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• Transcriptomic Analysis of Human Hematopoietic Progenitors from Healthy Donors and Bone Marrow Failure Patients

  The purpose of this study was to define transcriptional changes that occur in the rare and heterogeneous bone marrow progenitors that are affected in Shwachman-Diamond Syndrome. Data are reported for four genetically confirmed SDS patients ranging from 11-26 years old, 3 male and 1 female, and four healthy donors ranging from 25-29 years old, 2 male and 2 female. Subjects provided written, informed consent in accordance with the Declaration of Helsinki's Ethical Principles of Medical Research Involving Human Subjects. Single CD34+ cells were purified from fresh bone marrow and cDNA libraries were prepared using the SMARTer Ultra Low RNA Kit (Clontech; pre-2015) or SMART-Seq v4 Ultra Low RNA Kit (Clontech; post-2015). Libraries were sequenced on a HiSeq 2500 Instrument (Illumina, San Diego, CA) to a read depth of ~3 M paired-end, 25 bp reads per single cell. Paired-end reads were mapped to the hg38 human transcriptome (Gencode v24) using STAR v2.4.2a.

  Study phs001845

• Circulating Tumor DNA as a Biomarker in Patients with Stage III and IV Wilms Tumor: Analysis from a Children's Oncology Group Trial, AREN0533

  We evaluated the utility of circulating tumor DNA (ctDNA) as a biomarker in the serum and urine of 50 patients with Stage III or Stage IV Wilms tumor (WT) that were enrolled on Children's Oncology Group (COG) trial AREN0533. 49 out of 50 patients had matched tumor samples available for comparison. We profiled samples with ultra-low pass whole genome sequencing (ULP-WGS) and detected ctDNA in 82% of serum samples and 26% of urine samples. We also identified copy-number changes and single-nucleotide variants in the serum and urine samples, and compared them to the tumor data. Our study highlights the advantages of using ctDNA as non-invasive prognostic biomarker with the potential to detect tumor heterogeneity in patients with WT. We believe that prospective validation of ctDNA as a prognostic biomarker in patients with WT is warranted. The ULP-WGS and targeted next-generation sequencing (OncoPanel) data are available in this study.

  Study phs002847

• International Age-Related Macular Degeneration Genomics Consortium - Exome Chip Experiment

  Advanced age-related macular degeneration (AMD) is the leading cause of blindness in the elderly, with limited therapeutic options. To further our understanding of AMD genetics, we examined the contribution of common and rare genetic variation in the International AMD Genomics Consortium that included ~50,000 samples of 26 AMD case - control cohorts that were jointly genotyped. Analyzing 16,144 patients with late stage AMD and 17,832 controls, we identified 52 independently associated common and rare variants distributed across 34 loci. Besides these single variant signals, we also observed gene-based enrichment of very rare coding variants (frequency < 0.1%) in cases that implicated causal roles for CFH, CFI and TIMP3 in three of the known AMD risk loci. Our results support the hypothesis that rare coding variants can pinpoint causal genes within known genetic loci and illustrate that applying the approach systematically to detect new loci requires extremely large sample sizes.

  Study phs001039

• Integrative Age-Related Changes in Genome and Epigenome in Human Lung in Relation to Smoking

  The Integrative Age-Related Changes in Genome and Epigenome in Human Lung in Relation to Smoking study was designed to assess DNA methylation and gene expression profiles in cytologically normal bronchial progenitor "basal" cells. The cells were collected from 54 consented bronchoscopy specimen donors at standard airway locations during clinically indicated bronchoscopy, and then outgrown in primary cultures. DNA methylation profiles were assessed using Enzymatic-Methyl sequencing (EM-seq: 96% genomic coverage, 7.5x depth) in all 54 donors' samples. The gene expression profile was evaluated by bulk RNA-Seq in 39 donors' samples. The study participants were at the ages of 33 - 81 years old at enrollment. Of the 54 donors, 31 were newly diagnosed with lung cancer. As for tobacco smoke exposure, there were 19 current, 18, former, and 17 never smokers. There are 26 subjects whose specimens were used for single cell whole-genome sequencing study phs002758.

  Study phs003317

• Functional Variant rs9344 at 11q13.3 Regulates CCND1 Expression in Multiple Myeloma with t(11;14)

  Multiple myeloma (MM) is a plasma cell (PC) malignancy characterized by cytogenetic abnormalities, such as t(11;14)(q13;q32), resulting in CCND1 overexpression. The rs9344 G allele within CCND1 is the most significant susceptibility allele for t(11;14). We have found the G risk allele is enriched in both healthy individuals of African ancestry and African American individuals with MM. The overall aim of this study was to identify the mechanism behind why the G allele is enriched in t(11;14) MM. To reach this goal, we performed ATAC-seq from 100,000 CD138+ tumor cells from 26 patients with MM. In addition, we performed ChIP-seq using antibodies against H3K4me1, H3K27ac and H3K4me3 from 100,000 CD138+ tumor cells from 8 patients with MM. We used these data to evaluate whether the G allele of rs9344 is associated with elevated chromatin accessibility, H3K27ac and H3K4me3 in t(11;14) MM.

  Study phs003997

• SeqControl: Process Control for DNA Sequencing

  As next-generation sequencing (NGS) continues to increase in speed and throughput, routine clinical and industrial application draws steadily closer. These “production” uses of NGS will require enhanced quality-monitoring and quality-control to optimize output and reduce costs. We therefore developed a framework called SeqControl for predicting sequencing quality and coverage using a set of 15 metrics describing overall coverage, coverage distribution, base-wise coverage and base-wise quality. Using whole-genome sequences of 27 prostate cancers and 26 normal references we derive multivariate models that predict sequencing quality and depth. SeqControl robustly predicts how much sequencing is required to reach a given coverage depth (AUC = 0.993), accurately classifies clinically relevant formalin-fixed paraffin-embedded samples and makes predictions from as little as 1/8 of a lane of sequencing data (AUC = 0.967). These techniques can be immediately incorporated into existing NGS pipelines to monitor data quality in real-time. SeqControl represents a first step towards statistical process-control for NGS.

  Study EGAS00001000899

• Feasibility and safety of a multi-cancer blood test for screening and intervention

  We evaluated the feasibility and safety of blood testing for cancer in an interventional study of 10,006 women. Positive tests for DNA or protein were independently confirmed and diagnostic PET-CT imaging was used to localize disease. During the study, 26 cancers were first detected by blood testing, 24 more by standard-of-care screening, and 46 by neither approach. Surgicalexcision of the primary tumors was performed on 12 cancers first detected by blood testing.1.0% of participants underwent PET-CT imaging based on false positive blood tests, and 0.22% underwent a futile invasive diagnostic procedure. These data demonstrate that multi-cancer blood testing, when followed by PET-CT localization, can be safely incorporated into routineclinical care, in some cases leading to surgery with intent to cure. Further studies will be required to determine the clinical validity and utility of multi-cancer blood testing.

