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• Neoadjuvant immune checkpoint blockade in mismatch-repair proficient colon cancers

  Immune checkpoint blockade has led to paradigm shifts in the treatment of various tumour types, yet limited efficacy has been observed in patients with metastatic mismatch-repair proficient (pMMR) colorectal cancer. Here we report an in-depth analysis of patients with early-stage pMMR colon cancer from the phase II NICHE study (ClinicalTrials.gov: NCT03026140). A total of 31 patients received neoadjuvant treatment of nivolumab plus ipilimumab followed by surgery. The response rate was 26% and included six patients with a major pathological response (≤10% residual viable tumour). One patient with an ongoing clinical complete response did not undergo surgery. Responses were observed despite a low tumour mutational burden in all tumours, while chromosomal genomic instability scores were significantly higher in responders compared to non-responders. Responding tumours were more likely to be TP53 mutant, KRASG12 wildtype and had significantly higher baseline expression of proliferation signatures and TCF1. Imaging mass cytometry also revealed a higher percentage of Ki-67+ cancer and Ki-67+ CD8+ T cells in responders compared to non-responders. Meanwhile, in non-responders, we observed an enrichment for an inflamed-fibrotic microenvironment associated with TGF-β expression, hinting towards possible resistance mechanisms. These results provide a comprehensive analysis of response to neoadjuvant ICB in early-stage pMMR colon cancers and identify potential biomarkers for patient selection.

  Study EGAS50000000856

• Single_Cell_Sequencing_of_Sperm__scSperm_

  The aim of this project is to genotype and sequence single spermatozoa from two men, one in his twenties and the other in his seventies. The resulting data is used to quantify the mutations that have arisen in the gametes of both individuals in order to better understand the effect of aging on mutation rates and modes.Project Outline. In order to quantify mutations, semen from two individuals are sequenced. 48 single sperm cells are isolated from each individual, and their DNA is extracted. The resulting genomes are amplified using PicoPlex, GenomiPhi MDA, Repli-G MDA, and MALBAC. QC step is applied to check the quality of WGA DNA using standard Sequenom plex (26 SNPs). A subset of 32 amplification products which pass the intiall QC, are genotyped using Affymetrix SNP6 chips. 12 of the genotyped amplification products are also sequenced. In addition, one multi-cell sample per individual is sequenced as a reference and for validation purposes.Altogether, 12 single cell sperm genomes and two multi-cell genomes are sequenced, coming to a total of 14 genomes. Of the single cell sperm genomes, 2 are sequenced to 50x coverage, and the other 10 to 25x coverage. Both multi-cell genomes are sequenced to 25x coverage.

  Study EGAS00001000935

• Genome-wide genotyping and methylation data from Understanding Society

  Genome-wide genotyping and methylation data from Understanding Society. Please visit https://www.understandingsociety.ac.uk/ for further information.

  Study EGAS00001008417

• Unraveling the transcriptomic profile of utero-tubal lavage fluid of ovarian cancer patients

  The majority of ovarian cancers are diagnosed at an advanced stage and have a high mortality rate. Current screening strategies fail to improve prognosis because markers of early stage disease are lacking. This medical need justifies the search for biomarkers enabling early detection of ovarian cancer. In this study, we explore the extracellular transcriptome of utero-tubal lavage fluid obtained from 26 ovarian cancer patients and 48 controls using messenger RNA (mRNA) capture and small RNA sequencing. Because of its contact with the fallopian tube and the ovaries, collection of utero-tubal lavage might be the preferred non-invasive method to identify localized lesions compared with analyses based on peripheral blood samples. We observed an enrichment of ovarian and fallopian tube specific messenger RNAs in utero-tubal lavage fluid compared to other human biofluids. Over 300 mRNAs and 41 miRNAs were upregulated in ovarian cancer samples compared with controls. Upregulated genes were enriched for genes involved in cell cycle activation and proliferation, hinting at a tumor derived signal. In conclusion, we provide proof-of-principle that mRNA capture sequencing of utero-tubal lavage fluid is technically feasible, and that the extracellular transcriptome of utero-tubal lavage should be further explored in larger cohorts to assess the diagnostic value of the biomarkers identified in this study.

  Study EGAS00001005498

• A Chromatin Accessibility Atlas of the Developing Human Telencephalon

  Gene expression differs between cell types and regions within complex tissues such as the developing brain. To discover regulatory elements underlying this specificity, we generated genome-wide maps of chromatin accessibility in nine anatomically-defined regions of the developing human telencephalon. Additionally, we defined the histone modification landscape of the prefrontal cortex and generated chromatin accessibility maps of its upper and deep layers. We predicted a subset of open chromatin regions (18%) that are most likely to be active enhancers, many of which are dynamic with 26% differing between early and late mid-gestation and 28% present in only one brain region. These predicted regulatory elements (pREs) are enriched proximal to genes with expression differences across developmental stages, regions, and cortical laminae; they harbor distinct sequence motifs that suggest potential upstream regulators. We leveraged this atlas to predict and validate novel regulatory elements of genes that control cortex laminar identity and genes associated with autism spectrum disorder (ASD). These include enhancers proximal to FEZF2 and BCL11A that were validated in mouse, and an enhancer of ASD gene SLC6A1 containing two functional de novo mutations in individuals with ASD whose enhancer function we validated via CRISPRa. We also include data for transcription factor binding in mid-fetal cortex tissues, using CUT&RUN methods.

