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• DAC for Korean BC data

  Dac EGAC00001000740

• DAC for A Karadimitris Lab

  Dac EGAC00001001003

• Data Access Commitee for EGAS00001003258

  Dac EGAC00001001038

• Data access comittee for Institut Curie

  Dac EGAC00001001042

• DAC for the study EGAS00001003572

  Dac EGAC00001001174

• DAC for hepatitis B analysis

  Dac EGAC00001001228

• DAC for Wigler Group

  Dac EGAC00001001256

• DAC for panc_met data set

  Dac EGAC00001001480

• Center for Medical Genetics Ghent

  Dac EGAC00001001507

• DAC for mUC sequencing data

  Dac EGAC00001001710

• Data Access Commitee for ECA

  Dac EGAC00001001856

• DAC for Hypermutated Gliosarcoma project

  Dac EGAC00001001867

• Data Access Committee for EGAS00001005426

  Dac EGAC00001002194

• Data Access Committee for cfMeDIP

  Dac EGAC00001002250

• Center for Medical Genetics Ghent

  Dac EGAC00001002384

• DAC for intraphepatic cholangiocarcinoma

  Dac EGAC00001002521

• DAC for cfMethyl-Seq data

  Dac EGAC00001002534

• Data access committee for FL

  Dac EGAC00001002552

• Center for Medical Genetics Ghent

  Dac EGAC00001002909

• Center for Medical Genetics Ghent

  Dac EGAC00001003264

• Data Access Committee for EGAS00001007298

  Dac EGAC00001003422

• Data Access Committee for EGAS00001007299

  Dac EGAC00001003268

• DAC for noninvasive lung cancer subtyping

  Dac EGAC00001003474

• DAC for Molecular Oncology lab

  Dac EGAC50000000268

• DAC for EGAS00001007531

  Dac EGAC00001003437

• UCL Centre for Longitudinal Studies

  Dac EGAC00001003495

• DAC for MethylScan assay

  Dac EGAC00001003580

• EGAD00010000694

  HCC array for cnv

  Dataset EGAD00010000694

• Pathways Study

  The Pathways Study (NCI R01 CA105274, PI: Kushi), is a prospective cohort study of a diverse population of recently diagnosed breast cancer survivors in KPNC. The aims are to examine the effect on recurrence and survival of 1) lifestyle factors such as diet, physical activity, and use of complementary and alternative therapies and 2) molecular factors such as biomarkers of inflammation and tumor DNA methylation profiles. Recruitment into the cohort was from January 2006 to May 2013. Baseline data collection was by in-person interview (on average two months post-diagnosis), with follow-up via mailed or phone questionnaires at 6, 24, and 72 months and outcomes and comorbidities at 12, 24, 48, 72, and 96 months post-enrollment. The Pathways Study is now funded through May 2021 as a cancer cohort infrastructure grant (U01 CA195565, MPI: Kushi/Ambrosone). The Pathways baseline interview consists of interviewer- and self-administered questionnaires. Interviewer-administered questionnaires collected information including demographics, family health history, pregnancy health history, menstrual history, history of breast care screening procedures, smoking history, hormone use, medication history, and vitamin and mineral use. Self-administered questionnaires collected information on diet, physical activity, CAM use, lymphedema, and psychosocial and quality of life measures.

  Study phs001534

• NHLBI TOPMed: Recipient Epidemiology and Donor Evaluation Study-III Brazil Sickle Cell Disease Cohort (REDS-BSCDC)

  Establishing a Brazilian Sickle Cell Disease Cohort and Identifying Molecular Determinants of Response to Transfusions, Genetic Determinants of Alloimmunization, and Risk Factors Associated with HIV Infection. The REDS-III Brazil SCD Cohort study focused on transfusion practices and predictors of health outcomes in patients with Sickle Cell Disease (SCD) and began in the Fall of 2013. The four primary aims of this study are: 1) Aim A - Establish a cohort of SCD patients with a comprehensive centralized electronic database of detailed clinical, laboratory and transfusion information, as well as establish a repository of blood samples to support biological studies relevant to SCD pathogenesis and transfusion complications; 2) Aim B - Characterize changes in markers of inflammation in response to transfusion by analyzing chemokine/cytokine panels in serial post transfusion specimens; 3) Aim C - Identify single nucleotide polymorphisms (SNPs) that contribute to the risk of red blood cell alloimmunization in SCD by performing a genome-wide association (GWA) study in transfused SCD patients; and, 4) Aim D - Characterize risk of HIV and HIV outcomes in the Brazilian SCD population and compare SCD outcomes among HIV sero-positive and sero-negative SCD patients. Patients are enrolled from six hospitals affiliated with the participating four REDS-III Brazil hemocenters.

  Study phs001468

• Genetic analysis of Hirschsprung disease

  Hirschsprung disease (HSCR) is a birth defect resulting from the absence of nerve (ganglion) cells in the gastrointestinal tract. Hirschsprung disease has a population incidence of 1/5,000 live births and most often occurs as an isolated condition. However, approximately 30% of HSCR cases are associated with other birth defects such as Down syndrome, deafness, hypopigmentation, and Congenital Central Hypoventilation syndrome (CCHS). Hirschsprung disease is a genetic condition with autosomal dominant, autosomal recessive, and multigenic patterns of inheritance described. The goal of the research study is to identify genes harboring causative HSCR mutations and to better understand the complex inheritance of HSCR in families using whole genome mapping and sequencing studies with functional follow-up of candidate genes and variants. We intend to ascertain the frequency with which mutations in any human gene lead to familial and isolated forms of HSCR. Clinical information is collected to allow investigation of possible genotype - phenotype correlations. The subject population consists of individuals diagnosed with HSCR and their unaffected relatives. Individuals/families are ascertained through support groups, web-based listings of research studies and genetic testing services, an educational study website, and referrals from genetic counselors and physicians. Blood, or tissue, samples are requested from affected individuals and their unaffected relatives.

  Study phs000497

• Targeted MitoExome Sequencing of Mitochondrial OXPHOS Diseases (Massachusetts General Hospital)

  Human disorders of mitochondrial oxidative phosphorylation (OXPHOS) represent a devastating collection of inherited diseases. These disorders impact at least 1:5000 live births, and are characterized by multi-organ system involvement. They are characterized by remarkable locus heterogeneity, with mutations in the mtDNA as well as in over 77 nuclear genes identified to date. It is estimated that additional genes may be mutated in these disorders. To discover the genetic causes of mitochondrial OXPHOS diseases, we performed targeted, deep sequencing of the entire mitochondrial genome (mtDNA) and the coding exons of over 1000 nuclear genes encoding the mitochondrial proteome. We applied this 'MitoExome' sequencing to 124 unrelated patients with a wide range of OXPHOS disease presentations from the Massachusetts General Hospital Mitochondrial Disorders Clinic. The 2.3Mb targeted region was captured by hybrid selection and Illumina sequenced with paired 76bp reads. The total set of 1605 targeted nuclear genes included 1013 genes with strong evidence of mitochondrial localization from the MitoCarta database, 377 genes with weaker evidence of mitochondrial localization from the MitoP2 database and other sources, and 215 genes known to cause other inborn errors of metabolism. Approximately 88% of targeted bases were well-covered (>20X), with mean 200X coverage per targeted base.

  Study phs000339

• Clinical genome sequencing uncovers potentially targetable truncations and fusions of MAP3K8 in spitzoid and other melanomas

  Spitzoid melanoma is a specific morphologic variant of melanoma that most commonly affects children and adolescents and ranges on the spectrum of malignancy from low-grade to overtly malignant. These tumors are generally driven by fusions of ALK, RET, NTRK1/3, MET, ROS1 and BRAF. However, in approximately 50% of cases, no genetic driver has been established. Clinical whole genome and transcriptome sequencing (RNA-Seq) of a spitzoid tumor from an adolescent revealed a novel gene fusion of MAP3K8, encoding a serine−threonine kinase that activates MEK. The patient who had exhausted all other therapeutic options was treated with a MEK inhibitor and underwent a transient clinical response. We subsequently analyzed spitzoid tumors from 49 patients by RNA-Seq and found in-frame fusions or C-terminal truncations in 33% of cases. The fusion transcripts and truncated genes all contained MAP3K8 exons 1-8 but lacked the autoinhibitory final exon. Data mining of RNA-Seq from the Cancer Genome Atlas (TCGA) uncovered analogous MAP3K8 rearrangements in 1.5% of adult melanomas. Thus, MAP3K8 rearrangements - uncovered by comprehensive clinical sequencing of a single case - are the most common genetic event in spitzoid melanoma, are present in adult melanomas, and could be amenable to MEK inhibition.

