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• Reference epigenome SMC01_ChIP-Seq(H3K27me3) data generated from KEP study

  A SMC01_ChIP-Seq(H3K27me3) paired end data for skeletal muscle cells

  Dataset EGAD00001003845

• Reference epigenome SMC02_ChIP-Seq(H3K27me3) data generated from KEP study

  A SMC02_ChIP-Seq(H3K27me3) paired end data for skeletal muscle cells

  Dataset EGAD00001003846

• Reference epigenome SMC03_ChIP-Seq(H3K27me3) data generated from KEP study

  A SMC03_ChIP-Seq(H3K27me3) paired end data for skeletal muscle cells

  Dataset EGAD00001003847

• Reference epigenome SMC04_ChIP-Seq(H3K27me3) data generated from KEP study

  A SMC04_ChIP-Seq(H3K27me3) paired end data for skeletal muscle cells

  Dataset EGAD00001003848

• Reference epigenome SMC07_ChIP-Seq(H3K27me3) data generated from KEP study

  A SMC07_ChIP-Seq(H3K27me3) paired end data for skeletal muscle cells

  Dataset EGAD00001003851

• Reference epigenome SMC08_ChIP-Seq(H3K27me3) data generated from KEP study

  A SMC08_ChIP-Seq(H3K27me3) paired end data for skeletal muscle cells

  Dataset EGAD00001003852

• Reference epigenome SMC09_ChIP-Seq(H3K27me3) data generated from KEP study

  A SMC09_ChIP-Seq(H3K27me3) paired end data for skeletal muscle cells

  Dataset EGAD00001003853

• Reference epigenome SMC07_WGBS data generated from KEP study

  A SMC07_WGBS paired end data for skeletal muscle cells

  Dataset EGAD00001003875

• Reference epigenome SMC01_WGBS data generated from KEP study

  A SMC01_WGBS paired end data for skeletal muscle cells

  Dataset EGAD00001003871

• Reference epigenome SMC02_WGBS data generated from KEP study

  A SMC02_WGBS paired end data for skeletal muscle cells

  Dataset EGAD00001003872

• Reference epigenome SMC05_WGBS data generated from KEP study

  A SMC05_WGBS paired end data for skeletal muscle cells

  Dataset EGAD00001003873

• Reference epigenome SMC06_WGBS data generated from KEP study

  A SMC06_WGBS paired end data for skeletal muscle cells

  Dataset EGAD00001003874

• Reference epigenome SMC08_WGBS data generated from KEP study

  A SMC08_WGBS paired end data for skeletal muscle cells

  Dataset EGAD00001003876

• Reference epigenome SMC09_WGBS data generated from KEP study

  A SMC09_WGBS paired end data for skeletal muscle cells

  Dataset EGAD00001003877

• Reference epigenome SMC03_WGBS data generated from KEP study

  A SMC03_WGBS paired end data for skeletal muscle cells

  Dataset EGAD00001003888

• Reference epigenome SMC04_WGBS data generated from KEP study

  A SMC04_WGBS paired end data for skeletal muscle cells

  Dataset EGAD00001003889

• Reference epigenome KNIH010 mRNA-seq data generated from KEP study

  A KNIH010 mRNA-seq paired end data for podocytes

  Dataset EGAD00001002176

• Reference epigenome KNIH011 mRNA-seq data generated from KEP study

  A KNIH011 mRNA-seq paired end data for podocytes

  Dataset EGAD00001002177

• Reference epigenome KNIH010 miRNA-seq data generated from KEP study

  A KNIH010 miRNA-seq single end data for podocytes

  Dataset EGAD00001002769

• Reference epigenome KNIH011 miRNA-seq data generated from KEP study

  A KNIH011 miRNA-seq single end data for podocytes

  Dataset EGAD00001002770

• Brain mets external validation cohort targeted panel sequencing raw sequencing files

  Raw sequencing files for the 18 (brain tumour-only) samples within the external validation cohort.

  Dataset EGAD00001005984

• Brain mets discovery cohort, orthogonal validation raw sequencing files

  These are the raw sequencing files for the orthogonal validation brain tumour samples in the discovery cohort.

  Dataset EGAD00001005985

• RNA-seq for IgA BMPC project

  7 RNA-seq samples in total: CD19n_IgAn (x2) , CD19n_IgAp (x2) , CD19p_IgAn (x1), CD19p_IgAp (x2)

  Dataset EGAD00001006862

• Methylation tumour profiles for EGAS00001004572

  Bulk methylation tumour profiles from infinium methylation epic bead kit in EGAS00001004572

  Dataset EGAD00001006909

• KCL PRECSION SNP

  KCL SNP array samples for copy number analysis

  Dataset EGAD00001008379

• Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY)

  The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health (NIH) has sponsored a consortium of investigators to conduct a clinical treatment trial, Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY). The primary objective of the TODAY trial is to compare the efficacy of three treatment arms on time to treatment failure based on glycemic control. The secondary aims are to:compare and evaluate the safety of the three treatment arms;compare the effects of the three treatments on the pathophysiology of type 2 diabetes (T2D) with regards to beta cell function and insulin resistance, body composition, nutrition, physical activity and aerobic fitness, cardiovascular risk factors, microvascular complications, quality of life, and psychological outcomes;evaluate the influence of individual and family behaviors on treatment response; andcompare the relative cost effectiveness of the three treatment arms.The three treatment regimens are: (1) metformin alone, (2) metformin plus rosiglitazone, and (3) metformin plus an intensive lifestyle intervention called the TODAY Lifestyle Program (TLP). The study recruits patients over a three-year period and follows patients for a minimum of two years. Patients are randomized within two years of the diagnosis of T2D.

  Study phs002447

• Identification of Host Genetic Factors That Are Determinant for the Development of Severe Forms of COVID-19

  We conducted whole exome sequencing (WXS) on 21 cases of Multisystem Inflammatory Syndrome in Children (MIS-C) related to COVID-19 from Brazil. All patients who were hospitalized underwent serum (ELISA) and molecular (RT-PCR) testing for SARS-CoV-2, and the main clinical symptoms associated with SARS-CoV-2 infection were collected. During hospitalization, data on complications, medical interventions, and laboratory findings were also collected. Our results revealed in an unprecedented way the occurrence of several rare loss-of-function variants in the NLRP12 gene among the affected children, and three other SNVs, predicted to be highly pathogenic, were identified in the IL17RC gene. An additional nonsense variant, in the IFNA10 gene, was identified in a single patient. Through in vitro functional analysis, we unequivocally demonstrated that these mutations impact NF-kB activation. These findings are similar to those observed in NLRP12-associated systemic autoinflammatory disorders, characterized by altered innate immune response, with increased NF-κB activation and excessive production of inflammatory cytokines. To our knowledge, our study is the first to provide a plausible molecular mechanism for MIS-C involving inborn errors in NLRP12. We suggest that some patients with MIS-C may benefit from Interleukin (IL)-1 pathway blockade treatments.

  Study phs003512

• Exploring the Microbiome-Gut-Brain Axis with Respect to Psychoneurological Symptoms for Children with Solid Tumors

  The human body hosts tens of trillions of microbes, a number 10 times greater than the number of human body cells. The collection of these human-associated microbes and their genomes is called the “human microbiome”. More than 90% of these microbes live in the gastrointestinal (GI) tract, representing 500 species on average. With the development of high-throughput sequencing technology and bioinformatics tools (e.g., 16S ribosomal RNA or 16S rRNA sequencing and shotgun metagenomics analysis), recent progress has been made to elaborate the critical role that the gut microbiome plays in human health and disease. A significant disruption (dysbiosis) of the composition and function of the gut microbiome is associated with carcinogenesis, chemotherapeutic metabolism, and treatment-related symptom toxicities. The current state of science on the gut microbiome in cancer has only recently started in animal models and adults, and has not been well investigated in children diagnosed and treated for cancer, nor with respect to associations with cancer treatment-related toxicities. This proposed study will explore the hypothesis that dysbiosis of the gut microbiome is associated with cancer treatment-related GI and psychoneurological symptoms. We will collect both stool samples (for the gut microbiome) and patient-reported outcomes across chemotherapy.

  Study phs002960

• using-ega-account

  Using your EGA account The purpose of this page is to help you access and download the data you have been granted permission to view through your EGA account. To obtain an EGA account please register here. Once your account is created, you can find details on how to manage your EGA account here. EGA access policy (New account holders please read) Access to EGA services are only provided to EGA account holders. EGA accounts are created, updated and closed upon direct instruction from the relevant DAC contact, using the EGA account management tools or through EGA Helpdesk. As part of the EGA account creation process, the EGA account holder must reset their password when instructed. Password resets are checked and verified usually within 24 business hours, during which time the EGA account is inaccessible. EGA accounts are assigned on an individual basis for the exclusive use of the registered EGA account holder; log-in details must remain private and only be used by the EGA account holder. Controlled access data files are only provided, in accordance to the permissions set by the DAC, to EGA account holders. EGA controlled access data files are encrypted prior to download and must be decrypted on the EGA account holders side. EGA account holders are provided access to the EGA download streamer to download access approved datasets and files therein. The EGA download streamer represents the primary means for the EGA account holder to download access approved datasets and files therein. EGA account holders may be provided with an EGA download account for accessing approved datasets and files therein, using FTP or Aspera in response to clearly defined technical reasons, which may restrict the use of the EGA download streamer. It is the sole responsibility of the EGA account holder to ensure full compliance to all terms and conditions of the Data Access Agreement are met once data is downloaded from the EGA. Should you move institute you must contact all Data Access Committee's contacts to update your details and, if necessary, re-apply for data access. The Data Access Agreement (DAA) is a contract made between the DAC and the EGA account holder; the EGA is not responsible for enforcing the DAA. EGA reserves the right to place EGA accounts 'onhold', pending DAC approval to re-activate, should EGA account 'misuse' be suspected. Further information Introduction to the EGA Frequently Asked Questions Subscribe to the EGA mailing list

