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• Whole genome shotgun sequencing and somatic mutations data in Hepatocellular carcinoma

  Hepatocellular carcinoma (HCC) is the most common malignancy of the liver. Genomic analysis is conducted to identify genetic alterations in driver genes which are all druggable targets for cancer therapy.

  Study EGAS00001002578

• Genome-wide genotype data for 1,433 ni-Vanuatu

  Here, we generated genome-wide genotype data for 1,433 contemporary ni-Vanuatu and assessed their fine-scale genetic structure, in order to address central questions about the settlement of western Remote Oceania.

  Study EGAS00001005910

• Small intestinal neuroendocrine tumors

  The goal of this study was to gain insights into the transcriptomes, mutations and copy number variants present in small intestinal neuroendocrine tumors. The present dataset contains RNA-sequencing performed on seven such tumors.

  Study EGAS00001003358

• 20_Matched_Pair_Breast_Cancer_Genomes

  We propose to definitively characterise the somatic genetics of 20 breast cancers through generation of comprehensive catalogues of somatic mutations by high coverage genome sequencing coupled with integrated transcriptomic data.

  Study EGAS00001000170

• RNAseq of mCRC xenografts under cetuximab treatment, placebo or after treatment release

  Determine if cetuximab treatment selects any pre-existing resistant subclones or if the resistant cells, which in vivo determines residual disease, are driven by plasticity effects not linked to mutations.

  Study EGAS00001003765

• Whole Exome Sequences from Iberian Roma samples

  Study of high-depth Roma whole exomes to analyse the impact of complex demography on the functional genomic variation. This study also includes genome-wide array data of Iberian Roma individuals

  Study EGAS00001004599

• WES of mCRC xenografts under cetuximab treatment, placebo or after treatment release

  Determine if cetuximab treatment selects any pre-existing resistant subclones or if the resistant cells, which in vivo determines residual disease, are driven by plasticity effects not linked to mutations.

  Study EGAS00001003764

• Transcriptomic consequences of complex rearrangements inv8p23.1 and inv17q21.31 associated with Autism Spectrum Disorders

  We have performed an RNAseq analysis in order to elucidate the transcriptomic consequences of two complex rearrangements associated with Autism Spectrum Disorder, including patients and controls (total n=24).

  Study EGAS00001005612

• Integrative modeling of tumor genomes and epigenomes for enhanced cancer diagnosis by cell-free DNA.

  3784 whole genome sequencing bam files were generated from plasma cell-free DNA of healthy individuals and patients with cancer. Paired reads were mapped to hg19 human reference genome.

  Study EGAS00001006553

• Chromatin landscape of medulloblastoma reveals context dependent driver

  In this study, we defined subgroup specific chromatin landscape (H3K27ac, H3K27me3, RNA-Seq, 27ac hichip, WGS) of medulloblastoma to identify pathogenic epigenetic alterations that regulate expression of a context dependent driver gene.

  Study EGAS00001006741

• OMKar: optical map based automated karyotyping of genomes to identify constitutional disorders

  This dataset contains optical genome mapping (OGM) data from 56 samples, processed for structural variation and copy number analysis. The data includes .xmap, .cmap, and .smap files representing high-resolution genome maps and structural variant calls. These samples were used to identify complex rearrangements and reconstruct genome karyotypes.

  Dataset EGAD00001015674

• Learning from the thymic human cell atlas for T cell engineering: Paediatric RNA (2025-10-02)

  T cells are central to adaptive immunity and thus crucial for understanding and treating human disease. While extensively studied in model organisms, translating this knowledge to humans can sometimes be limited by their rapid cross-species evolution and diverse . This dataset contains all the data available for this study on 2026-03-10.

  Dataset EGAD00001015720

• Whole exome sequencing data of 57 matched esophageal tumor-normal pairs

  The dataset includes whole exome sequencing (WES) data on 57 matched esophageal tumor-normal pair. The Agilent Sure-Select Human All Exon V4 plus UTRs reagent was used to capture the target exons and UTRs and Illumina HiSeq 2000 instrument was used to sequence the target region with approximately 72-fold coverage.

  Dataset EGAD00001004542

• Tam-seq of tumor samples for HGSOC copy-number signatures study

  This dataset contains targeted amplicon sequencing of DNA extracted from 300 samples of 142 patients (158 methanol-fixed relapse biopsies and 142 FFPE archival diagnostic tissues). Samples were sequenced on Illumina HiSeq 2500 and were aligned to human genome assembly GRCh37 (hg19)to produce 600 bam files (2 technical replicates per sample).

  Dataset EGAD00001004173

• ENGAGE - Amendment "500 genes exon sequencing"

  The ENGAGE project is a FP7 funded EU project aiming to combine genetic and phenotype information from European population based cohorts. In this sub-project we aim to do whole exome sequencing of individuals selected from Health 2000 and FINRISK cohorts. Individuals have been selected based on their metabolic trait phenotypes

  Dataset EGAD00001000403

• Nimblegen

  The aim of this project is to identify rare variants in the 1q region associated with type 2 diabetes. To this end 651 case samples and 651 control samples from six populations have been pooled (pool sizes range from 27-33 individuals), and are being sequenced. The hybridization solution being used captures the exons and UTRs of genes in the 1q region.

  Dataset EGAD00001000424

• Ghana Breast Health Study

  The Ghana Breast Health Study (GBHS) was a multi-disciplinary, population-based case-control study conducted in Accra and Kumasi, Ghana that was designed to investigate breast cancer etiology in the West Africa region. The study enrolled 1,126 invasive breast cancer cases and 2,106 frequency matched population-based controls using census-based sampling. GHBS participants were between the ages of 18 to 74 years of age. Breast cancer cases were recruited at the time they presented with lesions suspicious of breast cancer at three hospitals: Korle Bu Teaching Hospital (Accra), Komfo Anoyke Teaching Hospital (Kumasi) and Peace and Love Hospital (Kumasi). These hospitals are the primary providers of treatment for breast cancer in Ghana, allowing for cases in our study to represent most breast cancers diagnosed in these areas during the study period. The following publications describe the GBHS in detail: 1) Brinton LA et al. Design considerations for identifying breast cancer risk factors in a population-based study in Africa. Int J Cancer 2017;140:2667-2677 (PMID:28295287). 2) Nyante SJ et al. Recruiting population controls for case-control studies in sub-Saharan Africa: The Ghana Breast Health Study. PloS one 2019;14:e0215347 (PMID:30990841)Among subjects with an available source of germline DNA genotyping was performed using the Infinium Global Screening Array-24 per the manufacturer’s guidelines using the Infinium automated protocol. We excluded probable duplicates and close relatives, and samples with a call rate < 95% or samples with extreme heterozygosity. Female sex was verified by Identifiler using X chromosome heterozygosity and the X chromosome inbreeding coefficient F statistics. The GLU genetics’ ld.tagzilla module was used to confirm African ancestry. To resolve more detailed population substructure, principal components analysis was conducted among all unrelated subjects using the EIGENSOFT v7.2.1. Imputation was performed using the Michigan imputation server Minimac3 with 1K genomes phase3 as reference panel.

  Study phs002387

• Assessment of Health-related Quality of Life in Rare Kidney Stones

  The purpose of this study is to learn about Health-related Quality Of Life (HRQoL) in patients enrolled in the Rare Kidney Stone Consortium (RKSC) registries. Quality of life studies look at different aspects of both physical and mental components of people's lives. HRQoL data for people affected by kidney stones are not currently available for people followed over time. All participants enrolled in the RKSC registries will be invited, via email or postal mail, to participate in this study. Health-related quality of life in people with rare kidney stones enrolled in the RKSC registries will be measured. Instruments used in this study are the SF-10 for pediatric participants and SF-36v2 for adult participants. The surveys will be completed online. Participants without a computer or internet access will participate using a paper version of the survey. These surveys will be done at enrollment and annually thereafter. The SF-36v2 includes 36 questions and is estimated to take 15 minutes for its completion, while the SF-10 includes 10 questions and could be completed in 5 minutes. The research questions are: Assessment of HRQoL in patients with rare kidney stones. Comparison of HRQoL results between rare kidney stone formers, general population and other populations with relevant chronic diseases. Comparison of HRQoL results in the same populations affected by different stones and analyzed with attention to the effects of various factors included in the disease registry, such as stone activity, burden of urologic interventions, medication and other treatments. Evaluation of HRQoL and its trends over time in patients undergoing treatment for rare kidney stones. About this study: The plan is to have 400 participants from all four registries take part in this multi-center study. The assessment of your HRQoL will be done annually for 5 years.