  Study EGAS00001003430

• Stereotyped B-cell responses are linked to IgG constant region polymorphisms in multiple sclerosis

  Clonally related B cells infiltrate the brain, meninges, and cerebrospinal fluid of multiple sclerosis (MS) patients, but the mechanisms driving the B-cell response and shaping the immunoglobulin repertoires remain unclear. Here, we used single-cell full-length RNA-seq and B-cell receptor reconstruction to simultaneously assess the phenotypes, isotypes, constant region polymorphisms, and the paired heavy- and light-chain repertoires in intrathecal B cells. We detected extensive clonal connections between the memory B cell and antibody-secreting cell compartments and observed clonally related cells of different isotypes, including IgM/IgG1, IgG1/IgA1, IgG1/IgG2, and IgM/IgA1. There was a strong dominance of the G1m1 allotype constant region polymorphisms in antibody-secreting cells, but not in memory B cells. Tightly linked to the G1m1 allotype, we found a preferential pairing of the immunoglobulin heavy-chain variable (IGHV)4 gene family with the κ variable (IGKV)1 gene family. The IGHV4-39 gene was most used and showed the highest frequency of pairing with IGKV1-5 and IGKV1(D)-33. These results link IgG constant region polymorphisms to stereotyped B-cell responses in MS and indicate that the intrathecal B-cell response in these patients could be directed against structurally similar epitopes.

  Study EGAS00001005745

• Center for Common Disease Genomics (CCDG) - Cardiovascular: Emory 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 Emory University Cardiovascular Biobank. 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. 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.

  Study phs001880

• A Whole Genome Association Search for Type 2 Diabetes Genes in African Americans

  Over 2.8 million African Americans have type 2 diabetes mellitus (T2DM). This represents approximately 13% of the African American population and a significant proportion of the 21 million Americans living with diabetes. On average, an African American individual is twice as likely to have T2DM as a European American peer. Our research group has been actively involved in the study of African American diabetes genetics for over 15 years. We hypothesize that genes contributing to the development of T2DM in African Americans exist and can be located using modern molecular genetic methods. With the exception of TCF7L2(Transcription factor 7-like 2) evidence to date suggests variants that contribute T2DM risk in European-derived populations are not significant contributors to African American T2DM risk. We have performed a SNP-based Whole Genome Association (WGA) analysis on the Affymetrix 6.0 in a case control population of over 1000 African American T2DM cases and over 1000 non-diabetic controls. The DNAs have been collected from participants using uniform criteria from North Carolina and neighboring states. Genotype data will be subjected to extensive genetic analysis with the goal of defining a priority list of SNPs for genotyping in independent populations for confirmation and further detailed analysis.

  Study phs000140

• Genomic Wide Scans for Female Osteoporosis Genes

  Osteoporosis is a condition of excessive skeletal fragility which results in high risk to low trauma fractures. It is the most prevalent metabolic bone disease and is a major public health problem which may result in devastating morbidity and mortality. The most powerful, measurable determinant of fracture risk is bone mineral density (BMD). More than 60% of BMD variation is attributable to genetic factors. There are gender differences in BMD that contribute to a substantially higher fracture risk among women than men. Genetic studies demonstrate that some osteoporosis risk genes/genomic regions are gender specific. However, specific such genes contributing to female BMD and to the sex differences of BMD are largely unknown. Recent rapid progresses in SNP genotyping technology, in our knowledge about human genome diversity and linkage disequilibrium (LD) patterns in the human genome as revealed have made it feasible and timely to pursue a powerful whole genome-wide association study (GWAS) to identify genes for BMD. The major goal of this project is to perform a powerful GWAS study in a large sample of US Caucasian subjects. Gender specific effects of the genetic variants will be examined. The significant genetic variants discovered will be used to design diagnostic DNA chips for prognosis for potential health problems of osteoporosis later in life.

  Study phs000390

• Precision Medicine for Dilated Cardiomyopathy in European and African Ancestry

  The DCM Precision Medicine Study is a multi-site consortium-based cross-sectional study of families with an embedded open-label randomized controlled trial. The aims of the study are to test the hypothesis that dilated cardiomyopathy (DCM) has a substantial genetic basis and to evaluate the effectiveness of a family communication intervention in improving the uptake of preventive screening and surveillance in at-risk first-degree relatives. The Study goal was to recruit 1,300 individuals (600 non-Hispanic African ancestry, 600 non-Hispanic European ancestry, and 100 Hispanic; 50% female) meeting rigorous diagnostic criteria for idiopathic DCM (probands) and 2,600 of their relatives. The probands were inpatients or outpatients identified by heart failure and cardiac transplant cardiovascular physicians and clinical research personnel in heart failure/heart transplant programs at sites in the DCM Consortium. The DCM phenotype was selected for this study because of its prevalence and its prior inclusion in the development of virtually all pharmacotherapy for non-ischemic heart failure from reduced ejection fraction. Study procedures included obtaining family history, cardiac history, medical record review, surveys, and blood sample collection. Exome data from 1219 idiopathic DCM probands and 127 idiopathic DCM relatives are included in dbGaP.

  Study phs002641

• FASTQ files of total RNA-Seq data from the POPS SGA (Small for Gestational Age) samples

  All the samples were obtained from the Pregnancy Outcome Prediction–a prospective cohort study of nulliparous women attending the Rosie Hospital, Cambridge (UK) for their dating ultrasound scan between January 14, 2008, and July 31, 2012. Ethical approval for the study was given by the Cambridgeshire 2 Research Ethics Committee (reference number 07/H0308/163) and all participants provided written informed consent. Cases of preeclampsia (PET) were defined on the basis of the 2013 ACOG criteria and cases of small for gestational age (SGA)infants were confined to severe SGA, i.e. a customized birth weight <5th percentile. Chorionic villi from the corresponding placentas (free from decidua, visible infarction, calcification, hematoma, or damage) were collected and processed within 30 minutes of separation from the uterus. After repeated washes in chilled phosphate buffered saline, the samples were placed in RNA later (Applied Biosystems) and stored at -80°C. Total placental RNA was extracted using mirVana Isolation Kit (Ambion). For each placenta, approximately 5 mg of tissue were homogenized in the Lysis/Binding solution for 20 sec at 6 m/s using a bead beater (FastPrep24) and Lysing Matrix D Tubes (MP Biomedicals). The samples were then spun at 13,000 rpm for 5 min at 4°C and the supernatants recovered. Afterwards, the manufacturer's instructions were followed. Immediately after the RNA extraction, placental RNA samples were DNase-treated using DNA-free DNA Removal Kit (Ambion), aliquoted, and stored in -80°C. Quantity and quality of the RNA samples were assessed using the Agilent 2100 Bioanalyzer, the Agilent RNA 6000 Nano Kit (Agilent Technologies), and Qubit fluorometer. Libraries were prepared starting with 300-500 ng of good quality total RNA (RIN ≥7.5) using the TruSeq Stranded Total RNA Library Prep Kit with Ribo-Zero Human/Mouse/Rat (Illumina), according to the manufacturer's instructions. The kit contains 96 uniquely indexed adapter combinations in order to allow pooling of multiple samples prior to sequencing. After determining their size (with the Agilent 2100 Bioanalyzer and the Agilent High Sensitivity DNA Kit by Agilent Technologies) and concentration (by qPCR with the KAPA Illumina ABI Prism Library Quantification Kit, Kapa Biosystems), libraries have been pooled and sequenced (single-end, 125 bp) using a Single End V4 Cluster Kit and an Illumina HiSeq2500 or HiSeq4000 instrument.

  Dataset EGAD00001003507

• Longitudinal evaluation of serum microRNAs as biomarkers for neuroblastoma burden and therapeutic p53 reactivation

  Accurate assessment of treatment response and residual disease is indispensable for the evaluation of cancer treatment efficacy. However, performing tissue biopsies for longitudinal follow-up poses a major challenge in the management of solid tumours like neuroblastoma. In the present study, we evaluated whether circulating miRNAs are suitable to monitor neuroblastoma tumour burden and whether treatment-induced changes of miRNA abundance in the tumour are detectable in serum. We performed small RNA sequencing on longitudinally collected serum samples from mice carrying orthotopic neuroblastoma xenografts that were exposed to treatment with idasanutlin or temsirolimus. We identified 57 serum miRNAs to be differentially expressed upon xenograft tumour manifestation, out of which 21 were also found specifically expressed in the serum of human high-risk neuroblastoma patients. The murine serum levels of these 57 miRNAs correlated with tumour tissue expression and tumour volume, suggesting potential utility for monitoring tumour burden. In addition, we describe serum miRNAs that dynamically respond to p53 activation following treatment of engrafted mice with idasanutlin. We identified idasanutlin-induced serum miRNA expression changes upon one day and 11 days of treatment. By limiting to miRNAs with a tumour-related induction, we put forward hsa-miR-34a-5p as a potential pharmacodynamic biomarker of p53 activation in serum.

