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• OncoArray: Oral and Pharynx Cancer

  Genetic factors play an important role in susceptibility to head and neck cancer and could also explain differences in response to treatment and outcome. The goal of this project is to investigate genetic variation involved in oral and oropharyngeal cancer susceptibility by performing the largest GWAS on these diseases, using a novel genotyping tool specifically designed for cancer studies by the OncoArray Network. This project encompasses data from approximately 6000 oral and pharynx cancer cases and 4000 controls derived from 12 epidemiological studies most of case-control design. The genotyping was centralized at the Center for Inherited Disease Research (CIDR), and the epidemiological data harmonization and analysis were completed at the International Agency for Research on Cancer (IARC). This study was supported by National Institute of Dental and Craniofacial Research (NIDCR) with direct funding to CIDR.

  Study phs001202

• Center for Common Disease Genomics (CCDG) - Cardiovascular: Cleveland Clinic Cohort

  The National Human Genome Research Institute (NHGRI) has funded the Centers for Common Disease Genomics (CCDG), a collaborative large-scale genome sequencing effort to comprehensively identify rare risk and protective variants contributing to common disease phenotypes and to better understand the general principles of genomic architecture underlying common, complex inherited diseases. This study contains variant calls derived from the whole genome sequence data of an early-onset coronary artery disease case-control cohort collected by the Cleveland Clinic. Case status was assigned based on the presence of myocardial infarction, coronary artery stenosis greater than 70% in at least one coronary artery, and/or revascularization (coronary angioplasty with or without stent placement or coronary artery bypass grafting) at an early age. For these samples, "early age" is defined as men 60 years of age or younger and women 70 years of age or younger.

  Study phs001871

• Modeling Malignant Progression in Glioma

  Gliomas are the most common primary brain tumor in humans. Low-grade gliomas (WHO grade II) invariably progress to high-grade gliomas (WHO grade III or IV). Although malignant progression may take many years, the survival rate after transformation to a high-grade glioma is poor, often only 12-15 months. In this data set, we have identified low-grade gliomas that have progressed to high-grade gliomas or high-grade gliomas that have progressed from low-grade gliomas. Some cases are matched pairs (meaning we have both the original low-grade tumor and the subsequent high-grade tumor). The samples deposited have been analyzed with bulk-RNA sequencing. They are also de-identified but are clinically annotated. When available, genetic information including IDH mutation status, 1p/19q deletion and histological subtype are also included.

  Study phs002607

• Women's Interagency HIV Study (WIHS)

  The Women's Interagency HIV Study (WIHS), a multicenter, prospective study, was established in August 1993 to carry out comprehensive investigations of the impact of HIV infection and its clinical, laboratory, and psychosocial effects in women. The purpose of this study is to collect and evaluate these data from HIV infected and at-risk women to better understand and provide support for women whom are currently HIV infected or who are at risk for HIV infection. Participants will have study visits every 6 months. Questionnaires regarding sexual behavior, health care utilization, medical and obstetric/gynecological history, psychosocial factors, and sociodemographics will be completed by participants. Physical, gynecological, and lipodystrophy examinations will also be conducted at each visit, and current medication regimen will be noted. Blood and other bodily fluid samples will be collected and registered in both local and national repositories of the WIHS in conjunction with NIAID.

  Study phs001503

• Molecular Basis of Neuroendocrine Prostate Cancer (Trento/Cornell/Broad 2015)

  A subset of advanced prostate cancers can progress from an androgen receptor (AR)-driven state to AR independence, often associated with low or absent AR expression and extensive neuroendocrine differentiation. Once neuroendocrine prostate cancer (NEPC) develops, patients typically demonstrate an aggressive clinical course and poor overall survival. Early diagnosis is important but remains challenging as the clinical and pathologic features associate with AR independence and NEPC are poorly defined. We performed whole exome sequencing of 114 metastatic tumors from 81 patients (35 with morphologic features of NEPC). Serial or synchronous samples were included to characterize heterogeneity and the transition from adenocarcinoma to NEPC. Computational analysis of clonality and allele specific quantification were performed using CLONET. Quantitative mRNA assessment including AR signaling genes and DNA methylation were evaluated in the context of genomic changes.

  Study phs000909

• NIDDK International IBD Genetics Consortium Repository Global Screening Array

  The purpose of this GWAS meta-analysis is to assess IBD risk alleles using data collected by members of the International IBD Genetics Consortium and their collaborators around the world. Data from over 30 cohorts have been identified and are being combined for analysis. Genotyping has been conducted using a variety of chips with most samples genotyped using GSAMD-24v1-0 or GSA-CHO-Custom. Individual level genotype data will be made available whenever possible (some groups are only able to provide summary statistics due to institutional and/or governmental restrictions on data sharing), together with information on sex, self-reported ancestry, IBD affection status and diagnosis. This first batch includes data from North American sites who are members of the NIDDK-funded IBD Genetics Consortium. Additional data will be provided in an update as soon as they have gone through the QC process.

  Study phs002336

• Yale Center for Mendelian Genomics (YCMG)

  From 2012-2021, Yale University was home to one of four national centers created by the National Institutes of Health (NIH) to study the genetics of rare inherited diseases. Researchers at Yale University, University of Washington, the Broad Institute and a center operated jointly by Baylor University and Johns Hopkins University analyzed the genomes of thousands of patients who suffer from more than 6,000 rare Mendelian disorders affecting more than 25 million individuals in United States. The Centers for Mendelian Genomics (CMG) applied next-generation sequencing and computational approaches to discover the genes and variants that underlie Mendelian disorders. The discovery of new genes that cause Mendelian conditions expanded our understanding about their biology to facilitate their diagnosis, and potentially indicate new treatments. The CMG provided free exome sequencing and analysis to collaborating investigators for qualified phenotypes.