  Documentation using-ega-account

• Using your EGA account

  Using your EGA account The purpose of this page is to help you access and download the data you have been granted permission to view through your EGA account. To obtain an EGA account please register here. Once your account is created, you can find details on how to manage your EGA account here. EGA access policy (New account holders please read) Access to EGA services are only provided to EGA account holders. EGA accounts are created, updated and closed upon direct instruction from the relevant DAC contact, using the EGA account management tools or through EGA Helpdesk. As part of the EGA account creation process, the EGA account holder must reset their password when instructed. Password resets are checked and verified usually within 24 business hours, during which time the EGA account is inaccessible. EGA accounts are assigned on an individual basis for the exclusive use of the registered EGA account holder; log-in details must remain private and only be used by the EGA account holder. Controlled access data files are only provided, in accordance to the permissions set by the DAC, to EGA account holders. EGA controlled access data files are encrypted prior to download and must be decrypted on the EGA account holders side. EGA account holders are provided access to the EGA download streamer to download access approved datasets and files therein. The EGA download streamer represents the primary means for the EGA account holder to download access approved datasets and files therein. EGA account holders may be provided with an EGA download account for accessing approved datasets and files therein, using FTP or Aspera in response to clearly defined technical reasons, which may restrict the use of the EGA download streamer. It is the sole responsibility of the EGA account holder to ensure full compliance to all terms and conditions of the Data Access Agreement are met once data is downloaded from the EGA. Should you move institute you must contact all Data Access Committee's contacts to update your details and, if necessary, re-apply for data access. The Data Access Agreement (DAA) is a contract made between the DAC and the EGA account holder; the EGA is not responsible for enforcing the DAA. EGA reserves the right to place EGA accounts 'onhold', pending DAC approval to re-activate, should EGA account 'misuse' be suspected. Further information Introduction to the EGA Frequently Asked Questions Subscribe to the EGA mailing list

  Documentation download/using_ega_account

• A somatic reference standard for cancer genome sequencing with COLO829

  Identification of somatic alterations in cancer has become feasible with the massive adoption of next generation sequencing. However, due to variability in sequencing and informatics pipelines, a common somatic reference is needed. We thus performed paired whole genome sequencing of a metastatic melanoma cell line (COLO829) and a matched lymphoblastoid line (COLO829BL) across three institutions (TGen, Illumina, Genome Sciences Centre at the British Columbia Cancer Agency). We performed a meta-analysis of all data, in combination with the originally reported analysis of these cell lines by Pleasance et al (PMID: 20016485), and report a somatic reference standard based on consensus events. DNA extractions, library preparation, sequencing, and analysis were separately performed at each site. Results were compiled with sequence data previously generated for the cell lines to identify true positive variants, collectively representing a somatic reference standard. Overall, common somatic events include point mutations, small insertion/deletions, and genes affected by concurrent copy number changes. We additionally show divergence of somatic mutations in COLO829 associated with differences in cell line lineage. We present this reference to the community as a standard for enabling interpretation and identification of somatic mutations across institutions and analytical pipelines.

  Study EGAS00001001385

• Centre Leon Berard - DAC - seq data Neuroendocrine tumors - B Gibert

  Review committee for the neuroendocrine tumor genetic data set uploaded by Benjamin GIBERT (CRCL), Anthony FERRARI (CLB) and Thomas WALTER (HCL)

  Dac EGAC50000000218

• DAC for "Capturing disease severity in LIS1-lissencephaly reveals proteostasis dysregulation in patient-derived forebrain organoids" with Julia Ladewig(Julia.ladewig@zi-mannheim.de), Moritz Mall(m.mall@dkfz-heidelberg.de), and Matteo Gasparotto(matteo.gasparotto@zi-mannheim.de)

  Dac EGAC00001003588

• Walter and Eliza Hall - Aix-Marseille Université

  Data Access Committee for the Liao et al. 2025 study, D4Z4End2End: complete genetic and epigenetic architecture of D4Z4 macrosatellites in FSHD, BAMS and reference cohorts.

  Dac EGAC50000000655

• Division of Cancer Evolution National Cancer Center Research Institute Data Access Committee

  Data Access Committee for data from Division of Cancer Evolution, National Cancer Center Research Institute

  Dac EGAC50000000737

• MD Anderson OPMD DAC

  Datasets and agreement used for the OPMD dataset access of the publication Reconstructing oral cavity tumor evolution through brush biopsy, Springer Nature, DOI: 10.1038/s41598-024-72946-3

  Dac EGAC50000000384

• SiMSen‑Seq

  High resolution amplicon-bases sequencing o screen for PIK3CA hot spot mutations

  Dataset EGAD50000001668

• GEOCODE Cohort

  Transcriptomic profile for whole blood after 24hours of stimulations

  Dataset EGAD50000001320

• Effects of interferon-gamma treatment on human small intestinal organoids.

  Intestinal organoids treated with interferon-gamma 1 ng/mL either for 6h or 18h.

  Dataset EGAD50000000115

• Medulloblastoma dataset

  This dataset contains a tumor + normal DNA sequence data and tumor RNA seq data for a medulloblastoma patient.

  Dataset EGAD50000000384

• gz_bjREP

  DNA for 2979 individuals from Guangzhou was extract from peripheral blood and genotyped by Sequenom, with digit-number working memory, visuospatial working memory, recent long-term memory measured.

  Dataset EGAD00010001528

• GabonDiv_SNP_genotyping

  Genome-wide SNP genotyping data for 1,235 western Africans by Illumina HumanOmniExpress-12 array, used in the EGAS00001002078 study

  Dataset EGAD00010001209

• CHUM HNSCC biobank

  This Data Access Committee is responsible for reviewing and approving access requests to denominalized datasets generated by the CHUM HNSCC biobank, ensuring compliance with participant consent and ethical approvals.

  Dac EGAC50000001004

• Reference epigenome CKD24_C_Podo_mRNA-Seq data generated from KEP study

  A CKD24_C_Podo_mRNA-Seq paired end data for Podocytes(CD90(-) Podocalyxin(+), kidney)

  Dataset EGAD00001003482

• Reference epigenome CKD25_C_Podo_mRNA-Seq data generated from KEP study

  A CKD25_C_Podo_mRNA-Seq paired end data for Podocytes(CD90(-) Podocalyxin(+), kidney)

  Dataset EGAD00001003483

• Reference epigenome OB57_D_PreA_mRNA-Seq data generated from KEP study

  A OB57_D_PreA_mRNA-Seq paired end data for Preadipocyte(fat)

  Dataset EGAD00001003487

• Reference epigenome OB56_N_PreA_smRNA-Seq data generated from KEP study

  A OB56_N_PreA_smRNA-Seq single end data for Preadipocytes(fat)

  Dataset EGAD00001003495

• Reference epigenome OB57_D_PreA_smRNA-Seq data generated from KEP study

  A OB57_D_PreA_smRNA-Seq single end data for Preadipocyte(fat)

  Dataset EGAD00001003496

• Reference epigenome CKD24_C_Podo_smRNA-Seq data generated from KEP study

  A CKD24_C_Podo_smRNA-Seq single end data for Podocytes(CD90(-) Podocalyxin(+), kidney)

  Dataset EGAD00001003498

• Reference epigenome CKD25_C_Podo_smRNA-Seq data generated from KEP study

  A CKD25_C_Podo_smRNA-Seq single end data for Podocytes(CD90(-) Podocalyxin(+), kidney)

  Dataset EGAD00001003499

• RNA-Seq Pair End

  RNA analysis of two patients 11 and 15 with WGS done on Illumina HiSeq2000. For research purpose and authorised user only.

  Dataset EGAD00001003429

• Illumina HiSeq 2000

  Three files of patients 20, 23 and 25 with WGS done on Illumina HiSeq 2000. For research purpose and authorised user only.

  Dataset EGAD00001003438

• Reference epigenome IPS02_N_NPC_WGBS data generated from KEP study

  A IPS02_N_NPC_WGBS paired end data for Neural progenitor cells(Nestin)

  Dataset EGAD00001003474

• Reference epigenome IPS03_N_ENeuron_WGBS data generated from KEP study

  A IPS03_N_ENeuron_WGBS paired end data for Early neuron cells(Tuj1)

  Dataset EGAD00001003475

• RNA sequencing data to study "A biobank of patient-derived pediatric braintumor models"

  RNA sequencing data for the PDOX model EPD-613FH

  Dataset EGAD00001003573

• ATAC-seq for placental and buffycoat cells.

  We performed ATAC-seq experiments using 2 placental samples and 2 buffycoat samples.

  Dataset EGAD00001004291

• Uncovering tumor intrinsic and extrinsic factors that regulate hepatocellular carcinoma growth using patient derived xenograft assays

  Exome Sequencing and RNA Sequencing Data for PDX Samples

  Dataset EGAD00001005734

• H3Africa SIREN Phenotype

  Phenotype data for 3421 Samples from Nigeria and Ghana, genotyped with the Illumina NestSeq 500.

  Dataset EGAD00001011075

• A Phase II Neoadjuvant Study of Palbociclib in Combination with Letrozole and Trastuzumab as Neoadjuvant Treatment of Stage II-III ER+ HER2+ Breast Cancer (PALTAN)

  Women with early stage ER+/HER2+ breast cancer (BC) are less likely to achieve pathological complete response (pCR) after chemotherapy with standard of care dual HER2 blockade than patients with ER-/HER2+ BC. Additionally, the toxicity burden of standard systemic therapy is high. Thus, this single arm phase 2 clinical trial investigated a novel de-escalation regimen with trastuzumab, letrozole, and palbociclib in those with early stage ER+/HER2+ BC. The aim was to determine if this treatment regimen will achieve similar pCR rates as conventional treatment and spare women the toxicity burden of regular treatments. The primary endpoint was pCR after 16 weeks of treatment with trastuzumab, letrozole, and palbociclib. Patients with newly diagnosed ER+ HER2+ invasive BC with clinical stages II and III were eligible for this protocol. Research biopsies were performed during the treatment course for whole exome and RNA sequencing, PAM50 molecular subtyping, and Ki67 assessment using immunohistochemistry for complete cell cycle arrest (CCCA: Ki67 ≤2.7%). Results showed a pCR of 7.7% and a rate of residual cancer burden at 0 or I of 38.5%. CCCA was observed in 85% at Cycle 1 day 15 post palbociclib, trastuzumab, and letrozole treatment (C1D15), compared to 27% at surgery after palbociclib was discontinued. PAM50 subtyping identified 31.2% HER2-E, 43.8% Luminal B, 25% Luminal A. 161 genes were differentially expressed comparing C1D15 to baseline. Whole exome and RNA sequencing data will be available through dbGaP.