  Study phs001770

• Center for Common Disease Genomics [CCDG] - Cardiovascular: PEGASUS-TIMI 54

  This study is a part of NHGRI's Center for Common Disease Genomics, which is a collaborative large-scale genome sequencing effort to comprehensively identify rare risk and protective variants contributing to multiple common disease phenotypes. Current estimates anticipate that the CCDG program will sequence approximately 140K whole genomes and 225K whole exomes during the life of the project. The Cardiovascular Disease working group of the CCDG considered five diseases: early-onset coronary artery disease (EOCAD), stroke, atrial fibrillation, congestive heart failure and type 2 diabetes. Atrial fibrillation will affect between 6-12 million individuals in the US by 2050. AF also is associated with increased risks of stroke, dementia, heart failure, death, and high health care costs. Many risk factors for AF have been identified, including advancing age, cardiovascular disease (CVD), and CVD risk factors. However, there is little knowledge how to prevent AF. Furthermore, therapies for AF are only partially effective, and are themselves associated with substantial morbidity. Previously, heritable forms of AF have been considered rare; yet in the last decade, it has been established that AF, and in particular early-onset forms of AF, are heritable. Genome-wide association studies (GWAS) provide a powerful tool to identify common variants underlying disease risk. The AFGen Consortium currently consists of investigators from more than 25 studies with >20,000 individuals with AF and >100,000 without AF. In the latest analyses, 14 loci have been identified for AF1 . Broadly, the loci implicate genes related to cardiopulmonary development, cardiac-expressed ion channels, and cell signaling molecules. Source: ccdg.rutgers.eduFor this study, The Broad Institute of MIT and Harvard generated genetic data for 7,481 individuals from the PEGASUS-TIMI 54 clinical trial run by Brigham and Women's Hospital TIMI study group using whole exome sequencing and whole genome genotyping (Infinium Global Screening Array); all samples serving as controls.  

  Study phs002243

• Genome-wide Association Study for Non-syndromic Clefts in the African Population: CIDR

  The focus of this project is to identify genetic variants that are associated with orofacial clefts in African populations in sub-Saharan Africa. Most genetic studies of CLP (including the vast majority of GWAS) have been conducted in populations of European origin with only a few focused on Asian or African populations. We choose to study the genetics of these complex traits in African populations because, African populations have the greatest genetic variation amongst the various populations in the world by virtue of being the primary ancestral population to modern humans (Cavalli-Sforza and Feldman, 2003; Ramsay et al., 2011). Therefore, the potential for finding novel loci for CLP is quite high. To date 6 genome wide association studies (GWAS) for cleft lip with or without cleft palate (CL/P) have been conducted and 18 risk loci identified (Birnbaum et al., 2009; Grant et al., 2009 ; Beaty et al., 2010; Mangold et al., 2010; Ludwig et al., 2012; Sun et al., 2015). All these studies have either been conducted in European populations, Asian populations or both. There is currently no published GWAS for clefts in African populations. African populations represent a novel and richly productive populations for genetic and environmental exposure studies for CL/P. Investigating the presence of genetic variants in diverse population groups can identify novel variants and candidate genes that are population specific. Environmental factors may also increase the risks in certain population groups due to genetic susceptibility and/or specific exposures. Understanding the role these susceptibility genes play in the effects of environmental risk factors can inform strategies designed towards reducing the outcome of these complex traits, e.g. through the modification of the environmental influences. The study population comprises a large number of individuals (3205 individuals) from Africa (Ghana, Ethiopia and Nigeria). There are cases, case triads (nuclear families), as well as controls with no history of OFC nor other developmental defects.

  Study phs001090

• Uncovering RNA Signatures of C9orf72-Linked ALS and Related Disorders

  Substantial clinical and pathological variability has been reported in patients carrying an expanded repeat in C9orf72, who are generally diagnosed with amyotrophic lateral sclerosis (ALS) and/or frontotemporal dementia (FTD). Emerging evidence suggests that C9orf72 expression, RNA foci, and dipeptide-repeat proteins contribute to C9orf72-related diseases; however, the majority of the clinicopathological variability remains unexplained. We hypothesize that RNA sequencing (RNA-Seq) might reveal individual genes or groups of highly correlated genes (modules) that could account for this variability, which may help to identify much-needed druggable targets and/or biomarkers. Our preliminary studies performed in the frontal cortex, where we compared C9orf72 expansion carriers to (disease) controls, demonstrated that the top differentially expressed gene was C9orf72 itself. We also noticed that differentially expressed genes were enriched for the endocytosis pathway, which is consistent with the reported function of the C9orf72 protein in vesicle trafficking. Furthermore, we detected a module enriched for vesicular pathways, and additionally, we discovered an association with survival after onset for several promising candidates involved in vesicular transport. To find new therapeutic targets and biomarkers, here we have completed RNA-Seq on an increased number of samples to examine another relevant region: the cerebellum. As such, we performed RNA-Seq on a well-characterized cohort of C9orf72 expansion carriers, patients without this expansion, and control subjects without neurological diseases. We used multivariable linear regression models for gene-level analysis, weighted correlation network analysis for module-level analysis, and leafcutter for splicing analysis. Using the cerebellar RNA-Seq data, we found a large number (>6,000) of differentially expressed genes, with a notable increase in expression of homeobox genes in C9orf72 expansion carriers, as well as many gene modules that were associated with C9orf72 expansion status. Additionally, using leafcutter, we detected over 1,000 differential splicing events and an increase in the number of cryptic splicing events in C9orf72 expansion carriers.

  Study phs003065

• Discovery, Biology, and Risk of Inherited Variants in Breast Cancer (DRIVE) - Genome-Wide Association Study Meta-Analysis

  Discovery, Biology, and Risk of Inherited Variants in Breast Cancer (DRIVE) was one of five projects funded in 2010 as part of the NCI's Genetic Associations and Mechanisms in Oncology (GAME-ON) initiative (http://epi.grants.cancer.gov/gameon/). GAME-ON's overall goal was to foster an intra-disciplinary and collaborative approach to the translation of promising research leads deriving from the initial wave of cancer GWAS. Specific goals included replication of previous GWAS findings and identification of new susceptibility loci through meta analyses of existing GWAS data and fine mapping of identified loci to better pinpoint causal variants; and identify germline variants that are associated with risk of multiple cancers. The other four funded GAME-ON projects were: the ColoRectal TransdisciplinaryStudy (CORECT), Elucidating Loci Involved in Prostate Cancer Susceptibility (ELLIPSE), Follow-up of Ovarian Cancer Genetic Association and Interaction Study (FOCI), and Transdisciplinary Research in Cancer of the Lung (TRICL). To identify additional cancer risk loci, improve the precision of fine-mapping, and facilitate cross-cancer analyses, DRIVE investigators performed a meta-analysis of eleven genome-wide association studies of breast cancer: The Australian Breast Cancer Family Study (ABCFS), the British Breast Cancer Study (BBCS), the Breast and Prostate Cancer Cohort Consortium (BPC3), the Breast Cancer Family Registries (BCFR), the Dutch Familial Bilateral Breast Cancer Study (DFBBCS), German Consortium for Hereditary Breast and Ovarian Cancer (GC-HBOC), the Helsinki breast cancer family Study (HEBCS), the Mammary Carcinoma Risk factor Investigation (MARIE), the Singapore and Sweden Breast Cancer Study (SASBAC), the Triple Negative Breast Cancer Study (TNBC), and the UK2 GWAS. These studies comprised a total of 16,062 cases and 46,157 controls. Imputation to the 1,000 Genomes Project Phase 1 v3 ALL reference panel was performed by study, and summary statistics from each study were combined using fixed-effect meta analysis.

