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• Sensitive circulating tumor DNA based residual disease detection in epithelial ovarian cancer

  We analyzed 264 plasma samples collected between June 2016 and September 2021 from 63 epithelial ovarian cancer patients using tumor-guided plasma cell-free DNA analysis to detect residual disease after treatment.

  Dataset EGAD50000000360

• The Dynamic Immune Behavior of Primary and Metastatic Ovarian Carcinoma

  Single-cell RNA-seq data of prospectively collected normal ovarian tissue sample from 1 healthy individual and tumor tissue samples with or without chemotherapy from 19 HGSOC patients.

  Dataset EGAD50000000057

• scRNAseq of T-cells from two responders to high-dose ipilimumab

  ScRNAseq of CD3 T-cells isolated from post-treatment bladder tissue from 2 samples from the NABUCCO 1 trial. Paired-end RNAsequencing was used on the Illumina NovaSeq 6000 sequencing platform.

  Dataset EGAD50000002557

• Whole Exome Data of RFWD3 Fanconi anemia patient

  Dataset contains one sample derived from gDNA of human fibroblasts. Files are in FASTQ format and were generated using the Agilent SureSelect Human All Exon 50Mb Kit and followed by Next Generation Sequencing on a HighSeq2000 instrument (Illumina).

  Dataset EGAD00001003311

• 200PT : WG Aligned Sequence (bam)

  200PT : WG Aligned Sequence (bam)/ Aligned WG sequence data in this dataset are from CPCGene Tumour/Normal Pairs used in the 200PT Study

  Dataset EGAD00001004061

• SLC9A3R1 variant associated with age-related hearing loss

  The dataset contains one BAM file that includes a SLC9A3R1 variant identified in two Italian patients affected by age-related hearing loss. Data have been produced by targeted re-sequencing, using Ion Torrent PGM platform.

  Dataset EGAD00001004171

• WGS on patients 1-4, study of metastatic prostate cancer

  Data from the study of subclonal metastatic expansion in prostate cancer. Whole genome shotgun sequencing of fifteen samples, tumour and whole blood, from the four initial patients.

  Dataset EGAD00001001343

• RNA-seq on patients 1-4, study of metastatic prostate cancer

  Data from the study of subclonal metastatic expansion in prostate cancer. RNA-seq of twelve samples, tumour and benign tissue, from the four initial patients.

  Dataset EGAD00001001345

• RNA sequencing of adult T-cell leukemia/lymphoma

  RNA sequencing of 57 tumor samples of adult T-cell leukemia/lymphoma as well as 3 samples of HTLV-1 carrier and 3 samples of healthy volunteers.

  Dataset EGAD00001001411

• Proteogenomic Landscape of Curable Prostate Cancer

  Aligned RNA-seq sequences in this dataset are from the Proteogenomic Landscape of Curable Prostate Cancer study

  Dataset EGAD00001004875

• Patient-derived lung cancer organoids

  Patient-derived lung cancer organoids cram files : targeted seq 13 samples, whole exome seq 12 samples mutation profiles of PDO and matched tissue : aggregated vcf 1 file details : https://www.nature.com/articles/s41467-019-11867-6

  Dataset EGAD00001005317

• Matched WXS of 147 lung cancer patients treated with immunotherapy

  This data includes whole exome sequencing of matched normal-tumor samples of patients who have received immunotherapy. '-1' refers to matched normal sample and '-2' refers to matched tumor sample.

  Dataset EGAD00001005211

• Phased melanoma whole genomes

  We have sequenced whole genomes of 10 melanoma samples (1 cell line; A375 and 9 patient derived short term cultures). Libraries were prepared with 10X linked reads technology in order to obtain phase information and subsequently sequenced on Illumina NovaSeq6000.

  Dataset EGAD00001005773

• PCa mtDNA data

  50 paired benign/cancer samples from prostate tissue generated in 2 different runs - on 3 plates on the IonTorrent Proton. Total of 200 fastq.gz single end runs. Read length ~300 bp. %GC 44 Sequences per file approx 1 Mio.

  Dataset EGAD00001005945

• Whole genome sequence of intratumor heterogeneity study

  This dataset contains whole genome sequence data from 12 samples from 1 patient, including 8 tumor sectors and 4 normal samples. All the experiments were performed on Illumina HiSeq platform with raw reads stored in fastq format.

  Dataset EGAD00001005452

• 1000IBD.eQTL.study.release.eQTLsummary&GeneTable

  intrstinal.eQTLsummary

  Dataset EGAD00001006790

• 1000IBD.eQTL.study.release.eQTLsummary&GeneTable

  eQTLsummary&GeneTable

  Dataset EGAD00001006792

• Whole exome DNA sequencing pre-treatment on tumor samples (n=24) matched with blood samples (n=24)

  Data from NABUCCO cohort 1 (NCT03387761). This dataset includes Whole exome DNA sequencing on bladder tumor samples (n=24) matched with blood samples (n=24). The data is pre-treatment.

