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• Single cell whole genome sequencing of 5 ovarian cancer specimens

  Single cell whole genome sequencing BAM files for five ovarian cancer specimens.

  Study EGAS50000001458

• Two lung cancer cell lines with EGFR mutations, PC-9 and KHM-3S, were either treated with Tarceva for 24 hours or left untreated. The gene expression profiles were examined by RNAseq, and the genome wide binding profiles of total STAT3 and pSTAT3 were characterized by ChIPseq.

  Lung cancers harboring activating EGFR mutants show dramatic responses to EGFR TKIs, such as Tarceva. However, nearly all patients show relapse within 1 year after initial treatment. To investigate the early signaling switches that are involved in the formation of drug resistance, and the role of STAT3 in the early signaling switches involved in the formation of drug resistance, we have treated two lung cancer cell lines with EGFR mutations, PC-9 and KMH-3S, with Tarceva for 24hours. The RNA samples with and without treatment were collected in triplicate for RNAseq experiment.The total STAT3 and pSTAT3 chromatinIP were done on samples with and without treatment for ChIPseq.

  Study EGAS00001000793

• A benchmarking resource for NGS testing of cancer predisposition genes

  A benchmarking resource of 639 individuals, to assess the analytical sensitivity of cancer predisposition gene (CPG) testing.The dataset includes sequencing data generated using the TruSight Cancer Panel (TSCP) a targeted NGS assay for analysis of CPGs and orthogonally generated data supporting at least one pathogenic variant in a CPG for a total of 645 pathogenic CPG variants.The set of pathogenic CPG variants includes strong representation of some of the most challenging types of pathogenic variants, with 339 indels, including 16 complex indels and 24 insertions or deletions with length greater than 5bp, and 74 exon CNVs, including 23 single exon CNVs. There are 502 pathogenic variants in BRCA1 or BRCA2, making this an important first-line validation dataset for laboratories performing NGS testing of BRCA1 and BRCA2.

  Study EGAS00001002993

• Mechanisms of Risk for Sulfonamide Hypersensitivity

  Hypersensitivity (HS) reactions to sulfonamide antibiotics occur uncommonly, but with potentially severe clinical manifestations. A familial predisposition to sulfonamide HS is suspected, but robust predictive genetic risk factors have yet to be identified. Strongly linked genetic polymorphisms have been used clinically as screening tests for other HS reactions prior to administration of high-risk drugs. The purpose of this study was to evaluate for genetic risk of sulfonamide HS in the immunocompetent population using genome-wide association. Ninety-one patients with symptoms after trimethoprim-sulfamethoxazole (TMP-SMX) attributable to "probable" drug HS based on medical record review and the Naranjo Adverse Drug Reaction Probability Scale, and 184 age- and sex-matched patients who tolerated a therapeutic course of TMP-SMX, were included in a genome-wide association study using both common and rare variant techniques. Additionally, two subgroups of HS patients with a more refined clinical phenotype (fever and rash; or fever, rash and eosinophilia) were evaluated separately. For the full dataset, no single nucleotide polymorphisms were suggestive of or reached genome-wide significance in the common variant analysis, nor was any genetic locus significant in the rare variant analysis. A single, possible gene locus association (COL12A1) was identified in the rare variant analysis for patients with both fever and rash, but the sample size was very small in this subgroup (n=16), and this may be a false positive finding. No other significant associations were found for the subgroups. No convincing genetic risk factors for sulfonamide HS were identified in this population. These negative findings may be due to challenges in accurately confirming the phenotype in exanthematous drug eruptions, or to unidentified gene-environment interactions influencing sulfonamide HS. Reprinted under PLOS ONE's open access license, CC-BY (http://www.plos.org/open-access).