  Study phs001263

• Bone Microarchitecture

  Osteoporosis affects more than 28 million people in the United States and the lifetime risk for osteoporosis-related morbidity is higher than a woman's combined risk for breast cancer, endometrial cancer and ovarian cancer. Health care expenditures for osteoporotic patients in this country are currently nearly 13 billion dollars per annum and are predicted to increase markedly in the next decades due the aging of the population; therefore, it is important to understand the factors that contribute to bone strength and fracture risk. With the advent of skeletal imaging modalities such as high resolution peripheral quantitative computed tomography (HR-pQCT), it is now possible to study the genetics of more highly refined peripheral skeletal microarchitecture phenotypes. Because these refined phenotypes have not been measured in many cohort studies, this project was a collaborative effort to include almost all the existing data on HR-pQCT of the radius and tibia, and genetics from around the world. Cohorts involved in the discovery included: 1) Framingham Osteoporosis Study, 2) Mayo Clinic cohort; 3) Geneva Retirees cohort; 4) OFELY cohort from Lyon France; 5) STRAMBO cohort from Lyon France; 6) Swedish Male cohorts. Replication cohorts undergoing de novo genotyping include: 1) QUALYOR cohort from Lyon France; 2) CaMOS cohort from Canada. Other than the Framingham cohort and the Swedish male cohorts, all discovery cohorts underwent genome wide genotyping with the Affymetrix Axiom Biobank array that had common variants along with exome content based on the early findings from the Exome Sequencing Project. All genotype data from the discovery cohorts were then imputed using the Haplotype Reference Consortium reference panel. Variants for replication genotyping using the Kasp technology were selected based on novelty compared with previously identified loci using DXA phenotypes, minor allele frequency, underlying LD structure within a locus, and likelihood of a variant being functional as assessed using various algorithms for coding and non-coding variants.    

  Study phs002102

• Clonal Evolution and Heterogeneity of Osimertinib Acquired Resistance Mechanisms in EGFR Mutant Lung Cancer

  Current understanding of acquired resistance to osimertinib in EGFR-mutant lung cancer is largely based on the use of targeted sequencing platforms and cell-free DNA. In this study we examined the clonal evolution and heterogeneity of acquired resistance mechanisms to osimertinib through whole exome and RNA-sequencing of prospectively collected pre-and post-osimertinib resistant tumors and metastases at rapid autopsy. We enrolled 34 patients with histologically confirmed EGFR mutant advanced lung adenocarcinoma in a prospective Phase II clinical trial to evaluate osimertinib treatment and the use of local ablative therapy (LAT) for oligoprogressive disease (NCT02759835) in EGFR mutant NSCLC from April 2016 until data cutoff in September 2019. Patients were not selected based on oligometastatic status, rather 32/34 patients had multiple organ involvement, including lung, liver, adrenal, brain and bone. Biopsies or surgeries were performed pre-osimertinib treatment and at first progression on osimertinib. A subset of patients also underwent biopsies at second progression on osimertinib, and following end of life in-patient hospice and rapid autopsy upon death. 63% (n=15/24) of first-line osimertinib and 50% (n=5/10) of second-line osimertinib treated patients had RECIST defined partial response. Overall, 21 patients had RECIST defined first progression on osimertinib. Two patients on this trial discontinued treatment and were lost to follow up. Of the 21 patients who had RECIST defined progression, 14 patients underwent LAT (8 first-line and 6 second-line). Twelve patients had paired pre- and post-osimertinib resistant tumors and three had post-osimertinib resistant tumors available for analysis. Four patients (LAT002, LAT006, LAT014 and LAT021) consented for a rapid autopsy protocol and underwent rapid autopsy after deatH. To elucidate acquired osimertinib resistance mechanisms, we performed whole-exome (WES), targeted sequencing and RNA-seq on 66 tumors and matched germline DNA from tumor tissue obtained from a total of 15 patients.

  Study phs002001

• Autism Sequencing Consortium (ASC)

  The ARRA Autism Sequencing Collaboration was created in 2010 bringing together expert large-scale sequencing center (at the Baylor College of Medicine, PI Richard Gibbs and the Board Institute of MIT and Harvard, PI Mark J. Daly) and a collaborative network of research labs focused on the genetics of autism (brought together by the Autism Genome Project and the Autism Consortium). These groups worked together to utilize dramatic new advances in DNA sequencing technology to reveal the genetic architecture of autism through comprehensive examination of the exotic sequence of all genes. The Autism Sequencing Consortium (ASC) was founded by Joseph D. Buxbaum and colleagues as an international group of scientists who share autism spectrum disorder (ASD) samples and genetic data. The PIs are Drs. Joseph D. Buxbaum (Icahn School of Medicine at Mount Sinai), Mark J. Daly (Broad Institute of MIT and Harvard), Bernie Devlin (University of Pittsburgh School of Medicine), Kathryn Roeder (Carnegie Mellon University, Matthew State and Stephan Sanders (University of California, San Francisco). The rationale for the ASC is described in Buxbaum et al. 2012, and this paper should be cited when referencing the data set. All shared data and analysis is hosted at a single site, which enables joint analysis of large-scale data from many groups. The ASC was first supported by a cooperative agreement grant to four lead sites funded by the National Institute of Mental Health (U01MH100233, U01MH100209, U01MH100229, U01MH100239), with additional support from the National Human Genome Research Institute. The NIMH recently renewed their support with a second grant (U01MH111661, U01MH111660, U01MH111658 and U01MH111662) to expand the project from 29,000 genomes to more than 50,000 exomes over the next 5 years. NHGRI provides ongoing sequencing support for the ASD through the Broad Center for Common Disease Genomics (UM1HG008895, Mark Daly, PI).

  Study phs000298

• Gene Environment Association Studies (GENEVA): Genetics of Early Onset Stroke (GEOS) Study

  The Genetics of Early Onset Stroke (GEOS) Study is a population-based case-control study designed to identify genes associated with early-onset ischemic stroke and to characterize interactions of identified stroke genes and/or SNPs with environmental risk factors such as smoking and oral contraceptive use. The GEOS study consists of 921 ischemic stroke cases with age of first stroke 16-50 years and a similar number of controls, identified from the Baltimore-Washington area. Cases and controls were recruited in 3 different time periods: Stroke Prevention in Young Women-1 (SPYW-1) conducted from 1992-1996, Stroke Prevention in Young Women-2 (SPYW-2) conducted from 2001-2003, and Stroke Prevention in Young Men (SPYM) conducted from 2003-2007. The overall GEOS sample includes 477 cases who self-reported their race as "white" and 396 cases who self-reported their race as "African American." Traditional stroke risk factors and other study variables, including age, ethnicity, and history of hypertension, diabetes, myocardial infarction (MI), current smoking status, and current oral contraceptive use (both defined as use within one month prior to event for cases and at a comparable reference time for controls), were also collected during standardized interview and were included as covariates in our analyses. This study is part of the Gene Environment Association Studies initiative (GENEVA, http://www.genevastudy.org) funded by the trans-NIH Genes, Environment, and Health Initiative (GEI). The overarching goal is to identify novel genetic factors that contribute to early-onset ischemic stroke through large-scale genome-wide association studies of cases and controls of European and African descent from the Baltimore-Washington area. Genotyping was performed at the Johns Hopkins University Center for Inherited Disease Research (CIDR). Data cleaning and harmonization were done at the GEI-funded GENEVA Coordinating Center at the University of Washington.

  Study phs000292

• Center for Common Disease Genomics [CCDG] - Cardiovascular: ENGAGE Atrial Fibrillation-TIMI 48

  This study is a part of NHGRI's Center for Common Disease Genomics, which is a collaborative large-scale genome sequencing effort to comprehensively identify rare risk and protective variants contributing to multiple common disease phenotypes. Current estimates anticipate that the CCDG program will sequence approximately 140K whole genomes and 225K whole exomes during the life of the project. The Cardiovascular Disease working group of the CCDG considered five diseases: early-onset coronary artery disease (EOCAD), stroke, atrial fibrillation, congestive heart failure and type 2 diabetes. Atrial fibrillation will affect between 6-12 million individuals in the US by 2050. AF also is associated with increased risks of stroke, dementia, heart failure, death, and high health care costs. Many risk factors for AF have been identified, including advancing age, cardiovascular disease (CVD), and CVD risk factors. However, there is little knowledge how to prevent AF. Furthermore, therapies for AF are only partially effective, and are themselves associated with substantial morbidity. Previously, heritable forms of AF have been considered rare; yet in the last decade, it has been established that AF, and in particular early-onset forms of AF, are heritable. Genome-wide association studies (GWAS) provide a powerful tool to identify common variants underlying disease risk. The AFGen Consortium currently consists of investigators from more than 25 studies with >20,000 individuals with AF and >100,000 without AF. In the latest analyses, 14 loci have been identified for AF1. Broadly, the loci implicate genes related to cardiopulmonary development, cardiac-expressed ion channels, and cell signaling molecules.Source: https://ccdg.rutgers.edu/sites/default/files/CCDG_CVD_EOAF_FINAL_w_link.pdfFor this study, The Broad Institute of MIT and Harvard generated genetic data for 13,667 individuals from the ENGAGE AF-TIMI 48 clinical trial run by Brigham and Women's Hospital TIMI study group using whole exome sequencing and whole genome genotyping (Infinium Global Screening Array); all cases with atrial fibrillation.