  Dataset EGAD00001006850

• Pre-treatment PD-L1 staining on tumor samples (n=24)

  Data from NABUCCO cohort 1 (NCT03387761). This dataset includes the pre-treatment PD-L1 staining on tumor samples (n=24). Details about the PD-L1 staining can be found on the paper (https://doi.org/10.1038/s41591-020-1085-z)

  Dataset EGAD00001006856

• Results of scRNA-seq analysis of a PBMC collected from a male with a mosaic 45,X/48,XYYY karyotype

  Results of scRNA-seq analysis of a PBMC collected from a male with a mosaic 45,X/48,XYYY karyotype

  Dataset EGAD00001008645

• Bolleboom-Gao peri-tumoral snRNA-seq glioblastoma dataset 2022/A

  Bolleboom-Gao peri-tumoral snRNA-seq glioblastoma dataset 2022/A

  Dataset EGAD00001009964

• Molecular analysis of cancer genomes in children with Lynch syndrome: exploring causal associations WXS

  Molecular analysis of cancer genomes in children with Lynch syndrome: exploring causal associations WXS

  Dataset EGAD00001010043

• Neuroblastoma deep-sequencing dataset part 1

  Dataset including paired tumor-normal whole-genome deep-sequenced samples from 18 neuroblastoma patients (part1 of a total of 36 patients).

  Dataset EGAD00001010059

• EORTC-26101 sequencing data

  The dataset contains panel sequencing data of 170 genes from 380 patients of the EORTC-26101 trial. The corresponding methylation data is available via the Gene Expression Omnibus (GEO, https://www.ncbi.nlm.nih.gov/geo/) repository with the accession number GSE237103.

  Dataset EGAD00001011160

• RNA sequencing data from the lungNENomics project

  Raw RNA-seq data from the lungNENomics cohort, comprising 319 pairs of FASTQ files from 179 individuals. This dataset also includes a gene count matrix, gene TPM matrix and gene expression VST matrix from 244 samples.

  Dataset EGAD00001015524

• Extensive and differential platinum chemotherapy mutagenesis in livers of children - RNA

  Bulk RNA sequencing of normal liver and liver tumours from children. Five of the children had liver cancer and samples was taken at surgery. Two children had non-liver type of cancer and liver samples were obtained postmortem.

  Dataset EGAD00001016117

• Research Program on Genes, Environment and Health (RPGEH)

  The Kaiser Permanente Research Program on Genes, Environment, and Health (RPGEH) is a resource developed to facilitate research on genetic and environmental factors on common diseases and healthy aging. The RPGEH resource links biospecimens, health surveys, and comprehensive electronic medical records on broadly consented adult members of Kaiser Permanente Medical Care Plan, Northern California Region (KPNC). KPNC is an integrated health care delivery system with a membership of approximately 3.3 million people in northern California. The membership of KPNC is representative of the general population in the 14 county area in which facilities are located, although extremes of income are underrepresented. At the end of 2013, the RPGEH resource included: (1) demographic and behavioral surveys from over 430,000 participants; (2) biospecimens (DNA, serum, plasma, and/or saliva) from over 204,000 participants, including over 13,000 pregnant women; (3) genome-wide genotype data (70 billion SNP genotypes) on over 100,000 participants, including the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort; and (4) the longitudinal electronic medical records of the participants. The RPGEH was developed beginning in 2005 at the Division of Research of Kaiser Permanente Northern California by Catherine Schaefer (Director), Neil Risch (Co-Director), Lisa Croen, Eric Jorgenson, Lawrence Kushi, Charles Quesenberry, Sarah Rowell, Carol Somkin, Stephen Van den Eeden, Larry Walter, and Rachel Whitmer. Funding of the RPGEH was provided to C. Schaefer (PI) and N. Risch (co-PI) by the Wayne and Gladys Valley Foundation, The Ellison Medical Foundation, the Robert Wood Johnson Foundation, Kaiser Permanente Northern California, and the Kaiser Permanente National and Regional Community Benefit Programs. The GERA cohort was funded by a grant from NIH to RPGEH and UCSF (RC2 AG036607; C. Schaefer and N. Risch, PIs). At the time of the award of the RC2 project in late 2009, the RPGEH had established a cohort of about 140,000 individuals who had answered a detailed survey, provided saliva samples for extraction of DNA, and given broad consent for the use of their data in studies of health and disease. Survey and Cohort Recruitment. Initially, the RPGEH developed electronic disease registries to enable identification of phenotypes, using algorithms applied to EMR data. In 2007, the RPGEH mailed a four page survey to 1.9 million adult (≥ 18 years old) members of KPNC who had been members for two years or more, to obtain data on demographic and behavioral factors complementary to the clinical data in the EMR. The survey materials included a cover letter introducing the RPGEH, a two page list of Frequently Asked Questions, and the survey, which included questions on demographic factors such as education, race-ethnicity, income and marital status, dietary factors, physical activity, smoking, and alcohol consumption, as well as reproductive history and reproductive health. Members whose electronic medical records indicated a preference for written communications in Chinese or Spanish received survey materials both in English and a Chinese or Spanish translation. Approximately 400,000 completed surveys were returned. Saliva Sample Collection. Beginning in July 2008, respondents to the survey were asked to sign and return a consent form and authorization for use and disclosure of protected health information. The consent form authorized broad use of biospecimens, survey data, and data from participants' electronic health records for use in studies of genetic and environmental influences on health and disease. Respondents who returned completed consent forms were mailed (Oragene) saliva collection kits; more than 132,000 saliva samples were collected in two years. Completed saliva kits were scanned and archived in a temporary biorepository at the KPNC Division of Research. In late 2009, the RPGEH began collection of saliva samples from the California Men's Health Study (CMHS), a cohort that had been previously assembled in 2002-2003 and had been excluded from the RPGEH survey mailing with the intent of later adding CMHS participants to the assembled RPGEH cohort. The CMHS was developed to facilitate research on prostate cancer and other conditions in older men; the study protocol is described in Enger, et al., 2006. It enrolled and surveyed more than 40,000 men in KPNC, ages 45-69 years, who were members of KPNC during 2002-2003. CMHS men completed two mailed surveys with demographic and behavioral data similar to that of the RPGEH. The data on analogous variables were reconciled and integrated with the data derived from the RPGEH cohort for use in the RPGEH resource. By 2011, RPGEH collected approximately 15,400 saliva samples from men participating in the CMHS. RPGEH Access and Collaborations Website and Procedures. The RPGEH maintains a web portal for inquiries and applications for collaboration and access to data. The url is: https://rpgehportal.kaiser.org/. RPGEH has an application process and an Access Review Committee that reviews applications for collaboration and use. For more information, please contact RPGEH through the website.