  Study phs001124

• RNA-seq as a tool for evaluating human embryo competence

  The majority of embryos that are created through IVF do not implant. One possibility for this inefficiency is an incomplete understanding of the molecular factors affecting embryo competence. Currently, the process of selecting an embryo for uterine transfer utilizes an ad-hoc combination of morphological criteria, the kinetics of development, and genetic testing for aneuploidy. However, no single criterion can ensure selection of a viable embryo. In contrast, RNA-sequencing of embryos could yield highly dimensional data, which may provide additional insight and illuminate the discrepancies among current selection criteria. Indeed, recent advances enabling the production of RNA-sequencing (RNA-seq) libraries from single cells have facilitated the application of this technique to the study of some transcriptional events in early human development. However, these studies have not assessed the quality of their constituent embryos relative to commonly used embryological criteria. Here, we perform proof-of-principle advancement to clinical selection procedures by generating high quality RNA-seq libraries from a trophectoderm biopsy as well as the remaining whole embryo. We combine state-of-the-art embryological methods with low-input RNA-seq to develop the first transcriptome-wide approach for use in future predictive embryology studies. Specifically, we demonstrate the capacity of RNA-seq as a promising tool in preimplantation screening by showing that biopsies of an embryo can capture valuable information content available in the whole embryo from which they are derived. Furthermore, we show that this technique can be used to generate a RNA-based digital karyotype, and to develop a foundational dataset for identifying candidate competence-associated genes. Together, these data establish the foundation for a future RNA-based diagnostic in IVF.

  Study EGAS00001003667

• NHLBI TOPMed: MESA and MESA Family AA-CAC

  The Multi-Ethnic Study of Atherosclerosis (MESA) is a study of the characteristics of subclinical cardiovascular disease (disease detected non-invasively before it has produced clinical signs and symptoms) and the risk factors that predict progression to clinically overt cardiovascular disease or progression of the subclinical disease. MESA researchers study a diverse, population-based sample of 6,814 asymptomatic men and women aged 45-84. Thirty-eight percent of the recruited participants are white, 28 percent African-American, 22 percent Hispanic, and 12 percent Asian, predominantly of Chinese descent. Comprehensive phenotypic and pedigree data for MESA study participants are available through dbGaP entry phs000209. MESA Participants were recruited from six field centers across the United States: Wake Forest University, Columbia University, Johns Hopkins University, University of Minnesota, Northwestern University and University of California - Los Angeles. Each participant received an extensive physical exam and determination of coronary calcification, ventricular mass and function, flow-mediated endothelial vasodilation, carotid intimal-medial wall thickness and presence of echogenic lucencies in the carotid artery, lower extremity vascular insufficiency, arterial wave forms, electrocardiographic (ECG) measures, standard coronary risk factors, sociodemographic factors, lifestyle factors, and psychosocial factors. Selected repetition of subclinical disease measures and risk factors at follow-up visits allows study of the progression of disease. Blood samples have been assayed for putative biochemical risk factors and stored for case-control studies. DNA has been extracted and lymphocytes cryopreserved (for possible immortalization) for study of candidate genes and possibly, genome-wide scanning, expression, and other genetic techniques. Participants are being followed for identification and characterization of cardiovascular disease events, including acute myocardial infarction and other forms of coronary heart disease (CHD), stroke, and congestive heart failure; for cardiovascular disease interventions; and for mortality. In addition to the six Field Centers, MESA involves a Coordinating Center, a Central Laboratory, and Central Reading Centers for Computed Tomography (CT), Magnetic Resonance Imaging (MRI), Ultrasound, and Electrocardiography (ECG). Protocol development, staff training, and pilot testing were performed in the first 18 months of the study. The first examination took place over two years, from July 2000 - July 2002. It was followed by five examination periods that were 17-20 months in length. Participants have been contacted every 9 to 12 months throughout the study to assess clinical morbidity and mortality. MESA Family The general goal of the MESA Family Study, an ancillary study to MESA funded by a grant from NHLBI, is to apply modern genetic analysis and genotyping methodologies to delineate the genetic determinants of early atherosclerosis. This is being accomplished by utilizing all the current organizational structures of the Multi-Ethnic Study of Atherosclerosis (MESA) and Genetic Centers at Cedars-Sinai Medical Center and University of Virginia. In the MESA Family Study, the goal is to locate and identify genes contributing to the genetic risk for cardiovascular disease (CVD), by looking at the early changes of atherosclerosis within families (mainly siblings). 2128 individuals from 594 families, yielding 3,026 sibpairs divided between African Americans and Hispanic-Americans, were recruited by utilizing the existing framework of MESA. MESA Family studied siblings of index subjects from the MESA study and from new sibpair families (with the same demographic characteristics) and is determining the extent of genetic contribution to the variation in coronary calcium (obtained via CT Scan) and carotid artery wall thickness (B-mode ultrasound) in the two largest non-majority U.S. populations. In a small proportion of subjects, parents of MESA index subjects participating in MESA Family were studied but only to have blood drawn for genotyping. The MESA Family cohort was recruited from the six MESA Field Centers. MESA Family participants underwent the same examination as MESA participants during May 2004 - May 2007. DNA was extracted and lymphocytes immortalized for study of candidate genes, genome-wide linkage scanning, and analyzed for linkage with these subclinical cardiovascular traits. While linkage analysis is the primary approach being used, an additional aspect of the MESA Family Study takes advantage of the existing MESA study population for testing a variety of candidate genes for association with the same subclinical traits. Genotyping and data analysis will occur throughout the study.