  Study EGAS00001004372

• Whole exome and Transcriptome sequencing of treatment-naïve esophageal adenocarcinoma biopsies and matched peripheral blood mononuclear cells

  Exome sequencing was performed on n=28 treatment-naïve esophageal adenocarcinoma (EACs). Three to four biopsies sampling different areas of each tumor were pooled before nucleic acid extractions to mitigate the elevated heterogeneity described for EAC. WES was performed on EAC biopsies at 120X average coverage, with autologous PBMCs used as germline controls at 80X average coverage. Libraries were prepared from 30 ng of input DNA using the SureSelect QXT Human All Exon V7 kit (Agilent Technologies) and sequenced on the NextSeq 550 (Illumina), 2x150 bp. BCL files were demultiplexed to FastQ files using bcl2fastq2 software (Illumina). Three paired end sequencing batches were analyzed independently (Batch1: samples 8, 10, 11, 12, 15, 17, 18; Batch2: samples 20, 24, 25, 26, 27, 29, 30, 31, 33, 34 ; Batch3: samples 35, 37, 39, 40, 41, 43, 45, 48, 54, 55, 57). RNA sequencing was performed on n=26 treatment-naïve esophageal adenocarcinoma (EACs). Three to four biopsies sampling different areas of each tumor were pooled before nucleic acid extractions to mitigate the elevated heterogeneity described for EAC. RNAseq libraries were prepared on 50 ng of total RNA (with RNA integrity index RIN >=7) with the TruSeq Stranded mRNA library preparation kit (Illumina) in accordance with low-throughput protocol. After PCR enrichment (15 cycles) and purification of adapter-ligated fragments, the concentration and length of DNA fragments were measured using D1000 Screen Tape System (Agilent), obtaining a median insert size of 311 nucleotides. Then, RNAseq libraries were sequenced using the Illumina NovaSeq platform, 1x100 bp, obtaining on average 100 million single reads per sample.

  Dataset EGAD00001010876

• Genome-wide cell-free DNA termini in patients with cancer

  The structure, fragmentation patterns and terminal sequences of cell-free DNA (cfDNA) are altered by nucleases and biological mechanisms in the blood of cancer patients. The cfDNA fragment-end composition recovered from low coverage WGS (<1 fold coverage) using a bespoke software (FrEIA) is aberrant in the plasma from cancer patient (n = 418, 655 samples) compared to controls (n = 117). As a standalone test FrEIA allows detection down to ~0.2% tumor fraction in vitro and in silico at 95% specificity, leading to a sensitivity of ~71% for detecting lung cancer (14/22 stage I-II, 27/38 stage III, 92/127 stage IV) and ~68% for detecting esophageal adenocarcinoma (26/44 stage II, 46/62 stage III). Additional cfDNA biological patterns can be combined with FrEIA increasing the diagnostic potential of low coverage WGS at minimal cost (mean AUROC = 0.96). Integrating multiple cfDNA biological signal augments the diagnostic performance of liquid biopsy.

  Study EGAS00001006142

• NHLBI TOPMed: Walk-PHaSST Sickle Cell Disease (SCD)

  Walk-PHaSST study is a multi-center clinical trial to evaluate the effects of sildenafil on Sickle Cell Disease (SCD) population with low exercise capacity associated with an increased Doppler-estimated pulmonary artery systolic pressure (as assessed by the tricuspid regurgitant velocity (TRV)). It is a double-blind, placebo-controlled trial to assess the safety, tolerability, and efficacy of sildenafil in patients with SCD who had both an elevated TRV and decreased exercise capacity. The screening phase of the study enrolled 720 subjects and 74 of them were randomized for the clinical trial. For the screening cohort, we have collected general demographics and race/ethnicity, hemoglobin genotype, physical examination, laboratory screening, transthoracic Doppler echocardiography, and 6 minute walk test in 9 US and 1 UK site. The walk-PHaSST biorepository have banked samples from 610 of the screening subjects. A total of 592 subjects from the screening phase are included in the TOPMed program for WGS.

  Study phs001514

• SEER Remote Access Pilot Test Data (2018)

  This is a limited use Surveillance, Epidemiology, and End Results (SEER) file for use in a pilot test of remote data access. The SEER Program of the National Cancer Institute (NCI) is an authoritative source of information on cancer incidence and survival in the United States. SEER currently collects and publishes cancer incidence and survival data from population-based cancer registries covering approximately 34.6 percent of the U.S. population. The SEER Program registries routinely collect data on patient demographics, primary tumor site, tumor morphology and stage at diagnosis, first course of treatment, and follow-up for vital status. The mortality data reported by SEER are provided by the National Center for Health Statistics. The population data used in calculating cancer rates is obtained periodically from the Census Bureau. The SEER research data files include SEER incidence and population data associated by age, sex, race, year of diagnosis, and geographic areas.

  Study phs002012

• 1000 Genomes Used for Cloud Testing

  WARNING: This is a test data set. The phenotype data was not checked to match 1000 Genomes project. Use with caution.This study provides public access to a demonstration subset of 1000 genomes sequence data in dbGaP. It is intended to be used by software developers who design, implement and validate pipelines for dbGaP data. While this project distributes only public data, it uses dbGaP security mechanisms which include a project-specific security key and a decryption password. Since the data are public, the key and password for this project will be included by SRA into public demonstration packages that permit users to test and validate the security of their computational pipelines. Note that all public users of this data will be logged under the same project and account ID. The datasets attached to this project must be restricted to 1000 Genomes data identical to the project's public FTP site. To access these test data using SRA toolkit use prj_phs710EA_test.ngc.

  Study phs000710

• ucfDNA workflows for molecular profiling of malignant disease

  Urinary cell-free DNA (ucfDNA) is a promising liquid biopsy analyte obtained by a non-invasive sampling method, particularly valuable in urological cancers due to the proximity of biofluids to the tumor site. However, extremely high fragmentation and low abundance of ucfDNA pose significant analytical challenges. Improper handling and storage can severely affect ucfDNA quality, necessitating optimized pre-analytical workflows for clinical applications. We evaluated multiple pre-analytical workflows, including urine stabilization approaches against unstabilized urine samples. Our results demonstrated that without stabilization, ucfDNA degraded rapidly and minimal quantities remaining after 72 hours. In contrast, urine stabilization preserved ucfDNA integrity, enabling successful downstream analyses, including digital PCR and next-generation sequencing, for mutation detection in cancer-related genes and genome wide copy number profiling. These findings underscore the critical role of stabilization for a reliable ucfDNA analysis and highlight its potential in molecular diagnostics as a complementary tool to plasma-based liquid biopsies.

  Study EGAS50000001093

• Tracking the origins and drivers of subclonal metastatic expansion in prostate cancer

  Tumour heterogeneity in primary prostate cancer is a well-established phenomenon. However, how the subclonal diversity of tumours changes during metastasis and progression to lethality is poorly understood. Here we reveal the precise direction of metastatic spread across four lethal prostate cancer patients using whole-genome and ultra-deep targeted sequencing of longitudinally collected primary and metastatic tumours. We find one case of metastatic spread to the surgical bed causing local recurrence, and another case of cross-metastatic site seeding combining with dynamic remoulding of subclonal mixtures in response to therapy. By ultra-deep sequencing end-stage blood, we detect both metastatic and primary tumour clones, even years after removal of the prostate. Analysis of mutations associated with metastasis reveals an enrichment of TP53 mutations, and additional sequencing of metastases from 19 patients demonstrates that acquisition of TP53 mutations is linked with the expansion of subclones with metastatic potential which we can detect in the blood.