  Study phs000788

• Genome-Wide Association Analysis of Biomarkers in the InCHIANTI and BLSA

  Version 1 The aim of this study was to identify gene(s) associated with serum iron concentrations. This dataset contains the results from a meta-analysis of 1919 subjects from the InCHIANTI and Baltimore Longitudinal Study of Aging (BLSA). Both studies are population based prospective studies that evaluate the contributors of normal aging. Version 2 We performed genome wide analysis of 93 circulating biomarkers in the InCHIANTI study of 1210 individuals, after imputation from the 1000 genomes project.

  Study phs000215

• Analysis of MPNST progression at single-cell resolution

  Malignant Peripheral Nerve Sheath Tumors (MPNST) are soft-tissue sarcomas with poor prognosis and a lack of treatment options. About half of them arise in people with Neurofibromatosis Type 1 (NF1). In this study, we set out to explore the malignant progression and tumor heterogeneity by exploring the different tumors along the MPNST progression at the single cell level. This work is part of the project "NF1-Associated Peripheral Nerve Sheath Tumors at Single-Cell Resolution: Heterogeneity, Tumor Growth, and Malignant Progression".

  Study EGAS50000001747

• Impact of allogeneic umbilical-cord derived mesenchymal stromal cells on B-cell scRNAseq in patients with systemic lupus erythematosus

  The impact of MSC(UC) on peripheral B cells from Systemic Lupus Erythematosus (SLE) patients was studied by 10X scRNAseq. This scRNAseq study encompassed 3 SLE patients at 3 time points: before or after (1 month, and 3 months) MSC injection in order to analyze B cell subsets and their DEG. The aim of this study was to observe the potential changes of B cell subsets after MSC(UC) injection in SLE patients.

  Study EGAS50000000325

• Transcriptome analysis of human iPSC-derived microglia in a novel human 3D cortical tissue model

  scRNA-seq analysis of human iPSC-derived microglia in a novel, human in vitro 3D cortical tissue model. Samples include three distinct conditions (each as biological duplicates): wild-type microglia extracted from cultures after 1 month (WT_1mo) and 3 months (WT_3mo) of culturing, as well as knock-in microglia extracted from cultures carrying three familial AD mutations in the APP gene (Swedish, Iberian, Arctic; introduced by CRISPR/Cas9-mediated knock-in) after 3 months of culturing (KI_3mo).

  Study EGAS50000000469

• Ballett

  TSO500 study: The project, called "BALLETT" (Belgian Approach of Local Laboratory Extensive Tumor Testing), has a double goal: (1) show the relevance of broad molecular profiling to improve oncological patients care, (2) demonstrate that broad molecular testing can be performed in a decentralized setting by local diagnostics laboratories in a fully standardized and uniform way while complying with the highest quality standards. NCT05058937 The publication number is: Your manuscript ID is bcr-2023-256124. Title: CUP and BRAF V600E meeting the BEACON combination.

  Study EGAS50000000478

• Immune activation in the tumor microenvironment of renal cell carcinoma

  Study describes immunological responses to immunotherapy (anti-PD-1, pembrolizumab) and targeted therapy (VEGFR inhibition, axitinib) as well as anti-CD3/CD28/CD2 (Immunocult) in a patient-derived ex vivo tumor model of renal cell carcinoma. Patient-derived ex vivo tumor models were established and their treatment response studied using material from eight renal cell carcinoma patients. Samples were collected under informed consent in HUS Helsinki University Hospital, Finland. The study aims to understand immunological treatment responses in the patient tumor microenvironment.

  Study EGAS50000001349

• AML_targeted_resequencing_study

  Genomic libraries will be generated from whole genome amplified genomic DNA derived from 3,000 myeloid neoplasms. Targeted capture will be performed by multiplexing 16 barcoded samples in each library. Pools of 96 DNA samples will be subjected to 1-2 lanes of HiSeq 75bp sequencing. Reads will be mapped to the current build of the human reference genome to facilitate the generation of a comprehensive catalog of somatic mutations associated with 116 known myeloid and cancer driver genes.

  Study EGAS00001000275

• Genome-wide association study of response to warfarin in a UK prospective cohort

  Genome-wide association study of Warfarin dosing in 714 British, recruited in Liverpool and Birmingham. Three phenotypes were investigated: warfarin mean dose, warfarin mean stable dose, and INR over 4 during first week of treatment. Stability was defined by at least three INR measurements within target in a three week period. The samples were genotyped on the Illumina 610K chip and imputed using Impute v2.1, with a combined filtered set composed of HapMap 3 release 2 and 1000 genomes pilot 1 CEU.