  Study phs002033

• Single cell targeted DNA-sequencing (and antibody sequencing) of high hyperdiploid B-ALL

  This dataset contains all sequencing data of the publication "Single-cell DNA and Surface Protein Characterization of High Hyperdiploid Acute Lymphoblastic Leukemia at Diagnosis and During Treatment". We provide both the raw fastq-files as well as the processed data in the form of .h5 files. There are 13 patients: XJ176, XH135, XJ180, XI145, XI148, XI167, XI150, XJ175, XJ178, XI162, XF98, XG111 and XG115. Of 9 patients, also follow-up samples during/after treatment were sequenced: XJ180, XI145, XI148, XI167, XI150, XJ175, XJ178, XI162 and XG111. To identify the cell types and distinguish between normal and leukemic cells, cell surface proteins were also captured for 6 samples: XF98, XG111 (at diagnosis and during treatment), XG115, XI162 (after treatment) and XJ175 (after treatment). All samples were processed on the MissionBio platform with a custom amplicon panel, and DaB-seq for the combined targeted DNA and protein sequencing.

  Dataset EGAD50000000829

• Characterization of mutational signatures in human cancer cell lines reveals episodic APOBEC mutagenesis

  Multiple signatures of somatic mutations have been identified in human cancer genomes. To investigate whether mutational signatures continue to be generated, and if so their temporal patterns of activity, subsets of cell lines were cultured in vitro for extended periods and subjected to single cell cloning and whole genome or exome sequencing or directly to single cell whole genome sequencing. As expected, signatures of past exogenous exposures, such as tobacco smoke and ultraviolet light, were not generated in vitro. In contrast, signatures of normal and defective DNA repair and replication continued to be generated at essentially constant mutation rates. Signatures of APOBEC cytidine deaminase DNA-editing activity exhibited a distinctive pattern with substantial fluctuations in mutation rate over time and episodic bursts of mutations. The initiating factors for these bursts are unclear although retrotransposon mobilisation may play a role. This cell line set now constitutes a comprehensive resource of live experimental models of mutational processes of both known and unknown aetiologies potentially retaining the patterns of activity and regulatory influences operative in human cells in vivo.

  Dataset EGAD00001004202

• Sporadic ALS Australia Systems Genomics Consortium (SALSA-SGC)

  In 2016 we established the Sporadic ALS Australia Systems Genomics Consortium (SALSA-SGC) funded by the Ice Bucket Challenge Grant administered by the Motor Neurone Disease Research Institute of Australia. The goals of the SALSA-SGC are to collect biological samples from clinics across Australia with matched in depth clinical and self-report phenotypes and to generate multiple levels of genetic and genomic data. In this first data generation exercise of the SALSA-SGC the majority of the samples were collected prior to the formal establishment of SALSA-SGC from clinics across Australia.Briefly, the cohort includes the University of Sydney’s Australian Motor Neuron Disease DNA Bank (MND Bank) cohort recruited April 2000 to June 2011), with study protocol approved by the Sydney South West Area Health Service Human Research Ethics Committee (HREC). Cases were recruited from around Australia via state-based MND associations with diagnosis verified by a neurologist. The remainder of the cases were recruited from clinics across Australia between 2015 and 2017 under HREC approvals from Royal Brisbane and Women’s Hospital, Macquarie University Multidisciplinary Motor Neurone Disease Clinic,  Calvary Health Care Bethlehem in Melbourne , Fiona Stanley Hospital in Perth, and from 2016 under HREC approvals at each site for the sporadic ALS Australia Systems Genomics Consortium (SALSA-SGC). The ALS cases were diagnosed with definite or probable ALS according to the revised El Escorial criteria. Some controls were recruited as either partners or friends of patients, healthy individuals free of neuromuscular diseases. We are providing GWAS and MWAS data in this dataset. Individual level GWAS data were generated using Illumina Infinium CoreExome-24 version 1.1 chips for N= 846 cases and N=665 controls. Individual MWAS data was generated using the Illumina Human methylation 450K array for N=782 cases and N=613 controls. There 1315 individuals where GWAS and MWAS data has been generated and is available. Further information on these data sets can be found: Paper 1: Restuadi, R, Garton, FC, Benyamin, B, Lin, T, et al. Amyotrophic Lateral Sclerosis Genetic Correlation with Cognitive Performance, educational attainment and schizophrenia: evidence from polygenic risk score analysis. (submitted) Paper 2: Nabais, MF, Lin, T, Benyamin, B et al. Significant out-of-sample classification from methylation profile scoring for amyotrophic lateral sclerosis. 2020. NPJ genomic medicine. 5(10). Files provided in this submission include: GWAS: This folder contains QCed genotype for the Australian ALS case-control cohort. Contains PLINK files for genotyping data (not imputed yet). The individuals selected here have: good consistency on phenotype data ethics approval registered as part of sporadic ALS studies unrelated by GRM cut-off 0.05 No ancestry QC yet MWAS: This folder contains the IDAT and post-QC normalized DNAm (beta) for the Australian ALS case-control cohort. 2019_AUS_ALS_PCTG_DNAm.tar.gz - IDATS for 1315 individuals analyzed in the MWAS study normalized_beta_values - Binary files (created with the OSCA software) containing information on the individuals, probes and the DNAm (beta) values obtained after QC phenotype_file - contains all the covariates analysed in the MWAS including: case-control status, coded 0 = Control and 1 = ALS, predicted age, predicted cell-type proportions, predicted smoking scores, slide and chip position and sex Important Notes: The DNAm data were normalized together with samples that were not part of this ALS case/control study and thus, the normalization procedure may not be 100% reproducible using only the IDAT files uploaded here. Summary data has been made publicly available and can be accessed directly: Data collection and sample processing were performed at several clinics across Australia. Genotyping and DNA methylation arrays were performed by the Human Studies Unit, at the Institute for Molecular Bioscience (University of Queensland). Quality control of the genotypic, phenotypic and DNA methylation data was done by the Program of Complex Traits Genomics, at the Institute for Molecular Bioscience (University of Queensland).