  Study phs003147

• Innate Immune Anti-Viral Deaminase Deregulation Fuels Pre-Leukemia Stem Cell Evolution

  This study evaluates the effect of Rebecsinib treatment on gene expression, isoform splicing, and ADAR1 mediated RNA editing in cells from an in vivo humanized mouse model which have been engrafted with human secondary AML cells. For analysis of cells from Rebesinib-treated animals, CD34+ cells were obtained from bone marrow and spleens of sAML-engrafted mice following once weekly treatment with 0 (Vehicle) or 5 or 10 mg/kg Rebecsinib. For analysis of cells from serial transplant recipients of cells harvested from Rebecsinib-treated mice, CD34+ cells were obtained from bone marrow and spleens of sAML-engrafted mice that were transplanted with cells from animals that received twice weekly treatment with 0 (Vehicle) or 10 mg/kg Rebecsinib. No further treatment was given to serial transplant recipients, thus allowing the analysis of molecular changes that are sustained following serial transplantation. Whole transcriptome sequencing was performed at The Scripps Research Institute Next Generation Sequencing Core on Illumina NextSeq 500 sequencers with 150bp paired-end reads.These data revealed a uniquely expressed ADAR1 splice isoform (with a retrained intronic region), global downregulation of normalized RNA editing events, and isoform switching from MCL1-L to MCL1-S in Rebecsinib-treated sAML-engrafted mice. These results demonstrate the anti-survival and anti-self-renewal effects of Rebecsinib treatment on the leukemia stem cell (LSC) population in sAML-engrafted mice as well as the reduction in the inflammation-induced, hyper-editing p150 isoform of ADAR1. Thus, Rebecsinib treatment has promise for reducing the LSC population in myeloproliferative disorders and associated cancers.

  Study phs002228

• Role of Tobacco Smoke in Clear Cell Renal Cell Carcinoma

  Background. Clear cell renal cell carcinoma (ccRCC) is the most common histologically defined renal cancer. However, it is not a uniform disease and includes several genetic subtypes with different prognoses. ccRCC is also characterized by distinguished metabolic reprogramming. Tobacco smoking (TS) is an established risk factor for ccRCC with unknown effects on tumor pathobiology.Methods. We investigated the landscape of ccRCCs and paired normal kidney tissues (NKTs) using integrated transcriptomic, metabolomic and metallomic approaches in a cohort of never smokers (NS) and long-term current smokers (LTS) Caucasian males. Results. All three Omics domains consistently identified a distinct metabolic subtype of ccRCCs in LTS, characterized by activation of oxidative phosphorylation (OxPhos) coupled with reprogramming of the malate-aspartate shuttle and metabolism of aspartate, glutamate, glutamine and histidine. Cadmium, copper and inorganic arsenic accumulated in LTS tumors showing redistribution among intracellular pools, including relocation of copper into the cytochrome c oxidase complex. Gene expression signature based on the LTS metabolic subtype provided prognostic stratification of The Cancer Genome Atlas (TCGA) ccRCC tumors that was independent from genomic alterations.Conclusions. The work identified the TS related metabolic subtype of ccRCC with vulnerabilities that can be exploited for precision medicine approaches targeting metabolic pathways. The results provided rationale for the development of metabolic biomarkers with diagnostic and prognostic applications using evaluation of OxPhos status. The metallomic analysis revealed the role of disrupted metal homeostasis in ccRCC highlighting the importance of studying effects of metals from e-cigarettes and environmental exposures.

  Study phs002083

• Whole Genome Bisulfite Sequencing of Circulating Cell-Free (CCF) DNA and its Cellular Contributors

  Background: Circulating cell free (ccf) fetal DNA has enabled non-invasive prenatal fetal aneuploidy testing without direct discrimination of the genetically distinct maternal and fetal DNA. Current testing may be improved by specifically enriching the sample material for fetal DNA. DNA methylation may allow for such a separation of DNA and thus support additional clinical opportunities; however, this depends on knowledge of the methylomes of ccf DNA and its cellular contributors. Results: Whole genome bisulfite sequencing was performed on a set of unmatched samples including ccf DNA from 8 non-pregnant (NP) and 7 pregnant female donors and genomic DNA from 7 buffy coat and 5 placenta samples. We found CpG cytosines within longer fragments were more likely to be methylated, linking DNA methylation and fragment size in ccf DNA. Comparison of the methylomes of placenta and NP ccf DNA revealed many of the 51,259 identified differentially methylated regions (DMRs) were located in domains exhibiting consistent placenta hypomethylation across millions of consecutive bases, regions we termed placenta hypomethylated domains. DMRs identified when comparing placenta to NP ccf DNA were recapitulated in pregnant ccf DNA, confirming the ability to detect differential methylation in ccf DNA mixtures. Conclusions: We generated methylome maps for four sample types at single base resolution, identified a link between DNA methylation and fragment length in ccf DNA, identified DMRs between sample groups, and uncovered the presence of megabase-size placenta hypomethylated domains. Furthermore, we anticipate these results to provide a foundation to which future studies using discriminatory DNA methylation may be compared.

  Study phs000846

• VCRC - Giant Cell Arteritis Longitudinal Study

  The development and validation of accurate biological markers and predictors of disease activity and outcome for Giant Cell Arteritis, a form of idiopathic vasculitis, would have a major positive impact on the clinical care of patients with this rare disease, be an important insight into the design of clinical trials and feasibility of new drug development, and provide important insight into the pathogenesis of this condition. Current measures of disease activity, including erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), while helpful in selected settings, are mostly considered highly flawed and markers whose poor correlation with disease flares makes them inadequate to help guide therapy. Similarly, ESR and CRP are clearly unhelpful as diagnostic tests for vasculitis. The current state of clinical investigation for vasculitis relies heavily upon determination of disease status solely by clinical presentation and investigator opinion. Thus, discovery and validation of more precise markers that quantifiably measure activity, predict disease course, and correlate with an important biological process, would be of great importance. Knowledge to be gained from this study could potentially be highly important. Discovery of effective biomarkers of vasculitis and assessment of long term disease course and complications by the collection of clinical and diagnostic imaging studies proposed could lead to better care and less toxic treatment regimens. Furthermore, insight into the pathophysiology of vasculitis could be gained and this might lead to better treatments and improved outcomes in terms of reduction of vascular and treatment related complications. Ideally, excellent biomarkers reflect a sophisticated understanding of the pathophysiology of a disease.

  Study phs000588

• The Neonatal Microbiome and Necrotizing Enterocolitis

  The Neonatal Microbiome and Necrotizing enterocolitis (NEC) study is a multi-centered case control study testing the hypothesis that NEC is a direct or indirect consequence of the enteric biomass, its products, or both. Very low birth weight infants (VLBW; birth weight ≤ 1500 grams) admitted to the neonatal intensive care unit are prospectively followed over the first 5 week or until they reach 36 weeks gestation, whichever occurs later. VLBW infants with a lethal clinical condition are excluded. Over the course of the study period, prospective samples are obtained on all infants, and include all stools, and weekly blood samples, palm and oral swabs. Clinical data is collected over the course of the entire hospitalization. Cases are identified based on Bell's staging for NEC, requiring Bell's stage II (abdominal clinical signs and radiographic evidence of pneumatosis, portal venous gas or pneumoperitoneum). Controls are identified from the pool of prospectively enrolled subjects, matching for gestational age, birth weight, post-natal age and birth date. The microbial components of stool and its products before and at the onset of NEC, are then compared between cases and controls. The Aims of this proposal are to (1) conduct a case cohort study in which we compare clinical data and biological specimens from cases and well-matched controls; (2) determine if the kind and density of intestinal biomass, its gene content, and transcriptional activity are associated with, and potential determinants of, NEC; and (3) determine if host risk alleles for intestinal inflammation play a role in the development of NEC.

  Study phs000247

• Digitalis Investigation Group (DIG-BioLINCC)

  Data Access NOTE: Please refer to the “Authorized Access” section below for information about how access to the data from this accession differs from many other dbGaP accessions. Objectives To determine the effect of increasing age on mortality, hospitalizations, and digoxin side effects in patients with heart failure (HF), and to determine whether the effect of digoxin on clinical outcomes varies as a function of age. Background The incidence and prevalence of HF increase with advancing age, but there are limited data on the clinical course and response to specific interventions in elderly patients with HF. Participants A total of 302 centers in the United States and Canada enrolled 7,788 patients between February 1991 and September 1993. Design The Digitalis Investigation Group (DIG) study was a prospective, randomized clinical trial involving 7,788 patients with HF randomized to digoxin or placebo and followed for an average of 37 months. Interactions between age and the following clinical outcomes were examined: total mortality, all-cause hospitalizations, HF hospitalizations, the composite of HF death or HF hospitalizations, hospitalization for suspected digoxin toxicity and withdrawal from therapy because of side effects. Conclusions Increasing age is associated with progressively worse clinical outcomes in patients with HF. However, the beneficial effects of digoxin in reducing all-cause admissions, HF admissions, and HF death or hospitalization are independent of age. Thus, digoxin remains a useful agent to the adjunctive treatment of HF due to impaired left ventricular systolic function in patients of all ages.

  Study phs003872

• Genetic Modifiers of Duchenne Muscular Dystrophy

  The primary determinant of disease severity in patients with severe Duchenne muscular dystrophy (DMD) or milder Becker muscular dystrophy (BMD) is whether their dystrophin gene (DMD) mutation disrupts the mRNA reading frame or permits the expression of a partially functional protein. However, even in the complete absence of dystrophin, variability in disease severity is observed, with candidate gene studies implicating several genes as potential DMD modifiers. This study undertakes a comprehensive genome-wide search for modifier loci influencing disease severity in DMD patients. The availability of subjects for such studies remains limited, resulting in modest sample sizes that challenge the GWAS design. To address this, we have implemented measures to minimize heterogeneity within the dataset at the dystrophin (DMD) gene itself, adopting a conservative approach to DMD mutation classification to limit the possibility of residual dystrophin expression. Additionally, the study employed statistical methods that are well-suited to smaller sample sizes, including the use of a novel linear regression-like residual for time to ambulatory loss and the application of evidential statistics, specifically the Posterior Probability of Linkage Disequilibrium (PPLD), to assess trait-SNP associations in the GWAS framework. With a sample size of 419 patients, this study has identified multiple candidate genetic modifier loci. The molecular data available in dbGaP includes 2,562,265 directly genotyped variants in 419 people using the Illumina Infinium Omni2.5Exome-8 Beadchip assay, achieving a genotyping rate of 0.998. The phenotypic data comprises age at ambulatory loss, steroid status, DMD gene mutation, and the PPLD value from the time-to-event (TE) phenotype.