  Study phs001416

• GAW16 Framingham and Simulated Data

  Important links to apply for individual-level data Genetic Analysis Workshop Instructions to Request Authorized Access Data Use Certification Requirements (DUC) Apply here for controlled access to individual level data Research Use Statement Questions regarding GAW16 should be directed to Vanessa Olmo at vanessa@business-endeavors.com. Problem 2: Description of the Framingham Heart Study In GAW16, we use data drawn from the Framingham Heart Study. The Framingham Heart Study — under the direction of National Heart, Lung, and Blood Institute; NHLBI — began in 1948 with the recruitment of adults from the town of Framingham, Massachusetts. At the time, little was known about the general causes of heart disease and stroke, but the death rates for cardiovascular disease (CVD) had been increasing steadily since the beginning of the 20th century and had become an American epidemic. The Framingham Heart Study is now conducted in collaboration with Boston University. The objective of the Framingham Heart Study was to identify the common factors or characteristics that contribute to CVD by following its development over a long period of time in a large group of participants who had not yet developed overt symptoms of CVD or suffered a heart attack or stroke. Between 1948 and 1953 the researchers recruited 5,209 subjects (2,336 men and 2,873 women) between the ages of 29 and 62 from the town of Framingham, Massachusetts and began the first round of extensive physical examinations and lifestyle interviews that they would later analyze for common patterns related to CVD development. Subjects were recruited from lists of addresses recorded for the town. Two out of every three households were approached for participation in the study. While there was no intention to recruit families for family studies, the plan was to recruit all household members in the ages 30-60 within each house that was selected for study. Hence, many biologically related individuals were recruited, including 1644 spouse pairs. Since 1948, these participants have returned to the study every two years for a detailed medical history, physical examination, and laboratory tests. Now in 2008 at 60 years of follow up, there remain about 500 participants from this cohort. Between 1971 and 1975 the study enrolled a second-generation group — 5,124 of the original participants' children and the spouses of these children — to participate in similar examinations. 2,616 subjects are offspring of the original spouse pairs and 34 are stepchildren. A total of 898 offspring are children of cohort members where only one parent was a study participant and 1,576 are spouses of the offspring. The Offspring Cohort has been followed every four years through 2001 (except between Exams 1 and 2 with an intervening 8 years) using protocols similar to those used for study of the Original Cohort. Between 2002 and 2005 the study enrolled the third generation (Gen3) of the Framingham Heart Study - 4095 offspring of the second generation. None of their spouses were recruited. An additional 103 parents of this third generation, who were not recruited between 1971 and 1975, were also recruited at this time. The latter group is not included in the GAW16 data. With the recruitment of this third generation, the study has increasingly focused on genetic factors associated with the development of cardiovascular disease and its associated risk factors. To date, there is only one examination of this generation of participants. A description of the recruitment of this third generation and comparison with the earlier generations at their initial recruitment is presented in Splansky GL et al., 2007. Further information on the Study can be found at http://www.nhlbi.nih.gov/about/framingham/index.html. Genome-wide Dense SNP Scan in Framingham Heart Study Genetic studies did not begin in the FHS until the 1990s. In the late 1980s and through the 1990s DNA was extracted from blood samples of surviving FHS participants. In 2007, the FHS entered a new phase with the conduct of genotyping for the FHS SHARe (SNP Health Association Resource) project, for which dense SNP genotyping was performed using approximately 550,000 SNPs (GeneChip® Human Mapping 500K Array Set and the 50K Human Gene Focused Panel) in 10,775 samples (some duplicates) from the three generations of subjects (including over 900 pedigrees). Affymetrix conducted all genotyping