  Study phs000744

• Center for Common Disease Genomics (CCDG) - Cardiovascular: eMERGE - Northwestern Cohort

  The National Human Genome Research Institute (NHGRI) has funded the Centers for Common Disease Genomics (CCDG), a collaborative large-scale genome sequencing effort to comprehensively identify rare risk and protective variants contributing to common disease phenotypes and to better understand the general principles of genomic architecture underlying common, complex inherited diseases. This study contains variant calls derived from the whole genome sequence data of an early-onset coronary artery disease case-control cohort selected from the NUgene Project biobank at Northwestern University. Case status was assigned based on the presence of myocardial infarction, coronary artery stenosis greater than 70% in at least one coronary artery, and/or revascularization (coronary angioplasty with or without stent placement or coronary artery bypass grafting) at an early age. In this study "early age" is defined as men 60 years of age or younger and women 70 years of age or younger.

  Study phs001913

• Genomic analysis of primary plasma cell leukemia reveals complex structural alterations and high risk mutational patterns

  Primary plasma cell leukemia (pPCL) is a rare and aggressive form of multiple myeloma (MM) that is characterized by poor overall survival despite advances in anti-MM therapy. The disease biology as well as molecular mechanisms that distinguish pPCL from non-pPCL MM remain poorly understood. In an attempt to identify key biological mechanisms that result in the aggressive pPCL phenotype we performed whole exome sequencing in 23 patients with newly diagnosed pPCL. The results reveal an enrichment of complex structural changes and high risk mutational patterns in pPCL that explain, at least in part, the aggressive nature of the disease. In particular pPCL patients with traditional low risk features such as translocation t(11;14) or hyperdiploidy accumulated adverse risk genetic events that could account for the poor outcome in this group.

  Study phs002022

• The Surveillance Monitoring for ART Toxicities (SMARTT) and the Women and Infants Transmission Study (WITS)

  Zidovudine (ZDV) is a nucleoside reverse transcriptase inhibitor (NRTI) which competitively inhibits HIV reverse transcriptase and is incorporated into the viral DNA, resulting in DNA chain termination. It was the first approved antiretroviral medication used for preventing HIV transmission from mother to child. However, in vitro and animal studies have suggested genotoxicity of ZDV and no study has evaluated potential impact of in utero ZDV exposure using genomic sequencing technologies. In this study, we investigate markers of genomic damage detected in peripheral blood mononuclear cell samples obtained from 91 ZDV-exposed and, for comparison, 94 NRTI-unexposed HIV-uninfected children born to HIV-infected mothers during the first week after birth. We utilize high-throughput DNA sequencing (whole exome sequencing) and genotype array methods to comprehensively identify potential clonal somatic single nucleotide variants (SNVs) and large acquired copy number alterations (SCNAs) related to ZDV exposure.

  Study phs002061

• Sexual dimorphism in human immune system aging

  We isolated peripheral blood mononuclear cells (PBMCs) from 172 community-dwelling healthy volunteers (91 women, 81 men) ages spanning adult lifespan: 54 young (ages 22-40: 23 men, 31 women), 59 middle-aged (ages 41-64: 31 men, 28 women), and 59 older subjects (65+: 27 men, 32 women). PBMCs were profiled using ATAC-seq (54 men, 66 women), RNA-seq (41 men, 34 women), and flow cytometry (62 men, 67 women). Flow cytometry data is publicly available, genomic data for 121 individuals are provided here. These datasets revealed immune system aging signatures in men and women and showed in which ways aging differentially affects the immune systems of men and women. A subset of these samples have been generated and analyzed previously and can be found at EGA (EGAS00001002605). This dataset on dbGaP include EGA samples as well.

  Study phs001934

• Consortium on Asthma among African-ancestry Populations in the Americas (CAAPA)

  Asthma is a complex disease where the interplay between genetic factors and environmental exposures influences susceptibility and disease prognosis. Asthmatics of African descent tend to have more severe asthma and more severe clinical symptoms than individuals of European ancestry. Advances in genetic and genomic technologies have revolutionized gene discovery for several complex diseases, but going to the next step in gene discovery for asthma among populations of African descent requires considering unique characteristics of this ethnic group, including adequate sample sizes and population stratification due to (European and African) admixture. Thus far, coverage of common genetic markers both in public databases and commercially available SNP chips has been inadequate to detect and measure genetic associations among African admixed populations. The aim of this study was therefore to catalog genetic diversity in populations of African descent, especially those whose ancestry reflects the African Diaspora in the Americas.

  Study phs001123

• Collaborative Cohort of Cohorts for COVID-19 Research (C4R): REasons for Geographic and Racial Differences in Stroke (REGARDS)

  Cohort DescriptionThe REasons for Geographic and Racial Differences in Stroke (REGARDS) cohort is one of the nation's largest, most comprehensive population-based cohorts, and it uses innovative home- and telephone-based data collection. REGARDS centrally recruited and initially examined 30,239 Black and White men and women aged ≥45 years in 2003-7 to understand why Southerners and Black Americans have a higher incidence of stroke and related diseases that affect brain health.Data Being Submitted Wave 1 questionnaire data includes 397 variables for 8109 REGARDS participants in C4R. Wave 2 questionnaire data includes 448 variables for 6421 REGARDS participants in C4R. Dried Blood Spot/Serosurvey data includes 7 variables for 4058 REGARDS participants in C4R. Derived data includes 43 variables for 8606 REGARDS participants in C4R. Phenotype data includes 113 variables for 7880 REGARDS participants in C4R.

  Study phs002919

• Infant Immune Responses to Early Life Vaccinations

  Infants are vulnerable to life-threatening infections due to an immature immune system. For this reason, vaccinations are provided early in life to increase protection against infectious agents. However, there is a limited understanding on how routine vaccinations alter the different immune cell populations in infants. Here, we profiled peripheral blood mononuclear cells (PBMCs) from six 2-month-old infants at the time of their routine vaccinations. Infants received the standard vaccinations including DTaP (diphtheria, tetanus and acellular pertussis), IPV (inactivated polio vaccine), Hep B (hepatitis B), Hib (Haemophilus influenzae type B), Rotavirus, and PCV13 (pneumococcus conjugate vaccine). Samples were obtained before vaccination, and subsequently around one week, and two-month post-vaccination (n=18 samples). This study sheds light on the dynamic nature of the infant peripheral immune cell transcriptome upon initial routine vaccine exposure. The processed data is available on GEO under GSE204716.