  Study phs003680

• Women's Ischemia Syndrome Evaluation (WISE-BioLINCC)

  Data Access NOTE: Please refer to the "Authorized Access" section below for information about how access to the data from this accession differs from many other dbGaP accessions. Objectives: This is a National Heart, Lung and Blood Institute sponsored, four-center study designed to: 1) optimize symptom evaluation and diagnostic testing for ischemic heart disease; 2) explore mechanisms for symptoms and myocardial ischemia in the absence of epicardial coronary artery stenoses, and 3) evaluate the influence of reproductive hormones on symptoms and diagnostic test response.Background: Women tend to have a higher prevalence of chest pain than men, yet a lower prevalence of epicardial coronary stenoses, and diagnostic tests such as exercise-induced ECG changes tend to have a higher false-positive rate in women than in men. Thus, accurate diagnosis of ischemic heart disease in women is a major challenge to physicians. In addition, prognosis in women with abnormal diagnostic tests is largely unknown and the role reproductive hormones play in this diagnostic uncertainty is unexplored. Moreover, the significance and pathophysiology of ischemia in the absence of significant epicardial coronary stenoses is unknown.Participants: In Phase I (1996-1997), a pilot phase, 256 women were studied. During Phase II (1997-1999) angiographic and baseline data were collected on an additional 680 women to bring total enrollment to 936. Baseline data was also collected on a reference population of 70 women.Conclusions: Among women without CAD, abnormal Magnetic Resonance Spectroscopy (MRS) consistent with myocardial ischemia predicted cardiovascular outcome, notably higher rates of anginal hospitalization, repeat catherization, and greater treatment costs.

  Study phs004310

• Target sequencing of 27 cancer-predisposing genes in Japanese colorectal cancer patients

  Background: National Comprehensive Cancer Network (NCCN) recently recommended germline genetic testing for all pancreatic cancer patients. However, the genes targeted by genetic testing and the feasibility of selecting patients likely to carry pathogenic variants have not been sufficiently verified. The purpose of this study was to genetically characterize Japanese patients and examine whether the current guideline is applicable in this population. Methods: Using targeted sequencing, we analyzed the coding regions of 27 cancer-predisposing genes in 1,005 pancreatic cancer patients and 23,705 controls in Japan. We compared the pathogenic variant frequency between cases and controls and documented the demographic and clinical characteristics of carrier patients. We then examined if it was possible to use machine learning to predict carrier status based on those characteristics. Findings: We identified 205 pathogenic variants across the 27 genes. Pathogenic variants in BRCA2, ATM, and BRCA1 were significantly associated with pancreatic cancer. Characteristics associated with carrier status were inconsistent with previous investigations. Machine learning classifiers had a low performance in determining the carrier status of pancreatic cancer patients, while the same classifiers, when applied to breast cancer data as a positive control, had a higher performance that was comparable to that of the NCCN guideline. Interpretation: Our findings support the clinical significance of multigene panel testing for pancreatic cancer and indicate that at least 3.4% of Japanese patients may respond to poly (ADP ribose) polymerase inhibitor treatments. The difficulty in predicting carrier status suggests that offering germline genetic testing for all pancreatic cancer patients is reasonable.

  Study JGAS000346

• Target sequencing of 27 cancer-predisposing genes in Japanese pancreatic cancer patients

  Background: National Comprehensive Cancer Network (NCCN) recently recommended germline genetic testing for all pancreatic cancer patients. However, the genes targeted by genetic testing and the feasibility of selecting patients likely to carry pathogenic variants have not been sufficiently verified. The purpose of this study was to genetically characterize Japanese patients and examine whether the current guideline is applicable in this population. Methods: Using targeted sequencing, we analyzed the coding regions of 27 cancer-predisposing genes in 1,005 pancreatic cancer patients and 23,705 controls in Japan. We compared the pathogenic variant frequency between cases and controls and documented the demographic and clinical characteristics of carrier patients. We then examined if it was possible to use machine learning to predict carrier status based on those characteristics. Findings: We identified 205 pathogenic variants across the 27 genes. Pathogenic variants in BRCA2, ATM, and BRCA1 were significantly associated with pancreatic cancer. Characteristics associated with carrier status were inconsistent with previous investigations. Machine learning classifiers had a low performance in determining the carrier status of pancreatic cancer patients, while the same classifiers, when applied to breast cancer data as a positive control, had a higher performance that was comparable to that of the NCCN guideline. Interpretation: Our findings support the clinical significance of multigene panel testing for pancreatic cancer and indicate that at least 3.4% of Japanese patients may respond to poly (ADP ribose) polymerase inhibitor treatments. The difficulty in predicting carrier status suggests that offering germline genetic testing for all pancreatic cancer patients is reasonable.

  Study JGAS000327

• Gene expression of human Th17 cells before and after activation

  Although gene expression of human Th17 clones has been studies, to date, molecular mechanisms for human Th17 development remain unclear. We have analyzed gene expression of human Th17 cells before and after activation. Th17-cell clones from peripheral blood CD4 T cells cultured with LPS-stimulated dendritic cells derived from monocytes stimulated by TNF were established by a limited dilution method. One of the Th17 clones was proliferated significantly, and high percentages (>70%) of Th17 cells in the cultured cells were maintained by addition of monocytes, IL-1b, and IL-15. CD161+CXCR3- cells (CD161+Th17) in the cultures were sorted and purified up to approximately 97% of IL-17-producing cells after treatment with PMA/ionomycin. Furthermore, these cells were treated with TCR-stimuli, IL-1b, and IL-23 for 2 days, and IL-17-producing Th17 cells (active-Th17) detected by IL-17-catch-up antibodies were sorted. Total RNA sampled from 1x 106 CD161+Th17, active-Th17, na?ve CD4 T cells, or CXCR3+ Th1 cells from combined CD4 T and dendritic cell cultures was used for SAGE. SAGE was performed by using SOLID TM SAGETM kit with barcoding adaptor molecules (Applied Biosystems). DNA sequence was analyzed by using AB5500 Genetic Analyzer (Applied Biosystems), and gene expression was analyzed by using SOLID? SAGETM software (Applied Biosystems). Our data shows high levels of IL-17A-mRNA expression by active-Th17; however, but only slight expression by CD161+Th17. Therefore, the data could provide alteration of gene expression by Th17 cells before and after stimulation.

  Study JGAS000005

• Heterogeneity of IKZF1 genomic alterations and risk of relapse in childhood B-cell precursor acute lymphoblastic leukemia

  Purpose Genomic alterations of IKZF1 are common and associated with adverse clinical features in B-ALL, but the relationship between the type of IKZF1 alteration, disease subtype and outcome are incompletely understood. Patients and Methods We used transcriptome and genomic sequencing, and SNP microarray data to determine leukemia subtype and genomic alterations for 688 pediatric patients with B-ALL enrolled into St. Jude Total Therapy 15 and 16 studies. Results IKZF1 alterations were identified in 115 (16.7%) patients, commonly in BCR::ABL1 (78%) and CRLF2-rearranged, BCR::ABL1-like B-ALL (70%), and were associated with five-year cumulative incidence of relapse (CIR) of 14.8 ± 3.3% compared to 5.0 ± 0.9% for patients without any IKZF1 alteration (P < 0.0001). IKZF1 deletions of exon 4-7 (P = 0.0002), genomic IKZF1plus with any IKZF1 deletion (P = 0.006) or with focal IKZF1 deletion (P = 0.0007), and unfavorable genomic subtypes (P < 0.005) were independently adversely prognostic. Patients with both IKZF1 exon 4-7 deletion and unfavorable genomic subtype had a significantly increased risk of relapse (HR = 58.3; 95% CI, 11.9 – 285.4, P < 0.0001) whereas IKZF1 sequence mutations were not independently predictive of outcome. Conclusions Genomic IKZF1plus with any IKZF1 deletion, IKZF1 deletion of exon 4-7, and unfavorable subtype confer increased risk of relapse. The combination of unfavorable genomic subtype and IKZF1 deletion of exon 4-7 identified patients at greatest risk of relapse despite MRD-directed therapy. The type of IKZF1 alteration together with subtype are informative for risk stratification and predict response in patients with B-ALL.

  Study EGAS50000000106

• DNA methylation and the adverse metabolic outcomes of adiposity

  Overweight and obesity affect ~1.5 billion people worldwide, and are major risk factors for type-2 diabetes (T2D), cardiovascular disease and related metabolic and inflammatory disturbances.1,2 Although the mechanisms linking adiposity to its clinical sequelae are poorly understood, recent studies suggest that adiposity may influence DNA methylation,3-6 a key regulator of gene expression and molecular phenotype.7 Here we use epigenome-wide association to show that body mass index (BMI, a key measure of adiposity) is associated with widespread changes in DNA methylation (187 genetic loci at P&lt;1x10-7, range P=9.2x10-8 to 6.0x10-46; N=10,261 samples). Genetic association analyses demonstrate that the alterations in DNA methylation are predominantly the consequence of adiposity, rather than the cause. We find the methylation loci are enriched for functional genomic features in multiple tissues (P&lt;0.05), and show that sentinel methylation markers identify gene expression signatures at 38 loci (P&lt;9.0x10-6, range P=5.5x10-6 to 6.1x10-35, N=1,785 samples). The methylation loci identified highlight genes involved in lipid and lipoprotein metabolism, substrate transport, and inflammatory pathways. Finally, we show that the disturbances in DNA methylation predict future type-2 diabetes (relative risk per 1SD increase in Methylation Risk Score: 2.3 [2.07-2.56]; P=1.1x10-54). Our results provide new insights into the biologic pathways influenced by adiposity, and may enable development of new strategies for prediction and prevention of type-2 diabetes and other adverse clinical consequences of obesity.