  Study EGAS00001000942

• Rna-Seq Leiomyosarcoma subtypes

  Leiomyosarcomas (LMS) are genetically heterogeneous tumors differentiating along smooth muscle lines. Currently, LMS treatment is not informed by molecular subtyping and is associated with highly variable survival. While disease site continues to dictate clinical management, the contribution of genetic factors to LMS subtype, origins, and timing are unknown. Here we analyzed 70 genomes and 130 transcriptomes of LMS, including multiple tumor regions and paired metastases. Molecular profiling highlighted the extremely early origins of LMS. Three specific subtypes of LMS develop from distinct lineages of smooth muscle cells. Of these, dedifferentiated LMS with high immune infiltration and tumors primarily of gynaecological origin acquired the highest burden of genomic mutation and are associated with worse survival. Homologous recombination defects lead to genome-wide mutational signatures, and a corresponding sensitivity to PARP and other DNA damage response inhibitors, suggesting a novel therapeutic strategy for LMS. Finally, by phylogenetic reconstruction, we present evidence that clones seeding lethal metastases arise decades prior to LMS diagnosis.

  Study EGAS00001004783

• Latency and interval therapy affect the evolution in metastatic colorectal cancer

  While comparison of primary tumor and metastases has highlighted genomic heterogeneity in colorectal cancer (CRC), previous studies have focused on a single metastatic site or limited genomic testing. Combining data from whole exome and ultra-deep targeted sequencing, we explored possible evolutionary trajectories beyond the status of these mutations, particularly among patient-matched metastatic tumors. Our findings confirm the persistence of known clinically-relevant mutations (e.g. those of RAS family of oncogenes) in CRC primary and metastases, yet reveal that latency and interval systemic therapy affect the course of evolutionary events within metastatic lesions. Specifically, our analysis of patient-matched primary and multiple metastatic lesions, developed over time, showed a similar genetic composition for liver metastatic tumors, which were 21-months apart. This genetic makeup was different from those identified in lung metastases developed before manifestation of the second liver metastasis. These results underscore the role of dormancy in the evolutionary path of metastatic CRC.

  Study EGAS00001003646

• Ongoing Replication Stress Tolerance and Clonal T Cell Responses Distinguish Liver and Lung Recurrence and Patient Outcomes in Pancreatic Ductal Adenocarcinoma

  Patients with metastatic pancreatic ductal adenocarcinoma (PDAC) survive longer when disease spreads to the lung but not to the liver. We generated overlapping, multi-omic datasets to identify molecular and cellular features that distinguish patients whose disease develops liver metastasis (liver cohort) from those whose disease progression results in lung metastasis without liver metastases (lung cohort). Lung cohort patients generally survived longer than liver cohort patients, independent of tumor subtype. We developed a pORG gene signature that distinguishes primary tumors in the liver and lung cohorts. We identified ongoing replication stress (RS) response pathways in high pORG/liver cohort tumors, while low pORG/lung cohort tumors had greater densities of lymphocytes and shared T cell clonal responses. Our study demonstrates that liver-avid PDAC is associated with tolerance to ongoing RS, limited tumor immunity, and less favorable outcomes; whereas low RS, lung-avid/liver-averse tumors are associated with active tumor immunity that may account for favorable outcomes. As expected, we found high frequencies of KRAS, TP53, CDKN2A, and SMAD4 gene alterations in our tumor samples. High pORG activity (GSVA scores) in our primary tumors appear to be positively correlated with alteration frequencies in both TP53 and CDKN2A. We did not see a correlation with alterations in KRAS as almost all the tumor samples have KRAS alterations. From a de-identified dataset of 1,873 patients diagnosed with and/or treated for PDAC at our institution between 2004 and 2020, we identified 422 patients for which we had specimens with sequencing data (N=374) and/or specific evidence of disease metastasis site(s) from the OHSU cancer registry or disease-relevant computed tomography (CT) scans to allow cohort classification. Note that our study includes RNA-Seq, DNA-Seq panel, and TCR-Seq (T-cell Receptor Sequencing) data, but that this dbGaP submission just includes the patients/samples with RNA-Seq and/or DNA-Seq panel data. Therefore, this submission includes 290 samples from 278 patients. TCR sequence data is available on the Adaptive Biotechnologies platform. Clinical course timepoints, patient demographics, stage, grade, nodal involvement, resection margins, and angiolymphatic invasion were provided as deidentified data by the OHSU cancer registry with quality control data verification in a subset by pathologists (BB and TM). We reviewed all available computed tomography (CT) scans for all patients with primary tumor resection dates recorded by the cancer registrar, with tumor samples analyzed by RNA-seq, DNA-seq, or TCR-seq, and/or with additional information indicating metastatic spread (e.g., metastatic samples received for related studies). We abstracted the site of all lesions proven to be metastatic by biopsy and/or that clearly increased in size during progression or decreased in size during treatment as long as a radiologist described the lesion as “likely”, “suspicious for”, “concerning for”, or “favor” metastasis. Clinical imaging was reviewed by a radiologist (AG) to validate patient assignments to the liver, lung, and neither liver nor lung (other recurrence site) cohorts. Time to recurrence was calculated from the earliest of either the recurrence date provided by the OHSU cancer registry, or the date of earliest lesion abstracted from CT reports. The subject attributes reported in this submission were up to date at the time of our data freeze, which occurred July 2021.

  Study phs003597

• 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

• Single-nucleus RNA-sequencing data of kidney biopsies from patients with primary FSGS, maladaptive FSGS, proteinuric controls and healthy controls

  This dataset includes FASTQ files of single-nucleus RNA sequencing of cryopreserved kidney biopsy cores from adult patients with diagnosed primary FSGS (n = 9, all nephrotic), maladaptive FSGS (n = 9, not nephrotic), proteinuric controls (PLA2R-positive membranous nephropathy, n = 3), and healthy controls (n = 4). A total of 120,751 high-quality nuclei were identified, including 2,471 podocytes and 1,574 parietal epithelial cells (PECs). In addition to the raw FASTQ files, the dataset includes processed data files from all 25 samples, generated using Seurat in R: barcode files, features, count matrices, and associated metadata. Details regarding the bioinformatics pipeline can be found at https://github.com/lambrechtslab/FSGS_Deleersnijder_et_al

  Dataset EGAD50000001557

• ICR96 exon CNV validation series

  A resource for assessment of exon CNV calling methods in targeted NGS data, we here present the ICR96 exon CNV validation series. The dataset includes high-quality sequencing data from a targeted NGS assay (the TruSight Cancer Panel) together with Multiplex Ligation-dependent Probe Amplification (MLPA) results for 96 independent samples. 66 samples contain at least one validated exon CNV and 30 samples have validated negative results for exon CNVs in 26 genes. The dataset includes 46 exon CNVs in BRCA1, BRCA2, TP53, MLH1, MSH2, MSH6, PMS2, EPCAM and PTEN, giving excellent representation of the cancer predisposition genes most frequently tested in clinical practice. Moreover, the validated exon CNVs include 25 single exon CNVs the most difficult exon CNV to detect.