for the FHS SHARe project, using the 250K Sty, 250K Nsp, and the supplemental 50K platforms. Eighty-nine percent of the DNA samples were collected during the 1990s. To maximize the power of the study, we also extracted DNA from 1133 blood samples, drawn from subjects who had no DNA, to include in the SHARe project. These samples had been sitting in our refrigerators for some time, a few as far back as the 1970s. We refer to these DNA samples as the legacy samples. These samples had a higher failure rate in the genotyping process (40%) than the other eighty-nine percent (3%). Affymetrix invoked its own criteria for a sample to succeed in genotyping. All non-legacy samples must succeed on all three platforms, while legacy samples needed to pass on at least one platform. When a sample failed, additional attempts were made. Samples that repeatedly failed 2-4 times were called failures. Other samples failed due to issues of genotyped sex identification not matching our records or low SNP concordance among SNPs common across arrays or contamination. Eighty-nine percent of the legacy samples for which genotyping results are available passed all three platforms. The genotyping data from the 10,043 samples from 9354 subjects that passed the Affymetrix criteria were additionally checked for gender consistency and consistency with family structure, resulting in genotyping data for 9,274 participants in FHS SHARe. Genotype calls were made with the BRLMM algorithm. The SHARe database is housed at the National Center for Biotechnology Information database of genotypes and phenotypes (NCBI dbGaP) and contains all ~550,000 SNPs. This genome-wide dense SNP scan and a subset of phenotypes from the Framingham Heart Study are the focus of the Genetic Analysis Workshop 16. Further information on the specific variables in the Problem 2 dataset can be found by clicking on the Documents tab at the top of the page. Problem 3: Description of the Simulated Data Set The focus of this simulation is gene discovery in genome-wide association scans (GWAS). The Framingham Heart Study data set (distributed as "Problem 2") is the basis for the FHS* simulated data. The pedigree structures are derived from the data distributed for Problem 2, and we distribute an accompanying triplet file (triplet_sim) containing person ID, father ID, mother ID, to ensure the identical subjects, pedigrees, and singletons are used in the simulated data analysis. Consistent with standard practice, founders and singletons are designated as subjects with both fshare and mshare equal to zero (missing). The simulated data includes a total of 6,479 subjects with both phenotype and genotype data, in 942 pedigrees distributed among 3 generations and 188 singletons. Data inclusion is consistent with the subjects' consent for use by both for-profit and not-for-profit researchers. The genotypes for all Problem 3 replicates are fixed as measured and distributed for Problem 2 for both the genomewide scan and the additional candidate gene SNPs, for a total of approximately 550,000 SNPs (GeneChip® Human Mapping 500K Array Set and the 50K Human Gene Focused Panel). Thus, to analyze the Problem 3 simulated data you also will need to download the Problem 2 genotypes. Note that there are slight discrepancies in counts between Problems 2 and 3 due to a change in consents between the two datasets. Several phenotypes that contribute to coronary heart disease (CHD) were simulated for all individuals with genotypes across three different time points, 10 years apart. All genotyped individuals have complete data; the effects of missing values can be investigated by user-specified missing value patterns. There are 200 longitudinal datasets created, based on the generating model, and each replication is found in a separate dataset. We suggest that if only one replication is to be analyzed, that it be replication 1 to enable more precise comparisons among analytical approaches. The 'shareid' will allow you to merge the simulated phenotype data with the Problem 2 genotype data, and reconstruction of the pedigrees using the distributed 'triplet_sim' file or for larger families' relationships with the triplet distributed with the Problem 2. The simulated data problem is further described in the associated readme file, and a data dictionary is provided defining all the variables. For disclosure of the generating model for these data, please contact Jean MacCluer at jean@sfbrgenetics.org.