  Study EGAS00001001922

• pancreatic ductal adenocarcinoma exomes in study: Pro-immunogenic Impact of MEK inhibition combined with an anti-CD40 immunostimulatory antibody

  Cancer types with lower mutational load and a non-permissive tumor microenvironment are intrinsically resistant to immune checkpoint blockade. While the combination of cytostatic drugs and immunostimulatory antibodies constitutes an attractive concept for overcoming this refractoriness, suppression of immune cell function by cytostatic drugs may limit therapeutic efficacy. Here we show that targeted inhibition of mitogen-activated protein kinase (MAPK) kinase (MEK) does not impair dendritic cell-mediated T-cell priming and activation. Accordingly, combining MEK inhibitors (MEKi) with agonist antibodies (Abs) targeting the immunostimulatory CD40 receptor resulted in potent synergistic anti-tumor efficacy. Detailed analysis of the mechanism of action of MEKi GDC-0623 by means of flow cytometric analysis of the tumor immune infiltrate and whole tumor transcriptomics showed that, in addition to its cytostatic impact on tumor cells, this drug exerts multiple pro-immunogenic effects, including the suppression of M2-type macrophages, myeloid derived suppressor cells and CD4+ T-regulatory cells. In addition, MEKi was found to induce tumor-cell intrinsic interferon signaling, which contributed to antigen presentation by tumor cells. Finally, the tumoridical impact of MEKi involves the activation of multiple pro-inflammatory pathways involved in immune cell effector function in the tumor microenvironment. Our data therefore indicate that the combination of MEK inhibition with agonist anti-CD40 Ab is a promising therapeutic concept, especially for the treatment of mutant Kras-driven tumors such as pancreatic ductal adenocarcinoma. The pancreatic ductal adenocarcinoma exomes were generated in the context of the Heidelberg Center for Personalized Oncology project HIPO-K28E.

  Study EGAS00001004196

• A Functional Network of Gastric-Cancer-Associated Splicing Events Controlled by Dysregulated Splicing Factors

  Except for a few genes known to have oncogenic spliceforms in gastric cancer, the full scope of aberrant splicing in gastric oncogenesis remains unclear. In this study, we elucidated the alternative splicing events associated with gastric carcinogenesis and identified upstream regulators governing these events. We performed RNA-seq on 19 matched tumor/normal pairs and a panel of gastric cancer cell lines, and identified 361 tumor associated (TA) alternative splicing events (ASEs), which included known oncogenic ASEs in genes such as INSR, FGFR2, CD44 and KRAS. We further identified 8 splicing factors dysregulated in gastric tumors, the expression of which are correlated to the splice ratio of the TA ASEs. We thereby constructed a dysregulated splicing network in gastric cancer, consisting of alternative splicing changes correlated to their potential regulators. This network featured three potential regulatory modules centered around the splicing factors ESRP2, MBNL1 and PTPB1. Knockdown of each splicing factor led to the expected changes in splicing of approximately half of the ASEs assayed. Thus, dysregulation of the splicing factors indeed was the cause of many of the TA ASEs. Pathway enrichment analysis showed that genes affected by tumor associated splicing were pre-dominantly involved in cytoskeletal organization. Concordant with this, knockdown of the splicing factors regulating the TA ASEs led to the expected changes in trans-well migration activity. Thus, we have established for the first time a comprehensive splicing network that likely drives gastric tumor progression, based on which novel therapeutic targets can be identified for further evaluation.

  Study EGAS00001002256

• High-throughput Detection of Clinically Relevant Mutations in Archived Tumor Samples By Multiplexed PCR and Next Generation Sequencing

  PURPOSE: Tailoring cancer treatment to tumor molecular characteristics promises to make personalized medicine a reality. However, reliable genetic profiling of archived clinical specimens has been hindered by limited sensitivity and high false positive rates. Here, we describe a novel methodology, MMP-seq, which enables sensitive and specific high-throughput, high content genetic profiling in archived clinical samples. EXPERIMENTAL DESIGN: We first validated MMP-seq’s technical performance in 66 cancer cell lines and a Latin square cross-dilution of known somatic mutations. We next characterized the performance of MMP-seq in 17 formalin-fixed paraffin embedded (FFPE) clinical samples using matched fresh frozen (FF) tissue from the same tumors as benchmarks. To demonstrate the potential clinical utility of our methodology, we profiled FFPE tumor samples from 73 endometrial cancer patients. RESULTS: We demonstrated that MMP-seq enabled rapid and simultaneous profiling of a panel of 88 cancer genes in 48 samples, and detected variants at frequencies as low as 0.4%. We identified DNA degradation and deamination as the main error sources and developed practical and robust strategies for mitigating these issues, and dramatically reduced the false positive rate. Applying MMP-seq to a cohort of endometrial tumor samples identified extensive, potentially actionable alterations in the PI3K and RAS pathways, including novel PIK3R1 hotspot mutations that may disrupt negative regulation of PIK3CA. CONCLUSIONS: MMP-seq provides a robust solution for comprehensive, reliable and high- throughput genetic profiling of clinical tumor samples, paving the way for the incorporation of genomic-based testing into clinical investigation and practice.

  Study EGAS00001000674

• Exome Sequencing Of 75 Individuals From Multiply Affected Coeliac Families

  Coeliac disease is a highly heritable common autoimmune disease involving chronic small intestinal inflammation in response to dietary wheat. The human leukocyte antigen (HLA) region, and 40 newer regions identified by genome wide association studies (GWAS) and dense fine mapping, account for ~40% of the disease heritability. We hypothesized that in pedigrees with multiple individuals with coeliac disease rare [minor allele frequency (MAF) &lt;0.5%] mutations of larger effect size (odds ratios of ~ 2 – 5) might exist. We sequenced the exomes of 75 coeliac individuals of European ancestry from 55 multiply affected families. We selected interesting variants and genes for further follow up using a combination of: an assessment of shared variants between related subjects, a model-free linkage test, and gene burden tests for multiple, potentially causal, variants. We next performed highly multiplexed amplicon resequencing of all RefSeq exons from 24 candidate genes selected on the basis of the exome sequencing data in 2,248 unrelated coeliac cases and 2,230 controls. 1,335 variants with a 99.9% genotyping call rate were observed in 4,478 samples, of which 939 were present in coding regions of 24 genes (Ti/Tv 2.99). 91.7% of coding variants were rare (MAF &lt;0.5%) and 60% were novel. Gene burden tests performed on rare functional variants identified no significant associations (P&lt;1x10-3) in the resequenced candidate genes. Our strategy of sequencing multiply affected families with deep follow up of candidate genes has not identified any new coeliac disease risk mutations.

  Study EGAS00001001093

• UK10K NEURO FSZNK

  In the UK10K project we propose a series of complementary genetic approaches to find new low frequency/rare variants contributing to disease phenotypes. These will be based on obtaining the genome wide sequence of 4000 samples from the TwinsUK and ALSPAC cohorts (at 6x sequence coverage), and the exome sequence (protein coding regions and related conserved sequence) of 6000 samples selected for extreme phenotypes. Our studies will focus primarily on cardiovascular-related quantitative traits, obesity and related metabolic traits, neurodevelopmental disorders and a limited number of extreme clinical phenotypes that will provide proof-of-concept for future familial trait sequencing. We will analyse directly quantitative traits in the cohorts and the selected traits in the extreme samples, and also use imputation down to 0.1% allele frequency to extend the analyses to further sample sets with genome wide genotype data. In each case we will investigate indels and larger structural variants as well as SNPs, and use statistical methods that combine rare variants in a locus or pathway as well as single-variant approaches. This Finnish schizophrenia sample set has been collected from a population cohort using national registers. The entire sample collection consists of 2756 individuals from 458 families of whom 931 are diagnosed with schizophrenia spectrum disorder. Families outside Kuusamo (n=288) all had at least two affected siblings. All diagnoses are based on DSM-IV and for a large fraction of cases there is cognitive data.For further details/descriptions with regard to this data set please contact Tiina Paunio (tiina.paunio@thl.fi)

  Study EGAS00001000119

• Longitudinal_profiling_of_the_immune_response_to_Plasmodium_vivax_in_naive_hosts_by_RNA_sequencing

  Plasmodium vivax offers unique challenges for control and elimination, and may prove a tougher hurdle to overcome than Plasmodium falciparum. And yet compared to P. falciparum we know very little about the innate and adaptive immune responses that need to be harnessed to reduce disease and transmission. We recently generated a blood bank of a new clonal field isolate of P. vivax (PvW1) for human challenge studies and used systems immunology tools to track the host response throughout infection and convalescence. As part of this study, RNA-sequencing was used to resolve changes in whole blood gene expression through time in 6 volunteers (7-9 time-points per volunteer). In summary, these data show that P. vivax induces two distinct transcriptional programmes in whole blood during and after infection. During infection, transcriptional profiling reveals the rapid mobilisation of an emergency myeloid response, which leads to systemic inflammation and the recruitment of all major T cell subsets into lymphoid tissues. Six days after infection, this innate response subsides and a transcriptional signature of proliferation is revealed. This most likely represents widespread activation of lymphocytes, which return to the circulation after parasite clearance - transcriptional profiling of T cells at this time-point could therefore reveal the outcomes of critical cell-cell interactions that take place within the spleen during infection. 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 EGAS00001003847

• These are from Korean HCC samples with exome sequencing

  Hepatic resection is the most curative treatment option for early-stage hepatocellular carcinoma, but is associated with a high recurrence rate, which exceeds 50% at 5 years after surgery. Understanding the genetic basis of hepatocellular carcinoma at surgically curable stages may enable the identification of new molecular biomarkers that accurately identify patients in need of additional early therapeutic interventions. Whole exome sequencing and copy number analysis was performed on 231 hepatocellular carcinomas (72% with hepatitis B viral infection) that were classified as early-stage hepatocellular carcinomas, candidates for surgical resection. Recurrent mutations were validated by Sanger sequencing. Unsupervised genomic analyses identified an association between specific genetic aberrations and postoperative clinical outcomes. Recurrent somatic mutations were identified in 9 genes, including TP53, CTNNB1, AXIN1, RPS6KA3, and RB1. Recurrent homozygous deletions in FAM123A, RB1, and CDKN2A, and high-copy amplifications in MYC, RSPO2, CCND1, and FGF19 were detected. Pathway analyses of these genes revealed aberrations in the p53, Wnt, PIK3/Ras, cell cycle, and chromatin remodelling pathways. RB1 mutations were significantly associated with cancer-specific and recurrence-free survival after resection (p = 0.016 and p = 0.001, respectively). FGF19 amplifications, known to activate Wnt signalling, were mutually exclusive with CTNNB1 and AXIN1 mutations, and significantly associated with cirrhosis (p = 0.017). RB1 mutations can be used as a prognostic molecular biomarker for resectable hepatocellular carcinoma. Further study is required to investigate the potential role of FGF19 amplification in driving hepatocarcinogenesis in patients with liver cirrhosis and to investigate the potential of anti-FGF19 treatment in these patients.

