genetics February 2008 by SLEGEN "Genome-wide association scan in women with systemic lupus erythematosus identifies susceptibility variants ITGAM, PXK, KIAA1542 and other loci". (Please see also Study Accession: phs000202.v1.p1)

  Study phs000216

• NIDDK IBD Genetics Consortium Repository Immunochip

  The Immunochip is a custom Illumina Infinium chip comprising 196,524 SNPs and small indels selected primarily based on GWAS analysis of 12 autoimmune and inflammatory diseases. The chip has two purposes: fine mapping of 289 established associations corresponding to 187 distinct loci, and deep replication of suggestive, but not yet proven, associations. Fine-mapping regions were defined as 0.2cM centered on GWAS hit SNPs, and all SNPs and short indels in these regions from the 1000 Genomes Project low coverage pilot CEU samples, as well as variants discovered in resequencing experiments conducted by groups collaborating in the chip design were selected for inclusion. Replication of autoimmune and inflammatory GWAS (including Crohn's disease and ulcerative colitis) contributed the bulk of the remaining SNP lists. Approximately 25,000 SNPs were included as replication of unrelated diseases as part of the WTCCC2 project, which serve as useful null SNPs for these analyses. In total, approximately 240,000 SNPs were selected for inclusion, with an assay design success rate of ~80%. Reprinted from Jostins et al. (2012), with permission from Springer Nature (see https://www.nature.com/reprints/permission-requests.html). Jostins, L., et al. (2012) Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature, 491, 119-24. PMID: 23128233.

  Study phs001721

• Cardiovascular Health Study (CHS) - Imaging

  The Cardiovascular Health Study (CHS) is a prospective study of risk factors for development and progression of coronary heart disease (CHD) and stroke in people aged 65 years and older. The 5,888 study participants were recruited from four U.S. communities and have undergone extensive clinic examinations for evaluation of markers of subclinical cardiovascular disease. The original cohort, enrolled in 1989-90, totaled 5,201 participants. A supplemental cohort of 687 predominantly African-American participants was enrolled in 1992-93. Clinic examinations were performed at study baseline and at annual visits through 1998-1999, and again in 2005-2006. Examination components included medical and personal history, medication inventory, ECG, blood pressure, anthropometry, assessment of physical and cognitive function, and depression screening. Other components done less frequently included phlebotomy, spirometry, echocardiography, carotid ultrasound, cerebral magnetic resonance imaging, measurement of ankle-brachial index and retinal exam. Participants were contacted by telephone annually between exams to collect information about hospitalizations and potential cardiovascular events. Since 1999, participants have been contacted every six months by phone, primarily to identify cardiovascular events and to assess physical and cognitive health. Standard protocols for the identification and adjudication of events were implemented during follow-up. The adjudicated events are myocardial infarction, angina, heart failure (HF), stroke, transient ischemic attack (TIA), claudication, and mortality.

  Study phs003639

• MutWP1: CRUK Grand Challenge Mutographs of Cancer: Kidney (1)

  The Mutographs project aims to advance our understanding of the causes of cancer through studies of mutational signatures. Led by Mike Stratton, together with Paul Brennan, Ludmil Alexandrov, Allan Balmain, David Phillips and Peter Campbell, this large-scale international research endeavour was awarded a Cancer Research UK Grand Challenge. Different patterns of somatic mutation are generated by the different environmental, lifestyle and genetic factors that cause cancer, many of them are still unknown. Within Mutographs, the International Agency for Research on Cancer is coordinating the recruitment of 5000 individuals with cancer (colorectal, renal, pancreatic, oesophageal adenocarcinoma or oesophageal squamous cancers) across 5 continents to explore whether different mutational signatures explain marked variation in incidence. In brief, through an international network of collaborators around the world, biological materials are collected, along with demographic, histological, clinical and questionnaire data. Whole genome sequences of tumour-germline DNA pairs are generated at the Wellcome Trust Sanger Institute. Somatic mutational signatures are subsequently extracted by non-negative matrix factorisation methods and correlated with risk factors data. Through an enhanced understanding of cancer aetiology, Mutographs unprecedented effort is anticipated to outline modifiable risk factors, lead to new approaches to prevent cancer, and provide opportunities to empower early detection, refine high-risk groups and contribute to further therapeutic development.