  Study phs002068

• JMML targeted sequencing (2013)

  Juvenile myelomonocytic leukemia (JMML) is a rare myelodysplastic myeloproliferative neoplasm of early childhood initiated by germline or somatic RAS-activating mutations (Chang, Dvorak et al. 2014). Clinical evolution is heterogeneous, with acute myeloid leukemia (AML) transformation in 1/3 of cases and frequent relapses after hematopoietic-stem-cell transplantation (HSCT), although some patients experience spontaneous remission (Locatelli, Nollke et al. 2005; Matsuda, Shimada et al. 2007; Takagi, Piao et al. 2013; Locatelli and Niemeyer 2015). The initiating lesion incompletely predicts outcome, suggesting the involvement of additional mutations. Genetic profiling of a large JMML cohort (n=118), including whole-exome sequencing (WES) in 30 cases, uncovered additional genetic abnormalities in 56 cases (47%). Somatic events were rare (0.38/case/Mb) and restricted to sporadic (47/78; 60%) or NF1-associated (8/8; 100%) JMML. Multiple concomitant genetic hits were identified targeting the RAS pathway in 13/78 (17%), RAC2D63V, which activates the PI3K/PDK1/AKT and the mTORC2 pathways, and a novel pathway for JMML, the polycomb repressive complex 2 (PRC2), in 26/78 (33%) of the sporadic JMML cases. Interestingly, PRC2 imbalance was recently shown to synergize with RAS activation (De Raedt, Beert et al. 2014). JMML outcome was associated to the mutational profile, suggesting a dose-dependent effect for RAS-pathway activation, distinguishing very aggressive JMML rapidly progressing to AML.

  Study EGAS00001001324

• RNA-seq of high grade serous ovarian tumours

  Somatic RNA for 40 samples matched to the WGS was extracted using the Qiagen Qiasymphony RNA protcol (cat no 931636). The tissue was initially homogenised using a Qiagen Bioruptor, followed by the manufacturers recommended protocol (including DNase digestion). The resulting RNA the underwent quality control as follows: firstly, A260 and A280nm were measured on a Denovix DS-11 Fx to qualitatively illustrate A260/280nm and A260/230nm ratios as measures of RNA purity. A260/280 had to be 2.0 and A260/230 had to be 2.0-2.2. Then RNA was quantified using LifeTechnologies Qubit RNA BR kit (cat no Q10210). RNAseq was carried out by the Edinburgh Clinical Research Facility on an Illumina NExtSeq500. Total RNA samples were assessed on the Agilent Bioanalyser (Agilent Technologies, #G2939AA) with the RNA 6000 Nano Kit (#5067-1512) for quality and integrity of total RNA, and then quantified using the Qubit 2.0 Fluorometer (Thermo Fisher Scientific Inc, #Q32866) and the Qubit RNA HS assay kit (#Q32855). Libraries were prepared from total-RNA sample using the NEBNext Ultra 2 Directional RNA library prep kit for Illumina (#E7760S) with the NEBNext rRNA Depletion kit (#E6310) according to the provided protocol. 400ng of totalRNA was then added to the ribosomal RNA (rRNA) depletion reaction using the NEBNext rRNA depletion kit (Human/mouse/rat) (#E6310). This step uses specific probes that bind to the rRNA in order to cleave it. rRNA-depleted RNA was then DNase treated and purified using Agencourt RNAClean XP beads (Beckman Coulter Inc, #66514). RNA was then fragmented using random primers before undergoing first strand and second strand synthesis to create cDNA. cDNA was end repaired before ligation of sequencing adapters, and libraries were enriched by PCR using the NEBNext Multiplex oligos for Illumina set 1 and 2 (#E7500). Final libraries had an average peak size of 271bp. Libraries were quantified by fluorometry using the Qubit dsDNA HS assay and assessed for quality and fragment size using the Agilent Bioanalyser with the DNA HS Kit (#5067-4626). Sequencing was performed using the NextSeq 500/550 High-Output v2 (150 cycle) Kit (# FC- 404-2002) on the NextSeq 550 platform (Illumina Inc, #SY-415-1002). Libraries were combined in an equimolar pool based on the library quantification results and run across 5 High-Output Flow Cell v2.5.