  Study EGAS00001001130

• PCR-free HiSeqX whole genome sequence data on 120 samples with triplet repeat expansions (premutation and full expansions)

  Whole genome sequence (WGS) data was generated on 120 Coriell samples with the following validated repeat expansions: Fragile X Syndrome, Huntington disease, Friedreich’s ataxia, Amyotrophic Lateral Sclerosis, Myotonic Dystrophy, Spinocerebellar Ataxia 1/3 and Dentatorubral-Pallidoluysian Atrophy. These samples were sequenced using 2x150bp reads on an Illumina HiSeqX sequencer and the repeat expansions were called using ExpansionHunter to demonstrate the ability to call large repeats from high throughput, PCR-free WGS data.

  Study EGAS00001002462

• RNA sequencing data of 66 matched primary and recurrent high grade serous ovarian cancer

  Gene expression profiles of matched primary and recurrent fresh frozen tumor tissues from 66 HGSOC patients were obtained by RNA sequencing. RNA libraries were created using the Illumina TruSeq RNA sample preparation kit V2 according to the manufacturer’s instructions and sequenced on a HiSeq2000 (Illumina, California, USA) using a V3 flowcell generating 1 x 50 bp reads. Raw sequencing reads were mapped to the transcriptome and the human reference genome (NCBI37/hg19) using TopHat 2.0 and Bowtie 2.0.

  Study EGAS00001002660

• Relapse series of two Pediatric ALL patients

  In this proof of principle study, we performed whole genome sequencing of two cases with multiple relapses in order to investigate whether groups of mutations separated in time show distinct mutational signatures. In patient 1, who experienced two relapses, the analysis unraveled a continuous interplay of aberrant AID/APOBEC-associated activities. Patient 2 had three relapses. We identified episodic mutational processes at diagnosis and first relapse leading to mutations resembling UV light-driven DNA damage, and thiopurine-associated damage at first relapse.

  Study EGAS00001005001

• Single-cell T-cell receptor sequencing data of peripheral blood mononuclear cells obtained from 30 ATL patients, 11 HTLV-1-infected asymptomatic carriers, and 4 healthy donors.

  Single-cell T-cell receptor sequencing (scTCR-seq) data of peripheral blood mononuclear cells (PBMCs) obtained from 30 ATL patients (34 samples including 4 sequential ones), 11 HTLV-1-infected asymptomatic carriers, and 4 healthy donors.

  Dataset EGAD00001007014

• MP2PRT: Evaluation of an Inflammation Polygenic Risk Score (iPRS) to Predict Cancer Related Cognitive Impairment and Fatigue in Patients Receiving Chemotherapy for Non-Metastatic Breast Cancer in URCC0701 and URCC10055

  This study is a secondary analysis of cancer related cognitive impairment (CRCI) and cancer related fatigue (CRF) among participants in URCC0701 and URCC10055 from the University of Rochester NCI Community Oncology Research Program (NCORP) Research Base. CRCI and CRF are common, troublesome, and dose-limiting toxicities reported by patients undergoing breast cancer chemotherapy that have an etiologic basis linked to low-grade systemic inflammation. Chronic, low-grade systemic inflammation is, in part, genetically determined with common single nucleotide polymorphisms (SNPs) capturing variation across individuals. This study aimed to 1) determine whether an inflammation polygenic risk score (iPRS) is associated with CRCI or CRF, 2) determine whether the relationship between the iPRS and CRCI or CRF is modified by exercise at the time of cancer treatment, 3) identify SNPs associated with serum cytokines measured at the time of cancer treatment, and 4) identify novel CRCI- and CRF-associated risk SNPs via genome-wide association analyses. We found that there was a significant inverse correlation between the iPRS and change in fatigue score from pre-chemotherapy to post-chemotherapy while there was no statistically significant association between the iPRS and cognitive impairment score. The inverse relationship between the iPRS and fatigue may be explained in part by the finding that the iPRS was also significantly associated with greater pre-chemotherapy fatigue, suggesting that women with a genetic predisposition to low-grade systemic inflammation (i.e., high iPRS) have more fatigue at the time of breast cancer diagnosis and, therefore, are less likely to worsen over the course of treatment. In contrast, women with a low iPRS had significantly less fatigue pre-chemotherapy and a significant worsening of fatigue from pre- to post-chemotherapy. The relationship between the iPRS and fatigue remained after adjustment for patient and cancer treatment covariates and was most pronounced in women who reported regularly exercising for at least 6 months prior to starting their cancer treatment. Exploratory genome-wide analysis identified a novel risk locus on chromosome chr6q27, tagged by rs9365961, associated with CRCI. This locus is upstream of TBXT, which encodes an embryonic nuclear transcription factor previously associated with susceptibility to neural tube defects. The genome-wide SNP data, patient-reported CRCI and CRF outcome measures, and covariate data used in this analysis are available through dbGaP.