  Study phs000128

• Molecular Analysis of Short- Versus Long-Term Survivors of High-Grade Serous Ovarian Carcinoma

  The underlying determinants for long-term survival (LTS, ≥10 years) versus short-term survival (STS, <3 years) of patients diagnosed with high-grade serous ovarian carcinoma (HGSC) are largely unknown. The present study sought to identify molecular predictors of LTS for women with HGSC. A cohort of 24 frozen HGSC samples (12 LTS and 12 STS) were collected and analyzed at DNA and RNA levels. Copy number variation and mutation did not indicate large differences between LTS and STS. From RNA-Seq analysis, 11 genes were found to be differentially expressed between the STS and LTS groups (fold change >2; false discovery rate <0.01). In the validation cohort, transmembrane protein 62 (TMEM62) was found to be related to LTS. Our in vitro and in vivo studies demonstrate that restoring TMEM62 may be a novel approach for treatment of HGSC. These findings may have implications for biomarker and intervention strategies to help improve patient outcomes.

  Study phs003020

• Genetic Effects on Gene Expression and Splicing during Human Neurogenesis

  Interpretation of the function of non-coding risk loci for neuropsychiatric disorders and brain-relevant traits via gene expression and alternative splicing quantitative trait locus (e/sQTL) analyses is generally performed in bulk post-mortem adult tissue. However, genetic risk loci are enriched in regulatory elements active during neocortical differentiation, and regulatory effects of risk variants may be masked by heterogeneity in bulk tissue. Here, we map e/sQTLs, and allele-specific expression in cultured cells representing two major developmental stages, primary human neural progenitors (n=85) and their sorted neuronal progeny (n=74), identifying numerous loci not detected in either bulk developing cortical wall or adult cortex. Using colocalization and genetic imputation via transcriptome-wide association, we uncover cell-type specific regulatory mechanisms underlying risk for brain-relevant traits that are active during neocortical differentiation. Specifically, we identified a progenitor-specific eQTL for CENPW co-localized with common variant associations for cortical surface area and educational attainment.

  Study phs002493

• NIDCD Otitis Media Genetic Susceptibility and Middle Ear Microbial Shifts

  The study funded by R01 DC015004 aims to: (1) Identify rare OM susceptibility variants within families and in probands; and (2) Identify differences in the middle ear microbiome due to OM susceptibility variants. This study will also elucidate mechanisms responsible for the formation and growth of cholesteatoma, and bony erosion and complications due to cholesteatoma e.g. intracranial, hearing/vestibular loss, facial nerve palsy. A better understanding of cholesteatoma pathogenesis will potentially reveal novel drug targets, which can lead to new non-surgical therapies for cholesteatomatous OM. Our specific aims for this administrative supplement are: Aim 1 -- Perform RNA-sequencing using cholesteatoma samples collected from Filipino and Colorado patients who will be screened for FUT2, SPINK5 and A2ML1 variants; and Aim 2 -- Using network analysis, identify bone-expressed proteins potentially interacting with FUT2, SPINK5 or A2ML1, then test protein expression in archival human temporal bone in direct contact with cholesteatoma.

  Study phs001941

• Characterizing Individual Cells Obtained from Bone Marrow Biopsies of MPN Patients

  We profiled the transcriptomes of individual cells obtained from bone marrow aspirates of 7 treatment-naïve newly diagnosed JAK2-mutant myeloproliferative neoplasm (MPN) patients (3 polycythemia vera and 4 essential thrombocythemia patients), and 2 healthy controls. The submitted data corresponds to sequencing reads mapped to the human reference genome GhRC38 build using CellRanger for a total of 9 samples (one per patient). In addition, to reconstruct the lineage histories of single cells in MPN patients, we performed whole-genome sequencing of single-cell-derived colonies of hematopoietic stem and progenitor cells from 2 essential thrombocythemia (ET) patients: 22 JAK2-mutant colonies and 20 WT colonies for patient ET 1; and 13 JAK2-mutant colonies and 21 WT colonies for patient ET 2. The submitted data consists of sequencing reads aligned to the human reference genome GhRC38 build using bwa-mem. Each file corresponds to the whole-genome sequencing data for one colony.

  Study phs002308

• ALLELE Consortium Glioblastoma Project

  Glioblastoma patient samples were sequenced for this project. The purposes of this project are: (1) to establish an umbrella protocol as a mechanism for identifying patients (in the USA and international sites) who agree to the collection, storage, and broad usage of their specimens and ongoing collection, and review of their medical information for the purposes of minimal-risk research and use of such data in clinical trials on which the patient may enroll; (2) to develop operations that facilitate investigator access to the data and/or tissue to conduct research, while minimizing risks to participants and promoting responsible conduct; and (3) to provide the infrastructure for the sharing of de-identified, coded samples, clinical data, and genomic data between participating investigators and institutions. Eligible patients include patients with known or suspected nervous system tumors or other neurologic diseases. Whole exome sequencing from the stated project will be released under this submission.