  Study phs002774

• Genetic Epidemiology Network of Arteriopathy (GENOA)

  The Genetic Epidemiology Network of Arteriopathy (GENOA): GENOA is one of four research networks that form the NHLBI Family Blood Pressure Program (FBPP). From its inception in 1995, GENOA's long-term objective was to elucidate the genetics of hypertension and its arteriosclerotic target-organ damage, including both atherosclerotic (macrovascular) and arteriolosclerotic (microvascular) complications involving the heart, brain, kidneys, and peripheral arteries. Two GENOA cohorts were originally ascertained (1995-2000) through sibships in which at least 2 siblings had essential hypertension diagnosed prior to age 60 years. All siblings in the sibship were invited to participate, both normotensive and hypertensive. These include non-Hispanic White Americans from Rochester, MN (n =1583 at the 1st exam) and African Americans from Jackson, MS (N=1854 at the 1st exam). During the second exam (2000-2005), approximately 80% of participants were re-recruited. The GENOA data consists of biological samples (DNA, serum, urine) as well as demographic, anthropometric, environmental, clinical, biochemical, physiological, and genetic data for understanding the genetic predictors of diseases of the heart, brain, kidney, and peripheral arteries. Family Blood Pressure Program (FBPP): GENOA's parent program, the FBPP, is an unprecedented collaboration to identify genes influencing blood pressure (BP) levels, hypertension, and its target-organ damage. This program has conducted over 21,000 physical examinations, assembled a shared database of several hundred BP and hypertension-related phenotypic measurements, completed genome-wide linkage analyses for BP, hypertension, and hypertension associated risk factors and complications, and published over 130 manuscripts on program findings. The FBPP emerged from what was initially funded as four independent networks of investigators (HyperGEN, GenNet, SAPPHIRe and GENOA) competing to identify genetic determinants of hypertension in multiple ethnic groups. Realizing the greater likelihood of success through collaboration, the investigators began working together during the first funding cycle (1995-2000) and formalized this arrangement in the second cycle (2000-2005), creating a single confederation with program-wide and network-specific goals.

  Study phs000379

• A Scalable, GMP-Compatible, Autologous Organotypic Cell Therapy for Dystrophic Epidermolysis Bullosa

  Gene editing in induced pluripotent stem (iPS) cells has been hailed for enabling new cell therapies for various monogenetic diseases including dystrophic epidermolysis bullosa (DEB). However, manufacturing, efficacy, and safety roadblocks have limited the development of genetically corrected, autologous iPS cell-based therapies. Dystrophic Epidermolysis Bullosa Cell Therapy (DEBCT), is a new generation, Good Manufacturing Practice-compatible (cGMP), reproducible, and scalable platform to produce autologous clinical-grade iPS cell-derived organotypic induced skin composite (iSC) grafts to treat incurable wounds of patients lacking type VII collagen (C7). DEBCT uses a single step, combined, high-efficiency reprogramming, and CRISPR-based genetic correction to generate genome scar-free, COL7A1 corrected clonal iPS cells from primary patient fibroblasts. Validated iPS cells are converted into epidermal, dermal, and melanocyte progenitors with a novel 2D organoid differentiation protocol, followed by CD49f enrichment and expansion to minimize maturation heterogeneity. iSC product characterization by single cell transcriptomics was followed by mouse xenografting for disease correcting activity at 1 month and toxicology analysis at 1-6 months. Culture-acquired mutations, potential CRISPR-off target effects, and cancer-driver variants were evaluated by targeted and whole genome sequencing. iPS cell-derived iSC grafts were reproducibly generated from four recessive DEB patients with different pathogenic mutations. Organotypic iSC grafts onto immune-compromised mice developed into stable stratified skin with functional C7 restoration. Single cell transcriptomic characterization of iSCs revealed prominent holoclone stem cell signatures in keratinocytes and the recently described Gibbin-dependent signature in dermal fibroblasts. The latter correlated with enhanced graftability. Multiple orthogonal sequencing and subsequent computational approaches identified random and non-oncogenic mutations introduced by the manufacturing process. Toxicology revealed no detectable tumors after 3-6 months in DEBCT-treated mice. In conclusion, DEBCT successfully overcomes previous roadblocks and establishes a robust, scalable, and safe cGMP manufacturing platform for the production of a CRISPR-corrected autologous organotypic skin graft to heal DEB patient wounds.

  Study phs003271

• Structure and Diversity of Urinary Cell-Free DNA Informative of Host-Pathogen Interactions in Human Urinary Tract Infection

  The risk of acquiring urinary tract infection (UTI) is very high for patients who have received kidney transplants; nearly half will develop bacteriuria and an eighth viruria via BK polyomavirus in the first three years following transplantation. Current methodology for diagnosing viral and bacterial infections, while well practiced, is often limited in scope. The advent of next generation sequencing of cell-free DNA has shown promise in its ability to capture multiple perspectives of human health from discovering the origin of cell-free DNA in plasma; such a diagnostic has not been readily applied to urinary cell-free DNA. In this study, we selected 141 urine samples from a cohort of kidney transplant patients, which were collected and stored at Weill Cornell Medical College - New York Presbyterian Hospital. Of these samples, 43 samples were determined to be culture positive (> 10,000 CFU) for one or more bacterial species, including E. coli, Enterococcus, Klebsiella, Haemophilus, and Raoultella. A separate 23 samples were confirmed for BK virus nephropathy, with presence of BK polyomavirus confirmed via qPCR. We also included 29 samples from 14 patients who did not develop UTIs in the first three months following transplantation, and 11 samples that were negative for BK virus nephropathy. For a full description of samples, please see the Supplementary Data 1 in https://pubmed.ncbi.nlm.nih.gov/29925834/. From these urine samples, we aimed to capture and sequence urinary cell-free DNA using a single-stranded library preparation. In addition, we performed whole-genome bisulfite sequencing to 170 plasma samples collected from 27 hematopoietic cell transplant patients who developed graft-versus host disease and BK polyomavirus infection. We also performed Sample-Intrinsic microbial DNA Found by Tagging and sequencing (SIFT-seq) on 196 cell-free DNA (cfDNA) samples (154 plasma and 42 urine) collected from five groups of subjects. For a full description of samples, please see publications in PMID: 35864089 and PMID: 35058359.

  Study phs001564

• Genomic Basis of Phenotypic Variability of Complex Disorders

  The 520-kbp deletion on chromosome 16p12.1 is associated with multiple neurodevelopmental outcomes, including intellectual disability/developmental delay (ID/DD), schizophrenia, autism, and epilepsy. This variant is inherited in >95% of cases from carrier parents manifesting neuropsychiatric features, while affected children with the deletion were more likely to carry another large Copy Number Variation (CNV) or rare deleterious mutation elsewhere in the genome, or "second-hits", compared to carrier parents. Thus, while the 16p12.1 deletion confers significant risk for a range of disorders, the ultimate phenotypic trajectory is determined by "second-hit" variants in the genetic background. However, outstanding questions remain about the genetic background in these disorders, including the functional effects of "second-hit" variants towards gene expression or developmental phenotypes, the full spectrum of "second-hit" variants, and the mechanisms driving accumulation of these variants.In version 1, we performed deep clinical phenotyping, whole-genome sequencing (WGS), SNP microarray analysis, and RNA-sequencing of lymphoblastoid cell lines of 32 individuals in five large families with the 16p12.1 deletion. We found that specific classes of rare single-nucleotide and structural variants in coding and non-coding regions contributed towards expression changes in affected children based on their inheritance patterns, including a subset of variants that acted synergistically with the deletion to alter expression. We further found that rare variant-mediated expression changes contribute to specific developmental phenotypes in the carrier children, suggesting a potential genetic mechanism for variable expressivity of the deletion.In version 2, we additionally analyzed genetic and phenotypic data from individuals with 16p12.1 deletion and their spouses to assess the role of assortative mating modulating phenotypic outcomes of the 16p12.1 deletion. We identified significant within- and cross- disorder phenotypic correlations between spouses, but observed no significant genetic correlations between spouses, in line with expectations.