  Dataset EGAD00001003335

• BRCA1 secondary splice-site mutations

  BRCA1 splice isoforms d11 and d11q can contribute to PARP inhibitor (PARPi) resistance by splicing-out mutation-containing exons, producing truncated, partially-functional proteins. However, the clinical impact and underlying drivers of BRCA1 exon skipping remain undetermined. We analyzed nine ovarian and breast cancer patient derived xenografts (PDX) with BRCA1 exon 11 frameshift mutations for splice isoform expression and therapy response.

  Study EGAS50000000022

• Luminal progenitor cell line iHBEC(CD117)

  Basal-like breast cancer originates in luminal progenitors, frequently with an altered PI3K pathway, and focally in close association with genetically altered myoepithelial cells at the site of tumor initiation. The exact trajectory behind this bi-lineage phenomenon remains poorly understood. Here we used a breast cancer relevant transduction protocol including hTERT, shp16, shp53, and PIK3CA(H1047R) to immortalize FACS isolated luminal cells, and we identified a candidate multipotent progenitor. We found that the apparent luminal phenotype of these oncogene transduced progenitors was metastable giving rise to basal-like cells dependent on culture conditions. After culturing the cells for more than 60 passages, cells were subjected to scRNA-seq as well as bulk RNA sequencing of two subpopulations (CD271+ and CD271-).

  Dataset EGAD50000000723

• 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

• Genetic Discovery and Application in a Clinical Setting: Continuing a Partnership (eMERGE Phase II)

  The electronic Medical Records and Genomics (eMERGE) Network is a consortium of ten participating sites funded by the NHGRI to investigate the use of electronic medical record systems for genomic research. The goal of eMERGE is to conduct genome-wide association studies in approximately 19,000 individuals using EMR-derived phenotypes and DNA from linked Biorepositories. The eMERGE Network brings together researchers with a wide range of expertise in genomics, statistics, ethics, informatics, and clinical medicine from leading medical research institutions across the country. Each center participating in the consortium is uniquely situated to provide critical resources to this highly collaborative and productive network. Each site combines a biobank or study cohort with extensive genomic data and access to clinical data derived from electronic medical records. Sites are geographically dispersed and have diverse patient populations, including two sites focusing specifically on pediatrics. The eMERGE Network is comprised of 9 sites and one coordinating center. Each site maintains its own biorepository where DNA specimens are linked to phenotypic data contained within EMRs. Children's Hospital of Pennsylvania, PI: Hakon Hakonarson, MD, PhD Cincinnati Children's Medical Center with Boston Children's Hospital, PI: John Harley, MD, PhD - CCHMC and Ingrid Holm, MD, MPH - BCH Geisinger Health System, PI: David Carey, PhD and Marc Williams, MD Group Health Cooperative with University of Washington, PI: Eric Larson, MD, MPH - GHC and Gail Jarvik, MD, PhD - UW Marshfield Clinic with Essentia Institute of Rural Health, PI: Catherine McCarty, PhD, MPH - Essentia and Murray Brilliant, PhD - Marshfield Mayo Clinic, PI: Christopher Chute, MD, DrPH and Iftikhar Kullo, MD Icahn School of Medicine at Mount Sinai, PI: Erwin Bottinger, MD Northwestern University, PI: Rex Chisholm, PhD and Maureen Smith, MS Vanderbilt University, PI: Dan Roden, MD eMERGE Coordinating Center - Vanderbilt University, PI: Paul Harris, PhD Using electronic phenotyping methods, the consortium used DNA samples from all participating sites to explore the genetic determinants of red cell indices, white blood count (WBC) differential, diabetic retinopathy, height, serum lipid levels, specifically total cholesterol, HDL (high density lipoprotein), LDL (low density lipoprotein), and triglycerides, and autoimmune hypothyroidism as well as using the phenome-wide association study (PheWAS) paradigm to replicate and discover relationships between targeted genotypes with multiple phenotypes.

  Study phs000948

• Discrepancies in Tumour Mutation Burden (TMB) reporting from sequential Endobronchial ultrasound trans bronchial needle aspiration (EBUS TBNA) samples within single lymph node stations

  Introduction: Tumour Mutation Burden (TMB) is a potential biomarker for immune therapies. Identifying factors that may affect TMB prediction is key to its utility as biomarker for treatment options. Here we investigated parameters that might affect TMB using cytology smears obtained from endobronchial ultrasound transbronchial needle aspiration (EBUS TBNA)-sampled malignant lymph nodes, which are often the only diagnostic samples collected in patients with advanced lung cancer. Methods: Individual Diff-Quik cytology smears were prepared for each needle pass from the same enlarged malignant mediastinal lymph nodes. DNA extracted from smears of each pass underwent sequencing using a large gene panel sequencing (TSO500, Illumina). TMB was estimated for each individual needle pass using the TSO500 Local App v. 2.0 (Illumina). Results: Twenty patients had two or more Diff-Quik smears (total 45 smears) which passed sequencing quality control. Average TMB for all smears was 8.7 ± 5.0 mutations per megabase (Mb). Sixteen of the 20 patients had paired samples with minimal differences in TMB score (average difference 1.3 ± 0.85). Paired samples from 13 patients had concordant TMB in terms of scores being below or above a threshold of 10 mutations/Mb. Samples from seven patients had discrepant TMB, with four cases in particular exhibiting an average difference of 11.3 ± 2.7 mutations/Mb. Factors affecting TMB calling involved tumour content of the samples, the amount of DNA used in sequencing as well as bone fide intra tumour heterogeneity between paired samples. Conclusions: TMB assessment is feasible from EBUS-TBNA derived Diff-Quik slides from a single needle pass. Repeated samples of one or more lymph nodes have minimal variation in TMB in most cases (80%), suggesting accuracy of the test overall. To enhance accuracy of the result, care should be taken in relation to the tumour content of the cytology smear. Further, clinicians should be aware that even slight differences in lymph node site selection could give rise to variable genomics and discrepant TMB due to tumour heterogeneity. Therefore, it would be reasonable for multi-lymph node site analysis of TMB to be performed using EBUS TBNA aspirates from different easily accessible lymph nodes. Further investigations need to determine whether these samples should be combined as one sample or tested separately.