  Study EGAS00001006678

• Childhood Cancer Survivor Study (CCSS)

  Background and Rationale for the Childhood Cancer Survivor Study (CCSS) Over the last several decades, advances in treatments for childhood and adolescent cancer have substantially improved survival following diagnosis. These improvements gave rise to the responsibility for investigating long-term treatment-associated morbidity and mortality. Early efforts to describe late effects were largely conducted through single-institution and limited consortia studies. However, by the mid-1980s, it became increasingly clear that these approaches had inherent limitations, including small sample size, convenience sampling, incompletely characterized populations, and limited length of follow-up. To overcome these limitations, the CCSS was proposed and funded by the National Cancer Institute (NCI) as a U01 grant in 1994. Subsequently, the strengths of the CCSS, including an efficient and extensive infrastructure, plus expanding database and biorepository, were recognized and appreciated. Thus, in consultation with the NCI, the CCSS was converted to a U24 (resource grant) funding mechanism to serve the scientific community in 2000. The overarching goal of the CCSS resource is to increase the conduct of innovative and high impact research related to pediatric cancer survivorship. CCSS has been used extensively by researchers from a wide range of disciplines to address a broad spectrum of topics. Strengths of the resource include its large size, comprehensive annotation of treatment exposures, ongoing longitudinal follow-up with characterization of a wide array of participant characteristics and outcomes, and an established biorepository. Design of the Childhood Cancer Survivor Study The Childhood Cancer Survivor Study (CCSS) is a multi-institutional, multi-disciplinary collaborative research resource comprised of a retrospective hospital-based cohort of survivors of childhood cancer and a comparison sibling cohort. Eligible survivors from 31 participating institutions were diagnosed between 1970 and 1999, prior to age 21 years, with selected common pediatric cancers (leukemia, central nervous system tumors, Hodgkin lymphoma, non-Hodgkin lymphoma, kidney tumors, neuroblastoma, soft tissue sarcoma, or bone tumors). All patients who survived five years from the date of diagnosis were eligible, regardless of disease or treatment status. The baseline questionnaire was completed by 24,368 survivors and 5,039 siblings recruited to serve as a comparison group. To date, participants have completed three general follow-up surveys, as well as a number of specialized surveys on specific topics (e.g. health care, insurance, screening practices, men's and women's health issues, adolescent health, sleep and fatigue). In addition, biological samples (buccal cells, saliva and/or blood) have been collected for over 11,000 participants. Full descriptions of the design and characteristics of the CCSS have been previously published (Robison et al; Leisenring et al.), and available data and samples are described at https://ccss.stjude.org/develop-a-study/gwas-data-resource.html. Treatment Data in the Childhood Cancer Survivor Study A key feature of CCSS is the availability of detailed treatment data, which were collected by abstraction of medical records for each individual member of the cohort. Detailed abstraction included dates of therapy, protocol information, and specific details regarding surgery, chemotherapy and radiation. Quantitative dose details were collected for 22 specific chemotherapeutic agents, including alkylating agents, anthracyclines, platinum compounds and epipodophyllotoxins. In addition to individual agent doses, algorithms have been created to calculate cumulative doses of all drugs in a specific class, such as anthracyclines (doxorubicin, daunomycin and idarubicin) or platinum agents (cisplatinum and carboplatinum). Data abstracted for surgeries included dates and both the names and corresponding International Classification of Diseases (9th revision) code. For radiation treatment data, all relevant records were sent to the Radiation Physics Center at M.D. Anderson Cancer Center for detailed abstraction and dosimetry. Initial body region dosimetry was performed for all participants, followed by more detailed dosimetry as needed for specific studies. Genomics Data in the Childhood Cancer Survivor StudyThe NCI's Division of Cancer Epidemiology and Genetics and CCSS investigators collaborated to conduct genomics studies (SNP array genotyping and whole exome sequencing) using samples from the CCSS Biorepository. Studies included all cohort participants with available DNA regardless of sex or ancestry when the genomics studies were initiated. Phenotype Data in the Childhood Cancer Survivor Study Vital status and cause of death for both participants and non-participants is determined via linkage with the National Death Index (NDI). Identification of subsequent neoplasms is based on self-report, followed by validation using medical records, or via NDI. A wide array of additional health outcomes have been ascertained via a comprehensive set of questions on the CCSS questionnaires, covering potential adverse events across a range of organ systems (hearing/vision/speech, urinary, hormonal, heart and circulatory, respiratory, digestive, brain and nervous systems). In addition to health outcomes, longitudinal data have been collected on demographics, health behaviors, family history, screening practices, insurance status, and a range of psychosocial and neurocognitive factors. A full listing of available variables and copies of the CCSS questionnaires are available at http://ccss.stjude.org. Research Areas in the Childhood Cancer Survivor Study Extensive use by the research community has resulted in over 265 published manuscripts on a wide range of topics, including associations between treatment factors and mortality, subsequent neoplasms, chronic health conditions, cardiac events, neurocognitive sequelae, psychosocial factors, fertility, and health status. Additional topics have included health behaviors, screening practices, health care access and utilization, statistical and exposure assessment methodology, and development of risk prediction models. A full listing of published manuscripts using CCSS data is available on the CCSS website at https://ccss.stjude.org/published-research/publications.html. The Childhood Cancer Survivor Study as a Resource for Investigators The CCSS is an NCI-funded resource (U24 CA55727) to promote and facilitate research among long-term survivors of cancer diagnosed during childhood and adolescence. Interested investigators are encouraged to develop research ideas and propose projects within CCSS, whether or not they are from a participating CCSS institution. The CCSS is now accepting proposals to collaborate with CCSS and NCI investigators in the use of genomics data and corresponding outcomes-related data to address innovative research questions relating to potential genetic contributions to risk for treatment-related outcomes. Any researcher, or group of researchers, qualified to conduct genetic research can submit a proposal. There are no restrictions relative to country, institution, or prior involvement in CCSS. A full description of the process for developing a proposal for genetic research in CCSS can be found at https://ccss.stjude.org/develop-a-study/gwas-data-resource.html, along with listings of approved proposals.

  Study phs001327

• eMERGE Geisinger eGenomic Medicine (GeM) Abdominal Aortic Aneurysm Project (AAAP)

  A large research cohort of Geisinger Abdominal Aortic Aneurysm (AAA) patients was created by enrolling and consenting patients of the Geisinger Department of Vascular Surgery. Consented patients provide blood, serum and DNA samples for research and authorize use of data in their medical record for research. They also complete a data questionnaire that asks information about family history of AAA and other vascular diseases, as well as information on known or suspected AAA risk factors, including smoking history, body mass index, hypertension, type 2 diabetes, and atherosclerotic disease. The AAA cases are 78% male, with a mean age of 74 years; 39% have undergone surgical or endovascular repair; more than 85% or current or past smokers; approximately 20% of cases report a positive family history of AAA. Geisinger AAA patients undergo regular imaging studies, typically every 6 months, to monitor the progression of aneurysm expansion. This allows the growth rates of their aneurysm to be calculated. DNA samples from a total of 910 AAA patients were used for whole genome genotyping; these results are included in the dbGaP.

  Study phs000387

• Rare germline sequence variants, copy number variations, expression alterations, methylation variations and disease susceptibility in familial melanoma

  Although a number of high-risk melanoma genes have been identified, they account for melanoma risk in less than 40% of melanoma-prone families. The major goals of our research are to identify novel high-penetrance genes for familial melanoma in melanoma-prone families without known mutations and to identify modifier factors, including genetic and epigenetic, in melanoma-prone families with and without known major mutations. We are using whole exome sequencing to identify additional high-risk susceptibility genes and using targeted sequencing to follow up on the top genes in additional family members and in population-based melanoma cases and controls. We are also using RNASeq to investigate genome-wide allele-specific expression and eQTLs in these families to identify genes with expression alteration, which will provide additional information for gene discovery. In addition, we also conducted genome-wide copy number variation (CNV), methylation, and miRNA expression profiling analyses in our melanoma families with the goal of identifying genetic and epigenetic factors as disease modifiers.