  Dataset EGAD00001009048

• RNA-seq of high grade serous ovarian tumours

  Somatic RNA for 37 samples was extracted using the Qiagen Qiasymphony RNA protcol (cat no 931636). The tissue was initially homogenised using a Qiagen Bioruptor, followed by the manufacturers recommended protocol (including DNase digestion). The resulting RNA the underwent quality control as follows: firstly, A260 and A280nm were measured on a Denovix DS-11 Fx to qualitatively illustrate A260/280nm and A260/230nm ratios as measures of RNA purity. A260/280 had to be 2.0 and A260/230 had to be 2.0-2.2. Then RNA was quantified using LifeTechnologies Qubit RNA BR kit (cat no Q10210). RNAseq was carried out by the Edinburgh Clinical Research Facility on an Illumina NExtSeq500. Total RNA samples were assessed on the Agilent Bioanalyser (Agilent Technologies, #G2939AA) with the RNA 6000 Nano Kit (#5067-1512) for quality and integrity of total RNA, and then quantified using the Qubit 2.0 Fluorometer (Thermo Fisher Scientific Inc, #Q32866) and the Qubit RNA HS assay kit (#Q32855). Libraries were prepared from total-RNA sample using the NEBNext Ultra 2 Directional RNA library prep kit for Illumina (#E7760S) with the NEBNext rRNA Depletion kit (#E6310) according to the provided protocol. 400ng of totalRNA was then added to the ribosomal RNA (rRNA) depletion reaction using the NEBNext rRNA depletion kit (Human/mouse/rat) (#E6310). This step uses specific probes that bind to the rRNA in order to cleave it. rRNA-depleted RNA was then DNase treated and purified using Agencourt RNAClean XP beads (Beckman Coulter Inc, #66514). RNA was then fragmented using random primers before undergoing first strand and second strand synthesis to create cDNA. cDNA was end repaired before ligation of sequencing adapters, and libraries were enriched by PCR using the NEBNext Multiplex oligos for Illumina set 1 and 2 (#E7500). Final libraries had an average peak size of 271bp. Libraries were quantified by fluorometry using the Qubit dsDNA HS assay and assessed for quality and fragment size using the Agilent Bioanalyser with the DNA HS Kit (#5067-4626). Sequencing was performed using the NextSeq 500/550 High-Output v2 (150 cycle) Kit (# FC- 404-2002) on the NextSeq 550 platform (Illumina Inc, #SY-415-1002). Libraries were combined in an equimolar pool based on the library quantification results and run across 5 High-Output Flow Cell v2.5.

  Dataset EGAD00001010139

• Single cell RNAseq FASTQ files of three PDAC organoid lines (P28, P40, P47) using SORT-seq

  This dataset contains raw FASTQ files from single cell RNA sequencing of three patient-derived pancreatic ductal adenocarcinoma (PDAC) organoid lines (P28, P40, P47) cultured under standard conditions. For each line, single cells were FACS sorted into 384-well capture plates, with each well containing a 50nl droplet of barcoded primers. Plates were processed following an adapted SORT-seq protocol, and cDNA libraries were generated using CEL-Seq2 with TruSeq small RNA primers (Illumina). Sequencing was performed on an Illumina NextSeq500 platform using paired-end reads (read 1: 26 cycles, index read: 6 cycles, read 2: 60 cycles). Data are controlled-access and intended for single cell transcriptomic analysis of PDAC organoid heterogeneity and WNT pathway activity.

  Dataset EGAD50000002220

• Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-be Heart Health Study (nuMoM2b Heart Health Study)

  Participants from study sites that recruited during the original study funded by NICHD of pregnant people, called nuMoM2b, participated in this study. The nuMoM2b-HHS1 was a prospective observational follow-up study of the nuMoM2b cohort consisting of interval contacts via phone or web every 6 months to about a year, and an in-person visit 2 to 7 years after the end of the nuMoM2b pregnancy including: Demographics Self-administered questionnaires Clinical measurements Lab results An in-home sleep breathing assessment for the subset of participants with at least one valid sleep breathing assessment during nuMoM2b Abstraction of medical records for pregnancies subsequent to nuMoM2b involving self-reported adverse pregnancy outcomes or multiple births Abstraction of medical records of selected cardiovascular risk-related events or procedures reported by participants. The study capitalized on the rich and unique data prospectively collected during nuMoM2b (biomarkers, uterine artery Doppler studies, fetal growth, psychosocial determinants, sleep, and blood pressure) and rigorous definitions of adverse pregnancy outcomes. These data are stored in the NICHD repository DASH (https://dash.nichd.nih.gov/study/226675). A total of 8,838 nuMoM2b participants were targeted for contact during nuMoM2b-HHS and 7,872 participants were reached, of whom 7,003 completed one or more interval contacts. Of these, 5,206 agreed to the visit, and 4,508 attended an in-person visit.