  Study EGAS00001007484

• Multi-site tumor sampling highlights molecular intra-tumor heterogeneity in malignant pleural mesothelioma

  Background:Malignant pleural mesothelioma (MPM) is a heterogeneous cancer. Better knowledge of molecular and cellular intra-tumor heterogeneity throughout the thoracic cavity is required to develop efficient therapies. This study focuses on molecular intra-tumor heterogeneity using the largest series to date in MPM and is the first to report on the multi-omics profiling of a substantial series of multi-site tumor samples. Methods:Intra-tumor heterogeneity was investigated in 16 patients from whom biopsies were taken at distinct anatomical sites. The paired biopsies collected from apex, side wall, costo-diaphragmatic or highest metabolic sites as well as 5 derived cell lines were screened using targeted sequencing. Whole exome sequencing, RNA sequencing, and DNA methylation were performed on a subset of the cohort for deep characterization. Molecular classification, recently defined histo-molecular gradients, and cell populations of the tumor microenvironment were assessed. Results:Sequencing analysis identified heterogeneous variants notably in NF2, a key tumor suppressor gene of mesothelial carcinogenesis. Subclonal tumor populations were shared among paired biopsies, suggesting a polyclonal dissemination of the tumor. Transcriptome analysis highlighted dysregulation of cell adhesion and extracellular matrix pathways, linked to changes in histo-molecular gradient proportions between anatomic sites. Methylome analysis revealed contribution of epigenetic mechanisms in two patients. Finally, significant changes in the expression of immune mediators and genes related to immunological synapse, as well as differential infiltration of immune populations in the tumor environment were observed and led to a switch from a hot to a cold immune profile in three patients. Conclusions:This comprehensive analysis reveals patient-dependent spatial intra-tumor heterogeneity at the genetic, transcriptomic and epigenetic levels and in the immune landscape of the tumor microenvironment. Results support

  Study EGAS00001005328

• The Mutational Landscape of CTCL and Sezary Syndrome

  Sezary syndrome is a leukemic and aggressive form of cutaneous T-cell lymphoma (CTCL) resulting from the malignant transformation of skin-homing central memory CD4+ T cells. To identify new genetic alterations involved in Sezary syndrome and CTCL transformation we performed whole-exome sequencing of tumor-normal sample pairs from 26 Sezary syndrome and 16 CTCL patients. These analyses revealed a distinctive pattern of somatic copy number alterations in Sezary syndrome including highly prevalent recurrent chromosomal deletions involving the TP53, RB1, PTEN, DNMT3A, and CDKN1B tumor suppressor genes. Mutation analysis identified a broad spectrum of somatic mutations involving key genes involved in epigenetic regulation (TET2, CREBBP, MLL3, BRD9, SMARCA4 and CHD3) and signaling, including mutations in MAPK1, BRAF, CARD11 and PRKG1 driving increased MAPK, NFKB and NFAT activity upon T-cell receptor stimulation. Collectively, our findings provide new insights into the genetics of Sezary syndrome and CTCL and support the development of personalized therapies targeting key oncogenically activated signaling pathways for the treatment of these diseases.

  Study phs000994

• Genetics of Glucose Regulation in Gestation and Growth (Gen3G) Cohort - Placenta Transcriptomics RNA Sequencing

  The overarching goals of Genetics of Glucose regulation in Gestation and Growth (Gen3G) are to increase our understanding of biological, environmental, and genetic determinants of glucose regulation during pregnancy and their impact on fetal/child development. Gen3G is a prospective cohort study: we initially recruited 1,024 pregnant women between 2010-2013 at Blood Sampling in Pregnancy Clinic during the first trimester of pregnancy (median 9 weeks of gestation) in Sherbrooke, Québec, Canada. We assessed 898 pregnant women at second trimester (median 26 weeks of gestation), when participants completed a 75g oral glucose tolerance test (OGTT) as clinically indicated for screening of gestational diabetes mellitus (GDM). We collected data for 854 mother-child dyads at delivery (from medical records), in addition to placenta and/or cord blood samples in majority of newborns.The overall goal of the grant that supported data that is included in this dbGaP submission was to discover novel placental factors that regulate glucose metabolism in pregnancy and predict GDM by conducting genome-wide transcriptomics (RNA and miRNA) in carefully collected placenta samples from Gen3G.

  Study phs003151

• Blood-based monitoring of relapsed/refractory cHL patients predict responses to PD-1 blockade treatment

  Hodgkin lymphoma (cHL) patients are uniquely susceptible to treatment with programmed cell death-1 (PD-1) treatment. However, monitoring with FDG-PET/CT, the current response detection standard, is challenging. Here, we address the potential applicability of tissue biomarkers and blood-based biomarkers in PD-1 treated cHL patients. We evaluated 9p24.1/PD-L1/PD-L2 alterations, and expression of PD-L1 and antigen presentation molecules (HLA class I/II) in 9 tissue biopsies of 4 patients. In addition, we assessed circulating tumor DNA (ctDNA), extracellular vesicle associated miRNAs (EV-miRNAs), soluble PD-L1 and serum TARC (sTARC) in 26 longitudinal blood samples of these patients during PD-1 treatment. We found that the predictive power of tissue biomarkers is dependent on the timing of the biopsy . The dynamics of blood-based biomarkers: sTARC, EV-miRNAs and ctDNA corresponded well immunotherapy treatment response. Therefore, blood-based biomarkers are promising monitoring strategies in PD-1 treated cHL patients and should be further explored in clinical trials or observational studies.

  Study EGAS00001005894

• Molecular stratification of endometrioid ovarian carcinoma predicts clinical outcome

  Endometrioid ovarian carcinoma (EnOC) is an under-investigated type of ovarian carcinoma. Here, we report the largest genomic study of EnOCs to date, performing whole exome sequencing of 112 cases following rigorous pathological assessment. High frequencies of mutation were detected in CTNNB1(43%), PIK3CA(43%), ARID1A(36%), PTEN(29%), TP53(26%) and SOX8(19%), a novel target of recurrent mutation in EnOC. POLE and mismatch repair protein-encoding genes were mutated at lower frequency (6%, 18%) with significant co-occurrence. A molecular taxonomy was constructed using a novel algorithm (PRISTINE), identifying clinically distinct EnOC subtypes: TP53m cases demonstrated greater genomic complexity, were frequently FIGO stage III/IV at diagnosis (48%) and incompletely debulked (44%), and demonstrated inferior survival; conversely, CTNNB1m cases demonstrated low complexity and excellent clinical outcome, were predominantly stage I/II at diagnosis (89%) and completely resected (87%). Tumour complexity provides further resolution within the TP53wt/CTNNB1wt group. Moreover, we identify the WNT, MAPK/RAS and PI3K pathways as good candidate targets for molecular therapeutics in EnOC.

  Study EGAS00001004366

• Single-cell RNA-seq of celiac disease-specific plasma cells

  Disease-specific plasma cells (PCs) reactive with transglutaminase 2 (TG2) or deamidated gluten peptides (DGP) are abundant in celiac disease (CeD) gut lesions. Their contribution toward CeD pathogenesis is unclear. We assessed expression of markers associated with PC longevity in 15 untreated and 26 treated CeD patients in addition to 13 non-CeD controls, and performed RNA-sequencing with clonal inference and transcriptomic analysis of 3251 single PCs. We observed antigen-dependent V-gene selection and stereotypic antibodies. Generation of recombinant DGP-specific antibodies revealed a key role of a heavy-chain residue that displays polymorphism, suggesting that immunoglobulin gene polymorphisms may influence CeD-specific antibody responses. We identified transcriptional differences between CeD-specific vs non-disease-specific PCs and between short-lived vs long-lived PCs. The short-lived CD19+CD45+ phenotype dominated in untreated and short-term-treated CeD, in particular among disease-specific PCs but also in the general PC population. Thus, the disease lesion of untreated CeD is characterized by massive accumulation of short-lived PCs that are not only directed against disease-specific antigens.