  Study EGAS00001000604

• Dilgom_Exome

  The Finrisk sample sets are part of the National FINRISK Study. It is a large population survey on risk factors of chronic, noncommunicable diseases. The survey is carried out since 1972 every five years using independent, random and representative population samples from different parts of Finland. The main results from the previous FINRISK 2007 survey are published.The National FINRISK Study Survey was carried out in 5 areas in Finland and 2000 inhabitants aged 25-75 years were invited to participate in each year. Among findings were that Finns continue to gain weight.Data from FINRISK surveys are used for many different research projects and for national health monitoring needs. The recent research activities deal, in addition to cardiovascular diseases and the classical risk factors, also with e.g. asthma and allergy, alcohol, socioeconomic factors and genetic epidemiology.The FINRISK study is part of the MORGAM Project (MONICA Risk, Genetics, Archiving and Monigraph), sponsored by the EU and MDECODE (Molecular Diversity and Epidemiology of Common Disease) program coordinated by the University of Michigan.The exome sequencing study will be part of the Dilgom study, which is a part of the larger Finrisk population based health study performed in Finland. It consists of 5000 individuals with a prospective aspect of metabolic traits. The cohort has been extensively phenotyped for their cardiovascular and metabolic status. So far, we have performed a 660K Illumina GWAS and a full genome wide expression study from peripheral blood cells of 500 individuals. The cohort has also been in total genotyped by the cardiometabochip

  Study EGAS00001000086

• Expanding the neurodevelopmental phenotypes of individuals with de novo KMT2A variants

  De novo loss-of-function (LoF) variants in the KMT2A gene are associated with Wiedemann-Steiner Syndrome (WSS). Recently, de novo KMT2A variants have been identified in sequencing studies of cohorts of individuals with neurodevelopmental disorders (NDDs). However, most of these studies lack the detailed clinical information required to determine whether those individuals have isolated NDDs or WSS (i.e. syndromic NDDs). We performed thorough clinical and neurodevelopmental phenotyping on six individuals with de novo KMT2A variants. From these data, we found that all six patients met clinical criteria for WSS and we further define the neurodevelopmental phenotypes associated with KMT2A variants and WSS. In particular, we identified a subtype of Autism Spectrum Disorder (ASD) in five individuals, characterized by marked rigid, repetitive and inflexible behaviours, emotional dysregulation, externalizing behaviours, but relative social motivation. To further explore the clinical spectrum associated with KMT2A variants, we also conducted a meta-analysis of individuals with KMT2A variants reported in the published literature. We found that de novo LoF or missense variants in KMT2A were significantly more prevalent than predicted by a previously established statistical model of de novo mutation rate for KMT2A. Our genotype-phenotype findings better define the clinical spectrum associated with KMT2A variants and suggest that individuals with de novo LoF and missense variants likely have a clinically unrecognized diagnosis of WSS, rather than isolated NDD or ASD alone. This highlights the importance of a clinical genetic and neurodevelopmental assessment for individuals with such variants in KMT2A.

  Study EGAS00001003521

• UK10K_RARE_THYROID

  In the UK10K project we propose a series of complementary genetic approaches to find new low frequency/rare variants contributing to disease phenotypes. These will be based on obtaining the genome wide sequence of 4000 samples from the TwinsUK and ALSPAC cohorts (at 6x sequence coverage), and the exome sequence (protein coding regions and related conserved sequence) of 6000 samples selected for extreme phenotypes. Our studies will focus primarily on cardiovascular-related quantitative traits, obesity and related metabolic traits, neurodevelopmental disorders and a limited number of extreme clinical phenotypes that will provide proof-of-concept for future familial trait sequencing. We will analyse directly quantitative traits in the cohorts and the selected traits in the extreme samples, and also use imputation down to 0.1% allele frequency to extend the analyses to further sample sets with genome wide genotype data. In each case we will investigate indels and larger structural variants as well as SNPs, and use statistical methods that combine rare variants in a locus or pathway as well as single-variant approaches.Two cohorts of subjects are being analysed: Individuals with Congenital Hypothyroidism (CH) due either to dysgenesis or dyshormonogenesis; Patients with Resistance to Thyroid hormone (RTH), a disorder characterized by elevated thyroid hormones and variable tissue refractoriness to hormone action. The CH cohort has been enriched for genetic aetiologies by recruiting cases that are familial, on a consanguineous background or syndromic. The RTH cohort consists of cases in which candidate gene analyses have been negative.For further information with regard to this cohort please contact Krishna Chatterjee (kkc1@medschl.cam.ac.uk).

  Study EGAS00001000131

• Sporadic and endemic Burkitt lymphoma have frequent FOXO1 mutations but distinct hotspots in the AKT recognition motif

  FOXO1 has an oncogenic role in adult germinal center derived lymphomas, in which mutations, predominately within the AKT recognition motif, cause nuclear retention of FOXO1 resulting in increased cell proliferation. To determine the prevalence and distribution of FOXO1 mutations in pediatric Burkitt lymphoma (BL), we sequenced a large number of sporadic and endemic BL patient samples. We report a high frequency of FOXO1 mutations in both sporadic and endemic BL at diagnosis, occurring in 23/78 (29%) and 48/89 (54%) samples respectively, as well as 8/16 (50%) cases at relapse. Mutations of T24 were the most common in sporadic BL but were rare in endemic cases, in which mutations of residue S22, also within the AKT recognition motif, were the most frequent. FOXO1 mutations were almost always present in the major tumor cell clone but were not associated with outcome. Analysis of other recurrent mutations reported in BL revealed that FOXO1 mutations were associated with mutations of DDX3X and ARID1A, but not MYC, TCF3/ID3 or members of the phosphatidylinositol 3’ OH kinase (PI3K) signaling pathway. We further show common nuclear retention of the FOXO1 protein, irrespective of mutation status, suggesting alternative unknown mechanisms for maintaining FOXO1 transcriptional activity in BL. CRISPR/Cas9 knockout of FOXO1 in an endemic cell line produced a significant decrease in cell proliferation, supporting an oncogenic role for FOXO1 in endemic BL. Thus, FOXO1 is frequently mutated in both sporadic and endemic BL and may offer a potential therapeutic target for pediatric BL patients worldwide.

  Study EGAS00001003719

• Evolution of a FLT3-TKD mutated subclone at meningeal relapse in acute promyelocytic leukemia (H021)

  Here we report the case of an acute promyelocytic leukemia (APL) patient who, though negative for FLT3 mutations at diagnosis, developed isolated FLT3-TKD positive meningeal relapse, which, in retrospect, could be traced back to a minute bone marrow subclone present at first diagnosis. Initially, the 48-year old female diagnosed with high-risk APL had achieved complete molecular remission after standard treatment with all-trans retinoic acid (ATRA) and chemotherapy according to the AIDA protocol. 13 months after start of ATRA maintenance the patient suffered clinically overt meningeal relapse along with minute molecular traces of PML/RARA in the bone marrow. Following treatment with arsenic trioxide (ATO) and ATRA in combination with intrathecal cytarabine and methotrexate, the patient achieved a complete molecular remission in both cerebrospinal fluid (CSF) and bone marrow, which currently lasts for two years after completion of therapy. Whole exome sequencing and subsequent ultradeep targeted re-sequencing revealed a heterozygous FLT3-TKD mutation in CSF leukemic cells (p.D835Y, c.2503G&gt;T, 1000/1961 reads (51%)), which was undetectable in the concurrent bone marrow sample. Interestingly, the FLT3-TKD mutated meningeal clone originated from a small bone marrow subclone present in a variant allele frequency of 0.4% (6/1553 reads) at initial diagnosis. This case highlights the concept of clonal evolution with a subclone harboring an additional mutation being selected as the “fittest” and leading to meningeal relapse. It also further supports earlier suggestions that FLT3 mutations may play a role for migration and clonal expansion in the CSF sanctuary site.H021

  Study EGAS00001001848

• A novel breast cancer cell line derived from a metastatic bone lesion of a breast cancer patient

  Purpose: We sought to generate and characterize a novel cell line from a breast cancer bone metastasis in order to better study the progression of the disease.Methods: The cell line, P7731, was derived from a metastatic bone lesion of a breast cancer patient and assessed for marker expression. P7731 was analyzed for DNA copy number variation, somatic mutations and gene expression and compared to the primary tumor. Results: P7731 cells are negative for estrogen receptor alpha (ERα), progesterone receptor (PR) and HER2 (triple-negative), strongly express vimentin (100% of cells positive) and also express cytokeratins 8/18 and 19 but at lower frequencies. Flow cytometry indicates P7731 cells are predominantly CD44+/CD49f+/EpCAM-, consistent with a primitive, mesenchymal-like phenotype. The cell line is tumorigenic in immunocompromised mice. Exome sequencing identified a total of 45 and 76 somatic mutations in the primary tumor and cell line respectively, of which 32 were identified in both samples and included mutations in known driver genes PIK3CA, TP53 and ARID1A. P7731 retains the DNA copy number alterations present in the matching primary tumor. Homozygous deletions detected in the cell line and in the primary tumor were found in regions containing three known (CDKN2A, CDKN2B and CDKN1B) and 23 putative tumor suppressor genes. Cell line specific gene amplification coupled with mRNA expression analysis revealed genes and pathways with potential pro-metastatic functions.Conclusion: This novel human breast cancer-bone metastasis cell line will be a useful model to study aspects of breast cancer biology, particularly metastasis-related changes from breast to bone.