  Dataset EGAD00001006427

• MRCA and MRCE SNP genotypes

  Gene expression levels can be an important link DNA between variation and phenotypic manifestations. Our previous map of global gene expression based on approximately 400K SNPs and 50K transcripts in 400 sib pairs from the MRCA family panel has been widely used to interpret the results of GWAS. Here, we more than double the size of our initial dataset with expression data on 550 additional individuals from the MRCE family panel using the Illumina whole genome expression array. We have used new statistical methods for dimension reduction to account for non-genetic effects in estimates of expression levels and we have also included SNPs imputed from the 1000 Genomes Project. Our methods reduced false discovery rates and increased the number of eQTLs mapped either locally or at a distance (i.e. in cis or trans) from 1,534 in the MRCA dataset to 4,452 (with <5% FDR). Imputation of 1000 Genomes SNPs further increased the number of eQTLs to 7,302. Using the same methods and imputed SNPs in the newly acquired MRCE dataset we identified eQTLs for 9000 genes. The combined results identify strong local and distant effects for transcripts from 14,177 genes. Our eQTL database (http://www.hsph.harvard.edu/faculty/liming-liang/software/eqtl/) based on these results is freely available to help define the function of disease-associated variants.

  Study EGAS00000000137

• Genome-Wide Association Study of Heparin-Induced Thrombocytopenia

  Heparin-induced thrombocytopenia (HIT) is an unpredictable, potentially catastrophic adverse effect resulting from an immune response to platelet factor 4 (PF4)/heparin complexes. We performed a genome-wide association study (GWAS) with positive functional assay as the outcome. Genetic associations were investigated in a cohort of functional assay-confirmed HIT cases, antibody-positive (function assay-negative) controls, and antibody negative controls. Both PF4-specific enzyme-linked immunosorbent assay (ELISA) and serotonin release assay (SRA) were positive in every HIT case. GWAS genotyping was performed at the Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences (IMS). All samples in the discovery and replication cohorts were genotyped using the lllumina&#174; Infinium HumanOmniExpressExome BeadChip, which contains 958,497 markers, including 273,000 functional exonic markers. Quality control was accomplished using sample and marker call rate &#8805;98%, sex mismatch, duplicate concordance, and removal of related samples through identity by descent. Genomic imputation was performed for samples using Minimac4 and the phase3 v5 reference panel data from the 1000 genomes project. The primary GWAS analysis used multivariable logistic regression assuming an additive genetic model with functional assay-confirmed case status as the outcome. Both PF4/heparin antibody negative and antibody positive controls were considered controls in the primary analysis. Logistic regressions were used to generate odds ratios and 95% confidence intervals (95%CIs) after adjustment for age, sex, and first three principal components.

  Study phs002863

• Genetic Basis of Hepatosplenic T Cell Lymphoma (HSTL)

  Hepatosplenic T cell lymphoma (HSTL) is a rare and lethal lymphoma; the genetic drivers of this disease are unknown.  Through whole exome sequencing of 68 HSTLs, we define recurrently mutated driver genes and copy number alterations in the disease. Chromatin modifying genes including SETD2, INO80 and ARID1B were commonly mutated in HSTL, affecting 62% of cases. HSTLs manifest frequent mutations in STAT5B (31%), STAT3 (9%), and PIK3CD (9%) for which there currently exist potential targeted therapies. In addition, we noted less frequent events in EZH2, KRAS and TP53. SETD2 was the most frequently silenced gene in HSTL. We experimentally demonstrated that SETD2 acts as a tumor suppressor gene. In addition, we found that mutations in STAT5B and PIK3CD activate critical signaling pathways important to cell survival in HSTL. Our work thus defines the genetic landscape of HSTL and implicates novel gene mutations linked to HSTL pathogenesis and potential treatment targets.