  Study EGAS00001004623

• Transcriptional Profiling of Macrophages In Situ in Metastatic Melanoma Reveals Localization-Dependent Phenotypes and Function

  Therapeutic interventions modulating immune function at the tumor site could improve outcomes in cancer. Here we analyzed metastatic melanoma, a tumor type highly responsive to T-cell based therapies, and found that the tumor-infiltrating T cells are localized closely to CD14+ monocytes/macrophages rather than to melanoma cells. Using novel immunofluorescence-guided laser capture micro-dissection, we analyzed transcriptomes of CD3+ T cells, CD14+ monocytes/macrophages and melanoma cells in non-dissociated tissue. CD14+ cells localized in tumors beds displayed specific transcriptional signatures distinct from CD14+ cells that were localized in tumor stroma.The 8 distinct metastatic melanoma samples are from the Cooperative Human Tissue Network (CHTN). 64 RNA-seq files are available from 16 intraCD14+, 16 stromaCD14+, 16 cancer cells, 8 intraCD3+ and 8 stromaCD3+ cells. 2 LCM harvests were completed for the CD14+ and cancer cells on two sections of the samples. One harvest was done for the CD3+ samples.The processed data (TPM/raw counts tables) are available on GEO under GSE180124. 

  Study phs002564

• Genomic Profiling of Sequentially Acquired Metastatic Sites from an "Exceptional Responder" Lung Adenocarcinoma Patient Reveals Extensive Genomic Heterogeneity and Novel Somatic Variants

  We employed next-generation sequencing to identify somatic alterations in multiple metastatic sites from an "exceptional responder" lung adenocarcinoma patient during his seven year course of ERBB2-directed therapies. The degree of heterogeneity was unprecedented, with ~1% similarity between somatic alterations of the lung and lymph nodes. One novel translocation, PLAG1-ACTA2, present in both sites, up-regulated ACTA2 expression. ERBB2, the predominant driver oncogene, was amplified in both sites, more pronounced in the lung, and harbored an L869R mutation in the lymph node. Functional studies demonstrated increased proliferation, migration, metastasis, and resistance to ERBB2-directed therapy due to L869R mutation and increased migration due to ACTA2 overexpression. Within the lung, a nonfunctional CDK12, due to a novel G879V mutation, correlated with down-regulation of DNA damage response genes, causing genomic instability, and sensitivity to chemotherapy. We propose a model whereby a sub-clone metastasized early from the primary site and evolved independently in lymph nodes.

  Study phs001159

• WES in HCCOs with varying Doxorubicin resistance

  We aimed to identify somatic mutations that could explain the resistance to Doxorubicin. Therefor, we purified Exomes from liver biopsies and HCC organoids using Agilent SureSelectXT (clinical research exome, HS2 V8, or Human all Exon V6 Cosmic) and performed WES. Matched non-tumoral liver biopsies served as the control for germline mutations. 12 of these samples were previously reported. Sequence reads were aligned to the reference human genome GRCh38 using Burrows-Wheeler Aligner (BWA, v0.7.17). Duplicate removal, base quality adjustment, mutation calling (Mutect2, intervals: SureSelectXT_HS_V8_S33266340, germline-recourse: gnomad.exomes.r2.1.1.sites.liftover_grch38, Panel-of-Normal: 1000g_pon.hg38), filtering of Mutect calls, and functional annotation (Funcotator, funcotator_dataSources.v1.7.20200521g) were performed using the Genome Analysis Toolkit (GATK, v4.4) according to the Broad Institute best practices in Somatic short variant discovery workflows. Mutations with a functional annotation of Deletion, Insertion, Non-stop, Splice-Site, Start-Codon and Missense mutations were kept. A list of 43 commonly mutated genes in HCC was analyzed in the HCC organoids [TCGA, Comprehensive and Integrative Genomic Characterization of Hepatocellular Carcinoma. Cell, 2017. 169(7): p. 1327-1341.e23].

  Study EGAS50000000043

• Systemic Inflammation and Lymphocyte Activation Precede Rheumatoid Arthritis

  The Allen Institute for Immunology-University of California, San Diego-University of Colorado Transition to Rheumatoid Arthritis (ALTRA) project is a prospective longitudinal cohort study to understand the pre-clinical development of rheumatoid arthritis (RA). We performed cross-sectional and longitudinal multi-omics analyses of peripheral immunity in the anti-citrullinated protein autoantibody-positive (ACPA+) at-risk for RA period. We provide FASTQ files from (1) single-cell RNA sequencing (scRNA-seq) of ACPA+ at-risk (n=45), ACPA+ early RA (n=11), and site-matched ACPA- controls (n=38); (2) scRNA-seq of longitudinal samples from ACPA+ at-risk who developed clinically active RA during our study (n=16 participants, n=75 samples) and ACPA- controls (n=29 subjects, n=89 samples); (3) trimodal TEA-seq of a subset of ACPA+ at-risk (n=7) and ACPA- controls (n=5). Using these data, we characterize pathogenesis prior to clinical RA diagnosis and suggest the at-risk state exhibits substantial immune alterations that could potentially be targeted for early intervention to delay or prevent autoimmunity.

  Study phs003944

• Recursive splicing in long vertebrate genes

  Recent studies have shown that expression of many genes with exceptionally long introns in the mammalian brain can be perturbed by regulatory factors linked to neurodevelopmental or neurodegenerative disorders1-3, suggesting unique regulatory mechanisms. Here we identify functional recursive splice sites (RSS) in long introns of genes expressed in the brain. These RSS are highly conserved in genes with extreme length across diverse vertebrate species and permit step-wise removal of long introns via recursive splicing. Recursive splicing requires initial definition of a “recursive exon” that is located downstream of RSS, and most often contains premature stop codons. Moreover, we show that RSS create a splicing switch driven by splice site competition in order to distinguish primary mRNA isoforms from alternative isoforms that are prevalent in long genes. The recursive exon is not detectable in the dominant mRNA isoform due to recursive splicing, but is completely included when cryptic promoters or other cryptic exons are used. Thus, by coupling inclusion of recursive exons with the use of cryptic elements, RSS act to distinguish new mRNA isoforms emerging from long genes.

  Study EGAS00001001170

• Exome-seq, RNA-Seq, SNP array profiling of gastric tumor samples and cell lines.

  Gastric cancer is the second leading cause of worldwide cancer mortality, yet the underlying genomic alterations remain poorly understood. Here we performed exome and transcriptome sequencing and SNP array assays to characterize 51 primary gastric tumors and 32 cell lines. Meta-analysis of the exome data and previously published data sets revealed 24 significantly mutated genes in MSS tumors, and 16 in MSI tumors. More than half of the patients in our collection could potentially benefit from targeted therapies. We identified 55 splice-site mutations accompanied by aberrant splicing products, in addition to mutation-independent differential isoform usage in tumors. The ZAK kinase isoform TV1 is preferentially upregulated in gastric tumors and cell lines relative to normal samples. This pattern is also observed in colorectal, bladder, and breast cancers. Overexpression of this particular isoform activated multiple cancer-related transcription factor reporters, while depletion of ZAK in gastric cell lines inhibited proliferation. These results reveal the spectrum of genomic and transcriptomic alterations in gastric cancer, and identify isoform-specific oncogenic properties of ZAK.