  Study phs002450

• International Cancer Proteogenome Consortium (ICPC): Proteogenomics of Oral Squamous Cell Carcinoma in Taiwan

  Oral cavity squamous cell carcinoma (OSCC) is the major subtype (~90%) of oral cancer, which is leading cancer with high mortality worldwide. The environmental risk factors associated with OSCC are quite different in Taiwan as compared to other populations. In most non-Taiwanese populations, OSCC is often associated with tobacco chewing, cigarette smoking, alcohol drinking, or human papillomavirus (HPV) infection. In Taiwan, in contrast, the OSCC occurs mainly in males aged 30 years or older who have habitual betel nut chewing, cigarette smoking, and alcohol drinking. To uncover molecular mechanisms and identify new therapeutic strategies of oral squamous cell carcinoma, this study recruited 112 treatment-naïve OSCC patients and generated multi-omics data, including WES, RNA-Seq, TMT-labeled proteomes, and phosphoproteomes from paired normal/tumor tissues. We have investigated our multi-omics data, covering molecular characterizations such as mutation signatures, impacts of mutations on RNA/protein/phosphoprotein, RNA-protein correlation, somatic copy number alteration, and the relationship with RNA & protein, proteome, and phosphoproteome analysis (T vs NAT), novel peptides (somatic variants, neoantigens, CT antigens, T cell receptors, etc.), as well as molecular subtyping (& pathway analysis). Notably, we have discovered a higher frequency of APOBEC3B deletion polymorphism in the Taiwanese population, and APOBEC3A is a potential prognostic biomarker. Our proteogenomic data enable us to further stratify patients into four groups based on APOBE3A expression level, which is found inversely correlated with EGFR expression. Therefore, the patients with high EGFR and low APOBEC3A expression may benefit from anti-EGFR therapy, while those with low EGFR and high APOBEC3A expression may benefit from immunotherapy. To clarify if there is an interaction between genetic polymorphisms and betel nut chewing habit in Taiwanese OSCC, we plan to concurrently evaluate the effect of habitual betel nut chewing on the gene mutation pattern, the dysregulated protein/phosphoproteins as novel biomarkers and/or therapeutic targets, and the molecular subtyping of patients for effective treatments. 

  Study phs002580

• Ipilimumab plus Decitabine for Patients with MDS or AML in Post-Transplant or Transplant Naïve Settings

  Design and AimsThis study was a phase 1 clinical trial investigating the combination of ipilimumab (IPI), a CTLA-4 checkpoint inhibitor, and decitabine (DEC), a hypomethylating agent, for treating relapsed/refractory (R/R) myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). The goal was to determine whether DEC could enhance the immune response to IPI without causing excessive immune toxicity. This study provides important insights into the use of immune checkpoint inhibitors with hypomethylating agents in treating high-risk MDS/AML and highlights the need for further research on optimizing immune-based therapies in these settings.Population InformationPost-HSCT arm: 25 patients (23 AML, 2 MDS; all relapsed/refractory).Transplant-naïve arm: 23 patients (15 AML, 8 MDS; 20 relapsed/refractory, 3 untreated).Data available through dbGaPDeidentified individual participant data, Multiplex immunofluorescence staining, Olink, RNA-Seq and Whole Exome SequencingPrincipal FindingsSafety & Tolerability: The maximum tolerated dose (MTD) for IPI was determined to be 10 mg/kg, though higher doses were associated with increased immune-related adverse events (irAEs).Efficacy: The overall response rate (ORR) was higher in transplant-naïve patients (52%) compared to post-HSCT patients (20%).Responses were more frequent at higher IPI doses (10 mg/kg). Some patients achieved durable remission (>1 year), often linked to irAE development.Toxicity: The most common grade ≥3 treatment-emergent adverse events included neutropenia (32%-48%), thrombocytopenia (28%-48%), and febrile neutropenia (36%-61%). irAEs were observed in 44%-48% of patients, with GVHD occurring only in the post-HSCT group.Survival Outcomes: Median overall survival and progression-free survival did not significantly differ between the two arms. However, in transplant-naïve patients, 1-year survival was higher in those who developed irAEs (72.7%) versus those who did not (33.3%).

  Study phs003292

• Perceptions, Prevalence, and Patterns of Cannabis Use among Cancer Patients in NCI-Designated Cancer Centers

  This study aimed to better understand the evolving landscape of cannabis use among patients undergoing cancer treatment across diverse geographic regions. It sought to characterize patterns of use, patient perceptions, and contextual influences such as legal status and provider engagement that affect cannabis use. Given the shifting legal environment, this study addresses a critical gap in the literature by providing data on how cancer patients integrate cannabis into their care. The available delivery methods of cannabis have also undergone dramatic changes and now include edibles, oils, tinctures, topicals, and inhaled forms. State-based policy changes are rapidly changing. Yet research on cannabis use by cancer patients across a variety of geographic settings remains limited. The extent of cannabis use, the perceived and real benefits and risks of use, potential interactions with cancer treatment and other medications, and impact on comorbid conditions are uncertain. Clinicians should be aware of the extent of use in order to assess potential drug-drug interactions, side effects, and contraindications; hence, an understanding of how cancer patients and clinicians engage in discussions about cannabis use is essential. Twelve NCI-designated cancer centers were awarded supplemental funding to conduct surveys assessing cannabis use among recently diagnosed cancer patients. Selected sites were in 8 states with varied legal status for medical and recreational cannabis use at the time of the survey. The 12 cancer centers independently received approval from their institutional review boards (IRB) and collected data from September 2021 to August 2023. Eligible participants were cancer patients or survivors who resided in their respective cancer center's catchment area. Cancer centers were responsible for sampling patients within their catchment area with the goal of 1,000 completed surveys. Ten out of 12 cancer centers drew probability samples of patients from patient lists defining their catchment area with some stratifying the sample in various ways including by cancer type, by sex, by race/ethnicity or by a combination of demographic variables.

  Study phs004046

• POU4F3 mutation screening in Japanese hearing loss patients.

  A variant in a transcription factor gene, POU4F3, is responsible for autosomal dominant nonsyndromic hereditary hearing loss, DFNA15. To date, 14 variants, including a whole deletion of POU4F3, have been reported to cause HL in various ethnic groups. In the present study, genetic screening for POU4F3 variants was carried out for a large series of Japanese hearing loss (HL) patients to clarify the prevalence and clinical characteristics of DFNA15 in the Japanese population. Massively parallel DNA sequencing of 68 target candidate genes was utilized in 2,549 unrelated Japanese HL patients (probands) to identify genomic variations responsible for HL. The detailed clinical features in patients with POU4F3 variants were collected from medical charts and analyzed. Novel 12 POU4F3 likely pathogenic variants (six missense variants, three frameshift variants, and three nonsense variants) were successfully identified in 15 probands (2.5%) among 602 families exhibiting autosomal dominant HL, whereas no variants were detected in the other 1,947 probands with autosomal recessive or inheritance pattern unknown HL. To obtain the audiovestibular configuration of the patients harboring POU4F3 variants, we collected audiograms and vestibular symptoms of the probands and their affected family members. Audiovestibular phenotypes in a total of 24 individuals from the 15 families possessing variants were characterized by progressive HL, with a large variation in the onset age and severity with or without vestibular symptoms observed. Pure-tone audiograms indicated the most prevalent configuration as mid-frequency HL type followed by high-frequency HL type, with asymmetry observed in approximately 20% of affected individuals. Analysis of the relationship between age and pure-tone average suggested that individuals with truncating variants showed earlier onset and slower progression of HL than did those with non-truncating variants. The present study showed that variants in POU4F3 were a common cause of autosomal dominant HL.