  Study phs001177

• Consanguinity and rare mutations outside of MCCC genes underlie non-specific phenotypes of MCC Deficiency

  3-Methylcrotonyl-CoA Carboxylase Deficiency (MCCD) is an autosomal recessive disorder of leucine catabolism, which has a highly variable clinical phenotype, ranging from acute metabolic acidosis to non-specific symptoms such as developmental delay, failure to thrive, hemiparesis, muscular hypotonia, and multiple sclerosis. Implementation of newborn screening for MCCD has resulted in broadening the range of phenotypic expression to include asymptomatic adults. The purpose of this study was to identify factors underlying the varying phenotypes of MCCD. We performed exome sequencing on DNA from 107 healthy controls and 33 cases. We examined these data for associations between either MCC mutational status, genetic ancestry or consanguinity and the absence or presence/specificity of clinical symptoms in MCCD cases. We determined that individuals with non-specific clinical phenotypes are highly inbred compared to cases that are asymptomatic and healthy controls. For five of these individuals we discovered a homozygous damaging mutation in a disease gene that is likely to underlie their non-specific clinical phenotypes previously attributed to MCCD.

  Study phs000776

• Genomic Analysis of Head and Neck Cancers

  These aggregate studies focus on specimens from head and neck squamous cell carcinoma (HNSCC) patients who were treated with standard of care or window of opportunity clinical trial approaches. Specimens were interrogated with exome and RNA-Seq analysis. Patient derived xenografts (PDXs) represent a robust platform for performing co-clinical trial approaches. In the first study we generated a large panel of PDXs and compared genomic profiles between the primary tumor and matched PDX with the patients blood serving as a source of somatic variants. In the second study, we performed a window of opportunity clinical trial in oral cavity squamous cell carcinoma patients using the MEK inhibitor trametinib. In addition, PDX models were generated from these specimens also and analyzed as in the first study. Finally, the third approach used pembrolizumab, an anti-PD1 blocking antibody, in a window of opportunity setting in HNSCC patients. For the latter two studies genomic matched sample analysis was performed to define response and resistance mechanisms. Together, these genomic data will inform several therapeutic approaches for HNSCC patients.

  Study phs001623

• Retinoblastoma Aqueous Humor Liquid Biopsy Repository

  This study involves the use of the aqueous humor (AH, the clear fluid in the front of the eye) as an organ specific liquid biopsy for retinoblastoma. This relatively new liquid biopsy platform was started at CHLA/USC and was developed to overcome the lack of tumor tissue -- due to contraindication to biopsy -- for this cancer. We have demonstrated that the aqueous humor is an enriched source of tumor DNA. Previously tumoral information was only available after the eye was removed for treatment failure. Due to the AH liquid biopsy, we are now able to assay tumor derived molecular information from these eyes at diagnosis and longitudinally during treatment -- as opposed to only eyes that have failed therapy. We have demonstrated that using the platform we can identify the specific mutations in the RB1 gene that initiate tumorigenesis in this cancer as well as the secondary chromosomal alterations the drive further tumor growth. This database will provide sequencing information as well as associated clinical information and globe salvage outcomes.

  Study phs003077

• Establishment of an iPSC Repository Derived from Healthy Volunteers

  Understanding the interaction between genetic variation and epigenetic variation remains a challenge due to the confounding role of environmental factors. We propose that human induced pluripotent stem cells (iPSCs) are an excellent model to study the relationship between genetic variation and epigenetic variation while controlling for consistent environmental factors. In this study, we have created a comprehensive resource of high-quality genomic, epigenomic, and transcriptomic data of six iPSC lines and three iPS-derived cell types (NSC, Motor Neuron, Monocyte) from three healthy donors. We found that epigenetic variation is most strongly associated with genetic variation at the iPSC stage, and that relationship weakens as epigenetic variation increases in the differentiated cells. Additionally, cell-type is a stronger source of epigenetic variation than genetic variation, highlighting that humans are far more similar than they are different, regardless of genetic background. Further, we have elucidated a utility of studying epigenetic variation in iPSCs and their derivatives for identifying important loci for GWAS studies and the cell-types in which they may be acting.

  Study phs003649

• Proteogenomic Analysis of CALGB40601 (ALLIANCE) a Neoadjuvant Phase III HER2-Positive Breast Cancer Trial

  80 frozen core needle biopsies from 54 HER2+ breast cancer patients from the CALGB 40601 trial (NCT00770809) were processed for proteogenomic analysis to identify genes, proteins, and phosphosites associated with pathological complete response to neodjuvant anti-HER2 therapies. The final set included 22 patients treated with trastuzumab plus lapatinib in combination with pacletaxel (THL arm), 24 patients treated with trastuzumab in combination with pacletaxel (TH arm), and 8 patients treated lapatinib in combination with pacletaxel (TL arm). Principal findings of this study included identifying negative cases misdiagnosed as HER2+ that did not respond to targeted therapy and observing higher levels of two biomarker candidates in non-pCR tumors. Mass spec-based proteomics and phosphoproteomics data generated from 75 biopsies (all 54 patients) will be made available via the Proteomic Data Commons. Whole exome- (67 biopsies from 49 patients) and RNA-sequencing (52 biopsies from 39 patients) data for the subset profiled with proteogenomics will be made available through dbGaP, but genomic and transcriptomic profiling data for the whole cohort has previously been deposited (phs001570).

  Study phs003576

• Fragmentomics Uncover Non-Mutational HRD Features

  Homologous recombination deficiency (HRD) is a key biomarker in prostate cancer (PCa), predicting response to PARP inhibitors and platinum-based therapies. However, current diagnostics often rely solely on BRCA1/2 mutations or genomic scars, missing cases driven by other mechanisms. Tissue-based testing is further limited by tumor heterogeneity and biopsy challenges in metastatic bone disease. Here, we applied a comprehensive multimodal approach to assess HRD in 106 advanced PCa patients using circulating tumor DNA (ctDNA). This included targeted sequencing of homologous recombination repair (HRR) genes, low-pass WGS for genomic instability (sHRD), WES for mutational signatures, and cfDNA fragmentomics and chromatin accessibility profiling. BRCA2 was the most frequently altered gene, often co-occurring with PTEN loss. High sHRD scores correlated with BRCA2/RB1 loss, somatic copy number alterations, and poor survival. HRD tumors showed enrichment of SBS3/ID6 signatures, altered fragment lengths, and reduced accessibility at zinc finger transcription factor sites. These results support ctDNA-based multimodal profiling as a non-invasive strategy for HRD detection and stratification.

  Study EGAS00001008190

• DHODH is a synthetic-lethal vulnerability in BCOR-deficient acute myeloid leukemia

  Acute Myeloid Leukemia (AML) remains challenging to treat, especially in cases with mutations in the BCL-6 co- repressor (BCOR), which are associated with poor prognosis and chemo-resistance. In this study, we reveal a synthetic lethal interaction between BCOR and dihydroorotate dehydrogenase (DHODH). We demonstrate that BCOR-deficient cells have a heightened sensitivity to DHODH inhibitors such as brequinar and leflunomide, that are already in clinical use. We confirm that DHODH inhibition selectively induces cell death in BCOR-mutant cells in multiple cellular models, in malignant and non-malignant cells, through chemical and genetic manipulation. Interestingly, we find that the dependency on DHODH does not stem from its role in de novo pyrimidine biosynthesis disruption. Rather, DHODH’s role in the electron transport chain, essential for mitigating reactive oxygen species, may be the physiological vulnerability that pushes BCOR-mutant cells toward cell death when DHODH is inhibited. DHODH inhibitors could be repurposed as targeted therapies for BCOR-mutant tumors, offering a promising strategy for precision medicine in AML and other cancers.

  Study EGAS50000001060

• DHODH is a synthetic-lethal vulnerability in BCOR-deficient acute myeloid leukemia

  Acute Myeloid Leukemia (AML) remains challenging to treat, especially in cases with mutations in the BCL-6 co- repressor (BCOR), which are associated with poor prognosis and chemo-resistance. In this study, we reveal a synthetic lethal interaction between BCOR and dihydroorotate dehydrogenase (DHODH). We demonstrate that BCOR-deficient cells have a heightened sensitivity to DHODH inhibitors such as brequinar and leflunomide, that are already in clinical use. We confirm that DHODH inhibition selectively induces cell death in BCOR-mutant cells in multiple cellular models, in malignant and non-malignant cells, through chemical and genetic manipulation. Interestingly, we find that the dependency on DHODH does not stem from its role in de novo pyrimidine biosynthesis disruption. Rather, DHODH’s role in the electron transport chain, essential for mitigating reactive oxygen species, may be the physiological vulnerability that pushes BCOR-mutant cells toward cell death when DHODH is inhibited. DHODH inhibitors could be repurposed as targeted therapies for BCOR-mutant tumors, offering a promising strategy for precision medicine in AML and other cancers.