  Study phs002926

• Pediatric Preclinical Testing Consortium (PPTC)

  The Pediatric Preclinical Testing Consortium (PPTC) is addressing the unmet need of streamlining the development of new therapies for childhood cancers. The PPTC seeks to develop robust biomarkers of anticancer drug activity, and the majority of these are predicted to be genetic mutations that can be detected in tumor DNA and/or RNA. In order to design the most impactful experiments that can be rapidly translated to the clinic, PPTC investigators require a complete genomic characterization of the patient-derived xenograft tumor models that are utilized across the consortium. This will not only allow for the most robust experimental design, but also will increase the engagement of industry partners who seek collaborators poised to provide the proof-of-concept necessary for drugs in their development pipelines. All data and models will be made available to academically qualified investigators.

  Study phs001437

• Transfer Learning Associates CAFs with EMT and Inflammation in Tumor Cells in Human Tumors and Organoid Co-Culture in Pancreatic Ductal Adenocarcinoma

  This study examined the transcriptional changes induced by cancer associated fibroblasts (CAFs) in pancreatic ductal adenocarcinoma patient-derived tumor organoids. We hypothesized that cancer associated fibroblasts impacted tumor cell transcription to promote tumorigenic behavior. Using patient-matched cells from 3 patients, we compared the transcriptional profiles of patient-derived organoids in monoculture to patient-derived organoids co-cultured with CAFs. Similarly, we looked at the transcriptional changes in matched patient-derived cancer associated fibroblasts grown in monoculture or co-cultured with patient-derived organoids. With a focus on intercellular crosstalk, we identified crosstalk between cancer associated fibroblasts and patient-derived organoids through VEGFA and NRP1. This was identified by bulk RNA sequencing and examined dynamically in organoid-CAF co-culture. This dbGaP deposit is the bulk RNA sequencing data for these 3 patients.

  Study phs003563

• Beta-Blocker Evaluation in Survival Trial (BEST-BioLINCC)

  Data Access NOTE: Please refer to the “Authorized Access” section below for information about how access to the data from this accession differs from many other dbGaP accessions. Objectives The Beta-Blocker Evaluation of Survival Trial was designed to determine whether bucindolol hydrochloride- a nonselective beta-adrenergic blocker and mild vasodilator- would reduce the rate of death from any cause among patients with advanced heart failure and to assess its effects in various subgroups defined by ethnic background and demographic criteria- specifically women and members of minority groups. Background Although beta-adrenergic-receptor antagonists reduce morbidity and Mortality in participants with mild-to-moderate chronic heart failure, their effort on survival in participants with more advanced heart failure is unknown. Participants There were 2,708 participants. Conclusions Bucindolol resulted in no significant overall survival benefit. (Krause-Steinrauf et al., 2001, PMID: 11386264).

  Study phs003730

• Immune Determinants of Resistance to PD-1 Blockade in Renal Cell Carcinoma

  We performed an integrated bulk and single-cell transcriptomic analysis of tumors from 102 advanced renal cell carcinoma patients enrolled in a phase II clinical trial of frontline nivolumab (NCT03117309) to investigate determinants of response to anti-PD1 monotherapy. The present study includes 112 archival or pre-treatment tumors of clear cell and non-clear cell histologies from 90 patients that underwent bulk RNA sequencing (RNA-seq). For 76 patients, 74 of whom had matched RNA-seq, whole exome sequencing (WES) was also performed on tumor samples as well as matched peripheral blood. Additionally, 19 fresh tumor samples from 17 patients, including pre and post-treatment samples and mixed histologies, were locally cryopreserved and centrally processed for single cell RNA (scRNA-seq) and TCR (scTCR-seq) sequencing. 7 patients had matched scRNA/scTCRseq, RNAseq, and WES.

  Study phs003618

• Platinum Pedigree Consortium Long-Read Sequencing

  Platinum Pedigree Consortium includes whole genome sequencing of blood-derived DNA using five technologies on a 4-generation family. This is the CEPH-Utah (CEU) family 1463 and includes 4 grandparents from 1st generation, 2 parents from 2nd generation, 5 children from 3rd generation, 9 individuals from the 4th generation representing 2 branches of the 3rd generation, and their 2 additional parents. Family was not selected for disease, rather large size to study genetic transmission and human variation.Data available through dbGaP include raw sequence data: PacBio HiFi reads in unaligned BAM formats, Ultra-Long Oxford Nanopore (ONT) reads in FASTQ formats, Illumina sequencing, strand-seq and Element sequencing data in FASTQ format. Additionally, alignment files for HiFi reads mapped to the GRCh38 and CHM13v2.0 reference genomes, as well as de novo genome assemblies generated for this project are included.

  Study phs003793

• Longitudinal Study of Vaginal Flora

  This prospective observational study aims to advance our knowledge of the natural history and abnormal alteration in vaginal microbial flora, and to identify risk factors that are associated with these changes. A total of 5500 healthy, non-pregnant women of reproductive age will be enrolled and followed up in Birmingham, Alabama, for one year (baseline visit plus once every three months afterwards, totaling 5 visits). Detailed information on sociodemographic status, medical history, hygiene practice, sexual behavior and psychosocial stress will be collected through in-person interviews. Routine gynecological and dental examinations will be carried out during the study visits. Samples of vaginal secretion and blood will be collected. Laboratory tests to quantify vaginal microbial flora and to identify infection of bacterial vaginosis as well as common sexually transmitted diseases will be conducted. Future submissions may contain metadata or molecular data from additional subjects.