  Study phs003000

• Childhood Cancer Data Initiative (CCDI): Integrating Longitudinal Clinical, Sociodemographic and Genomic Data into the NCCR

  The goal of this study is to contribute clinical and genomic data from a large institutional cohort of pediatric cancer patients who had tumor genomic profiling between 2013 and 2019 at Dana-Farber/Boston Children's Hospital Cancer and Blood Disorders Center. Clinical data include demographics, diagnosis (classified according to the International Classification of Diseases for Oncology (ICD-O-3.2), stage, and biospecimen associated data. Tumors were sequenced with OncoPanel, a targeted next-generation DNA sequencing panel of up to 447 cancer genes for detection of single-nucleotide variants (SNV), insertions, and deletions, and copy number alterations (CNA), as well as selected intronic regions for up to 60 genes for the detection of structural variants (SV). This dataset includes a patient and sample identifier (GENIE ID) that can be used to link the genomic data included in this dataset to additional longitudinal clinical cancer data on a subset of patients that was submitted to the National Childhood Cancer Registry (NCCR).

  Study phs002677

• Spatial Transcriptomics Reveals Discrete Tumor Microenvironments and Autocrine Loops Within Ovarian Cancer Subclones

  Ovarian masses from patients with high grade serous ovarian carcinoma undergoing debulking surgery were subjected to spatial transcriptomics profiling using the 10x Genomics Visium (fresh frozen) platform. Copy number inference using inferCNV predicted the presence of subclones with mutually exclusive copy number alterations (CNAs) in 5 of the 8 patient samples studied. In one patient, 3 subclones were predicted. For this patient sample, a serial section of the same tumor was used to microdissect regions corresponding to each of these subclones, and a 'normal' region predicted to contain only fibroblasts and no tumor cells. These microdissected regions were processed for low pass whole genome sequencing (WGS) and CNAs recorded using ichorCNA. An oral biopsy lacking tumor cells from an unrelated donor was used as a negative control for CNA inference. The CNAs predicted by inferCNV for the three subclones were validated by the low pass WGS and no CNAs were observed in the normal region containing fibroblasts.

  Study phs003561

• Liquid Biopsy Detection of Tumor-specific Structural Variants in High Grade Serous Ovarian Cancer

  WGS Liquid Biopsy. Recurrence is frequent for most patients with high grade serous ovarian cancer (HGSOC), even after effective chemotherapy induced remission. However, after achievement of complete clinical response, the minimal residual disease is often insufficient for genomic analysis. Therefore, methods to interrogate the clonal composition and molecular properties of minimal residual disease are needed to better understand the mechanisms of HGSOC relapse. To address this unmet need, we developed and validated a novel cfDNA-based approach for tracking disease burden using NGS-informed tumor specific structural variants (SVs). Methods: The optimization of the methodology was first performed using synthetic cfDNA generated by ultrasonication of gDNA from ovarian cancer cell lines. Following the optimized workflow, whole genome sequencing of multisite biopsies from pre-treatment HGSOC patients were performed and high confidence SVs were called by consensus of multiple published SV callers. Real-time PCR and digital droplet PCR (ddPCR) were used for assays development.

  Study EGAS50000001044

• NHLBI TOPMed: Genomic Summary Results for the Trans-Omics for Precision Medicine Program

  The NHLBI Trans-Omics for Precision Medicine (TOPMed) program aims to identify the genetic basis of variation in biomedical phenotypes, with emphasis on those related to heart, lung, blood and sleep disorders, as part of a broader Precision Medicine Initiative. The TOPMed program has provided whole genome sequencing (WGS) to over 80 different studies that had previously recruited participants and collected extensive phenotype data. Many TOPMed investigators affiliated with these studies have organized their activities into phenotype-focused Working Groups and have developed genotype-phenotype association projects. These analyses have resulted in valuable cross-study Genomic Summary Results (GSR) that include whole genome association test results of both common and rare variants. Most of the analyses include data from multiple studies, some of which are based on sensitive populations, precluding public sharing of GSR. This dbGaP accession provides a mechanism for sharing sensitive GSR, using the controlled-access mechanisms of dbGaP to provide protections for sensitive populations.