  Study EGAS00001000736

• An essential role for MYB in driving oncogenic EVI1 expression in enhancer-rearranged leukemias

  In acute myeloid leukemia (AML) with inv(3)(q21;q26) or t(3;3)(q21;q26), a translocated GATA2 enhancer drives oncogenic expression of EVI1. We generated an EVI1-GFP AML model and applied an unbiased CRISPR/Cas9 enhancer scan to uncover sequence motifs essential for EVI1 transcription. Using this approach, we pinpoint a single regulatory element in the translocated GATA2 enhancer that is critically required for aberrant EVI1 expression while being dispensable for GATA2 expression from its endogenous locus. This element contains a DNA binding motif for the transcription factor MYB that heavily occupies this site specifically at the translocated allele. MYB knockout as well as peptidomimetic blockade of p300-dependent MYB function resulted in downregulation of EVI1 but not of GATA2. Targeting MYB or mutating its DNA-binding motif within the GATA2 enhancer resulted in myeloid differentiation and cell death, suggesting that interference with MYB-driven EVI1 transcription provides a potential entry point for therapy of inv(3)/t(3;3) AMLs.

  Study EGAS00001004839

• An Isogenic Cell Line Panel for Sequence-based Screening of Targeted Anti-cancer Drugs

  We describe the creation and characterization of an isogenic cell line panel representing common cancer pathways, with multiple features optimized for high-throughput screening. More than 1,800 cell lines from three normal human cells were generated using CRISPR-technologies. Surprisingly, we discovered most of these lines did not result in complete gene inactivation, despite integration of sgRNA at the desired genomic site. However, a subset of the lines harbored true, biallelic disruptions of the targeted tumor suppressor gene, yielding a final panel of 100 well-characterize lines covering 19 pathways frequently subject to loss of function in cancers. This panel included genetic markers optimized for sequence-based ratiometric assays for drug-based screening assays. To illustrate the potential utility of this panel, we developed a multiplexed high-throughput screen that identified Wee1 inhibitor MK-1775 as a selective growth inhibitor of cells with inactivation of TP53. These cell lines and screening approach should prove useful for researchers studying a variety of cellular and biochemical phenomena

  Study EGAS00001005974

• Genomic analysis and evolutionary modeling of breast and larynx cancer, based on specimens from Polish population

  We explore the genomic characteristics of the original dataset of breast and larynx cancer specimens of several cell types from the collection of the Department of Applied Radiology of the Maria Sklodowska-Curie National Research Institute of Oncology, Krakow (Poland) Branch and Institute of Human Genetics Polish Academy of Sciences. DNA from paired tissue samples from primary tumor locations and concurrent metastasis to regional lymph nodes was sequenced and matched to controls. A range of genomic analyses was carried out, such as estimation of variant allele frequencies (VAF) and copy number variation (CNV). They show that subsets of variants from primary tumors are present in metastatic lymph nodes and that the CNV pattern is similar, but not identical to that known in the literature. In addition to that, we fit the VAF data to theoretical site frequency spectra predicted by multiple models found in the literature. Analysis suggests existence of secondary advantageous subclones arising on the clonal background as well as of a number of neutral or slightly deleterious passenger mutations.

  Study EGAS00001006456

• Epigenetic and metabolomic data from type 2 diabetes adolescents

  Objective: Rates of type 2 diabetes (T2D) among adolescents are on the rise. Epigenetic changes could be associated with the metabolic alterations in adolescents with T2D. Methods: We performed a cross-sectional integrated analysis of DNA methylation data from peripheral blood mononuclear cells with serum metabolomic data from First Nation adolescents with T2D and controls participating in the Improving Renal Complications in Adolescents with type 2 diabetes through REsearch (iCARE) cohort study, to explore the molecular changes in adolescents with T2D. Results: Our analysis showed that 43 serum metabolites and 36 differentially methylated regions (DMR) were associated with T2D. Several DMRs were located near the transcriptional start site of genes with established roles in metabolic disease and associated with altered serum metabolites (e.g. glucose, leucine, and gamma-glutamylisoleucine). These included the free fatty acid receptor-1 (FFAR1), upstream transcription factor-2 (USF2), and tumor necrosis factor-related protein-9 (C1QTNF9), among others. Conclusions: We identified DMRs and metabolites that merit further investigation to determine their significance in controlling gene expression and metabolism which could define T2D risk in adolescents.

  Study EGAS00001003816

• MicroRNAs, Hypertension and End Organ Damage in Humans

  Study 1) Profiling of microRNAs in plasma of patients with hypertension complicated or not by metabolic syndrome or chronic kidney disease Hypertension (HTN) or high blood pressure is associated with subclinical target organ damage such as cardiac, vascular and kidney injury, which may lead to complications and death. In this study, we investigated circulating microRNAs as biomarkers of target organ damage in HTN patients. We profiled circulating microRNAs by RNA sequencing in platelet-poor plasma of normotensive subjects and patients with HTN complicated or not by metabolic syndrome (MetS) or chronic kidney disease (CKD) (n=15 each group). Differentially expressed microRNAs were identified with a threshold of false discovery rate <0.1. Differentially expressed microRNAs were identified uniquely to associate with HTN (8), MetS (1) or CKD (13), and 8 were similarly differentially expressed in different groups. This study identified the association of differentially expressed circulating microRNAs with target organ damage in HTN patients, which could have some pathophysiological and therapeutic implications. Study 2) Profiling of microRNAs in gluteal subcutaneous small arteries of patients with hypertension complicated or not by chronic kidney disease Hypertension (HTN) is associated with vascular damage characterized by endothelial dysfunction and vascular remodeling and stiffening, which contributes to kidney injury leading to chronic kidney disease (CKD). MicroRNAs are short non-coding RNAs which repress/degrade target mRNAs. The microRNA role in vascular injury in HTN remains unclear. In this study, we aimed to identify differentially expressed microRNAs in small arteries of patients with HTN associated or not with CKD, in order to shed light on the pathophysiological molecular mechanisms. Normotensive subjects and HTN patients associated or not with CKD grades 3-4 were studied (n=15-16). Small arteries were isolated from subcutaneous gluteal biopsies, RNAs were extracted, and small and total RNA sequencing was performed by Illumina HiSeq-2500. Differentially expressed genes were identified with a P<0.05 and fold change (FC) >1.3. Differentially expressed microRNAs and mRNAs were identified uniquely to associate with HTN (microRNAs: 10, mRNAs: 68), CKD (microRNAs: 68, mRNAs: 395), and both groups (microRNAs: 2, mRNAs: 32). This study identified differentially expressed microRNAs and mRNAs in small arteries with target organ damage in HTN, which could have some pathophysiological and therapeutic implications.

  Study phs002389

• IMCISION DNAseq

  Whole-exome sequencing of 32 primary head and neck squamous cell carcinoma samples prior to treatment with neoadjuvant anti-PD-1 (n=6) or anti-PD-1 + anti-CTLA-4 (n=26) immunotherapy. DNA quantity used: 50ng. Library Preparation Kit: Twist Human Core Exome Plus (Twist Bioscience). Sequencing parameters: NovaSeq 6000, 2x 100 bp. File type: fastQ.