  Study phs002367

• Immediate Postoperative Minimal Residual Disease Detection with MAESTRO Predicts Recurrence and Survival in Head and Neck Cancer Patients Treated with Surgery

  We selected 24 patients with locally advanced head and neck squamous cell carcinoma (HNSCC) who were surgically treated. MAESTRO, our ultrasensitive, tumor-informed, mutation enrichment sequencing assay, was applied in a pooled format (MAESTRO-Pool) to plasma samples collected from these patients at baseline (pre-op) and postoperatively. We show that detection of circulating tumor DNA (ctDNA) 1 to 9 days after surgery is associated with significantly worse survival. Many plasma samples also had tumor fractions detected below 100 parts-per-million, the detection limit for first-generation commercial assays, highlighting the need for more sensitive ctDNA assays. Here we provide whole genome sequencing of matched tumor biopsy and normal germline DNA from 24 patients that were used to identify somatic single nucleotide variants (SNVs) to be tracked using our MAESTRO-Pool assay.

  Study phs003981

• SUDC Registry and Research Collaborative

  The Sudden Unexplained Death in Childhood Registry and Research Collaborative (SUDCRRC), created at NYU Langone Health in 2014, connects academic investigators, forensic pathologists, and medical examiner and coroner partner offices to study sudden unexpected pediatric deaths, aged 1 month to 18 years, whose death is unexplained or unclear at the end of the public mandated investigation, including autopsy. Each case includes collection and analysis of all records (medical history from prenatal records throughout life, death scene investigation, autopsy/toxicology/ancillary death investigation reports including photographs and histology slides), biospecimens, and in-depth family interviews. Whole exome sequencing is performed on each deceased child and both biological parents. Additional studies are pursued when indicated by pathology review. Each case receives a multidisciplinary masked review process and parental written consent is obtained. The NYU institutional review board approved this study.

  Study phs003383

• Disease-Linked Regulatory DNA Variants and Homeostatic Transcription Factors in Epidermis

  The role of non-coding variants in polygenic skin disease and their connection to homeostatic transcription factors (TFs) in epidermis was investigated. Homeostatic TFs were identified by perturb-seq in differentiating keratinocytes, using either 10x or split-pool approaches to sequencing, with follow-up validation by siRNA and RNA-seq. TF binding events were profiled by population sampling Cleavage Under Targets & Release Using Nuclease (CUT&RUN), in which a random population of neonatal foreskin keratinocytes were assayed by CUT&RUN for homeostatic TFs under progenitor growth and differentiation conditions. Heterozygous alleles were identified from the TF binding data and examined for allele specific binding events (ASBs). ASBs were then compared with non-coding variants linked to skin disease. Variants with potentially pathogenic effects were identified. Promoters and high TF occupancy genomic regions were found to be "buffered" against variants causing ASBs.

  Study phs003977

• Childhood Cancer Data Initiative (CCDI): Molecular Characterization Initiative

  The National Cancer Institute's (NCI) Childhood Cancer Data Initiative (CCDI) focuses on the critical need to collect, analyze, and share data to address the burden of cancer in children, adolescents, and young adults (AYAs). The Molecular Characterization Initiative (MCI) will further the CCDI's goals by providing access to better diagnostic tests for pediatric and AYA patients. The molecular characterizations of solid tumors, soft tissue sarcomas, and rare diseases are performed in a CLIA-certified setting as results may be used to screen for and/or confirm clinical trial eligibility, direct treatment, or otherwise contribute to the conduct of the trial. The following molecular characterization assays were performed:Tumor/Normal Whole Exome sequencing Methylation arraysArcher fusion panel Deidentified clinical reportsNote: New data will be added periodically, please check the CCDI Hub Explore site for updates.

  Study phs002790

• LifeChange Data Access Committee

  The LifeChange study aimed at tracking the biological consequences of the societal changes undergone by the Yakut people of Far Eastern Siberia, after the colonization of the region by Russians in the 17th century. This study builds upon more than 15 years of archaeological research conducted in Yakutia, Sakha Republic, an autonomous region of the Russian Federation located in northeastern Siberia. The fieldwork was conducted under the MAFSO program (“Mission Archéologique Française en Sibérie Orientale”, or “French Archaeological Mission in Eastern Siberia”), a collaboration between French researchers and local Yakut experts, including scholars from North-Eastern Federal University in Yakutsk. The program was supported by several inter-university collaborative research agreements, notably between Université Paul Sabatier, Krasnoyarsk State Medical University, and North-Eastern Federal University in Yakutsk. It also received endorsement from the Institute of Ecology and Evolution at CNRS through the International Associated Laboratory “Co-evolution Human-Environment in Eastern Siberia”. The LifeChange Data Access Committee, composed of French and Russian archaeogeneticists, geneticists and archaeologists, reviews any access request to LifeChange data, consisting of genomes of ancient and modern Yakut, Eveni and Evenki individuals sampled in Eastern Siberia for the LifeChange study. The DAC grants access to any academic researcher aiming to study the population history of autochthonous peoples from Siberia. When reviewing data access requests, the DAC members ensure that the applicant will not re-use the data to trace present-day descendants of studied ancient individuals. They also ensure that secondary use of the modern genomic data is conducted in full respect of the conditions stipulated in living participants’ informed consent. Specifically, the applicant is not authorised to (i) use the data for diagnostic purposes, (ii) store the data outside of secure servers, (iii) reidentify research participants, and (iv) share the data with a third party.