  Study EGAS00001002182

• High-depth whole genome sequencing of paired ductal carcinoma in-situ (DCIS) and germline control samples from 51 individuals.

  Deposited here are whole-genome sequencing data for 51 paired breast cancer DCIS and matched-normal samples taken from the same individual. Average sequence depth is 110x for DCIS samples and 39x for matched-normals. Matched-normals are from blood (n=14) or adjacent normal breast (n=37). Sequencing was performed on Illumina HIseqX (n=70) or Illumina Novoseq (n=32). They are a part of a broader project that uses high-depth WGS to investigate the somatic mutation genomic landscape of DCIS in order to uncover biological insights into breast cancer progression as well as possible methods to stratify DCIS patients for individualised therapy or disease monitoring.

  Dataset EGAD50000002071

• mutation analysys of Gorlin syndrome

  Gorlin syndrome is a genetic disorder of autosomal dominant inheritance that predisposes the affected individual to a variety of disorders that are attributed largely to heterozygous germline patched1 (PTCH1) mutations. PTCH1 is a hedgehog (Hh) receptor as well as a repressor, mutation of which leads to constitutive activation of Hh pathway. Hh pathway encompasses a wide variety of cellular signaling cascades, which involve several molecules; however, no associated genotype?phenotype correlations have been reported. Recently, mutations in Suppressor of fused homolog (SUFU) or PTCH2 were reported in patients with Gorlin syndrome. These facts suggest that multi-layered mutations in Hh pathway may contribute to the development of Gorlin syndrome. We demonstrated multiple mutations of Hh-related genes in addition to PTCH1, which possibly act in an additive or multiplicative manner and lead to Gorlin syndrome. High-throughput sequencing was performed to analyze exome sequences in four unrelated Gorlin syndrome patient genomes. Mutations in PTCH1 gene were detected in all four patients. Specific nucleotide variations or frameshift variations of PTCH1 were identified along with the inferred amino acid changes in all patients. We further filtered 84 different genes which are closely related to Hh signaling. Fifty three of these had enough coverage of over ?30. The sequencing results were filtered and compared to reduce the number of sequence variants identified in each of the affected individuals. We discovered three genes, PTCH2, BOC, and WNT9b, with mutations with a predicted functional impact assessed by MutationTaster2 or PolyPhen-2 (Polymorphism Phenotyping v2) analysis. It is noticeable that PTCH2 and BOC are Hh receptor molecules. No significant mutations were observed in SUFU. Multi-layered mutations in Hh pathway may change the activation level of the Hh signals, which may explain the wide phenotypic variability of Gorlin syndrome.

  Study JGAS000099

• Mutations in SPINK2 induce azoospermia

  Azoospermia, characterized by the absence of spermatozoa in the ejaculate is a common cause of male infertility with a poorly characterized etiology. Exome sequencing analysis of two azoospermic brothers allowed the identification of a homozygous splice mutation in SPINK2, encoding a serine protease inhibitor believed to target acrosin, the main sperm acrosomal protease. In accord with these findings we observed that homozygous Spink2 KO male mice had azoospermia. Moreover, despite normal fertility, heterozygous male mice had a high rate of morphologically abnormal spermatozoa and a reduced sperm motility. Further analysis demonstrated that in the absence of Spink2, protease-induced stress initiates Golgi fragmentation and prevents acrosome biogenesis leading to spermatid differentiation arrest. We also observed a deleterious effect of acrosin overexpression in HEK cells, effect that was alleviated by SPINK2 coexpression confirming its role as acrosin inhibitor. These results demonstrate that SPINK2 is necessary to neutralize proteases during their cellular transit towards the acrosome and that its deficiency induces a pathological continuum ranging from oligoasthenoteratozoospermia in heterozygotes to azoospermia in homozygotes.