  Study EGAS50000001108

• Targeted sequencing (paired) of HR genes in primary and metastatic patient-derived xenografts (PDXs) of colorectal cancer (CRC)

  Chemotherapy is the standard-of-care treatment for metastatic colorectal cancer (mCRC) and benefits some patients, but what distinguishes responders from non-responders is unclear. In this study, we leveraged a comprehensive collection of 69 molecularly annotated patient-derived xenografts to uncover functional predictors of response to 5-FU and irinotecan combination therapy (FOLFIRI) in mCRC. Genetic analyses revealed that treatment sensitivity was marked by genomic scars indicative of BRCAness, suggesting homologous recombination (HR) deficiency as a key determinant. Accordingly, we surveyed a manually curated panel of 44 genes with a documented role in HR for the potential presence of pathogenic mutations. We did not observe a specific enrichment of HR gene mutations based on response to FOLFIRI. This result, combined with the absence of widespread biallelic inactivation of the analyzed genes and the predominance of mutations categorized as variants of unknown significance, suggests that FOLFIRI sensitivity is not primarily governed by underlying mutations in HR genes responsible for mitigating the genotoxic effects of this therapeutic regimen.

  Study EGAS50000000075

• Shallow Whole Genome Sequencing of Patient Derived Xenografts

  Chemotherapy is the standard-of-care treatment for metastatic colorectal cancer (mCRC) and benefits some patients, but what distinguishes responders from non-responders is unclear. In this study, we leveraged a comprehensive collection of 27 molecularly annotated patient-derived xenografts to uncover functional predictors of response to 5-FU and irinotecan combination therapy (FOLFIRI) in mCRC. Genetic analyses revealed that treatment sensitivity was marked by genomic scars indicative of BRCAness, suggesting homologous recombination (HR) deficiency as a key determinant. Accordingly, we surveyed a manually curated panel of 44 genes with a documented role in HR for the potential presence of pathogenic mutations. We did not observe a specific enrichment of HR gene mutations based on response to FOLFIRI. This result, combined with the absence of widespread biallelic inactivation of the analyzed genes and the predominance of mutations categorized as variants of unknown significance, suggests that FOLFIRI sensitivity is not primarily governed by underlying mutations in HR genes responsible for mitigating the genotoxic effects of this therapeutic regimen.

  Study EGAS50000000191

• Assessment of candidate high-grade serous ovarian carcinoma predisposition genes through integrated germline and tumour sequencing

  High-grade serous ovarian carcinoma (HGSOC) has a significant hereditary component, only half of which is explained. Previously, we performed germline exome sequencing on BRCA1 and BRCA2-negative HGSOC patients, revealing three proposed and 43 novel candidate genes enriched with rare loss-of-function variants. For validation, we undertook case-control analyses using genomic data from disease-free controls. This confirms enrichment for nearly all previously identified genes. Additionally, one-hundred-and-eleven HGSOC tumours from variant carriers were sequenced alongside other complementary studies, seeking evidence of biallelic inactivation as supportive evidence. PALB2 and ATM validate as HGSOC predisposition genes, with 6/8 germline carrier tumours exhibiting biallelic inactivation accompanied by characteristic mutational signatures. Among candidate genes, only LLGL2 consistently shows biallelic inactivation and protein expression loss, supporting it as a novel HGSOC susceptibility gene. The remaining candidate genes fail to validate. Integrating case-control analyses with tumour sequencing is thus crucial for accurate gene discovery in familial cancer studies.

  Study EGAS50000000770

• CD8+ T-cell exhaustion induced by leukemic cells drives progression in Chronic Lymphocytic Leukemia

  In order to shed light on mechanisms that lead to CLL progression, we investigated longitudinal changes in both the genetic and immunological landscapes. For that, we analyzed paired samples obtained from CLL patients at diagnosis and progression before front-line treatment or at diagnosis and long-term asymptomatic follow-up. By whole-exome sequencing (WES), we found that CLL cells displayed limited genetic evolution at progression. Conversely, T cells from progressing patients showed significant immunophenotypical and transcriptional changes over time not observed in patients that did not progress. Specifically, we found that CD8+ T cells at progression were characterized by an increasing terminally exhausted effector phenotype (T-betdim/- Eomeshi PD1hi) with high co-expression of inhibitory receptors (PD1, CD244 and CD160). This exhausted status in CD8+ T cells was induced by progressing leukemic cells mainly through a mechanism dependent on soluble factors, including IL-10. Thus, we demonstrate that immunological changes are of paramount importance for CLL clinical progression, thereby providing a rationale for the use of early immunotherapeutic intervention in this disease.

  Study EGAS00001004116

• TGF-β attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells.

  We examined tumours from a large cohort of patients with metastatic urothelial bladder cancer (mUC) treated with an anti–PD-L1 agent (atezolizumab) and identified major determinants of clinical response and immune escape. Whole transcriptome profiles were generated for 368 patients using TruSeq RNA Access technology (Illumina). Somatic mutations were determined via whole exome sequencing for a subset of these patients. - Response was associated with CD8+ T effector cell phenotype and, to an even greater extent, high neoantigen or tumour mutation burden (TMB). On the other hand, lack of response was associated with a transforming growth factor β (TGF-β) signature, particularly in patients with CD8+ T cells preferentially residing in collagen-rich matrix surrounding tumours. Integration of these three independent biological features provided the best basis for understanding outcome in this setting. -

  Study EGAS00001002556

• Integrated genomic analyses identify ARID1A and ARID1B alterations in the childhood cancer neuroblastoma

  Neuroblastomas are tumors of peripheral sympathetic neurons and are the most common solid tumor in children. To determine the genetic basis for neuroblastoma we performed whole-genome sequencing (6 cases), exome sequencing (16 cases), genome-wide rearrangement analyses (32 cases), and targeted analyses of specific genomic loci (40 cases) using massively parallel sequencing. On average each tumor had 19 somatic alterations in coding genes (range, 3-70). Among genes not previously known to be involved in neuroblastoma, chromosomal deletions and sequence alterations of chromatin remodeling genes, ARID1A and ARID1B, were identified in 8 of 71 tumors (11%) and were associated with early treatment failure and decreased survival. Using tumor-specific structural alterations, we developed an approach to identify rearranged DNA fragments in sera, providing personalized biomarkers for minimal residual disease detection and monitoring. These results highlight dysregulation of chromatin remodeling in pediatric tumorigenesis and provide new approaches for the management of neuroblastoma patients.Data Provider: Johns Hopkins Sidney Kimmel Comprehensive Cancer Center (SKCCC)

  Study EGAS00001000369

• Analysis of four key cell types (epithelial, fbroblast, myeloid and T cells)

  Alterations of the normal prostate epithelial cell genome trigger the emergence of carcinoma, however cancer-only analyses of genomic aberrations have resulted in little clinical translation. A deep understanding of the tumor microenvironment is likely to inform on key drivers of disease progression and novel therapeutic opportunities. We investigated the role of key cell types along disease progression, profiling the RNA abundance of 52 samples from 13 patients enriched for one of four key cell types, spanning a wide CAPRA-S risk score range. Using a novel differential transcription Bayes method, TABI, we avoided a priori patient stratification, and mapped transcriptional alteration events to specific risk scores. The developmental and cell-type resolution yielded a landscape of concurrent transcriptional alterations from the tumour microenvironment, including key hallmarks. These transcriptional signatures permitted the identification of a “high survival” patient cluster in an independent prostate cancer dataset. Most importantly, together with our integrated transcriptional analysis, differential tissue composition analysis provided evidence for a key role for monocytes and macrophages in prostate cancer progression and disease recurrence.

  Study EGAS00001003579

• Scalable whole-genome single-cell library preparation without pre-amplification

  Single-cell genomics is critical for understanding cellular heterogeneity in cancer, but existing library preparation methods are expensive, require sample preamplification and introduce coverage bias. Here we describe direct library preparation (DLP), a robust, scalable, and high-fidelity method that uses nanoliter-volume transposition reactions for single-cell whole-genome library preparation without preamplification. We examined 782 cells from cell lines and triple-negative breast xenograft tumors. Low-depth sequencing, compared with existing methods, revealed greater coverage uniformity and more reliable detection of copy-number alterations. Using phylogenetic analysis, we found minor xenograft subpopulations that were undetectable by bulk sequencing, as well as dynamic clonal expansion and diversification between passages. Merging single-cell genomes in silico, we generated "bulk-equivalent" genomes with high depth and uniform coverage. Thus, low-depth sequencing of DLP libraries may provide an attractive replacement for conventional bulk sequencing methods, permitting analysis of copy number at the cell level and of other genomic variants at the population level.