  Dac EGAC50000000713

• Dynamic Evolution of Fibroblasts Revealed by Single Cell RNA Sequencing of Human Pancreatic Cancer

  Understanding the constituents of the pancreatic ductal adenocarcinoma (PDAC) microenvironment may illuminate more efficacious targets for treating this aggressive malignancy. However, the compositional changes occurring in untreated and treated PDAC relative to both normal and inflamed pancreas have not been well characterized. To provide a more comprehensive understanding of the PDAC tumor microenvironment relative to the non-cancerous pancreas, we performed single-cell expression profiling (10X Genomics Chromium) on samples of upfront resectable PDAC, FOLFIRINOX-based treated PDAC, chronic pancreatitis, and normal pancreas specimens from 19 patients. Spatial gene expression profiling (10X Genomics Visium) was performed to gain additional insight into cell populations. Our analysis revealed that fibroblasts are central mediators of cell-cell communication in both inflamed and malignant settings and defined unique roles for these cell populations in different disease contexts.

  Study phs003751

• Controlling cell differentiation with precision through understanding the structure and dynamics of gene regulatory networks

  We established a set of transgenic human ES cell lines that carry inducible expression gene cassette for singe transcriptional factor induction with Tet-ON system. Transcriptome data was obtained 48h after transgene induction by Microarray. We established inducible human ES lines about more than 700 genes, and achieved microarray analysis on 115 genes. Our data set has multiple characteristic properties; 1) the same platform across data set, 2) analyzed with dynamic cell status, 3) pre-determined initiation point on gene perturbation, 4)inducible in different cell status. In parallele, we also performed RNA sequenncig analysis on 435 transgene induced ES lines as well. 32 transgene induced transcriptome data were obtained from both Microarray and RNA sequencing, normalizing technical gaps between them. We hope those systematic data set to reveal transcriptional network structure and molecular mechanisms of cell differentiation.

  Study JGAS000121

• Genomics characterization of primary central nervous system lymphoma

  Primary central nervous system lymphoma (PCNSL) is a rare malignancy confined to the central nervous system (CNS). Despite low tendency of systemic dissemination, its prognosis is poor with median overall survival of 2?4 years. Due to its rarity, knowledge of genomic alterations underling PCNSL pathogenesis is severely limited. Here we performed whole-exome sequencing on 44 PCNSL and paired normal specimens, revealing high penetrance of nonsynonymous somatic mutations in PIM1 (95.5%), BTG2 (88.6%) and MYD88 (81.8%). Interestingly we found oncogenic mutations in GRB2, and this effect was cancelled when transformed cells are treated with inhibitors to downstream kinases MAP2K1/2. Further, when tumor cells carries MYD88 mutations, the same mutations were also found at low frequency in peripheral blood mononuclear cells (PBMNC), implying that MYD88 mutation?positive precancerous cells originate outside CNS and develop to lymphoma with additional genetic hits that fit the CNS environment.

  Study JGAS000021

• Establishment of xenogfafts and cultured cell lines from clinical samples

  The purpose of the present study was to clarify the presence or absence of alterations in the molecular properties of patient-derived xenografts (PDXs) with up to eight passages in endometrial carcinomas. Alterations in the proportion of immunohistochemically positive/negative cells for PAX8, estrogen receptor, PAX2, and PTEN were observed in established PDXs of endometrioid carcinomas and carcinosarcomas, whereas proportions of cells with AE1/AE3, TP53, ARID1A PMS2, and MSH6 were maintained. Variants of cancer-associated genes in PDX compared to those in the parental tumors were examined in two cases, a frameshift deletion in BRCA1 was observed in the parental tumor tissue, and additional genomic alterations were found in the PDXs of this case. Genomic and phenotypic alterations in endometrial carcinoma PDXs relative to the parental tumors were observed and were partly associated with endometrial cancer-specific characteristics in cellular differentiation and gene mutations.

  Study JGAS000585

• Single-cell bisulfite-seq analyses of 1-year-old prospermatogonia and adult spermatogonial stem cell

  To examine the timing of de novo methylation during human male germ cell development, single-cell bisulfite sequencing was carried out on human germ cells. FACS-purified Prospermatogonia from three teratoma patients (1-year-0-month, 1-year-5-months, and 1-year-8-months) and spermatogonial stem cells from a 29-year-old obstructive azoospermia patient with normal spermatogenesis were analyzed. The three 1-year-old prospermatogonia exhibited average methylation levels of 41.4% (23.1-54.4%, 1-year-0-month), 53.1% (32.0-62.4%, 1-year-5-months), and 32.6% (10.2-54.7%, 1-year-8-months). In contrast, adult spermatogonia showed an average level of 75.7% (73.3-76.8%). Although teratoma may have influenced the developmental timing of prospermatogonia within the same testes, prospermatogonia across all 1-year-old samples remained in an intermediate phase of DNA methylation establishment.

  Study JGAS000887

• Single-cell bisulfite-seq analyses of 29-year-old prospermatogonia and adult spermatogonial stem cell

  To examine the timing of de novo methylation during human male germ cell development, single-cell bisulfite sequencing was carried out on human germ cells. FACS-purified Prospermatogonia from three teratoma patients (1-year-0-month, 1-year-5-months, and 1-year-8-months) and spermatogonial stem cells from a 29-year-old obstructive azoospermia patient with normal spermatogenesis were analyzed. The three 1-year-old prospermatogonia exhibited average methylation levels of 41.4% (23.1-54.4%, 1-year-0-month), 53.1% (32.0-62.4%, 1-year-5-months), and 32.6% (10.2-54.7%, 1-year-8-months). In contrast, adult spermatogonia showed an average level of 75.7% (73.3-76.8%). Although teratoma may have influenced the developmental timing of prospermatogonia within the same testes, prospermatogonia across all 1-year-old samples remained in an intermediate phase of DNA methylation establishment.

  Study JGAS000888

• Genetic landscape of pediatric Retinoblastoma

  Retinoblastoma is a pediatric cancer of the developing retina. All retinoblastomas are believed to initiate with biallelic inactivation of the RB1 gene. To identify subsequent genetic lesions in retinoblastoma, we performed whole genome sequencing of tumor and normal DNA of 4 children with retinoblastoma and one matched orthotopic xenograft. Both alleles of RB1 were inactivated in the tumor samples. 3 of the patients had sporadic retinoblastoma and one patient had inherited retinoblastoma. Overall, there were few single nucleotide changes in coding regions of the genome and some of the tumors had few chromosomal lesions. There were very few new genetic lesions in the xenograft compared to the primary tumor. These data suggest that the genome in retinoblastoma is more stable than previously believed and there are relatively few recurrent genetic lesions in known cancer pathways other than the RB1 pathway.