  Study phs001974

• INCLUDE: Down Syndrome Early Post-Natal Brain Multiome

  Neurodevelopmental deficiencies and neuronal dysfunction contribute to cognitive impairment in individuals with Down syndrome, but what molecular pathways underlie the defects that lead to intellectual disability remain unclear. Human brain development is precisely choreographed through tightly regulated transcriptional programs. Proper regulation of these transcriptional programs is necessary for developing the numerous functionally distinct regions, cell types, and connections of the brain, and forming the basis for human-specific social, cognitive, and motor abilities. These data establish a reference of molecular features of the DS developing brain. Such foundational information will provide not only a reference for any existing and future models, but also a basis for understanding disrupted neural development and impaired cognition in DS.Dataset 1 contains single-nucleus RNAseq and ATACseq from frozen postmortem human basal forebrain tissue. Dataset 2 contains single-nucleus RNAseq and ATACseq from frozen postmortem human dorsolateral prefrontal tissue. Dataset 3 contains single-nucleus RNAseq and ATACseq from frozen postmortem human caudate nucleus tissue.

  Study phs004098

• Sequencing cancer mutations in various types of lung cancer using the long-read, portable sequencer

  In this study, we used a long-read and portable sequencer MinION to identify cancer mutations in lung adenocarcinoma cells. We performed cDNA amplicon sequencing for various types of mutations such as point mutations in EGFR and KRAS and oncogenic fusion transcripts in ALK and RET. Using the long reads of MinION, we also conducted mutation phasing of EGFR TKI-sensitive and resistant mutations, which would provide useful information to next thrapeutic approaches for cancers. We applied this method to identify mutation genotypes of eight clinical samples from Japanese lung adenocarcinomas. This method could provide new sequencing-based diagnostic approaches for lung cancers. Additinally we also performed cancer mutation identification of risk-dependent unique samples. Usual interstitial pneumonia (UIP) is a risk factor for lung carcinogenesis. This study was performed to characterize mutagenesis and mutational target genes underlying lung carcinogenesis in patients with UIP.We performed whole exome sequencing of lung adenocarcinoma with usual interstitial pneumonia.

  Study JGAS000065

• Resequencing_candidate_genes_for_male_spermatogenic_impairment

  This study aims to identify novel candidate variants from human Y-chromosomal genes DAZ, BPY2 and CDY1 by resequencing the coding regions of these genes from male patients with spermatogenic impairment. The coding regions of the genes have been amplified by standard PCR, amplicon lengths range from 244 to 486 bp. A total of 61 amplicons were amplified for each of the 96 patients, totalling to approx. 25 kb per sample. Amplicons were quantified by gel electrophoresis and pooled in approx. equimolar concentrations per patient. For each of the 96 submitted samples, approx. 1 microgram of amplified DNA pool is provided in a total volume of 120 microlitres. The samples need to be indexed and libraries prepared for a PE250bp Illumina MiSeq run. This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/

  Study EGAS00001002157

• Rare disruptive mutations in ciliary function genes contribute to testicular cancer susceptibility

  Testicular germ cell tumor (TGCT) is the most common cancer in young men1,2. Here we aimed to identify novel risk factors for TGCT using whole-exome sequencing, which was performed on 328 affected individuals from 153 families, 634 sporadic cases and 1,644 controls. We searched for genes that were recurrently affected by rare variants (minor allele frequency <0.01) with potentially damaging effects and evidence of segregation in families. 8.7% of families carried rare disruptive mutations in the cilia-microtubule genes (CMG) as compared to 0.5% of controls3 (P=2.1x10-8). The most significantly mutated CMG was DNAAF1 with biallelic inactivation and loss of DNAAF1 expression shown in tumors from carriers. DNAAF1 as a cause of TGCT was supported by a DNAAF1Hu255h(+/-) zebrafish model with 94% penetrance for TGCT compared to 14% in wildtype fish. These data implicate cilia-microtubule inactivation as a cause of TGCT development and are the first evidence for CMGs as cancer susceptibility genes.

  Study EGAS00001001789

• Next_gen_seq_of_eye_cancers

  Retinoblastoma (RB), the commonest eye cancer in children was the first cancer for which a genetic cause was identified: the Rb1 gene is a tumour suppressor gene that is mutated in RB. The Rb1 gene defect alone does not predict the clinical outcome. We propose to study other possible mechanisms: 1. Stepwise further mutations occur in RB, increasing its carcinogenesis. We will sequence the whole genome in RB tissue, and relate the different genes expressed to the treatments used. 2. Extracellular matric proteins contribute to a tumour permissive environment for RB to continue to grow. This includes Samll Leucine Rich Proteoglycans (SLRP), a family of 15 secreted extracellular matrix proteins involved in eye development. 3. Cancer stem cells (CSC), a subpopulation of treatment resistant cells, drive RB tumours, and whether these stem cells can be manipulated for new therapies. The aim of this study is to assist finding targeted diagnostic techniques and treatments for RB.