  Study EGAS00001002450

• The interface of malignant and immunologic clonal dynamics in high-grade serous ovarian cancer

  High-grade serous ovarian cancer exhibits extensive intratumoral heterogeneity coupled with widespread intraperitoneal disease. Despite this, metastatic spread of tumor clones is non-random, implying the existence of local microenvironmental factors that shape tumor progression. We interrogated the molecular interface between tumorinfiltrating lymphocytes (TIL) and cancer cells in 143 samples from 21 patients using whole-genome sequencing, immunohistochemistry, histologic image analysis, gene expression profiling, and T- and B-cell receptor sequencing. We identify 3 immunologic response categories, which frequently co-exist within individual patients. Furthermore, epithelial CD8+ TIL were inversely associated with malignant cell diversity, evidenced by subclonal neoepitope elimination and spatial tracking between tumor and T-cell clones. Intersecting mutational signatures and immune analysis showed that foldback inversion genomic aberrations lead to worse outcomes even in the presence of cytotoxic TIL (n=433). Thus, regional variation in immune contexture mirrors the pattern of intraperitoneal malignant spread, provoking new perspectives for treatment of this challenging disease.

  Study EGAS00001002839

• Cross-species Comparison Reveals Therapeutic Vulnerabilities Halting Glioblastoma Progression

  The growth of a tumor is tightly linked to the distribution of its cells along a continuum of activation states. Here, we systematically decode the activation state architecture (ASA) in a glioblastoma (GBM) patient cohort through comparison to adult murine neural stem cells. Modelling of these data forecast how tumor cells organize to sustain growth and identifies rate of activation as the main predictor of growth. Accordingly, patients with a higher quiescence fraction exhibit improved outcomes. Further, DNA methylation arrays enable ASA- related patient stratification. Comparison of healthy and malignant gene expression dynamics reveals dysregulation of the Wnt- antagonist SFRP1 at the quiescence to activation transition. SFRP1 overexpression renders GBM quiescent and increases overall survival of tumor-bearing mice. Surprisingly, it does so through reprogramming the tumor’s stem-like methylome into an astrocyte- like one. Our findings offer a framework for patient stratification with prognostic value, biomarker identification, and therapeutic avenues to halt GBM progression.

  Study EGAS00001008155

• Isotype-resolved sequencing of B cell receptor in measles virus infection (2017-09-13)

  Isotype-resolved sequencing of B cell receptor in measles virus infection 1) 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 please see http://www.sanger.ac.uk/datasharing/ This dataset contains all the data available for this study on 2017-09-13.

  Dataset EGAD00001003749

• IBD Whole Genome Sequencing (2019-08-14)

  Whole genome sequences at 15X depth of patients with Inflammatory Bowel Disease. 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/ . This dataset contains all the data available for this study on 2019-08-14.

  Dataset EGAD00001005254

• IMMUcan SCCHN1 cohort

  The goal of IMMUcan is to understand how the immune system interacts with tumors and how therapeutic interventions influence this interaction. This cohort includes patients with confirmed locally recurrent and/or metastatic squamous cell carcinoma of the head and neck (SCCHN) who receive first-line treatment with immune checkpoint inhibitors (ICI) or ICI combined with chemotherapy. Comprehensive profiling data are integrated with longitudinally collected clinical information. Cellular profiling of the same tumor samples was performed using multiplex immunofluorescence imaging, imaging mass cytometry, and H&E staining.