  Study EGAS00001000346

• Human papillomavirus integration induces oncogenic host gene fusions in oropharyngeal cancers

  HPV integration disrupts host genomic structure and expression, but whether these alterations promote cancer development remains unclear. Multiple genomic analyses of oropharyngeal cancers identified several host gene fusions, including recurrent FGFR3-TACC3 fusions, expressed from rearranged genomic loci adjacent to HPV integration sites. Evolutionary modeling implicated integration of virus concatemers into the host genome as a common initiating event in fusion formation. Co-expression of HPV16 E6/E7 and FGFR3-TACC3, but neither alone, was sufficient for tumor development in both xenograft and syngeneic mouse models and led to unique transcriptional programs implicated in carcinogenesis. FGFR3-TACC3 expression decreased the ubiquitination and degradation of E6 and E7, thereby increasing oncoprotein abundance. We conclude that expression of HPV16 oncoproteins and host gene fusions generated from HPV integration sites can be sufficient for cancer development.

  Study EGAS50000000892

• Long-read sequencing of saliva collected and stablized at room temperature in Oragene devices on the PacBio Revio

  Saliva collected in Oragene™ devices and extracted with Nanobind kits yields high‑molecular‑weight DNA suitable for PacBio HiFi whole‑genome sequencing, offering a convenient alternative to blood collection (“High-quality HMW DNA was obtained from all samples…”). Sequencing of paired saliva and blood samples on the Revio system produced comparable HiFi read lengths, yields, and 30–39× genome coverage. Methylation profiles were also highly similar, with minor differences attributable to small amounts of non‑human DNA present in saliva (“DNA extracted from saliva is typically ~75–95% human…”). Variant calling using PacBio WGS pipelines showed high concordance between saliva and blood from the same donor for both SNVs and structural variants. These results demonstrate that saliva enables reliable, high‑throughput HiFi sequencing workflows with performance equivalent to blood.

  Study EGAS50000001666

• TenK10K Phase 1:  Single Cell

  Understanding the genetic basis of gene expression can shed light on the regulatory mechanisms underlying complex traits and diseases. Single-cell resolved measures of RNA levels and single-cell expression quantitative trait loci (sc-eQTLs) have revealed genetic regulation that drives sub-tissue cell states and types across diverse human tissues. Here, we describe the first phase of TenK10K, the largest- to-date dataset of matched whole-genome sequencing (WGS) and single-cell RNA-sequencing (scRNA-seq). We leverage scRNA-seq data from over 5 million cells across 28 immune cell types and matched WGS from 1,925 individuals. This provides power to detect associations between rare and low-frequency genetic variants that have largely been uncharacterised in their impact on cell-specific gene expression. We map the effects of both common and rare variants in a cell type specific manner using SAIGE-QTL.

  Study EGAS50000001653

• Raw human sequencing data for “Characterization of intestinal immune responses in generalized human and murine lipodystrophy”

  This dataset contains raw FASTQ files generated from peripheral blood and intestinal biopsy samples collected for the study “Characterization of intestinal immune responses in generalized human and murine lipodystrophy.” Peripheral blood sequencing was performed on samples from three healthy donors as controls and from a patient with acquired generalized lipodystrophy and Crohn’s disease (AGLCD) at two distinct timepoints. Intestinal biopsy–derived immune cells were sequenced from three individuals with Crohn’s disease as disease controls, as well as from the AGLCD patient (single timepoint). The data include paired-end FASTQ files derived from single-cell RNA sequencing and T-cell receptor repertoire profiling, enabling analyses of immune composition, transcriptional states, and clonal T-cell expansion. All data are controlled-access human genomic datasets and require appropriate authorization for secondary use.

  Study EGAS50000001517

• DEPArray-based sorting of pure carcinoma and stromal populations from formalin-fixed paraffin-embedded (FFPE) tissues followed by shallow whole genome sequencing

  To overcome the challenges of low DNA yields, degraded DNA by formalin fixation and diluted signal of genomic aberrations by non-carcinoma components in the heterogeneous FFPE samples, we isolated pure carcinoma and stromal cells using the DEPArray™ NxT system, a microchip-based digital sorter that allows isolation of pure, homogeneous subpopulations of cells from FFPE samples. We isolated pure carcinoma and stromal cell populations from 12 FFPE tissues, including tissues from 9 primary and metastatic breast cancer and 3 primary ovarian high-grade serous carcinomas. This was followed by downstream shallow whole genome sequencing (WGS) for copy number landscape profiling for 10 samples. Seven out of 10 samples (even some with low tumour content or of old age) produced good quality genomic data, detecting sCNA in all carcinoma population samples but not in the stromal populations.

  Study EGAS50000001328

• Molecular Sub-grouping of CNS-PNET

  In our study we aimed to define CNS-PNET subgroups. We performed Expression, Genotyping and/or Immunohistochemistry on 142 samples from 20 worldwide centers. Using these techniques, we have identified three molecular subgroups with distinct expression and copy number patterns, as well as, unique clinical characteristics. Specifically, these molecular subgroups were distinguished by primitive neural (group 1), oligoneural (group 2), and mesenchymal lineage (group 3) gene-expression signatures with differential expression of cell-lineage markers LIN28 and OLIG2. Our report underscores the importance of concerted, collaborative efforts to study large retrospective cohorts of tumours and patients to accelerate biological and ultimately therapeutic studies of rare tumours. The outcome of such a collaboration allowed us to identify LIN28 and OLIG2 as promising diagnostic and prognostic molecular markers for CNS PNET that warrant further assessment in prospective clinical trials.