  Study EGAS00001002170

• Mutant KIT as imatinib-sensitive target in metastatic sinonasal carcinoma (H021)

  Sinonasal carcinomas (SNCs) comprise various rare tumor types that are characterized by marked histologic diversity and largely unknown molecular profiles, yet share an overall poor prognosis owing to an aggressive clinical course and frequent late-stage diagnosis. The lack of effective systemic therapies for locally advanced or metastatic SNC poses a major challenge to therapeutic decision making for individual patients. Here, we used whole-exome and transcriptome sequencing to identify a KIT exon 11 mutation (c.1733_1735del, p.578_579del) as actionable target in a patient with metastatic SNC whose tumor, despite all diagnostic efforts, could not be assigned to any known SNC category and was refractory to multimodal therapy. Molecularly guided treatment with imatinib resulted in a dramatic and durable response with remission of nearly all tumor manifestations, indicating a dominant driver function of mutant KIT in this tumor. This observation highlights the potential of unbiased genomic profiling for uncovering the vulnerabilities of individual malignancies, particularly in rare and unclassifiable tumors, and underscores that KIT exon 11 mutations represent tractable therapeutic targets across different histologies.H021

  Study EGAS00001001845

• Integrative genomic profiling of large-cell neuroendocrine carcinomas reveals distinct subtypes of high-grade neuroendocrine lung tumors

  Large-cell neuroendocrine lung carcinomas (LCNEC) have similarities with other lung cancers, but their precise relationship has remained unclear. We conducted comprehensive genomic (n=60) and transcriptomic (n=69) analyses of 75 LCNECs and identified two molecular subgroups: “type I LCNECs” with bi-allelic TP53 and STK11/KEAP1 alterations (37%), and “type II LCNECs” enriched for bi-allelic inactivation of TP53 and RB1 (42%). Despite sharing genomic alterations with adenocarcinomas and squamous cell carcinomas, no transcriptional relationship was found; instead LCNECs form distinct transcriptional subgroups with closest similarity to SCLC. While type I LCNECs and SCLCs exhibit a neuroendocrine profile with ASCL1high/DLL3high/NOTCHlow, type II LCNECs bear TP53 and RB1 alterations and differ from most SCLC tumors with reduced neuroendocrine markers, a pattern of ASCL1low/DLL3low/NOTCHhigh and upregulation of immune-related pathways. In conclusion, LCNECs are comprised of two molecularly defined subgroups, and distinguishing them from SCLC may allow for stratified targeted treatments for high-grade neuroendocrine lung tumors.

  Study EGAS00001000708

• ALPI deficiency causes refractory Inflammation Bowel Disease

  Herein, we report the first identification of biallelic-inherited mutations in ALPI as a Mendelian cause of inflammatory bowel disease in two unrelated patients. ALPI encodes for intestinal phosphatase alkaline, a brush border metalloenzyme that hydrolyses phosphate from the lipid A moiety of lipopolysaccharides and thereby drastically reduces Toll-like receptor 4 agonist activity. Prediction tools and structural modelling indicate that all mutations affect critical residues or inter-subunit interactions, and heterologous expression in HEK293T cells demonstrated that all ALPI mutations were loss of function. ALPI mutations impaired either stability or catalytic activity of ALPI and rendered it unable to detoxify lipopolysaccharide-dependent signalling. Furthermore, ALPI expression was reduced in patients' biopsies, and ALPI activity was undetectable in ALPI-deficient patient's stool. Our findings highlight the crucial role of ALPI in regulating host-microbiota interactions and restraining host inflammatory responses. These results indicate that ALPI mutations should be included in screening for monogenic causes of inflammatory bowel diseases and lay the groundwork for ALPI-based treatments in intestinal inflammatory disorders.

  Study EGAS00001003350

• Whole-genome sequencing of rare disease patients in a national healthcare system

  Most patients with rare diseases do not receive a molecular diagnosis and the aetiologicalvariants and mediating genes for more than half such disorders remain to be discovered. Weimplemented whole-genome sequencing (WGS) in a national healthcare system to streamlinediagnosis and to discover unknown aetiological variants, in the coding and non-coding regionsof the genome. In a pilot study for the 100,000 Genomes Project, we generated WGS data for13,037 participants, of whom 9,802 had a rare disease, and provided a genetic diagnosis to1,138 of the 7,065 patients with detailed phenotypic data. We identified 95 Mendelianassociations between genes and rare diseases, of which 11 have been discovered since 2015and at least 79 are confirmed aetiological. Using WGS of UK Biobank1, we showed that rarealleles can explain the presence of some individuals in the tails of a quantitative red blood cell(RBC) trait. Finally, we reported 4 novel non-coding variants which cause disease through thedisruption of transcription of ARPC1B, GATA1, LRBA and MPL. Our study demonstrates asynergy by using WGS for diagnosis and aetiological discovery in routine healthcare.

  Study EGAS00001004364

• Comprehensive pharmacogenomic characterization of gastric cancer

  Gastric cancer is among the most lethal human malignancies. Previous studies have identified molecular aberrations that constitute dynamic biological networks and genomic complexities of gastric tumors. However, the clinical translation of molecular-guided targeted therapy is hampered by challenges. Notably, solid tumors often harbor multiple genetic alterations, complicating the development of effective treatments. To address such challenges, we established a comprehensive dataset of molecularly annotated patient derivatives coupled with pharmacological profiles for 60 targeted agents to explore dynamic pharmacogenomic interactions in gastric cancers. We identified lineage-specific drug sensitivities based on histopathological and molecular subclassification, including substantial sensitivities toward VEGFR and EGFR inhibition therapies in diffuse- and signet ring-type gastric tumors, respectively. We identified potential therapeutic opportunities for WNT pathway inhibitors in ALK-mutant tumors, a significant association between PIK3CA-E542K mutation and AZD5363 response, and transcriptome expression of RNF11 as a potential predictor of response to gefitinib. Collectively, our results demonstrate the feasibility of drug screening combined with tumor molecular characterization to facilitate personalized therapeutic regimens for gastric tumors.

  Study EGAS00001004106

• Sensitive detection of tumor mutations from blood and its application to immunotherapy prognosis

  Cell-free DNA (cfDNA) is attractive for many applications, including cancer detection, locating, and monitoring. A fundamental task underlying these applications is the SNV calling from cfDNA, which, however, faces a new challenge, namely, the generally very low tumor content in cfDNA. Thus all existing callers fail to achieve satisfactory performance. Here we present cfSNV, a method incorporating multi-layer error suppression and hierarchical mutation calling, to address this important challenge. Furthermore, by leveraging cfDNA’s comprehensive coverage of clonal landscape, for the first time cfSNV can profile mutations even in subclones. In both simulated and real patient data, cfSNV vastly outperforms existing tools, showing tens of times increase in sensitivity in detecting mutations with low allele frequency while maintaining high precision. cfSNV can enhance the clinical utilities of cfDNA by dramatically reducing the required sequencing depth and therefore reduce the cost by magnitudes, and further make the Whole-Exome-Sequencing of cfDNA a viable option. As an example, we demonstrate that cfDNA-WES allows a new biomarker to effectively select patients for immunotherapy.

  Study EGAS00001004373

• Three-dimensional human alveolar stem cell culture models reveal infection response to SARS-CoV-2

  Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2), which is the cause of a present global pandemic, infects human lung alveolar type 2 (hAT2) cells. Characterizing pathogenesis is crucial for developing vaccines and therapeutics. However, the lack of models mirroring the cellular physiology and pathology of hAT2 cells limits the study. Here, we develop a feeder-free, long-term three-dimensional (3D) culture technique for hAT2 cells derived from primary human lung tissue, and investigate infection response to SARS-CoV-2. By imaging-based analysis and single-cell transcriptome profiling, we reveal rapid viral replication and the increased expression of interferon-associated genes and pro-inflammatory genes in infected hAT2 cells, indicating robust endogenous innate immune response. Further tracing of viral mutations acquired during transmission identifies full infection of individual cells effectively from a single viral entry. Our study provides deep insights into the pathogenesis of SARS-CoV-2, and the application of defined 3D hAT2 cultures as models for respiratory diseases.