  Study phs002808

• Whole Exome Sequencing of Chronic Lymphocytic Leukemia

  The somatic genetic basis of chronic lymphocytic leukemia (CLL), a common and clinically heterogenous adult leukemia, remains poorly understood. Massively parallel sequencing technology now provides a method for systematic discovery of genetic alterations that underlie disease, and for uncovering new therapeutic targets and biomarkers. In study version 2 we presented a dataset consisting of DNA sequencing from 169 CLL samples (with matched germline controls). Samples were collected from patients displaying a wide range of characteristics representing the broad clinical spectrum of CLL. Understanding the mutational landscape of CLL provides a starting point for systematic analyses to address fundamental questions in CLL, including how mutated genes alter cellular networks and phenotypes, and thereby contribute to disease heterogeneity. Intratumoral heterogeneity plays a critical role in tumor evolution. To define the contribution of DNA methylation to heterogeneity within tumors, we performed genome-scale bisulfite sequencing of >100 primary chronic lymphocytic leukemias (CLLs; data presented in study version 3). Compared with 26 normal B cell samples, CLLs consistently displayed higher intrasample variability of DNA methylation patterns across the genome, which appears to arise from stochastically disordered methylation in malignant cells. Transcriptome analysis of bulk and single CLL cells revealed that methylationdisorder was linked to low-level expression. Disordered methylation was further associated with adverse clinical outcome. We therefore propose that disordered methylation plays a similar role to that of genetic instability, enhancing the ability of cancer cells to search for superior evolutionary trajectories.

  Study phs000435

• Osteoporotic Fractures in Men (MrOS)

  The Osteoporotic Fractures in Men Study (MrOS) is a multi-center prospective, longitudinal, observational study of risk factors for vertebral and all non-vertebral fractures in older men, and of the sequelae of fractures in men. The original specific aims of the study include: (1) to define the skeletal determinants of fracture risk in older men, (2) to define lifestyle and medical factors related to fracture risk, (3) to establish the contribution of fall frequency to fracture risk in older men, (4) to determine to what extent androgen and estrogen concentrations influence fracture risk, (5) to examine the effects of fractures on quality of life, (6) to identify sex differences in the predictors and outcomes of fracture, (7) to collect and store serum, urine and DNA for future analyses as directed by emerging evidence in the fields of aging and skeletal health, and (8) define the extent to which bone mass/fracture risk and prostate diseases are linked. The MrOS study population consists of 5,994 community dwelling, ambulatory men aged 65 years or older from six communities in the United States (Birmingham, AL; Minneapolis, MN; Palo Alto, CA; Monongahela Valley near Pittsburgh, PA; Portland, OR; and San Diego, CA). Inclusion criteria were designed to provide a study cohort that is representative of the broad population of older men. The inclusion criteria were: (1) ability to walk without the assistance of another, (2) absence of bilateral hip replacements, (3) ability to provide self-reported data, (4) residence near a clinical site for the duration of the study, (5) absence of a medical condition that (in the judgment of the investigator) would result in imminent death, and (6) ability to understand and sign an informed consent. To qualify as an enrollee, the participant had to provide written informed consent, complete the self-administered questionnaire (SAQ), attend the clinic visit, and complete at least the anthropometric, DEXA, and vertebral X-ray procedures. There were no other exclusion criteria. The baseline examination was completed over a 25-month period from March 2000 to April 2002. Participants completed questionnaires regarding medical history, medications, physical activity, diet, alcohol intake, and cigarette smoking. Objective measures of anthropometric, neuromuscular, vision, strength, and cognitive variables were obtained at a clinic visit. Skeletal assessments included DEXA, calcaneal ultrasound, and vertebral radiographs. Vertebral and proximal femoral QCT was performed on a subset (65%) of participants. Serum, urine, and whole blood specimens were collected. During the study period, participants complete a tri-annual questionnaire every four months that obtains information concerning the occurrence of incident falls and fractures. Follow-up is over 99% complete. All reported fractures are confirmed using physician review of radiology reports or study radiologist review of x-rays. All deaths are also centrally adjudicated using death certificates and recent hospitalization records. In additional to the baseline study visit and tri-annual questionnaires, all surviving active participants were invited to follow-up visits and questionnaires. A second comprehensive clinic visit was completed between March 2005 and May 2006 or about 4.5 years after baseline. Most baseline measures, including vertebral radiographs, were repeated at the second visit. A third comprehensive clinic visit was completed between March 2007 and March 2009 or about 7.0 years after baseline. Many baseline measures were repeated at the third visit. A measure of energy expenditure was also obtained utilizing an accelerometer based armband device. Surviving participants have also completed two extensive mailed questionnaires designed to updated information obtained at clinic visits. The first questionnaire was mailed between baseline and visit 2 between July 2002 and March 2004. The second questionnaire was mailed after the third questionnaire between March 2009 and February 2011. The MrOS Sleep Study, an ancillary study of the parent MrOS cohort, was conducted between December 2003 and March 2005 and recruited 3,135 MrOS participants for a comprehensive sleep assessment. Men were screened for nightly use of mechanical devices during sleep including pressure mask for sleep apnea (CPAP or BiPAP), mouthpiece for snoring or sleep apnea, or oxygen therapy and were generally excluded. The sleep visit included objective measures of sleep using actigraphy and polysomnography. Other measures at the sleep visit include neuropsychiatric measures, performance measures, health related questionnaires, routine exam measures previously completed at MrOS clinic visits and a urine and serum specimen collection. During the sleep study period, participants complete a tri-annual questionnaire every four months that contains information about incident cardiovascular events. All reported events are centrally adjudicated utilizing hospital records, study ECGs and other supporting documentation. The Hip Osteoarthritis study, another ancillary study of the parent MrOS cohort, was completed at the second clinic visit between March 2005 and May 2006. Participants were asked for consent for a hip x-ray and osteoarthritis measurements were obtained from these x-rays. DNA was extracted from baseline whole blood samples for use in genetic research. Consent for use of DNA was obtained through written consent. Raw GWAS data is housed at the study's coordinating center and not released as part of the dbGAP release. The raw data can be requested from the study's coordinating center. Only QC cleaned Plink files are available on dbGAP.