  Study EGAS00000000116

• SCANDARE MACARON

  Among gynecological cancers, high-grade serous ovarian cancer has the highest prevalence and more than 75% of patients have advanced stage at diagnosis with a 5-year survival of 40%. When the initial complete surgical removal is not possible (60% of patients), an interval surgery can be considered after three to four cycles of neoadjuvant chemotherapy to reduce the tumor mass. However, in approximately 50% of cases the tumor has little or no response to neoadjuvant chemotherapy. Therefore, identification of potential drug targets, biomarkers and/or pathways whose modulation can help in the prevention, interception, or curing of the disease is essential to address the unmet need. Therefore, MACARON project aims to address these issues through the identification of shared neoantigens arising out of somatic alterations and aberrant transcriptional programs in ovarian cancer DNA/RNA datasets.

  Study EGAS50000000145

• Co-culture experiment (hashed samples)

  The principles governing tissue architecture and the mechanisms underlying its disruption in disease remain poorly understood. Here, we utilized single-cell and spatial mapping to interrogate the mechanisms directing immune cell organization in human lymph nodes and its disruption in architecturally distinct lymphoma entities: indolent follicular lymphoma (FL) and aggressive diffuse large B cell lymphoma (DLBCL). Our data substantiate the central role of lymph node stromal cells in chemokine-driven lymphocyte zonation and reveal an inflammatory feedback loop fueled by tumor-reactive T cells, triggering stromal remodeling, progressive loss of homeostatic chemokine gradients and tissue organization from non-malignant to FL and DLBCL. Loss of homeostatic chemokines was associated with adverse patient survival, identifying the underlying architectural rearrangement as a key event during lymphomagenesis. Collectively, our results highlight the principles of lymph node organization and suggest how lymphoma-induced microenvironmental reprogramming drives loss of tissue organization.

  Study EGAS50000001252

• Evolutionary Trajectories of Small Cell Lung Cancer under Therapy

  Small cell lung cancer (SCLC) is one of the deadliest human cancers with a five-years survival rate of less than 7%. The standard of care for extensive-stage SCLC consists of systemic treatment with platinum and etoposide, recently combined with PD-L1 immune checkpoint inhibitors (ICI). SCLC patients show high sensitivity to platinum-based chemotherapy, followed by rapid recurrence, which distinguishes SCLC from most human cancers. Unfortunately, second-line treatment with other chemotherapeutics or immunotherapy is only marginally effective, and patients ultimately succumb to their disease. We performed whole exome sequencing, whole genome sequencing and transcriptome sequencing of multiple tumor regions from 65 patients with SCLC. We determined tumor phylogenies at diagnosis and throughout chemotherapy and immunotherapy by multi-region sequencing of 160 tumors from 65 patients, to thus decipher the evolutionary processes underlying the remarkable sensitivity of small cell lung cancer (SCLC) to chemotherapy.

  Study EGAS50000000169

• Multimodal epigenetic sequencing analysis of cell-free DNA identifies biomarkers for ALS diagnosis and progression

  The role of the circulating epigenome in ALS remains understudied. We aim to develop diagnostic and prognostic blood-based biomarkers for Amyotrophic Lateral Sclerosis (ALS) by profiling methylome signatures in circulating cell-free DNA (cfDNA) in 20 sporadic ALS cases, 10 C9orf72-associated ALS cases, 10 asymptomatic C9orf72 expansion carriers, and 21 healthy controls using targeted enzymatic methyl-sequencing (EM-seq) of ~4 million CpG loci. We detected numerous differentially methylated genes, including several implicated in ALS risk and pathobiology, and integrated multiple epigenetic features with our Multimodal Epigenetic Sequencing Analysis (MESA) algorithm, achieving an ROC AUC of 0.91 and detecting ~70% of ALS cases at ~100% specificity. Methylation at a subset of loci also correlated with clinical progression and cerebrospinal-fluid neurofilament levels, supporting the potential of cfDNA-based biomarkers for ALS diagnosis and monitoring.

  Study EGAS50000001267

• Single-cell RNA sequencing of 16 NPM1 mutated AML patients

  NPM1 mutated AML is the largest class in WHO classification, however several subtypes within NPM1 were already reported. Here, we sequence 16 NPM1 mutated AML samples with single-cell RNA-sequencing and multi-color flow cytometry from three major NPM1 subtypes we previously identified, totaling more than half a million cells. We show that the differences among three NPM1 subtypes are mainly driven by cell composition, and these differences are also reflected at cell surface protein level. With the re-analysis of CITE-seq data from another cohort and single cell variant calling on our data, we also report two distinct stem cell phenotypes: one with leukemic (CD34dimCD38-CD45RA+) and another with pre-leukemic (CD34+CD38-CD45RA-) origin. We believe that our data and findings provide novel insights regarding the etiology of NPM1 mutated AML.

  Study EGAS50000000332

• Identification and characterization of tertiary lymphoid structures in brain metastases

  Brain metastases (BrM) are the most common cancers in the brain. We performed transcriptome-wide gene expression profiling combined with spatial immune cell profiling to characterize the tumor immune microenvironment in BrM from different primary tumors. We found that BrM from lung carcinoma and malignant melanoma showed overall higher immune cell infiltration as compared to BrM from breast carcinoma. RNA sequencing-based immune cell deconvolution revealed gene expression signatures indicative of tertiary lymphoid structures (TLS) in subsets of BrM from lung cancer and melanoma. This finding was corroborated by multiplex immunofluorescence staining of immune cells in BrM tissue sections. Detection of TLS signatures was associated with prolonged survival after BrM diagnosis in lung cancer patients. Our findings highlight the cellular diversity of the tumor immune microenvironment in BrM of different cancer types and suggest a role of TLS formation for BrM patient outcome.