  Study JGAS000093

• Molecular analysis of diffuse cerebellar gliomas

  Among diffuse gliomas, oligodendrogliomas show relatively better prognosis, respond well to radiotherapy and chemotherapy, and seldom progress to very aggressive tumors. To elucidate the genetic and epigenetic background for such behavior and tumor evolution during tumor relapse, we comparatively analyzed 12 pairs of primary and recurrent oligodendrogliomas with 1p/19q-codeletion. Initial treatment for these patients was mostly chemotherapy alone. Temozolomide was used for 3, and procarbazine, nimustine and vincristine (PAV chemotherapy) were used for 7 patients. World Health Organization histological grade at recurrence was mostly stable; it was increased in 2, the same in 9, and decreased in 1 cases. Whole-exome sequencing demonstrated that the rate of shared mutation between the primary and recurrent tumors was relatively low, ranging from 3.2-57.9% (average, 33.3%), indicating a branched evolutionary pattern. The trunk alterations that existed throughout the course were restricted to IDH1 mutation, 1p/19q-codeletion, and TERT promoter mutation, and mutation of the known candidate tumor suppressor genes CIC and FUBP1 were not consistently observed between primary and recurrent tumors. Multiple sampling from different regions within a tumor showed marked intratumoral heterogeneity. Notably, in general, the number of mutations was not significantly different after recurrence, remaining under 100, and no hypermutator phenotype was observed. FUBP1 mutation, loss of chr. 9p21, and TCF12 mutation were among a few recurrent de novo alterations that were found at recurrence, indicating that these events were clonally selected at recurrence but were not enough to enhance malignancy. Genome-wide methylation status, measured by Illumina 450 K arrays, was stable between recurrence and the primary tumor. In summary, although oligodendroglioma displays marked mutational heterogeneity, histological malignant transformation accompanying events such as considerable increase in mutation number and epigenetic profile change were not observed at recurrence, indicating that noticeable temporal and spatial genetic heterogeneity in oligodendrogliomas does not result in rapid tumor progression.

  Study JGAS000106

• A prospective study identifies MisMatch Repair genes as candidate predisposing genes for uveal melanoma.

  Objective: The aim of this study is to identify new predisposing genes for uveal melanoma (UM), the most common intraocular malignancy in adults. Design: Prospective cohort study from Institut Curie. Participants: 381 unselected patients diagnosed with UM between July 2021 and February 2023 at Institut Curie. Methods: All patients received genetic counseling and consented to extended genetic testing. A panel of 122 genes was analyzed by targeted sequencing on germline DNA from these patients. Main outcomes measures: UM was diagnosed by ophthalmologists at Institut Curie, and a senior pathologist confirmed the diagnosis when tumor or biopsy was available. Classification of the germline genetic variants was performed according to the ACMG guidelines. Results: We identified at least one pathogenic variant (PV) in 79 patients. Among those variants, 20 were found in clinically relevant genes for the patient’s follow-up and genetic counseling. We found a significant enrichment of germline pathogenic variants in Mismatch Repair (MMR) MLH1, MSH2 and MSH6 genes in this UM cohort, suggesting that MMR germline alterations could predispose to UM. From this cohort, one tumor was available from a patient carrying a MLH1 germline mutation. The tumor was characterized by a monosomy 3, in line with a loss of heterozygosity (LOH) of MLH1, located on chromosome 3. Loss of expression of MLH1 and PMS2 was observed by immunohistochemistry, and MMR mutational signatures SBS6, ID1 and ID2 were identified from the whole genome sequencing of the tumor. These data suggest that MLH1 is implicated in the oncogenesis of this UM. Conclusions: This study is the largest prospective constitutional study performed on UM patients, and the first demonstrating that MMR germline alterations are significantly enriched among these patients. Further analyses will be needed to estimate the risk of developing UM for patients with Lynch syndrome

  Study EGAS50000000914

• Emirati Genome Project subset of 43,608 WGS samples for population-scale variant discovery and allele frequency mapping.

  Here, we present a comprehensive genomic characterization of a cohort of 43,608 Emirati genomes sequenced as part of the Emirati Genome Program (EGP). This study identified more than 421 million single nucleotide variants and indels and more than 600 million copy number- and structural variants. Small variants had 756 million molecular effects annotated. Of the identified variants, 69.04% were observed with more than one allele. Of 7.7 million polymorphic variants having an allele frequency (AF) of more than 5% in EGP, 1,348 have a predicted deleterious effect on a protein. Characterization of global variation reveals that EGP represents a genetic continuum encompassing the range of African, Asian, and European populations. It is best described by two Arabian, an Eurasian, and an African component, with the predominant Arabian component linked to mitochondrial haplogroups J and T, which are commonly attributed to the Middle East. Various aneuploidies of sex chromosomes were detected in 93 individuals overall and of chromosome 21 in 41 individuals. The median inbreeding coefficient and cumulative runs of homozygosity (ROHs) lengths were increased due to extensive consanguinity, being largest in the groups with Arabian main ancestry components and higher than reported for Qatar. Families were identified based on genetic relatedness and classified into 264 families with unrelated parents and 247 families with third- and fourth-degree consanguineous parents. Representative consanguineous pedigrees of families in EGP were outlined. Cumulative ROHs were affected by the main ancestry component and significantly increased in offspring of consanguineous parents, with a pronounced difference between 3rd and 4th-degree relatedness. Investigation of cumulative AFs of variants causing Mendelian diseases highlighted genes related to alpha- and beta-thalassemia (HBB, HBA2). It showed a high burden of variants causing severe recessive diseases, metabolic and retinal disorders, and hearing loss. In summary, EGP represents a landmark effort in characterizing the genetic diversity of the Emirati population, leveraging the largest Middle Eastern cohort reported to date.

  Study EGAS50000001071

• Identification of intronic sequences promoting natural skipping of ABCA4 exon 15 using long-read transcriptomics and midigene assays

  Stargardt disease is an inherited retinal disease that leads to progressive loss of vision, and is caused by biallelic variants in the ABCA4 gene. A significant proportion of ABCA4 variants of variable penetrance affect pre-mRNA splicing. Previously, we observed the exclusion of certain ABCA4 exons into the final transcript in the absence of any disease-causing variants. In this study, we explored this phenomenon that we coined natural exon skipping (NES) for the entire ABCA4 transcript, using targeted RT-PCR analysis as well as long-read transcriptome sequencing of control retina samples. For the most abundant NES event, which is skipping of ABCA4 exon 15, overlapping ABCA4 deletion constructs were employed to identify responsible cis-regulatory sequence motifs. Subsequently, antisense oligonucleotides (AONs) were designed and tested to reverse NES and restore fully-spliced ABCA4 mRNA. We identified intronic regions on each side of exon 15 that, when deleted, increased the inclusion of exon 15 in the final transcripts. Interestingly, these motifs appear to work in a synergistic manner. Further fine-mapping of these regions revealed several cis-regulatory motifs that may be responsible for inducing NES, on each side of the exon. AONs targeting these motifs unfortunately did not decrease the skipping of exon 15. In conclusion, we discovered an intriguing phenomenon that, in the absence of disease-causing variants, results in the skipping of one or more exons in the ABCA4 transcript. These NES events appear to be regulated by cis-regulatory motifs within the flanking introns. This work captured the extend of NES throughout ABCA4 transcript and the role of cis-regulatory motifs in pre-mRNA splicing.. The use of AONs targeting cis-regulatory motifs is an innovative strategy for splicing modulation, suitable for complementing future variant-specific splicing modulation therapies in ABCA4 retinopathies.