  Study EGAS00001002840

• Identification of Therapeutic Targets in Rhabdomyosarcoma Through Integrated Genomic, Epigenomic, and Proteomic Analyses

  Personalized cancer therapy based on the somatic mutations identified in patient tumors is becoming an increasingly emphasized approach to improve outcomes of patients with cancer. There are also examples of therapeutic vulnerabilities in cancer that result from changes in gene expression that are a direct or indirect result of tumor specific epigenetic perturbations. These genomic and epigenomic changes are ultimately manifest in the tumor proteome and phosphoproteome. In this study, we integrated genomic, epigenomic and proteomic data for rhabdomyosarcoma (RMS) to identify therapeutic vulnerabilities. RMS was selected for this analysis because RAS pathway mutations in rhabdomyosarcoma (RMS) are the most common potentially actionable lesions across pediatric solid tumors. The epigenomic data was useful for identifying deregulated developmental pathways in RMS including the WNT, HH, BMP, adenyl cyclase, p38/MAPK and PI3K pathways. Perturbations in those 6 myogenic signal transduction pathways were also evident in the proteome and phosphoteome data. In addition, the proteomic/phosphoproteomic data revealed that the cell cycle checkpoint, unfolded protein response and RB/E2F pathways were deregulated in RMS relative to normal muscle. Recent success targeting CDK4/6 and MEK in adult cancers with RAS mutations led us to test the value of these targets in RMS tumors. We also targeted the unfolded protein response pathway and cell cycle checkpoint pathway using molecular targeted therapeutics in orthotopic patient derived xenografts. Taken together, these data demonstrate the value of integrating epigenomic and proteomic data to identify tumor vulnerabilities that extend beyond somatic mutations identified in the genome.

  Study EGAS00001002967

• Spatiotemporal evolution and inter-patient heterogeneity in primary and recurrent/metastatic head and neck squamous cell carcinoma

  Head and neck cancer squamous cell carcinomas (HNSCCs) are heterogeneous in terms of origin and aetiology. In addition, there is uncertainty about the spatiotemporal genetic evolution from initial diagnosis to recurrence/metastasis (R/M) after primary treatments and further disease progression following systemic treatment. Changes in the genetic profile have implications on the selection of appropriate treatments for patients, especially in the era of targeted therapies and immunotherapies. Here, we analysed a cohort of 11 HNSCC patients with metachronous R/M, among whom nine had paired primary and R/M samples suitable for next-generation sequencing (multiple R/M samples collected at different time points were available for some of the patients). At the genomic level, the R/M samples shared a fraction of the somatic single nucleotide variants (SNVs) with the index primary tumours, but they also acquired many additional mutations, while losing only a few others. A similar behaviour was also observed when examining the changes of mutational signatures between primary and R/M samples. Overall, R/M appeared thus more genetically diverse than the respective primary tumours. The transcriptomic analysis showed that R/M samples had lower immune cell infiltration and several genes related to immune response were significantly downregulated compared to the primary samples. Our results underline the importance of analysing multiple samples per patient to obtain a more complete picture of the patient’s tumour and advocates a re-biopsy in the event of R/M and treatment failure, in order to select the most appropriate therapeutic strategy.

  Study EGAS00001007464

• Peripheral blood DNA methylome in adalimumab-treated patients with rheumatoid arthritis

  Background and aims Rheumatoid arthritis (RA) patients are currently treated with biological agents mostly aimed at cytokine blockade such as anti-TNFα therapy. Currently, there are no biomarkers to predict therapy response to these agents. Here, we aimed to predict response to adalimumab (ADA) treatment in RA patients using DNA methylation in peripheral blood Methods DNA methylation profiling on whole peripheral blood from 92 RA patients before the start of adalimumab (ADA) was determined using Illumina HumanMethylationEPIC BeadChip Array. After 6 months, treatment response was assessed according to the Alliance of Associations for Rheumatology (EULAR) criteria for disease response. Patients were classified as responders (DAS28&lt;3.2 or decrease of 1.2 points) or as non-responders (DAS28&gt;5.1 or decrease of less than 0.6 points). Machine learning models were built with gradient boosting and stability selection models to predict response prior to ADA treatment with predictor DNA methylation markers. Results We demonstrated a 27-feature panel of DNA methylation markers or CpG classifiers that predict response in RA patients treated with ADA. Forty-nine patients were assigned as responder and 43 patients assigned as non-responders. We differentiate responders from non-responders with a high sensitivity (AUC 0.76). The predictor CpGs annotated to genes involved in immunological- and pathophysiological pathways related to RA such as T-cell signaling, B-cell pathology and angiogenesis. Conclusion Our findings indicate that DNA methylation signatures discriminate responders and non-responders to ADA treatment and can serve as a tool for therapy prediction.

  Study EGAS00001007578

• Ipilimumab plus Decitabine for Patients with MDS or AML in Post-Transplant or Transplant Naïve Settings

  Design and AimsThis study was a phase 1 clinical trial investigating the combination of ipilimumab (IPI), a CTLA-4 checkpoint inhibitor, and decitabine (DEC), a hypomethylating agent, for treating relapsed/refractory (R/R) myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). The goal was to determine whether DEC could enhance the immune response to IPI without causing excessive immune toxicity. This study provides important insights into the use of immune checkpoint inhibitors with hypomethylating agents in treating high-risk MDS/AML and highlights the need for further research on optimizing immune-based therapies in these settings.Population InformationPost-HSCT arm: 25 patients (23 AML, 2 MDS; all relapsed/refractory).Transplant-na&#239;ve arm: 23 patients (15 AML, 8 MDS; 20 relapsed/refractory, 3 untreated).Data available through dbGaPDeidentified individual participant data, Multiplex immunofluorescence staining, Olink, RNA-Seq and Whole Exome SequencingPrincipal FindingsSafety &#38; Tolerability: The maximum tolerated dose (MTD) for IPI was determined to be 10 mg/kg, though higher doses were associated with increased immune-related adverse events (irAEs).Efficacy: The overall response rate (ORR) was higher in transplant-na&#239;ve patients (52%) compared to post-HSCT patients (20%).Responses were more frequent at higher IPI doses (10 mg/kg). Some patients achieved durable remission (>1 year), often linked to irAE development.Toxicity: The most common grade &#8805;3 treatment-emergent adverse events included neutropenia (32%-48%), thrombocytopenia (28%-48%), and febrile neutropenia (36%-61%). irAEs were observed in 44%-48% of patients, with GVHD occurring only in the post-HSCT group.Survival Outcomes: Median overall survival and progression-free survival did not significantly differ between the two arms. However, in transplant-na&#239;ve patients, 1-year survival was higher in those who developed irAEs (72.7%) versus those who did not (33.3%).

  Study phs003292

• Spatial Transcriptomics of Vaccine Therapy With or Without Cyclophosphamide in Treating Patients Undergoing Chemotherapy and Radiation Therapy for Stage I or Stage II Pancreatic Cancer That Can Be Removed by Surgery

  Pancreatic ductal adenocarcinoma (PDAC) is a rapidly progressing cancer that responds poorly to immunotherapies. Intratumoral tertiary lymphoid structures (TLS) have been associated with rare long-term PDAC survivors, but the role of TLS in PDAC and their spatial relationships within the context of the broader tumor microenvironment remain unknown. Here, spatial transcriptomics data were generated from 16 pancreatic cancer patients treated with GVAX, whose tumors presented with induced intratumoral TLS. Resected tumor specimens were embedded in OCT media and freshly frozen. Sections were cut into 6.5 x 6.5 mm dimensions compatible with Visium spatial transcriptomics slides. TLS-positive tumor sections from 14 patients (14 tumor samples in total) and lymph nodes from remaining patients (2 lymph node samples in total) were selected by an expert pathologist for profiling. We used 4 Visium slides and covered the 16 capture areas with sections cut in a cryostat at 10 &#181;m. The fresh frozen Visium protocol was followed according to manufacturer's recommendations (10x Genomics Spatial 3' v1). Tissue permeabilization and library construction was carried out according to the manufacturer's protocols. Permeabilization time was optimized to 30 minutes. The captured tissue sections were permeabilized to allow RNA to be captured onto the slide where it reverse-transcribed to cDNA. The cDNA was then amplified, and sequencing libraries were prepared using the 10x Genomics Visium Spatial Gene Expression Reagent Kit for Library Preparation. The libraries were then sequenced using an Illumina NovaSeq sequencer. The raw data obtained from the sequencing were processed using the SpaceRanger (spaceranger-1.2.0) pipeline for alignment onto the GRCh38-2020-A reference transcriptome quantification of gene expression. Unsupervised learning generated a TLS-specific spatial gene expression signature that significantly associates with improved survival in PDAC patients. These analyses demonstrate TLS-associated intratumoral B cell maturation.

  Study phs003862

• DNA Methylation in Prostate Tumor and Paired Benign Tissue for African and European Ancestry Men

  We recruited prostate cancer (PCa) patients undergoing robotic-assisted laparoscopic radical prostatectomy at the University of Chicago Medical Center Urology Clinic between 2011 and 2017. Our study includes 76 African American (AA) and 75 European American (EA) men with PCa of Gleason Score (GS) &#8805;7, recruited by the Epidemiology Research Recruitment Core at the University of Chicago. All patients consented to the collection of questionnaire data, prostate tissue, and medical records. The study was approved by the Institutional Review Board of the University of Chicago. Following prostatectomy, prostate tissue was sent to the Human Tissue Research Center (HTRC) at the University of Chicago. Each sample underwent histological examination and Gleason scoring by University of Chicago genitourinary pathologists. The presence of adenocarcinoma was confirmed by overexpression of alpha-methylacyl-coenzyme-A racemase (AMACR) and areas for DNA extraction were marked. Tissue samples used for DNA extraction were obtained using with either a 1mm biopunch or laser microdissection of a 100 &#181;m2 area of tissue. Genome-wide DNA methylation profiles were generated using Illumina's Infinium MethylationEPIC BeadChip array kit. Genome-wide SNP data was generated (from benign tissue DNA) using the Illumina Infinium Multi-Ethnic Global-8 v1.0 array at the University of Chicago Genomics Core Facility. We performed imputation using the Haplotype Reference Consortium (HRC, Version r1.1 2016) panel, which includes all samples from the 1,000 Genomes Project (Phase 3), using the Michigan Imputation Server. The imputed SNP data for mQTL analysis was imputed based on genotype SNP data which was all from benign tissue DNA and the methylation data was identified in both tumor and benign tissue, both AA and EA men, and identified QTLs co-occuring with prostate cancer susceptibility loci.Data including SNP genotypes, DNA methylation, tissue type, and participant characteristics will be available in dbGaP.