  Study phs003688

• Neurodevelopmental Genomics: Trajectories of Complex Phenotypes

  This study is a collaboration between the Center for Applied Genomics (CAG) at Children's Hospital of Philadelphia (CHOP) and the Brain Behavior Laboratory at the University of Pennsylvania (Penn). The cohort consists of youths aged 8-21 years who consulted the CHOP network and volunteered to participate in genomic studies of complex pediatric disorders. All participants underwent clinical assessment, including a neuropsychiatric structured interview and review of electronic medical records. They were also administered a neuroscience based computerized neurocognitive battery (CNB) and a subsample underwent neuroimaging. These are described separately below. Clinical Testing: GOASSESS, a computerized, structured screener developed from a modified version of the Kiddie-Schedule for Affective Disorders and Schizophrenia (K-SADS, Kaufman et al. 1997, PMID: 9204677). Components of the interview include a timeline of life events, demographics and medical history, Global Assessment of Functioning, and Interviewer Observations. A psychopathology symptom and criterion-related assessment of mood disorders (depression, mania/hypomania), anxiety disorders (overanxious/generalized-, separation-, social-anxiety, specific phobia, panic disorder, agoraphobia, obsessive compulsive disorder, post-traumatic stress disorder), behavioral disorders (attention deficit hyperactivity disorder, oppositional defiant disorder, conduct disorder), psychosis spectrum (psychosis and prodromal symptoms), eating disorders, suicidal thinking and behavior, and treatment history. This is also based on K-SADS. An abbreviated Family Interview for Genetics Studies (FIGS) to assess major domains of psychopathology in the proband's first-degree relatives. Computerized Neurocognitive Battery: The CNB, developed for large-scale studies, yields measures of accuracy and speed for domains of executive-control functions (abstraction, attention, working memory), episodic memory (verbal, facial, spatial), complex cognitive processing (language reasoning, nonverbal reasoning, spatial processing), social cognition (emotion identification, emotion intensity differentiation, age differentiation) and sensorimotor and motor speed. The following neurobehavioral domains were assessed: Penn Conditional Exclusion Test is a measure of abstraction and concept formation. Participants decide which of 4 objects does not belong with the other 3, based on one of three sorting principles, which change. Feedback is used. Attention: The Penn Continuous Performance Test. Participants respond to a set of 7-segment displays whenever they form a digit or letter. Working Memory: The Letter N-back Test displays sequences of uppercase letters with a stimulus duration of 500 ms (ISI 2,500 ms.) In the 0-back condition, participants respond to a single target (i.e., X). In the 1-back condition they respond if the letter is identical to that preceding it. In the 2-back condition, they respond if the letter is identical to that presented two trials back. Verbal Memory: The Penn Word Memory Test presents 20 target words that are then mixed with 20 distracters equated for frequency, length, concreteness and low imageability. A 20 min delayed recall procedure is also administered. Face Memory: The Penn Face Memory Test presents 20 digitized faces that are then mixed with 20 distracters equated for age, gender and ethnicity. The procedure is repeated at 20 min delay. Spatial Memory: The Visual Object Learning Test uses Euclidean shapes as stimuli with the same paradigm as the word and face. Language and Analogical Reasoning: The Penn Verbal Reasoning consists of verbal analogy problems. Spatial Processing: Penn Line Orientation Test presents two lines at an angle, and participants click on a button that makes one line rotate until it has the same angle as the other. Emotion Processing: Facial displays of 4 emotions (Happy, Sad, Anger, Fear) and Neutral faces, 8 each, are presented and the subject identifies the emotion in a multiple-choice format. The facial stimuli are balanced for gender, age, and ethnicity. Sensory-motor Processing Speed: The task requires moving the mouse and clicking on a green square that disappears after the click. The square gets increasingly small and appears in unpredictable locations. Neuroimaging Protocol: Studies were performed at Penn using a Siemens Trio (Erlangen, Germany) 3T scanner equipped with 40mT/m gradients and 200 mT/m/s slew-rates. RF transmission utilized a quadrature body-coil, and reception a 12-channel head coil optimized for parallel imaging. Total image acquisition time was about 45 min. Structural Imaging: The T1-weighted protocol utilized a 3D, inversion-recovery, and magnetization-prepared rapid acquisition gradient echo. Relevant imaging procedures include: Structural magnetic imaging Diffusion tensor imaging ASL perfusion BOLD fMRI Neuroimaging tasks: Fractal N-Back Task of Spatial Working Memory Face Emotion Identification Task Neuroimages: The current data release includes over 9700 MRI images that may be downloaded through Authorized Access.

  Study phs000607

• Environmental Influences on Child Health Outcomes (ECHO) - PATHWAYS - Conditions Affecting Neurocognitive Development and Learning in Early Childhood (CANDLE)

  Pregnant women are exposed daily to multiple chemical and non-chemical stressors, including air pollutants, phthalates, and psychosocial stress. The Developmental Origins of Health and Disease model (DOHaD) states that exposure to these stressors in pregnancy affects fetal development in a manner that impacts offspring health across the life course. Yet epidemiologic data in these areas is limited, particularly with U.S. samples. It is also poorly understood whether these exposures prenatally affect childhood neurodevelopment and airway health in an independent or combined manner, and likely moderators of effects, such as the sex of the child, are infrequently addressed. We propose to unify three diverse extant pregnancy cohorts: TIDES (N=717, 2010-12), GAPPS (N=1133, 2012-16), and CANDLE (N=1385, 2007-11), for a combined sample size of 3235 mother-child dyads in the PATHWAYS study. PATHWAYS will investigate how chemical (air pollutants and phthalates) and non-chemical (psychosocial stress) exposures during pregnancy are related to placental gene expression (transcriptome) and childhood neurodevelopment and airway health (at ages 4-6, 8-9, and 10-11 years). Each cohort has rich resources of prenatal data and banked specimens (urine, blood, and placenta) that will be harmonized for the PATHWAYS study and will contribute to the ECHO consortium. We will develop a national model with high spatiotemporal resolution of key air pollutants and assess urinary markers of maternal exposure. A composite measure will capture multilevel maternal psychosocial stress across pregnancy, and urinary phthalate and blood stress hormone [Corticotropin-releasing hormone (CRH)] levels in the second and third trimesters will provide individual assessment of those exposures in potential critical periods. We will characterize the placental transcriptome using RNA sequencing (RNA-Seq) and will assess neurodevelopment and airway health prospectively into middle childhood. PATHWAYS will examine how these prenatal exposures are related to the placental transcriptome and child health outcomes in main effect and interactive models, with emphasis on sex-specific associations. For both neurodevelopment and airway health, we propose to measure both phenotypic precursors of health outcomes (i.e. fluid cognition, lung function growth), which yield dimensional tests of proposed associations, as well as clinically meaningful and policy relevant outcomes (i.e. asthma, mental health). Our study is powered to assess interactive effects of chemical and non-chemical stressors and will be the first study to characterize how prenatal environmental exposures relate to placental transcriptome pathways in relation to childhood health outcomes. This represents a significant scientific advance in testing DOHaD hypotheses. Major contributions to the ECHO Consortium include: 1) the development of a state of the art national model of air pollution, 2) a large, diverse pregnancy cohort with extensive biorepositories and extant prenatal and postnatal biomarkers, placental transcriptome, psychosocial and environmental data, and 3) an experienced, interdisciplinary team that will contribute meaningfully to the ECHO program of work.The sequencing data in this submission pertains only to the 794 subjects from the CANDLE study for whom placental tissue transcriptomics was performed.