  Study EGAS50000001533

• Integrated Genomic Analysis of Periampullary Tumors at The Human Genome Sequencing Center, Baylor College of Medicine (HGSC-BCM)

  Adenocarcinomas arising in the complex environment of the ampulla of Vater constitute a histopathological heterogenous group, presumably originating from the different epithelial cellular constituents present at the site: pancreas, bile duct, and intestinal duodenum. These tumors have been described in many different ways: intra-ampullary, periampullary, intra-ampullary papillary-tubular neoplasm, ampullary-ductal, periampullary-duodenal, and ampullary-not otherwise specified. These varied classifications reflect the difficulty in classifying these tumors into specific groups. Only the tumors clearly localized in the bile duct or duodenum are identified as distal cholangiocarcinomas (CAC) or duodenal adenocarcinomas (DUOAC). The current classification is based on macroscopic features that may distinguish the epithelium of origin, microscopic features, clinicopathological criteria, histopathology and expression of differential markers. This classification is subjective and prone to inter-observer variability and significantly impacts on treatment selection and therapeutic development. In order to define subtypes of periampullary cancer with clinical relevance, we performed whole exome sequencing and copy number analysis of 160 cancers arising in the periampullary region, 62 of these clearly arising from either the bile duct (n = 44), or the duodenum (n = 18) and 98 periampullary cancers (AMPAC) where the epithelium of origin could not be clearly defined.

  Study phs000895

• The mutational landscape and its longitudinal dynamics in relapsed and refractory Hodgkin lymphoma

  In classical Hodgkin-lymphoma (cHL), only a few cases recur, and only a limited fraction of patients is primary-refractory to standard-polychemotherapy. Underlying genomic features of unfavorable clinical courses remain sparsely characterized. Here, we investigated the genomic characteristics of primary-refractory/relapsed cHL in contrast with long-term-responders (LTR). In total, data from 84 samples were submitted.

  Study EGAS50000000149

• Induction of fetal meiotic oocytes from embryonic stem cells in cynomolgus monkeys

  Human in vitro oogenesis provides a framework for clarifying the mechanism of human oogenesis. To create its benchmark, it is vital to promote in vitro oogenesis using a model physiologically close to humans. Here, we establish a foundation for in vitro oogenesis in cynomolgus (cy) monkeys: cy female embryonic stem cells harboring one active and one inactive X chromosome (Xa and Xi, respectively) differentiate robustly into primordial germ cell-like cells, which in xenogeneic reconstituted ovaries develop efficiently into oogonia and, remarkably, further into meiotic oocytes at the zygotene stage. This differentiation entails a comprehensive epigenetic reprogramming, including Xi reprogramming, yet, as partly observed in vivo, Xa and Xi remain epigenetically asymmetric with incomplete Xi reactivation. In humans and monkeys, the Xi epigenome in pluripotent stem cells functions as an Xi-reprogramming determinant. We further show that developmental-pathway over-activations with suboptimal up-regulation of relevant meiotic genes impede in vitro meiotic progression. Cy in vitro oogenesis exhibits critical homology with the human system, including with respect to bottlenecks, providing a salient model for advancing human in vitro oogenesis.

  Study JGAS000573

• Rare Germline Variants in CDKN2A-Negative Children and Adolescents with Cutaneous Melanoma

  Cutaneous melanoma is a complex disease influenced by both environmental and genetic factors. Inherited susceptibility plays a significant role, involving a combination of high-, intermediate-, and low-penetrance genes. Melanoma in children and adolescents has been speculated to have a stronger genetic component due to the early onset. This study investigates germline variants in early-onset melanoma through exome sequencing of 154 patients in Australia diagnosed with cutaneous melanoma before the age of 20.

  Study EGAS50000001311

• Arcagen – thoracic malignancies

  Arcagen is an EORTC/SPECTA pan-European project that aims to recruit 1000 rare cancer patients from different tumour domains of EURACAN. This study collected samples from advanced or metastatic rare cancer from patients older than 12, and analysed them using Foundation Medicine next-generation sequencing (NGS) panels (FoundationOne CDx for FFPE samples or FoundationOne Liquid CDx for blood samples). Here we are submitting the dataset that contain NGS files from rare thoracic malignancies (n=102)

  Dataset EGAD50000000168