  Study phs000373

• PD-L1 blockade in combination with carboplatin as immune induction in metastatic lobular breast cancer: the GELATO-trial

  Invasive lobular breast cancer (ILC) is the second most common histological breast cancer subtype but published data on trials specific for ILC are so far lacking. Translational research revealed that a subset of ILCs may be immune-related and more sensitive to DNA-damaging agents such as platinum. In murine ILC models, synergy between immune checkpoint blockade and platinum has been observed. Here, we tested this concept in the phase II, GELATO-trial (NCT03147040), in which patients with metastatic ILC were treated with weekly carboplatin (AUC 1.5) as immune induction treatment for 12 weeks and atezolizumab (PD-L1 blockade; every three weeks) from the third week onwards until disease progression. Four out of 23 evaluable patients had a partial response (17%, 95%CI 5-39%) and two patients had stable disease for at least 24 weeks, resulting in a clinical benefit rate of 26% (95%CI 10-48%). Out of these six patients, four patients had triple-negative ILC (TN-ILC). In serial biopsies of metastatic lesions, we observed higher CD8 T-cell infiltration, expression of immune checkpoints, and exhausted T cells upon carboplatin/PD-L1 blockade. This is the first report of a clinical trial specifically for ILC and we demonstrate promising anti-tumor activity of atezolizumab with carboplatin as immune induction, in particular for TN-ILC. While activity of carboplatin/PD-L1 blockade in classical ER+ ILC was limited, our translational data yield important insights for the design of highly needed clinical trials in ILC.

  Study EGAS00001006902

• 10x Genomics raw data of intestinal plasma cells

  The dataset contains raw fastq files (fastq.gz) for Chromium Single Cell 5’ gene expression (GEX), human B cell VDJ and feature barcode (CSP) sequencing from transglutaminase 2-specific and other small intestinal plasma cells isolated from four untreated celiac disease patients. Single cell 5’ gene expression, V(D)J-enriched and cell surface protein libraries were generated using Chromium single cell kits, and barcoded cDNA from a total of 5,000-10,000 cells per sample was generated using the 10x Genomics Chromium Controller. The libraries were pooled prior to sequencing on a NovaSeq 6000 instrument (Illumina) using the following configuration: read 1: 26 cycles, read 2: 89 cycles, index read 1: 8 cycles.

  Dataset EGAD50000000342

• Prognostic and therapeutic significance of leukemia subtypes and minimal residual disease measurements in pediatric acute lymphoblastic leukemia treated with contemporary risk-directed trial: a cohort study