  Study EGAS50000000071

• High-throughput telomere length measurement at nucleotide resolution using the PacBio high fidelity sequencing platform

  Telomeres are specialized nucleoprotein structures at the ends of linear chromosomes that are essential for the stability as well as the complete replication of the human genome. The progressive shortening of steady-state telomere length in normal human somatic cells is a promising biomarker for age-associated diseases. However, there remain substantial challenges in quantifying telomere length in clinics and research laboratories due to the lack of accurate and high-throughput telomere length measurement method. Here, we describe a novel workflow to capture and analyze telomeres accurately at the single-nucleotide resolution. By using newly designed telobaits that are complementary to the single-stranded G-rich 3’ telomeric overhangs, we can specifically and efficiently capture full-length telomeres and subject them to single-molecule real-time (SMRT) sequencing. We show that the telomere length can be measured at nucleotide resolution using the PacBio high fidelity (HiFi) sequencing platform, which provides the necessary accuracy and throughput to uncover the steady-state telomere length distribution in human culture cell lines as well as clinical patient samples. This new method is a valuable tool not only in population-wide epidemiology studies but also for the longitudinal assessment of telomere attrition in individuals. Our results also reveal the extreme heterogeneity of telomeric variant sequences (TVSs) that is dispersed throughout the telomere repeat region. Importantly, the unique distribution pattern and sequence of TVSs in individuals may be used as a fingerprint for sample identification. In addition, the presence of TVSs disrupts the continuity of the canonical (5’-TTAGGG-3’)n telomere repeats, which could affect the binding of shelterin complexes at the chromosomal ends. Therefore, TVSs may act as a form of genetic polymorphisms that impairs telomere protection. Together with the absolute telomere length in each individual, TVSs may have profound implications in human aging and diseases.

  Study EGAS00001006103

• Liver biopsy derived induced pluripotent stem cells provide an unlimited supply for the generation of patient-specific hepatocyte-like cells

  Background: Hepatocyte-like cells (HLCs) differentiated from induced pluripotent stem cells (iPSCs) have emerged as a promising cell culture model to study metabolism, biotransformation, viral infections and genetic liver diseases. However the derivation of iPSCs is restricted by ethical and procedural constraints. Furthermore, incomplete HLC differentiation remains a major challenge. iPSC may carry-on a tissue of origin dependent expression memory influencing iPSC differentiation into different cell types. If liver derived iPSCs (Li-iPSCs) maintain a liver specific gene expression profile is not known. It is also not known, if Li-iPSCs would allow the generation of more fully differentiated HLCs.Methods: Primary liver cells (PLCs) were expanded from liver needle biopsies and reprogrammed into Li-iPSCs using a non-integrative Sendai virus-based system. Li-iPSCs were differentiated into HLCs using established differentiation protocols. The HLC phenotype was characterized at the protein, functional and transcriptional level. RNA sequencing data were generated from the originating liver biopsies, the Li-iPSCs, fibroblast derived iPSCs, and differentiated HLCs, and used to characterize and compare their transcriptome profiles.Results: PLCs were obtained from small pieces of liver biopsies and could be reprogrammed into Li-iPSCs. Li-iPSCs indeed retain a liver specific transcriptional footprint. Li-iPSCs can be propagated to provide an unlimited supply of cells for differentiation into Li-HLCs. Similar to HLCs derived from fibroblasts, Li-HLCs could not be fully differentiated into hepatocytes. Relative to the originating liver, Li-HLCs showed lower expression of liver specific transcription factors and increased expression of genes involved in the differentiation of other tissues.Conclusions: PLCs and Li-iPSCs obtained from small pieces of human needle liver biopsies constitute a novel unlimited source for the production of HLCs. Despite the preservation of a liver specific gene expression footprint in Li-iPSCs, the generation of fully differentiated hepatocytes cannot be achieved with the current differentiation protocols.

  Study EGAS00001002676

• Local In Time Statistics for processual research

  Background: Functional genomics in a processual analysis cover the time-dependent changes in transcriptomics and epigenetics before diagnosis of a disease, reflecting the changes in both life style and disease processes. The aim of this paper is to explore the dynamic, time-dependent mechanisms of the metastatic processes, using blood transcriptomics and including time in a continuous manner. For achieving this goal we develop new statistical methods based on statistics that are local in time. Methods: The new statistical method, Local In Time Statistics (LITS), is based on calculating statistics in moving windows and randomization. The method has been tested for the analysis of a dataset that collectively provides information on the blood transcriptome up to eight years before breast cancer diagnosis. The dataset from the NOWAC Post-genome Cohort consists of 467 case-control pairs matched on birth year and time of blood sampling. The data for a pair is the difference in log2 gene expression between the case and control. The stratified analyses are based on important biological differences like metastatic versus non-metastatic cancer, and the mode of cancer detection, i.e. screening detected versus clinically detected cancers. The dataset was used for examining whether the gene expression profile varies between cases and controls, with time, or between cases with and without metastases. Results: The null hypotheses of no differences between cases and controls, no time-dependent changes, and no differences between different strata were all rejected. For screening detected cancers the probability of correct prediction of metastasis status was best in year 1 before diagnosis compared to year 3 and 4 before diagnosis for clinically detected cancers. The predictor was not very sensitive to the number of genes included.Conclusions: Using a new statistical method, LITS, we have demonstrated time-dependent changes of the blood transcriptome up to eight years before breast cancer diagnosis.

  Study EGAS00001002520

• Short and long-read genome sequencing methodologies for somatic variant detection; genomic analysis of a patient with diffuse large B-cell lymphoma

  Recent advances in throughput and accuracy mean that the Oxford Nanopore Technologies (ONT) PromethION platform is a now a viable solution for WGS. New bioinformatic methods have been developed to take advantage of this long read data, however much of the validation of these tools has focussed on calling germline variants (both SNVs and structural variants). Somatic variants are outnumbered many-fold by germline variants and their detection is further complicated due to their frequency varying depending on tumour purity/subclonality. Here, we evaluate the extent to which Nanopore WGS enables genome-wide detection and analysis of somatic variation. We do this through sequencing tumour and germline genomes for a patient with diffuse B-cell lymphoma. We examine the capability of currently available tools for calling somatic variants in ONT data by comparing the data with results from 150bp short-read sequencing of the same samples. We then conduct a detailed analysis of the performance of multiple long-read mappers and structural variant callers for calling large, somatic structural variants (SVs) in ONT data. Our protocol achieved yields of up to 96 mapped Gb per PromethION flow cell with average read lengths of ~5kb. Calling germline SNVs from these data achieved good specificity and sensitivity. However, results of somatic SNV calling highlight the need for the development of specialized joint calling algorithms. Our analysis of structural variants shows that the comparative performance of different tools varies significantly between SV types, and suggest long reads are especially advantageous for calling large somatic deletions and duplications. Finally, we highlight the utility of long reads for phasing clinically relevant variants by using the ONT data to confirm that a somatic 1.6Mb deletion and a p.(Arg249Met) mutation involving TP53 are oriented in trans.

  Study EGAS00001004266

• High-throughput telomere length measurement at nucleotide resolution using the PacBio high fidelity sequencing platform, P49-P104 and run1 replicates

  Telomeres are specialized nucleoprotein structures at the ends of linear chromosomes that are essential for the stability as well as the complete replication of the human genome. The progressive shortening of steady-state telomere length in normal human somatic cells is a promising biomarker for age-associated diseases. However, there remain substantial challenges in quantifying telomere length in clinics and research laboratories due to the lack of accurate and high-throughput telomere length measurement method. Here, we describe a novel workflow to capture and analyze telomeres accurately at the single-nucleotide resolution. By using newly designed telobaits that are complementary to the single-stranded G-rich 3’ telomeric overhangs, we can specifically and efficiently capture full-length telomeres and subject them to single-molecule real-time (SMRT) sequencing. We show that the telomere length can be measured at nucleotide resolution using the PacBio high fidelity (HiFi) sequencing platform, which provides the necessary accuracy and throughput to uncover the steady-state telomere length distribution in human culture cell lines as well as clinical patient samples. This new method is a valuable tool not only in population-wide epidemiology studies but also for the longitudinal assessment of telomere attrition in individuals. Our results also reveal the extreme heterogeneity of telomeric variant sequences (TVSs) that is dispersed throughout the telomere repeat region. Importantly, the unique distribution pattern and sequence of TVSs in individuals may be used as a fingerprint for sample identification. In addition, the presence of TVSs disrupts the continuity of the canonical (5’-TTAGGG-3’)n telomere repeats, which could affect the binding of shelterin complexes at the chromosomal ends. Therefore, TVSs may act as a form of genetic polymorphisms that impairs telomere protection. Together with the absolute telomere length in each individual, TVSs may have profound implications in human aging and diseases.