  Study phs003516

• Na?ve Treg-specific genomic DNA hypomethylation for autoimmune disease susceptibility

  Naturally occurring regulatory T (Treg) cells, which are specifically expressing the transcription factor FOXP3, CD25 and CTLA-4, are indispensable for the maintenance of immunological self-tolerance and homeostasis. Mutations of the FOXP3, CD25 and CTLA4 genes compromise the function of natural FOXP3+CD25+CD4+ Treg cells and cause severe autoimmune diseases showing Mendelian inheritance. Also, altered Treg-specific epigenetic changes, such as DNA hypomethylation and enhancer activation, impair the expression of these molecules in developing Treg cells, causing autoimmune diseases. It is obscure, however, whether Treg cells significantly contribute to the development of polygenic common autoimmune diseases (such as type 1 diabetes and rheumatoid arthritis), which afflict ~10% of the population. Recent genome-wide association study (GWAS) of common autoimmune diseases has revealed many autoimmune disease-associated single nucleotide polymorphisms (SNPs) in enhancer regions of immune cells, for example, in non-coding regions of T cell activation-associated genes such as CD25 and CTLA4. These findings, especially the involvement of common T-cell genes in the functions of both Treg cells and effector T cells, prompt one to ask whether autoimmune disease-associated causative SNPs impact on the functions of either disease-causing effector T cells or disease-suppressing Treg cells. Here, we have explored epigenetic profiles of human Treg and conventional T (Tconv) cells in na?ve or activated states, and found that autoimmune disease-associated SNPs are predominantly enriched in Treg-specific CpG demethylated regions (Treg-DRs), which were mostly included in Treg-specific super-enhancers. Treg-DRs are developmentally established in na?ve Treg cells before antigenic stimulation, distinct from activation-induced CpG hypomethylation in Treg or Tconv cells, and highly associated with Treg cell-specific transcriptional and epigenetic changes. Taken together, genetic variants affecting endogenous development of natural Treg cells and their Treg-intrinsic functions are causative of common autoimmune diseases, indicating natural Treg cells as a key target for their treatment and prevention.

  Study JGAS000145

• A prospective study identifies MisMatch Repair genes as candidate predisposing genes for uveal melanoma.

  Objective: The aim of this study is to identify new predisposing genes for uveal melanoma (UM), the most common intraocular malignancy in adults. Design: Prospective cohort study from Institut Curie. Participants: 381 unselected patients diagnosed with UM between July 2021 and February 2023 at Institut Curie. Methods: All patients received genetic counseling and consented to extended genetic testing. A panel of 122 genes was analyzed by targeted sequencing on germline DNA from these patients. Main outcomes measures: UM was diagnosed by ophthalmologists at Institut Curie, and a senior pathologist confirmed the diagnosis when tumor or biopsy was available. Classification of the germline genetic variants was performed according to the ACMG guidelines. Results: We identified at least one pathogenic variant (PV) in 79 patients. Among those variants, 20 were found in clinically relevant genes for the patient’s follow-up and genetic counseling. We found a significant enrichment of germline pathogenic variants in Mismatch Repair (MMR) MLH1, MSH2 and MSH6 genes in this UM cohort, suggesting that MMR germline alterations could predispose to UM. From this cohort, one tumor was available from a patient carrying a MLH1 germline mutation. The tumor was characterized by a monosomy 3, in line with a loss of heterozygosity (LOH) of MLH1, located on chromosome 3. Loss of expression of MLH1 and PMS2 was observed by immunohistochemistry, and MMR mutational signatures SBS6, ID1 and ID2 were identified from the whole genome sequencing of the tumor. These data suggest that MLH1 is implicated in the oncogenesis of this UM. Conclusions: This study is the largest prospective constitutional study performed on UM patients, and the first demonstrating that MMR germline alterations are significantly enriched among these patients. Further analyses will be needed to estimate the risk of developing UM for patients with Lynch syndrome

  Study EGAS50000000914

• Metadata Public API

  Metadata Rest Endpoints Common Aspects Functionality Identifiers Requests and Responses Request Response Querying Querying by Object Cross-Querying by Object Common Aspects Functionality The Metadata REST API allows EGA users to request metadata from the EGA. Using this api you will be able to obtain the publicly available information from EGA study, sample, experiment, run, analysis, policy, dac and dataset. The API also allows for objects to be cross-referenced in order to obtain for example all the datasets linked to a dac. Identifiers EGA objects can be identified by their unique accession. These are ID's displayed everywhere, shared among all EGA locations and specific for each data type (More information on the list below) EGA Accession ID EGA Object description EGAS EGA Study Accession ID EGAC EGA DAC Accession ID EGAP EGA Policy Accession ID EGAN EGA Sample Accession ID EGAR EGA Run Accession ID EGAX EGA Experiment ID EGAZ EGA Analysis Accession ID EGAD EGA Dataset Accession ID EGAB EGA Submission ID EGAF EGA File Unique Accession ID Server Request and Response Request All the endpoints implement these two HTTP methods, GET and HEAD. Moreover, there is an authentication layer that allows to disclose the private information about each object if the user runs the endpoint with their token and has permissions to the related dataset. HTTP Method Description GET Returns the objects and their public information (including private information if the user has permissions) HEAD Returns the count of objects to be returned Response API responses are diverse but they always return a status call. Below you have a summary on what these codes mean and some tips that can help you troubleshooting them: HTTP Status Code Description Resolution 200 OK No error handling necessary 206 Partial Content Expected status code when paginating the results. No error handling necessary 400 BAD REQUEST Request incorrectly formulated 401 UNAUTHORISED/FORBIDDEN You do not have permissions over the object you are trying to access. / The authorised user is not permitted to make the given request. 404 NOT FOUND The object/resource you are trying to access does not exist. 500 INTERNAL SERVER ERROR This is a server-side error, try later. If the issue persists, contact the Heldpesk. Querying Querying by Object In the below documentation, worked examples can be found on how to use the API, to query about each unique EGA object. https://metadata.ega-archive.org/analyses/{id} https://metadata.ega-archive.org/dacs/{id} https://metadata.ega-archive.org/datasets/{id} https://metadata.ega-archive.org/runs/{id} https://metadata.ega-archive.org/samples/{id} https://metadata.ega-archive.org/studies/{id} Worked example for the EGA data access committee(DAC) EGAC00001000514 https://metadata.ega-archive.org/dacs/EGAC00001000514 Points to notice Please, be advised that all EGA objects can be queried by using the same endpoint. For example: https://metadata.ega-archive.org/datasets Returns all the datasets registered at the EGA. https://metadata.ega-archive.org/datasets?limit=5&offset=15 Returns 5 results skipping the initial 15 results. Cross-Querying by Object The EGA REST API Metadata also allows for the crossquerying of public metadata. For example, should I want to query the datasets included in the ICGC DAC: https://metadata.ega-archive.org/dacs/EGAC00001000010/datasets Below, you can find worked examples on how to perform the call to the API. https://metadata.ega-archive.org/datasets/EGAD00001000645/analyses https://metadata.ega-archive.org/datasetsEGAD00001000645/files https://metadata.ega-archive.org/datasets/EGAD00001000620/runs https://metadata.ega-archive.org/datasets/EGAD00001000620/samples https://metadata.ega-archive.org/samples/EGAN00001092114/datasets https://metadata.ega-archive.org/files/EGAF00000056146/dacs https://metadata.ega-archive.org/files/EGAF00000056146/datasets https://metadata.ega-archive.org/files/EGAF00000056146/studies There are more endpoints included in this category. Please, find all the possibilities (green tick) in the table below. Table The table displays in a ordered fashion the objects that can be crossreferenced using the metadata API. BY Analysis Dac Dataset Experiment Policy Run Sample Study File Analysis ✔ ✔ Dac ✔ ✔ Dataset ✔ ✔ ✔ ✔ Experiment ✔ ✔ ✔ ✔ Policy ✔ Run ✔ ✔ ✔ Sample ✔ ✔* ✔ Study ✔ ✔ ✔ ✔ ✔ ✔* File ✔ *: These cross queries do not include data from Array-File submissions. Check out the SPEC

  Documentation discovery/metadata/public-metadata-api

• The ERASMUSMC-HEMA Data Access Committee controlling appeals for 3q26-rearranged acute myeloid leukemia datasets from the department of Hematology at Erasmus MC

  Dac EGAC00001000162

• TUM Experimental Neuroimmunology

  This DAC will decide about all data requests to human data deposited at EGA that was primarily produced at the Institute for Experimental Neuroimmunology at the Technical University Munich, Germany.

  Dac EGAC50000000093

• Genetic Mechanisms of Disease Lab DAC

  Data access for raw and processed H3K27ac ChIP-seq and ATAC-seq data from "Effect of ETS2 modulation on chromatin accessibility and enhancer activity in human macrophages".

  Dac EGAC50000000087

• Amsterdam UMC Head and Neck Cancer Biology and Immunology

  This data access committee oversees data and assesses requests for the Head and Neck Cancer Biology and Immunology lab of Amsterdam UMC, location VUmc.

  Dac EGAC50000000350

• DAC "Genotyping based on SNPs covered by targeted NGS"

  DAC for the dataset from the article "Genotyping from targeted NGS data based on a small set of SNPs correctly matches patient samples"

  Dac EGAC50000000358

• DAC for "High-Resolution Spatial Transcriptomics Uncover Epidermal-Dermal Divergences in Merkel Cell Carcinoma: Spatial Context Reshapes the Gene Expression Landscape" with Jürgen C. Becker(j.becker@dkfz-heidelberg.de) and Nalini Srinivas(n.srinivas@dkfz-heidelberg.de )

  Dac EGAC00001003599