  Dataset EGAD00001008139

• Cergentis FFPE-TLC sequencing of colorectal carcinoma

  In this study, formalin-fixed paraffin-embedded targeted locus capture (FFPE-TLC) sequencing is used as a novel technology for targeted detection of tumor-specific genomic structural variants (SVs) in the primary tumor of 29 colorectal cancer patients with metastatic disease. The tumor region was macrodissected and sequenced for 29 patients, and the "normal" region of the same slide was macrodissected and sequenced for 8 of these patients. SVs were found in the common fragile site (CFS)-associated genes MACROD2, PRKN, FHIT and WWOX as well as SVs caused by three LINE transposable elements. Tumor-specificity of selected SVs was independently verified by droplet digital PCR of tumor tissue DNA and their applicability as plasma circulating tumor DNA biomarkers was demonstrated. This dataset contains the hg19 reference alignment of the FFPE-TLC sequences for all 29 colorectal cancers and 8 adjacent normals.

  Dataset EGAD50000000618

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  Documentation cookies

• Defining Cutaneous Gene Expression Signatures in Juvenile Dermatomyositis

  Skin inflammation in juvenile dermatomyositis (JDM) can signal disease onset or flare up and prevent complete disease remission. Our objective was to evaluate JDM cutaneous expression signatures through tape stripping in both lesional and non-lesional skin and as compared to paired blood. A total of 28 JDM and 20 control (CTL) patients participated in the study. All patients had tape strip sampling of non-lesional (NL) skin at enrollment visit. Within our JDM cohort, paired lesional (L) skin was additionally sampled if rash was present. 16/28 of JDM patients had at least one additional skin sample associated with a follow-up (FU) visit (total number of follow-up samples included = 26 NL and 4 L). We identified a common innate immune signature in both lesional and non-lesional JDM skin. Using unsupervised hierarchical clustering of skin expression data, we distinguished a JDM molecular subgroup characterized by a mitochondrial dysfunction signature. In comparison to blood expression data, we determined that skin may more effectively highlight the JDM subgroup characterized by a mitochondrial dysfunction expression signature. Data available include bulk RNA-sequencing data from tape strips and blood of the JDM and control patients from this study.

  Study phs003884

• Pediatric Whole Genome Sequencing Diagnostic Utility

  The standard of care for first-tier clinical investigation of the etiology of congenital malformations and neurodevelopmental disorders is chromosome microarray analysis (CMA) for copy number variations (CNVs), often followed by gene(s)-specific sequencing searching for smaller insertion-deletions (indels) and single nucleotide variant (SNV) mutations. We compared diagnostic rate of WGS to CMA and targeted gene testing of 100 patients referred to The Hospital for Sick Children Genetics clinic in 2014. WGS identified genetic variants meeting clinical diagnostic criteria in 34% of cases, representing a 4-fold increase in diagnostic rate over CMA (8%) (p-value = 1.42e-05) alone and >2-fold increase in CMA plus targeted gene sequencing (13%) (p-value = 0.0009). WGS identified all rare clinically significant CNVs that were detected by CMA. In an additional 26 patients, WGS revealed indel and missense mutations presenting in a dominant (63%) or a recessive (37%) manner. We found four subjects with mutations in at least two genes associated with distinct genetic disorders, including two cases harboring a pathogenic CNV and SNV. When considering medically actionable secondary findings in addition to primary WGS findings, 38% of patients would benefit from genetic counselling.

  Study EGAS00001001623

• PATL2 is a key actor of oocyte maturation whose invalidation causes infertility in women and mice

  The genetic causes of oocyte meiotic deficiency (OMD), a form of primary infertility characterised by the production of immature oocytes, remain largely unexplored. Using whole exome sequencing, we found that 26% of a cohort of 23 subjects with OMD harboured the same homozygous nonsense pathogenic mutation in PATL2, a gene encoding a putative RNA-binding protein. Using Patl2 knockout mice, we confirmed that PATL2 deficiency disturbs oocyte maturation, since oocytes and zygotes exhibit morphological and developmental defects respectively. PATL2's amphibian orthologue is involved in the regulation of oocyte mRNA as a partner of CPEB. However, Patl2's expression profile throughout oocyte development in mice, alongside colocalisation experiments with Cpeb1, Msy2 and Ddx6 (three oocyte RNA-regulators) suggest an original role for Patl2 in Mammals. Accordingly, transcriptomic analysis of oocytes from WT and Patl2-/- animals demonstrated that in the absence of Patl2, expression levels of a select number of highly relevant genes involved in oocyte maturation and early embryonic development are deregulated. In conclusion, PATL2 is a novel actor of mammalian oocyte maturation whose invalidation causes OMD in humans.

  Study EGAS00001002903

• Whole Exome Sequencing in Alopecia Areata Identifies Rare Mutations in KRT82

  Alopecia areata (AA) is an autoimmune disorder, in which the body's own immune cells attack hair follicels resulting in hair loss. It is a complex genetic disease with 14 associated loci previously identified in our genome-wide association study (GWAS). In the study, we performed the whole-exome sequencing (WES) on 849 AA patients with the aim to identify the novel rare variants in genes contributing to AA susceptibility. We performed gene-collapsing analyses and identified keratin 82 (KRT82 Gene ID: 3888) as the highest associated AA gene in the three rare damaging collapsing models with p<6.7E-07 in one of the models. The KRT82 gene is a hair-specific type II keratin expressed in the hair shaft cuticle during the anagen phase of the hair cycle. We reported the lower expression of KRT82 in AA hair follicles, compared to controls, and the KRT82 expression is absent from the bulb region, the site of AA immune attack. This study emphasizes the significance of using WES and gene collapsing analyses to identify rare variation in a functionally relevant risk gene using a moderate sample size.  

  Study phs002632

• Genetic Underpinnings of Ethnic Disparities in Bone Toxicities Between Hispanic and Non-Hispanic Children Treated for Acute Lymphoblastic Leukemia

  Acute lymphoblastic leukemia (ALL) is the most common malignancy among children and young adolescents. More than 90% of children are cured with a combination of multiple chemotherapeutic drugs. Some may suffer from debilitating toxicities due to the cytotoxic drugs, necessitating pharmacogenetic research to search for genetic markers predictive of treatment toxicities, so that treatment can be better tailored based on patients' genetic makeup. Bone toxicities, including osteonecrosis and fractures, most often due to glucocorticoids, are the most common complications in ALL, which have long-lasting detrimental impact on the still developing skeletons in children. In DFCI ALL Consortium Protocol 05-001, a multi-center clinical trial for childhood ALL conducted in Canada and the US, we found that Hispanic children had less drug toxicities to their bones than non-Hispanic children. Although reasons for the observed ethnic differences are largely unknown, patients' inherited genetic background may be at play. This study seeks to perform a novel pharmacogenomic study based on multi-site clinical trials DFCI ALL Consortium Protocol 05-001 and 11-001 to identify genetic underpinnings of ethnic disparities in bone toxicities.

  Study phs002317