  Study phs003619

• Environmental Influences on Child Health Outcomes (ECHO) - PATHWAYS - Global Alliance to Prevent Prematurity and Stillbirth (GAPPS)

  Pregnant women are exposed daily to multiple chemical and non-chemical stressors, including air pollutants, phthalates, and psychosocial stress. The Developmental Origins of Health and Disease model (DOHaD) states that exposure to these stressors in pregnancy affects fetal development in a manner that impacts offspring health across the life course. Yet epidemiologic data in these areas is limited, particularly with U.S. samples. It is also poorly understood whether these exposures prenatally affect childhood neurodevelopment and airway health in an independent or combined manner, and likely moderators of effects, such as the sex of the child, are infrequently addressed. We propose to unify three diverse extant pregnancy cohorts: TIDES (N=717, 2010-12), GAPPS (N=1133, 2012-16), and CANDLE (N=1385, 2007-11), for a combined sample size of 3235 mother-child dyads in the PATHWAYS study. PATHWAYS will investigate how chemical (air pollutants and phthalates) and non-chemical (psychosocial stress) exposures during pregnancy are related to placental gene expression (transcriptome) and childhood neurodevelopment and airway health (at ages 4-6, 8-9, and 10-11 years). Each cohort has rich resources of prenatal data and banked specimens (urine, blood, and placenta) that will be harmonized for the PATHWAYS study and will contribute to the ECHO consortium. We will develop a national model with high spatiotemporal resolution of key air pollutants and assess urinary markers of maternal exposure. A composite measure will capture multilevel maternal psychosocial stress across pregnancy, and urinary phthalate and blood stress hormone [Corticotropin-Releasing Hormone (CRH)] levels in the second and third trimesters will provide individual assessment of those exposures in potential critical periods. We will characterize the placental transcriptome using RNA sequencing (RNA-Seq) and will assess neurodevelopment and airway health prospectively into middle childhood. PATHWAYS will examine how these prenatal exposures are related to the placental transcriptome and child health outcomes in main effect and interactive models, with emphasis on sex-specific associations. For both neurodevelopment and airway health, we propose to measure both phenotypic precursors of health outcomes (i.e., fluid cognition, lung function growth), which yield dimensional tests of proposed associations, as well as clinically meaningful and policy relevant outcomes (i.e., asthma, mental health). Our study is powered to assess interactive effects of chemical and non-chemical stressors and will be the first study to characterize how prenatal environmental exposures relate to placental transcriptome pathways in relation to childhood health outcomes. This represents a significant scientific advance in testing DOHaD hypotheses. Major contributions to the ECHO Consortium include: 1) the development of a state of the art national model of air pollution, 2) a large, diverse pregnancy cohort with extensive biorepositories and extant prenatal and postnatal biomarkers, placental transcriptome, psychosocial and environmental data, and 3) an experienced, interdisciplinary team that will contribute meaningfully to the ECHO program of work.The sequencing data in this submission pertain only to the 408 subjects from the GAPPS study for whom placental tissue transcriptomics was performed.

  Study phs003620

• Resistance to Checkpoint Blockade Therapy Through Inactivation of Antigen Presentation

  Although immune checkpoint blockade (CPB) leads to prolonged responses in 15-40% of patients with metastatic melanoma, treatment refractory disease and progression after initial response remain major causes of mortality. While predictors of response have been reported, the common mechanisms of both primary and acquired resistance are poorly understood. To identify mechanisms of resistance and examine the evolving landscape in response to CPB, we performed whole exome sequencing (WES), immunohistochemistry (IHC), and RNA-sequencing (RNAseq) of longitudinal tumor biopsies from 17 metastatic melanoma patients treated with various CPB therapies. We found no significant changes in both mutational and neoantigen loads over time between responders and nonresponders. However, we identified abnormalities in one gene, beta-2-microglobulin (B2M), an essential component of MHC Class I antigen presentation, that were present in samples during disease progression but not regression. In total, we identified B2M aberrations in 29.4% of patients, including multiple early frameshift mutations, loss of heterozygosity (LOH) overlapping B2M, and absence of tumor-specific B2M protein expression. Additional defects in the antigen presentation and IFNγ pathways were identified but were not restricted to progressing lesions in our cohort. In two independent cohorts of 105 and 38 melanoma patients treated with ipilimumab (anti-CTLA4) and pembrolizumab (anti-PD1) respectively, we found that B2M LOH was enriched 3-fold in nonresponders (~30%) vs. responders (~10%) and associated with poorer overall survival (log-rank p=0.01, p=0.006). Loss of both copies of B2M was found only in nonresponders. We also found evidence for association of LOH overlapping IFNGR1 with poorer overall survival exclusively in the anti-PD1 cohort. Thus, B2M loss is likely a common mechanism of primary and acquired resistance to therapies targeting CTLA4 or PD-1.