  Study EGAS50000000563

• Whole genome sequencing data from tumor and normal samples

  Whole genome sequencing FASTQ files from tumor and normal samples from 202 patients. All experiments reported in this article were performed in the Clinical Laboratory Improvement Amendments (CLIA)-certified and College of American Pathologists (CAP)-accredited laboratories at Personalis Inc., as guided by the Association for Molecular Pathology (AMP) and CAP’s joint recommendations52. Preferred input material consisting of FFPE slides (enabling H&E and macrodissection which is part of the standard NeXT Personal process) was not available for the majority (94%) of tumor samples. Most tumor samples (72%) were processed from FFPE curls, with the remaining processed from pre-extracted DNA and fresh frozen material. Where FFPE material on slide was available, tumor sections were macrodissected to increase tumor content, with a minimum allowable cellularity threshold of 20% determined by pathological review. The tumor cellularity threshold of 20% was chosen based on prior work demonstrating that no significant correlation is observed between tumor purity and assay limit of detection (LOD) at this threshold31. Genomic DNA was isolated from tumor and normal samples and WGS libraries prepared as previously described31. Genomic DNA was isolated from matched tumor and normal samples using the Qiagen AllPrep DNA/RNA FFPE Tissue Kit or the QIAamp DNA Mini Kit (QIAGEN, Germantown, MD, USA) using internally optimized workflows. WGS sequencing libraries were prepared with 120-500 ng of acoustically sheared genomic DNA (Covaris LLC, Woburn, MA, USA) using the KAPA HyperPrep Kit (Roche Sequencing Solutions, Pleasanton, CA, USA) and customized methods. Libraries were cleaned-up using AMPure XP beads and then quantified using the KAPA Library Quantification Kit (Roche Sequencing Solutions, Pleasanton, CA, USA), before being sequenced to 30X depth of coverage using a NovaSeq 6000 instrument (Illumina, San Diego, CA, USA).

  Dataset EGAD50000001909

• RAG mediated recombination is the predominant driver of oncogenic rearrangement in ETV6-RUNX1 Acute Lymphoblastic Leukemia (Whole_Genome_sequencing_data)

  The ETV6-RUNX1 fusion gene, found in 25% of childhood acute lymphoblastic leukemia (ALL), is acquired in utero but requires additional somatic mutations for overt leukemia. We used exome and low-coverage whole-genome sequencing to characterize the critical secondary events associated with leukemic transformation. RAG-mediated deletions emerge as the dominant mutational process, accounting for at least 43% of genomic rearrangements and characterized by the presence of recombination signal sequence motifs near the breakpoints; incorporation of non-templated sequence at the junction and a ten-fold enrichment at promoters and enhancers of genes actively transcribed in early B-lineage development. Single-cell tracking shows that this mechanism is not restricted to one founder cell but is rather active throughout leukemic evolution. Integration of point mutation and rearrangement data identifies recurrent inactivation of ATF7IP and MGA as two new tumor suppressor genes.Thus, a remarkably parsimonious mutational process transforms ETV6-RUNX1 lymphoblasts, striking promoters and enhancers of the genes that normally control B-cell differentiation.

  Dataset EGAD00001000634

• RAG mediated recombination is the predominant driver of oncogenic rearrangement in ETV6-RUNX1 Acute Lymphoblastic Leukemia (Rearrangement_sequencing_data)

  The ETV6-RUNX1 fusion gene, found in 25% of childhood acute lymphoblastic leukemia (ALL), is acquired in utero but requires additional somatic mutations for overt leukemia. We used exome and low-coverage whole-genome sequencing to characterize the critical secondary events associated with leukemic transformation. RAG-mediated deletions emerge as the dominant mutational process, accounting for at least 43% of genomic rearrangements and characterized by the presence of recombination signal sequence motifs near the breakpoints; incorporation of non-templated sequence at the junction and a ten-fold enrichment at promoters and enhancers of genes actively transcribed in early B-lineage development. Single-cell tracking shows that this mechanism is not restricted to one founder cell but is rather active throughout leukemic evolution. Integration of point mutation and rearrangement data identifies recurrent inactivation of ATF7IP and MGA as two new tumor suppressor genes.Thus, a remarkably parsimonious mutational process transforms ETV6-RUNX1 lymphoblasts, striking promoters and enhancers of the genes that normally control B-cell differentiation.

  Dataset EGAD00001000635

• RAG mediated recombination is the predominant driver of oncogenic rearrangement in ETV6-RUNX1 Acute Lymphoblastic Leukemia (Whole_exome_sequencing_data)

  The ETV6-RUNX1 fusion gene, found in 25% of childhood acute lymphoblastic leukemia (ALL), is acquired in utero but requires additional somatic mutations for overt leukemia. We used exome and low-coverage whole-genome sequencing to characterize the critical secondary events associated with leukemic transformation. RAG-mediated deletions emerge as the dominant mutational process, accounting for at least 43% of genomic rearrangements and characterized by the presence of recombination signal sequence motifs near the breakpoints; incorporation of non-templated sequence at the junction and a ten-fold enrichment at promoters and enhancers of genes actively transcribed in early B-lineage development. Single-cell tracking shows that this mechanism is not restricted to one founder cell but is rather active throughout leukemic evolution. Integration of point mutation and rearrangement data identifies recurrent inactivation of ATF7IP and MGA as two new tumor suppressor genes.Thus, a remarkably parsimonious mutational process transforms ETV6-RUNX1 lymphoblasts, striking promoters and enhancers of the genes that normally control B-cell differentiation.

  Dataset EGAD00001000636

• Genome and transcriptome sequence data from a metastatic pancreatic cancer patient

  Genome and transcriptome sequence data from a metastatic pancreatic cancer patient, generated as part of the BC Cancer Agency's Personalized OncoGenomics (POG) study

  Dataset EGAD00001004683

• Genome and transcriptome sequence data from a metastatic adenocarcinoma of the GE junction patient

  Genome and transcriptome sequence data from a metastatic adenocarcinoma of the GE junction patient, generated as part of the BC Cancer Agency's Personalized OncoGenomics (POG) study

  Dataset EGAD00001004684