  Background Genomic analyses to identify leukemia subtypes and refinement of minimal residual disease (MRD) determination are two recent advances that would have substantial impact on the management of children with acute lymphoblastic leukemia (ALL). However, the combined application of these two approaches to determine the prognostic and therapeutic significance of MRD measurement and full spectrum of leukemia subtypes in the context of contemporary risk-directed therapy has not been studied comprehensively.MethodsBetween October 29, 2007 and March 26, 2017, 598 consecutive children with newly diagnosed ALL were enrolled in a clinical trial at St. Jude Children’s Research Hospital. Patients were provisional classified according to the presenting clinical and laboratory features including immunophenotype and cytogenetics. Patients with ETV6-RUNX1 and high hyperdiploid B-progenitor ALL were provisionally included in the low-risk groups; those with TCF3-PBX1, hypodiploidy and T-cell ALL in the standard (intermediate)-risk group; and patients with BCR-ABL1, KMT2A and early T-cell precursor ALL in the high-risk group. Final risk assignment was based primarily on MRD levels measured by flow cytometry on Day 15 (≥1%) and Day 42 (<0.01% or ≥1%) of remission induction. Using genomic classification based on cytogenetics and genomic analysis (single nucleotide polymorphism array analysis and transcriptome, exome, and genome sequencing), patients were classified into 17 subtypes. The primary aim was to determine the event-free survival, overall survival and cumulative risk of relapse according to specific leukemia subtypes and MRD levels on Days 8, 15 and 42 of remission induction. This clinical trial was registered at ClinicalTrials.gov, number NCT00549848.FindingsPatients with ETV6-RUNX1, high hyperdiploidy and DUX4-rearranged B-ALL all received low- or standard-risk therapy, and had the highest 5-year event-free survival rates: 98.4% (95% CI, 95.9-100), 95.3% (91.2-99.4), and 95.0% (84.2-100), respectively. All 142 patients with Day 8 MRD<0.01%, except two with KMT2A-rearranged ALL and one with TCF3-PBX1, were in continuous complete remission. The TCF3-PBX1, PAX5alt, T-cell, early T-cell precursor, iAMP21 and hypodiploid ALL had intermediate outcome with 5-year event-free survival rates ranging from 80.0% (39.4-100) to 88.2% (71.7-100). Patients with KMT2A-rearranged, BCR-ABL1, BCR-ABL1-like and ETV6-RUNX1-like ALL had the worst outcomes, with 5-year event-free survival rates between 64.1% (43.9-84.3) and 76.2% (51.9-100), despite most patients receiving standard- or high-risk therapy. Treatment intensification based on MRD and genotype improved outcome. Relapse did not occur in any of the patients with ETV6-RUNX1, DUX4-rearranged, TCF3-PBX1, iAMP21, ZNF384-rearranged, hypodiploid, or BCR-ABL1-like B-ALL who had day 15 MRD≥1% and received standard-risk therapy. However, day 42 MRD<0.01% did not preclude relapse in patients with intermediate-risk or unfavorable subtypes including TCF3-PBX1, PAX5alt, T-cell, iAMP21, BCR-ABL1, BCR-ABL1-like, ETV6-RUNX1-like, KMT2A-rearranged, and MEF2D-rearranged ALL, despite intensified treatment in the standard- or high-risk arms. InterpretationContemporary risk-directed treatment based on genotypes and MRD can cure virtually all patients with ETV6-RUNX1, hyperdiploid>50 and DUX4-rearranged ALL. While intensified treatment improve outcome for patients with high MRD during induction, substantial proportions of patients with intermediate-risk or unfavorable subtypes would still relapse even achieving negative MRD status at the end of induction and require novel therapeutics to improve outcome.

  Study EGAS00001004739

• Effects of Metformin on Transcriptomic and Metabolomic Profiles in Breast Cancer Survivors Enrolled in the Randomized Placebo-Controlled MetBreCS Trial

  RNA from snap-frozen breast tissue biopsies were purified after lysing by tissuelyser (Qiagen) and using RNA Purification Plus Kit (Norgen biotek CORP, 47700) with additional on-column DNase-I treatment (Qiagen, 79254) at 27 °C. RNA purity and integrity (RIN) were quantified using RNA 6000 Nano kit (Agilent Technologies, 5067-1511) on the 4200 TapeStation (Agilent, Santa Clara, USA). Library preparation and 2x75bp paired-end of 160 ng total RNA input was performed using Illumina Stranded Total RNA Prep Ligation kit and Illumina HiSeq4000 system (Illumina, Sand Diego, CA, USA). RNA sequencing data from HiSeq4000 were quality checked and aligned to GRCh38 (GCA_000001405.15) reference genome using HISAT2 2.0.5 and submitted to subread v.1.5.2 for feature counts calculation. Finally, 36 paired biopsies samples (metformin n=26 and placebo n=12) were sequenced and included in the final analyses.

  Dataset EGAD50000001274

• Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE-BioLINCC)

  Accessing Data Please refer to “Authorized Access” below regarding accessing data through the BioData Catalyst ecosystem. The data from this accession is not available for download through dbGaP. Objectives To test whether pulmonary artery catheter use was safe and could improve clinical outcomes in participants hospitalized with recurrent heart failure. Background Pulmonary artery catheters have been used to guide adjustment of therapy in multiple settings, but recent studies have raised concern that pulmonary artery catheters may lead to increased mortality in hospitalized participants. Participants A total of 433 participants at 26 sites were enrolled, and randomly assigned to receive therapy guided by clinical assessment and the pulmonary artery catheter or clinical assessment alone. Patients with acute decompensation in which the attending heart failure physician considered pulmonary artery catheterization (PAC) was required or likely to be required within the next 24 hours were entered into a PAC registry. A total of 439 patients were added to the registry. Conclusions Therapy to reduce volume overload during hospitalization for heart failure led to marked improvement in signs and symptoms of elevated filling pressures, with or without the pulmonary artery catheter. Addition of the pulmonary artery catheter to careful clinical assessment did not impact overall mortality and hospitalization. Future trials should test noninvasive assessments with specific treatment strategies that could be used to better tailor therapy for both survival time and survival quality as valued by participants. (Binanay, C. et al., JAMA, 2005)