  Study EGAS00001004508

• Exome Sequecning of MDS xenografted samples

  Pre-clinical research of Myelodysplastic Syndromes (MDS) is hampered by a lack of feasible disease models. Previously, we have established a robust patient-derived xenograft (PDX) model for MDS. Here, we demonstrate for the first time that this model is applicable as a pre-clinical platform to address pending clinical questions by interrogating the efficacy and safety of the thrombopoietin receptor agonist eltrombopag. Our pre-clinical study included n=49 xenografts generated from n=9 MDS patient samples. Substance efficacy was evidenced by FACS-based human platelet quantification, and clonal bone marrow evolution was reconstructed by serial whole exome sequencing of the PDX samples. In contrast to clinical trials in humans, this experimental setup allowed vehicle- and replicate-controlled analyses on a patient-individual level deciphering substance-specific effects from natural disease progression. We found that eltrombopag effectively stimulated thrombopoiesis in MDS PDX without adversely affecting the patients’ clonal composition. In conclusion, our MDS PDX model is a useful tool for testing new therapeutic concepts in MDS preceding clinical trials.

  Study EGAS00001005329

• Epigenomic priming of immune genes implicates oligodendroglia in multiple sclerosissusceptibility

  Multiple sclerosis (MS) is characterized by a targeted attack on oligodendroglia (OLG)and associated myelin by immune cells, which are thought to be the main drivers of MS susceptibility. Assessing chromatin accessibility and the transcriptome simultaneously at the single cell level, we found that immune genes exhibit a primedchromatin state in mouse and human OLG in a non-disease context, compatible withrapid transitions to immune-competent states in MS. We identified transcription factors as BACH1 and STAT1 involved in immune gene regulation in oligodendrocyteprecursor cells (OPCs). A subset of immune genes present bivalency of H3K4me3/H3K27me3 in OPCs, with Polycomb inhibition leading to their increased activation upon interferon-gamma (IFNg) treatment. Some MS susceptibility single-nucleotide polymorphisms (SNPs) overlap with these regulatory regions in mouse andhuman OLG, and treatment of mouse OPCs with IFNg leads to chromatin architecture remodeling at these loci and altered expression of interacting genes. Our data indicates that susceptibility for MS may involve OLG, which therefore constitute novel targets for immunological-based therapies for MS.

  Study EGAS00001005911

• Whole-exome sequencing of glioblastomas with long-term relapse interval

  Treatment options for GBM patients have not changed over the last 15 years, and the success of targeted therapy or immunotherapy has been disappointinglimited. Thus, the standard of care for GBM patients remains surgical resection followed by concomitant DNA alkylating agent therapy with temozolomide (TMZ) and radiation therapy (RT). However, the time to relapse is generally short (6.9 months on average) owing to the tumor’s ability to infiltrate normal parenchyma and its intrinsic resistance to radio-chemotherapy. Due to the lack of alternative treatment options, elucidating underlying resistance mechanism has come into major focus of research, with the hope for opening new ways of therapeutic intervention overcoming resistance. To explore therapy resistance driving events, we performed a study using a single-centric collective of matched pairs of therapy-naïve and post-therapeuticc tissue from GBM patients, selected based on a maximally long interval between resections of the initial and the recurrent tumors. This rare collective was analyzed by whole exome sequencing (WES), mRNA expression and miRNA expression profiling.

  Study EGAS00001006022

• The clinical utility of genomics in childhood cancer extends beyond targetable mutations - WGS data

  We deeply sequenced 864 cancer-associated genes and the complete genomes and transcriptomes for 300 pediatric and adolescent/young adult (AYA) patients with poor prognosis or rare tumors. Using integrative somatic-germline analyses, we assessed the clinical utility of cancer genomics in this population. Clinically actionable variants were identified in 56% of patients. Improved diagnostic accuracy led to modified management in a subset. Therapeutically targetable variants, found in 54% of patients, were of unanticipated timing and type, with over 20% of these derived from the germline. Enrichment in corroborating mutational signature 3 (‘BRCAness’) in patients with germline homologous recombination defects suggests they are drivers of pediatric cancers and potential targets for PARP inhibition. Comprehensive somatic-germline cancer genomic profiling is useful at multiple points in the care trajectory for pediatric/AYA patients, supporting its integration into early clinical management. Re-biopsy at the time of relapse should be considered, and specific attention to mutational burden is indicated. Defective DNA repair genes in the germline may represent important targetable drivers.

  Study EGAS00001006610

• The clinical utility of genomics in childhood cancer extends beyond targetable mutations - Cancer Panel data

  We deeply sequenced 864 cancer-associated genes and the complete genomes and transcriptomes for 300 pediatric and adolescent/young adult (AYA) patients with poor prognosis or rare tumors. Using integrative somatic-germline analyses, we assessed the clinical utility of cancer genomics in this population. Clinically actionable variants were identified in 56% of patients. Improved diagnostic accuracy led to modified management in a subset. Therapeutically targetable variants, found in 54% of patients, were of unanticipated timing and type, with over 20% of these derived from the germline. Enrichment in corroborating mutational signature 3 (‘BRCAness’) in patients with germline homologous recombination defects suggests they are drivers of pediatric cancers and potential targets for PARP inhibition. Comprehensive somatic-germline cancer genomic profiling is useful at multiple points in the care trajectory for pediatric/AYA patients, supporting its integration into early clinical management. Re-biopsy at the time of relapse should be considered, and specific attention to the mutational burden is indicated. Defective DNA repair genes in the germline may represent important targetable drivers.

  Study EGAS00001006642

• Human NXPE1 mediates variation in sialic acid O-acetylation in Colon Tissue

  Sialylation, and its modifications, have important consequences for development, differentiation and immune system regulation in nearly all human tissues. An accounting of all the genes responsible for modifying sialic acids is incomplete, with only one pathway for O-acetylation being well-defined in humans. Using whole genome sequencing of normal human colorectal tissue we identify a haplotype on chromosome 11 that is associated with differences in mild periodic acid Schiff staining (mPAS), a marker of acetylation of sialic acids. Of the genes in this region, only SNPs from NXPE1 correlate perfectly in a validation data set. NXPE1 protein expression by IHC also correlates with mPAS staining patterns in homozygous, as well as heterozygous colon crypts that have undergone spontaneous gain of the mPAS phenotype. Manipulation of NXPE1 expression with CRISPR-Cas9 causes changes to modified sialic acid levels in both 2D cell line and 3D normal colon organoid models. These findings suggest NXPE1 may cause O-acetylation of sialic acids in colorectal tissue, potentially defining NXPE as a new family of sialic acid-modifying genes.

  Study EGAS00001007704

• NHLBI's Collection of Datasets for General Research Use (Public Posting of Genomic Summary Results: Allowed)

  This collection contains all of NHLBI's authorized individual-level genomic datasets currently in dbGaP that are approved for General Research Use (GRU) and have no further limitations beyond those outlined in the model Data Use Certification Agreement. Genomic Summary Results (GSR) sharing is allowed (unrestricted) or not applicable. To request access to this study collection, select phs003132 in the dbGaP Authorized Access System.

  Study phs003132

• MicroRNA Biomarkers for Prediction of Preeclampsia

  Maternal serum was collected between 17-28 weeks gestation. Samples were obtained from the high-risk Placental Study at the University of California, San Diego (n=48) and from the average-risk Proteomic Assessment of Preterm Risk (PAPR) Study at Sera Prognostics (n=164). RNA was extracted from 500 microliter of maternal serum using the miRNeasy Micro kit (Qiagen). NEBNext Small RNAseq Library Preparation Kit was used for library construction.

  Study phs002016

• Large Scale Meta-analysis Characterizes Genetic Architecture for Common Psoriasis-associated Variants

  The genotypes obtained from the Affymetrix Biobank Plus array constituted one of eight Caucasian datasets used in a large genome-wide meta-analysis of the association of psoriasis cases versus unaffected controls. With a combined effective sample size of > 39,000 individuals, this study identified 16 new psoriasis loci achieving genome-wide significance, increasing the total number of identified psoriasis loci for European-ancestry populations to 63.

  Study phs001306

• T-bet+ CXCR3+ B cells drive hyperreactive B-T cell interactions in multiple sclerosis

  Data Access Committee means the following members of the Institute of Experimental Immunology, UZH, and investigators of the publication, to which the Data Access refers and who are responsible for making the data access decisions for the genotype and gene expression generated by UZH or respectively the epigenetic data, which had been generated at Karolinska Institute. Christian Münz, PhD; Co-Director of Institute of Experimental Immunology, University of Zurich Roland Martin, MD; Affiliated Group Leader (to Institute Münz) of Institute of Experimental Immunology Institute of Experimental Immunology Ivan Jelcic, PhD, Roche Pharma Research and Early Development (pRED), Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland Maja Jagodic, PhD, Department of Clinical Neuroscience, Karolinska Institutet, Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden

  Dac EGAC50000000464

• Bulk RNAseq FASTQ files of three PDAC organoid lines treated with LGK974 or DMSO for 24h

  This dataset contains raw FASTQ files from bulk RNA sequencing of three patient-derived pancreatic ductal adenocarcinoma (PDAC) organoid lines (P28, P40, P47). Each organoid line was treated with either the WNT secretion inhibitor LGK974 or DMSO for 24 hours, with three biological replicates per treatment condition. RNA was extracted using the Qiagen QiaSymphony SP system, and libraries were prepared with the Illumina Truseq stranded polyA kit. Sequencing was performed on an Illumina NextSeq2000 platform using single-end 50bp reads. Quality control was conducted with FastQC, and reads were trimmed with TrimGalore as appropriate. Data are controlled-access and intended for transcriptomic analysis of WNT pathway perturbation in PDAC organoid models.