  Study EGAS00001002309

• Targeted sequencing of head and neck squamous cell carcinomas

  Overall survival remains very poor for patients diagnosed with head and neck squamous cell carcinoma (HNSCC). Identification of additional biomarkers and novel therapeutic strategies are important for improving patient outcome. Patient-derived xenografts (PDXs), generated by implanting fresh tumor tissue directly from patients into immune-deficient mice, recapitulate many of the features of their corresponding clinical cancers, including histopathological and molecular profiles. Using a large collection of PDX models of HNSCC we demonstrate that rapid engraftment into immune-compromised mice is highly prognostic, and show that genomic deregulation of the G1/S checkpoint pathway correlates with engraftment. Furthermore, CCND1 and CDKN2A genomic alterations are predictive of response to the CDK4/6 inhibitor abemaciclib. Overall, our study supports the pursuit of CDK4/6 inhibitors as a therapeutic strategy for a substantial proportion of HNSCC patients, and demonstrates the potential of using PDX models to identify novel targeted therapies for those patients who have the poorest outcomes.

  Study EGAS00001002979

• Spatial Transcriptomics on prostate cancer heterogeneity

  Intratumor heterogeneity is one of the biggest challenges in cancer treatment today. Here we investigate tissue-wide gene expression heterogeneity throughout a multifocal prostate cancer using the spatial transcriptomics (ST) technology. Utilizing a novel approach for deconvolution, we analyze the transcriptomes of nearly 6750 tissue regions and extract distinct expression profiles for the different tissue components, such as stroma, normal and PIN glands, immune cells and cancer. We distinguish healthy and diseased areas and thereby provide insight into gene expression changes during the progression of prostate cancer. Compared to pathologist annotations, we delineate the extent of cancer foci more accurately, interestingly without link to histological changes. We identify gene expression gradients in stroma adjacent to tumor regions that allow for re-stratification of the tumor microenvironment. The establishment of these profiles is the first step towards an unbiased view of prostate cancer and can serve as a dictionary for future studies.

  Study EGAS00001003001

• Robust detection of translocations in lymphoma FFPE samples using Targeted Locus Capture-based sequencing - NGS targeted capture control cohort

  In routine diagnostic pathology, cancer biopsies are preserved by Formalin-Fixed, Paraffin-Embedding (FFPE) procedures for examination of (intra-) cellular morphology. Such procedures inadvertently induce DNA fragmentation, which compromises sequencing-based analyses of chromosomal rearrangements. Yet, rearrangements drive many types of hematolymphoid malignancies and solid tumors, and their manifestation is instructive for diagnosis, prognosis and treatment. Here, we present FFPE-Targeted Locus Capture (FFPE-TLC) for targeted sequencing of proximity-ligation products formed in FFPE tissue blocks, and PLIER, a computational framework that allows automated identification and characterization of rearrangements involving selected, clinically-relevant, loci. FFPE-TLC, blindly applied to 149 lymphoma and control FFPE samples, identifies the known and novel rearrangement partners. It outperforms fluorescence in situ hybridization (FISH) in sensitivity and specificity, and shows clear advantages over standard capture-NGS methods, finding rearrangements involving repetitive sequences which they typically miss. FFPE-TLC is therefore a powerful clinical diagnostics tool for accurate targeted rearrangement detection in FFPE specimens.

  Study EGAS00001005325

• Interethnic comparability in blood pressure GWAS

  We carried out a genome-wide association and replication study for blood pressure in a two-stage approach (max N = 289,038) with a discovery stage sample of 130,777 East Asian individuals, identifying 19 new genetic loci. We found a significant genetic heterogeneity between East Asian and European-descent populations at several blood pressure loci, conforming to “a common ancestry-specific variant association model”. At 6 unique loci, distinct non-rare (or common) ancestry-specific variants co-localized within the same linkage disequilibrium block despite the significantly discordant direction of effects for the proxy shared variants between the ethnic groups. The genome-wide transethnic correlation of causal-variant effect sizes is 0.898 and 0.851 for systolic and diastolic blood pressure, respectively. Some of the ancestry-specific association signals were also influenced by a selective sweep. Our results provide new evidence for the role of common ancestry-specific variants and natural selection in the occurrence of ethnic differences in complex traits such as blood pressure.

  Study EGAS00001002991