  Study phs003782

• Non-coding mutations reveal cancer driver cistromes in luminal breast cancer

  Whole-genome sequencing of primary breast tumors enabled the identification of cancer driver genes and non-coding cancer driver plexuses from somatic mutations. However, differentiating between driver and passenger events among non-coding genetic variants remains a challenge to understand the etiology of cancer and inform the delivery of personalized cancer medicine. Herein, we reveal enrichment of non-coding mutations in cis-regulatory elements that cover a subset of transcription factors linked to tumor progression in luminal breast cancers. Using a cohort of 26 primary luminal ER+PR+ breast tumors, we compiled a catalogue of ~100,000 unique cis-regulatory elements from ATAC-seq data. Integrating this catalogue with somatic mutations from 350 publicly available breast tumor whole genomes, we identified four recurrently mutated individual cis-regulatory elements. By then partitioning the non-coding genome into cistromes, defined as the sum of binding sites for a transcription factor, we uncovered cancer driver cistromes for ten transcription factors, namely CTCF, ELF1, ESR1, FOSL2, FOXA1, FOXM1 GATA3, JUND, TFAP2A, and TFAP2C in luminal breast cancer. Nine of these ten transcription factors were shown to be essential for growth in breast cancer, with four exclusive to the luminal subtype. Collectively, we present a strategy to find cancer driver cistromes relying on quantifying the enrichment of non-coding mutations over cis-regulatory elements concatenated into a functional unit drawn from an accessible chromatin catalogue derived from primary cancer tissues.

  Study EGAS00001005235

• Germline RUNX1 Variation and Predisposition to Childhood Acute Lymphoblastic

  Somatic mutations of RUNX1, which encodes the myeloid and lymphoid transcriptional factor RUNX1, are common in both B- and T- acute lymphoid leukemia (ALL) and are associated with poor prognosis of T-ALL. However, there has been no comprehensive investigation of the pattern or prevalence of RUNX1 germline mutation in both B- and T-ALL. Here we report germline RUNX1 variants in 1.23% of B-ALL and 2.11% of T-ALL, identifying 31 unique variants in 62 B-ALL and 18 unique variants in 26 T-ALL children. The majority of frameshift and nonsense variants affected RUNX1 function in transcriptional regulation, hematopoiesis, and cellular proliferation. We identified JAK3 as the most frequent somatic mutation in T-ALL with RUNX1 variants. These results not only identify RUNX1 as a leukemia predisposition gene but also further underline the importance of germline genetic variants to the development of ALL

  Dataset EGAD00001007793

• Pooled Genome-Wide Analysis of Kidney Cancer Risk (KIDRISK)

  Incidence rates of renal cell carcinoma (RCC) are rising and the latest estimates show that it accounts for over 300,000 cases and 120,000 deaths worldwide each year. Mechanisms underlying RCC occurrence are not fully understood and a large part of the disease heritability remains unexplained. The study aimed at augmenting the size of available RCC genome-wide association studies to increase the statistical power to detect genetic variants associated with the disease. The study includes genome-wide genotyping data from RCC cases (n=2,781) and controls (n=2,526) recruited in Western Europe, Central and Eastern Europe, and Australia.

  Study phs001271

• Neoadjuvant combination PD-L1 plus CTLA-4 blockade in patients with cisplatin-ineligible operable urothelial carcinoma

  Immune checkpoint therapy (ICT) is being tested in the neoadjuvant setting for patients with localized urothelial carcinoma (UC), with one study reporting data in cisplatin-ineligible patients who received anti PD-L1 monotherapy. The study reported that patients with bulky tumors, a known high-risk feature defined as greater than clinical T2 disease, had fewer responses, with pathologic complete response (pCR) rate of 17%. Here, we report on the first pilot combination neoadjuvant trial (NCT02812420) with anti-PD-L1 (durvalumab) plus anti-CTLA-4 (tremelimumab) in cisplatin-ineligible patients, with all tumors identified as having high risk features (N=28). Primary endpoint was safety and we observed 6 of 28 patients (21%) with grade ≥3 immune-related adverse events, consisting of asymptomatic laboratory abnormalities (N=4), hepatitis and colitis (N=2). We also observed pCR of 37.5% and downstaging to pT1 or less in 58% of patients who completed surgery (N=24). In summary, we provide initial safety, efficacy and biomarker data with neoadjuvant combination anti-PD-L1 plus anti-CTLA-4, which warrants further development for patients with localized UC, especially cisplatin-ineligible patients with high-risk features who do not currently have an established standard-of-care neoadjuvant treatment. Publication: Gao et al. Neoadjuvant PD-L1 plus CTLA-4 blockade in patients with cisplatin-ineligible operable high-risk urothelial carcinoma. Nature Medicine volume 26, pages1845–1851(2020)

  Study EGAS00001004074

• Cell-free DNA sequencing data of healthy control, atrophic gastritis, and gastric cancer patients’ blood

  Sample cohort (n=48) is consisted of healthy, atrophic gastritis and gastric cancer patients. Some of the gastric cancer patients samples are collected at the separate time points: -1 before the operation; -2 after the operation; -3 during the control visit. For the hybridisation capture of the genes unique 15 gastric cancer-related gene panel was developed and very deep sequencing using TruSight Oncology Unique Molecular Identifier (UMI) Reagents (Illumina) was used.

  Dataset EGAD00001011153