  Dataset EGAD50000002219

• Whole exome sequencing data for patients with Bosma arhinia microphthalmia syndrome (BAMS).

  The datasets includes 21 samples from 7 families with Bosma arhinia microphthalmia (BAMS). For details of the study please refer to the manuscript "De novo mutations in SMCHD1 cause Bosma arhinia microphthalmia syndrome and abrogate nasal development", Nature Genetics 2017. Each sample was exome sequenced and the family ID in sample description refers to the Individual ID in Supplementary figure 2 of the manuscript.

  Study EGAS00001002193

• We evaluate the PGD/PGS including 129 couples with NGS test and 266 couples with SNP-array test for the detection of embryonic chromosomal abnormalities.

  A total of 395 couples were subjected to IVF-PGD treatment, including 129 couples with NGS test and 266 couples with SNP-array test for the detection of embryonic chromosomal abnormalities. The NGS test was performed using low coverage whole genome sequencing with HiSeq 2000 platform. And the SNP array test was using Affymetrix Gene Chip Mapping Nsp I 262K.

  Study EGAS00001000981

• WGS data for MMML for Study EGAS00001002199

  Whole genome sequencing data for MMML (24 tumor/control pairs), fastq-files

  Dataset EGAD00001003276

• WGS data for MMML for Study EGAS00001002198

  Whole genome sequencing data for MMML (28 tumor/control pairs)

  Dataset EGAD00001003207

• WGS data for MMML for Study EGAS00001002198

  Whole genome sequencing data for MMML (12 tumor/control pairs)

  Dataset EGAD00001003208

• WGS data for MMML for Study EGAS00001002198

  Whole genome sequencing data for MMML (cell_line)

  Dataset EGAD00001003210

• Computational approach to discriminate human and mouse sequences in patient-derived tumour xenografts

  Whole Exome Sequencing was performed in a dilution series containing known amounts of human and mouse DNA, 3x 100% human 0% mouse, 2x 90/10, 3x 50/50, 2x 25/75 and 3x 0/100. A set of breast cancer clinical samples, matched normal tissue and matched PDTXs (total number = 14) were also analysed. Paired-end 75bp sequences for the dilution series and paired-end 125bp for the clinical samples were obtained on Illumina HiSeq2500; fastq files are provided. A triplicate analysis of the transcriptome using RNA-seq was also performed for the Universal Human RNA Reference and the Universal Mouse RNA Reference samples. Paired-end 150bp fastq files obtained on Illumina HiSeq4000 are provided.

  Dataset EGAD00001003800

• Long-read sequencing for cell-free DNA analysis (human)

  In this study, we compared the two long-read sequencing platforms, namely the single-molecule real-time sequencing by Pacific Biosciences and nanopore sequencing by Oxford Nanopore Technologies, for the analysis of cell-free DNA from plasma. Cell-free DNA from plasma samples of 31 pregnant women at different trimesters, 6 hepatitis B carriers, and 8 patients with hepatocellular carcinoma were sequenced with the two platforms.

  Study EGAS00001006328

• DNA sequencing for human normal endometrial glands

  To elucidate the timing and mechanism of the clonal expansion of somatic mutations in cancer-associated genes in the normal endometrium, we conducted whole-exome and whole-genome sequencing for 56 endometrial glands and matched blood samples from 4 women. By collecting endometrial glands from different parts of the endometrium, we showed that multiple glands with the same somatic mutations occupied substantial areas of the endometrium.

  Study EGAS00001005822

• ENU-NCI-H508-Cetuximab-SecondRound

  Cetuximab is a targeted monoclonal antibody against the epidermal growth factor receptor (EGFR) which is used therapeutically for the treatment of KRAS wild-type colorectal cancer (CRC). The Cetuximab sensitive KRAS wild-type CRC cell line NCI-H508 has been treated with a fixed concentration of ENU for 24 hours and then selected with Cetuximab until drug resistant clones were ready to be picked and grown up as sub-clones of the parental cell line. These will have genes causally implicated in cancer sequenced to identify common point mutations in multiple independently derived drug resistant clones as a forward genetic screen for mechanisms of resistance to Cetuximab in CRC

  Dataset EGAD00001002065

• Paired RNA-Seq of fCAB treated and bisulfite treated VDH01, partly depleted for NSUN3

  Paired RNA-seq of bisulfite treated VDH01 samples control or depleted for NSUN3 (4 replicates each). The samples were prepped with NEBNext Ultra II DNA library prep kit and sequenced on MiSeq. Paired RNA-seq of fCAB treated vdh01 samples control or depleted for NSUN3(4 replicates each). the samples were prepped with NEBNext Ultra II DNA library prep kit and sequenced on MiSeq. Paired RNA-seq of fCAB treated VDH01 samples (3). the samples were prepped with NEBNext Ultra II DNA library prep kit and sequenced on MiSeq. Paired RNA-seq of bisulfite treated VDH01 samples (3). the samples were prepped with NEBNext Ultra II DNA library prep kit and sequenced on MiSeq.

  Dataset EGAD00001008742

• PPGL WES dataset

  Dataset includes fastq files for WES experiments for tumor samples of PPGL patients. Paired end reads fastq files are available for 87 different samples

  Dataset EGAD00001008579

• Berlin Neuroblastoma Patient Genomic Data from Targeted Sequencing for Detection of TERT rearrangement breakpoints to monitor neuroblastoma

  Our objective was to establish a liquid biopsy-based monitoring strategy for pediatric high-risk neuroblastomas that are harboring genomic TERT rearrangements at diagnosis. TERT rearrangement breakpoints are detected by a hybrid capture-based neuroblastoma DNA panel sequencing (published in PMID: 34442335) in tumor material and are reflected in cell-free tumor DNA and can serve as robust biomarkers for disease activity. Within the dataset, 5 tumors of 4 pediatric patients with a neuroblastoma were DNA sequenced. Provided are FASTQ data files, bam and bambai files, as well as breakpoint spanning and encompassing read (enspan) bam and bambai files. Sequencing bam data files are aligned to GRCh37.p13 reference genome (processed).

  Dataset EGAD00001011088

• PCA Atlas Chromium scRNA-seq and demultiplexing support (FASTQs, BAMs, capture-level VCFs and mapping tables)

  This dataset contains Chromium single-cell RNA-seq data and demultiplexing support for the PCA Atlas study EGAS00001008332. Included data objects: - 16 Chromium scRNA-seq FASTQ runs (EGAR accessions) for captures PCa1–PCa16. - 16 aligned BAM analyses (one Cell Ranger possorted_genome_bam.bam per capture). - 16 capture-level genotype VCF analyses derived from the Axiom UK Biobank array, used as demultiplexing panels. - demux_map.csv (EGAZ00001945520): donor–capture–sample mapping for genotype-based demultiplexing. - chromium.csv (EGAZ00001945537): run-level mapping linking captures, EGA samples, runs (EGAR), experiments (EGAX) and BAM analyses. Together these objects provide a complete view of the Chromium scRNA-seq data and the genotype-based demultiplexing support needed to reproduce donor assignment and downstream analyses.See also https://zenodo.org/records/17372603

  Dataset EGAD00001015795

• DAC for the study EGAS00001001738

  Dac EGAC00001000450

• DAC for sputum fungal microbiome data

  Dac EGAC00001003006

• DAC for Oncogenomics QIMR Berghofer

  Dac EGAC00001001088

• Data Access Committee for WES RCC

  Dac EGAC00001003161

• DAC for study Vel Exome Sequencing

  Dac EGAC00001000012

• DAC for Sardinia FACS pilot project

  Dac EGAC00001000132

• DAC for study POT1 splice

  Dac EGAC00001000184

• DAC for SNP phenotyping Kiel

  Dac EGAC00001000316

• DAC for Mesothelioma Genomics Study

  Dac EGAC00001000615