  Study phs001427

• Aspirin and Inflammation: Mutations, Genes, Pathways and Prevention in Barrett's Esophagus

  Background: Use of aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) has been shown to protect against tetraploidy, aneuploidy, and chromosomal alterations in the metaplastic condition Barrett's esophagus (BE) and to lower the incidence and mortality of esophageal adenocarcinoma (EA). The esophagus is exposed to both intrinsic and extrinsic mutagens resulting from gastric reflux, chronic inflammation and exposure to environmental carcinogens such as those found in cigarettes. Here we test the hypothesis that NSAID use inhibits accumulation of point mutations/indels during somatic genomic evolution in BE. Methods: Whole exome sequences were generated from 82 purified epithelial biopsies and paired blood samples from a cross-sectional study of 41 NSAID users and 41 nonusers matched by sex, age, smoking, and continuous time using or not using NSAIDs. Results: NSAID use reduced overall frequency of point mutations across the spectrum of mutation types, lowered the frequency of mutations even when adjusted for both TP53 mutation and smoking status, and decreased the prevalence of clones with high variant allele frequency. Never smokers who consistently used NSAIDs had fewer point mutations in signature 17, which is commonly found in EA. NSAID users had on average a 50% reduction in functional gene mutations in nine cancer-associated pathways and also had less diversity in pathway mutational burden compared to nonusers. Conclusions: These results indicate NSAID use functions to limit overall mutations on which selection can act and supports a model in which specific mutant cell populations survive or expand better in the absence of NSAIDs. Galipeau PC, et al. Genome Med. 2018 Feb 27;10(1):17. PMID: 29486792.

  Study phs001654

• The Human Pancreas Analysis Program (HPAP)

  The past decade has seen a dramatic improvement in our ability to phenotype and molecularly profile human tissues with unprecedented resolution at the genomic, epigenomic, protein, and functional levels. The Human Pancreas Analysis Program (HPAP), part of the Human Islet Research Network and supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) through multiple NIH grants, is performing deep phenotyping of the human endocrine pancreas to better understand the cellular and molecular events that precede and lead to beta-cell loss and/or dysfunction in type 1 diabetes (T1D) and type 2 diabetes (T2D) as well as to accumulate, analyze, and distribute high-value data sets to the diabetes research community through the HPAP PANC-DB database (and additional details provided at that site). To this end, HPAP employs state-of-the-art technologies to perform comprehensive analyses of pancreas biology as it pertains to organ donors with T1D, autoantibody-positive donors without diabetes, donors with T2D, and control donors. Pancreas procurement and analyses take advantage of the expertise and extensive network of Organ Procurement Organizations (OPOs) and autoantibody screening centers established through the JDRF/The Lenona M. and Harry B. Helmsley Charitable Trust (HCT) – funded nPOD program. In contrast to nPOD, the major product provided by HPAP is not archived biomaterial subject to broad distribution, but rather, the delivery of extensive and high-quality molecular data sets to the diabetes research community in order to facilitate further discovery. Together, nPOD and HPAP are complementary programs that assist the diabetes community and afford the maximal opportunity for advancing knowledge about the pathogenesis of T1D and T2D.

  Study phs002465

• Stockholm-Tartu Atherosclerosis Reverse Network Engineering Task (STARNET)

  STARNET is a genetics of RNA expression study of multiple disease-relevant tissues obtained from living patients with cardiovascular disease. Tissue samples are obtained from blood, atherosclerotic-lesion-free internal mammary artery (MAM) and atherosclerotic aortic root (AOR), subcutaneous fat (SF), visceral abdominal fat (VAF), skeletal muscle (SKLM), and liver (LIV) during open thorax surgery of 600 coronary artery disease (CAD) patients. All patients gave written informed consent. The inclusion criterion was eligibility for coronary artery by-pass graft (CABG) surgery. Patients with other severe systemic diseases, such as active systemic inflammatory disease or cancer, were excluded. The primary clinical end points were the SYNTAX score based on the extent of coronary atherosclerosis assessed from preoperative angiograms. The STARNET patients are Caucasians (31% females); 32% had diabetes, 75% had hypertension, and 67% had hyperlipidemia; and 33% had an MI before age 60. By New York Heart Association criteria, 45% were class I, 42% class II, 9% class III, and 1% class IV. TYPES AND RNA SEQUENCING: 566 DNA genotype and 3577 RNA-seq profiles from seven tissues from 600 STARNET CABG patients passed quality control (on average 511 RNA-seq profiles/tissue). DNA was genotyped with the OmniExpress Exome array (Illumina, ~900k SNPs) and imputed to a total of 14,098,063 DNA variant calls (6,245,505 with minor allele frequency >5%). The STARNET subjects mainly overlap with Caucasian of Northern European (Finnish) descent. RNA sequencing was performed using the HighSeq2000 platform, poly-A (LIV, SKLM, VAF, SF and blood) and ribo-zero (AOR, MAM) protocols with 50-100 bp read lengths, single end to 15-30 million read depth.

  Study phs001203

• CCR8-targeted specific depletion of clonally expanded Treg cells in tumor tissues evokes potent tumor immunity with long-lasting memory

  Foxp3-expressing CD25+CD4+ regulatory T cells (Tregs) are abundantly infiltrating into tumor tissues, hindering effective anti-tumor immunity. Here, assuming that such tumor Tregs were clonally expanding by recognizing tumor-associated antigens, we attempted to characterize them by their gene expression profiling and T-cell receptor (TCR) clonotyping at the single-cell level. We found that they predominantly expressed the chemokine receptor CCR8: ~40% of tumor Tregs, less than 10% of Tregs in other tissues, and few tumor-infiltrating conventional T cells expressed CCR8 in mice and humans. CCR8+ tumor Tregs were phenotypically highly differentiated and functionally stable. One injection of anti-CCR8 mAb with high antibody-dependent cellular cytotoxic activity was indeed able to specifically deplete clonally expanded tumor Tregs and thereby eradicate established tumors in mice. The depletion predominantly expanded tumor-infiltrating CD8+ effector T cells, which were different in activated or exhausted patterns from those seen after immune checkpoint blockade by anti-PD-1 mAb. The treatment also evoked potent secondary immune responses against the same tumor cell line inoculated several months after tumor eradication, indicating that the anti-CCR8-induced memory-type tumor-reactive effector T cells were, once induced, resistant to recovered Treg suppression. In contrast to such evocation of potent tumor immunity, anti-CCR8 treatment scarcely elicited discernable autoimmunity in mice, contrasting with a similar treatment for systemic whole Treg depletion, which induced histologically and serologically evident autoimmunity. Thus, temporary and specific depletion of clonally expanded Tregs in tumor tissues by cell-depleting anti-CCR8 mAb is sufficient to evoke potent tumor immunity with long-lasting memory and without serious autoimmunity.

  Study JGAS000312

• Integrated genomic analyses reveal molecular correlates of clinical response and resistance to atezolizumab in combination with bevacizumab in advanced hepatocellular carcinoma

  Atezolizumab (anti–programmed death-ligand 1 [anti-PD-L1]) and bevacizumab (anti-vascular endothelial growth factor [anti-VEGF]) combination therapy has become the new standard of care in patients with unresectable hepatocellular carcinoma. However, potential predictive biomarkers and mechanisms of response and resistance remain less understood. We report integrated molecular analyses of tumor samples from 358 patients enrolled in the GO30140 phase 1b or IMbrave150 phase 3 trials who were treated with atezolizumab combined with bevacizumab, atezolizumab alone, or sorafenib. Pre-existing immunity assessed by high expression of CD274 (PD-L1 mRNA), T-effector signature, and intratumoral CD8+ T cell density were associated with response and better clinical outcomes with the combination treatment. Less clinical benefit was associated with high regulatory T cell (Treg) to effector T-cell ratio and high expression of oncofetal genes such as GPC3 and AFP. Improved outcomes from the combination vs atezolizumab alone appeared to be associated with high expression of KDR (VEGFR2), Treg, and myeloid inflammation signatures, indicating anti-VEGF may contribute by targeting these axes. These findings were further validated by transcriptome analysis of paired pre- and post-treatment biopsies, in situ analysis by multiplex IHC and digital pathology, and in vivo study of an immunogenic hepatocellular carcinoma mouse model. Our findings highlight that anti-VEGF therapy might augment antitumor immunity and enhance anti–PD-L1 immunotherapy by targeting VEGF-mediated angiogenesis, Treg proliferation, and myeloid cell inflammation. Furthermore, our study identified candidate biomarkers for predicting response and resistance to anti–PD-L1 and anti-VEGF combination therapy.

  Study EGAS00001005503

• An analysis of humoral and cellular immune responses following COVID-19 vaccination.

  Two dose mRNA vaccination provides excellent protection against SARS-CoV-2. However, there are few data on vaccine efficacy in elderly individuals above the age of 801. Additionally, new variants of concern (VOC) with reduced sensitivity to neutralising antibodies have raised fears for vulnerable groups. Here we assessed humoral and cellular immune responses following vaccination with mRNA vaccine BNT162b22 in elderly participants prospectively recruited from the community and younger health care workers. Median age was 72 years and 51% were females amongst 140 participants. Neutralising antibody responses after the first vaccine dose diminished with increasing age, with a steep drop in participants over 80 years old. Sera from participants below and above 80 showed significantly lower neutralisation potency against B.1.1.7, B.1.351 and P.1. variants of concern as compared to wild type. Those over 80 were more likely to lack any neutralisation against VOC compared younger participants following first dose. Binding IgG and IgA antibodies were lower in the elderly, as was the frequency of SARS-CoV-2 Spike specific B- cells. We observed a trend towards lower somatic hypermutation in participants with suboptimal neutralisation, and elderly participants demonstrated clear reduction in class switched somatic hypermutation, driven by the IgA1/2 isotype. SARS-CoV-2 Spike specific T- cell IFN?? and IL-2 responses were secreted primarily by CD4 T cells, and impaired in the older age group. We conclude that the elderly are a high risk population that warrant specific measures in order to mitigate against vaccine failure, particularly where variants of concern are circulating. Specifically, the dosing interval should not be extended in this group.

  Study EGAS00001005380