  Study EGAS00001006595

• Whole genome and whole exome sequencing of serial biopsies of relapsed/refractory diffuse large B-cell lymphoma.

  Purpose: Diffuse large B-cell lymphoma (DLBCL) is cured in more than 60% of patients, but outcomes remain poor for patients experiencing disease progression or relapse (refractory or relapsed DLBCL [rrDLBCL]), particularly if these events occur early. Although previous studies examining cohorts of rrDLBCL have identified features that are enriched at relapse, few have directly compared serial biopsies to uncover biological and evolutionary dynamics driving rrDLBCL. Here, we sought to confirm the relationship between relapse timing and outcomes after second-line (immuno)chemotherapy and determine the evolutionary dynamics that underpin that relationship. Patients and methods: Outcomes were examined in a population-based cohort of 221 patients with DLBCL who experienced progression/relapse after frontline treatment and were treated with second-line (immuno)chemotherapy with an intention-to-treat with autologous stem-cell transplantation (ASCT). Serial DLBCL biopsies from a partially overlapping cohort of 129 patients underwent molecular characterization, including whole-genome or whole-exome sequencing in 73 patients. Results: Outcomes to second-line therapy and ASCT are superior for late relapse (>2 years postdiagnosis) versus primary refractory (<9 months) or early relapse (9-24 months). Diagnostic and relapse biopsies were mostly concordant for cell-of-origin classification and genetics-based subgroup. Despite this concordance, the number of mutations exclusive to each biopsy increased with time since diagnosis, and late relapses shared few mutations with their diagnostic counterpart, demonstrating a branching evolution pattern. In patients with highly divergent tumors, many of the same genes acquired new mutations independently in each tumor, suggesting that the earliest mutations in a shared precursor cell constrain tumor evolution toward the same genetics-based subgroups at both diagnosis and relapse. Conclusion: These results suggest that late relapses commonly represent genetically distinct and chemotherapy-naïve disease and have implications for optimal patient management.

  Study EGAS00001007053

• Exome Sequencing to Identify Medically Relevant Associations in Finnish Sub-Isolate Samples from the FINRISK Cohort

  We propose to undertake, at the McDonnell Genome Institute of Washington University, a collaborative exome sequencing project of ~10,000 samples from a large Finnish population cohort, FINRISK, a participating component of the Sequencing Initiative Suomi (SISu) consortium. Together these sequenced samples will provide a unique resource for identification of infrequent or rare variants with a large impact on cardiovascular and metabolic disorders as well as on a wide range of heritable, disease-related quantitative phenotypes. Our collaborative group has already shown, in exome sequencing studies of smaller Finnish samples, that numerous loss of function variants are dramatically more frequent in Finland compared to other European populations, and that such variants demonstrate strong associations to several disease-related traits. Finland is the largest population isolate in Europe and the enrichment of these variants reflects its rapid growth from a severe population bottleneck about 100 generations ago. Northern and Eastern parts of Finland experienced additional, more recent bottlenecks, and therefore the enrichment of particular high-impact variants in these regions is even more extreme (Stoll et al., 2013, PMID: 23912948). We therefore propose to focus exome sequencing efforts on about 10,000 members of FINRISK who are specifically drawn from these sub-isolate regions. As a very wide range of phenotypes are available from this cohort (including cardiovascular and metabolic disease outcomes obtained from national registries) we hypothesize that the proposed exome sequencing will identify numerous new disease-related associations. Within the National Biobanks of Finland (www.nationalbiobanks.fi) we have DNA and tissue samples from over 200,000 individuals of whom 50,000 have GWAS data; these samples provide an exceptional resource for both imputation from the sequencing studies proposed here, as well as for replication of associations.

  Study phs000756

• Impact of Genetic Variation on Response to GO Therapy in COG-AML Trials AAML03P1 and AAML0531

  The 340 de novo Acute Myeloid Leukemia (AML) patients (ages 1 month to 21 years) were enrolled in COG-AAML03P1 (NCT00070174). Everyone received standard chemotherapy regimen of ara-C, daunorubicin and etoposide (ADE) with addition of one 3 mg/m2 dose of Gemtuzumab Ozogamicin (GO) in induction 1 as well as in intensification II phase. The 1022 de novo AML patients (ages 0–30 years) were enrolled in COG-AAML0531 (NCT01407757). They were randomly assigned to receive either the standard ADE regimen (ADE arm, n = 511) or with the addition of one 3 mg/m2 dose of GO, during induction I as well as intensification II phase (ADE+GO arm, n = 511). Detailed study design, treatment regimen, and clinical outcomes of these two trials have been previously published (Cooper TM, Franklin J, Gerbing RB, et al., PMID:21766293 and Gamis AS, Alonzo TA, Meshinchi S, et al., PMID:25092781). The current study used genomic DNA from 1,225 pediatric patients treated in these two trials with 470 patients treated with standard chemotherapy in COG-AAML0531 (ADE arm) and 755 patients treated with addition of GO to standard therapy in COG-AAML03P1 and COG-AAML0531 trials (ADE+GO arm). The 132 SNPs in 42 genes within DNA-damage repair (DDR) pathways or genes implicated in mediating calicheamicin were selected for genotyping. These SNPs were genotyped using the Sequenom platform at the Biomedical Genomics Center, University of Minnesota. All SNPs had a call rate of more than 0.98 and were in accordance with the Hardy–Weinberg equilibrium. These genotypes were used to test for association with clinical endpoints as defined in the COG-AAML03P1 and COG-AAML0531 trials.

  Study phs003490

• DAC for Central African ancient demography processes NGS dataset

  Title DAC Ancient tree-topologies and gene-flow processes among human lineages in Africa Contacts: Paul Verdu +33144057317 paul.verdu@mnhn.fr CNRS-MNHN-Université de Paris UMR7206 Eco-anthropology Short description The Data Access Committee for acess to genotype and sample information used in the article "Ancient tree-topologies and gene-flow processes among human lineages in Africa" by Gwenna Breton et al. 2025 ensures that data-access requests comply with the Informed Consent provided by donors, and with ethical and deontological guidelines with respect to privacy. DNA samples from individuals were collected with the subjects’ informed consent following the Declaration of Helsinki guidelines and approved by the following Ethics committees: Institut de Recherche pour le Développement (IRD, France); Cameroon Ministry of Scientific Research and Technology; Central African Republic Ministère de l’Enseignement Supérieur et de la Recherche Scientifique; France Ministère de l’Enseignement Supérieur, de la Recherche et de l’Innovation (Comité de Protection des Personnes DC-2016-2740); French Commission Nationale Informatique et Liberté CNIL (declaration n°1972648); Uganda National Council for Science and Technology; Institutional Review Board of the University of Chicago Biological Sciences Division and the Pritzker School of Medicine University of Chicago Hospitals (protocol number 16986A); Committee for the Protection of Human Subjects of the Trustees of Dartmouth College and the Dartmouth-Hitchcock Medical Center (protocol number 22410); Human Research Ethics Committee (Medical) at the University of the Witwatersrand, Johannesburg (Protocol Numbers: M980553, M050902, M090576, M10270, M180654); Working Group of Indigenous Minorities in Southern Africa (WIMSA); South African San Council (SASC); and the Swedish Ethical Review Authority (Dnr 2019-05174). Requests for accessing all or part of the Central African data used in the article "Ancient tree-topologies and gene-flow processes among human lineages in Africa", by Gwenna Breton et al. 2024 (doi - PENDING), should be addressed to the DAC providing: 1) Data can only be used to explore human genetic evolution, evolutionary ecology and population history 2) The research institution where data will be stored and were analyses will be conducted. 3) The detailed coordinates of the researcher responsible for data storage and analyses. 4) A description (max 20 sentences) of the scientific finality and context of the project and classes of methodological analyses that will be performed to achieve it using the requested data. 5) When applicable, mention also other previously published data sets that will be used jointly with the requested datas et For accessing any or all the Central African genetic data used in the article "Ancient tree-topologies and gene-flow processes among human lineages in Africa", by Gwenna Breton et al. 2024 (doi - PENDING), the requester hereby ensures that: 1) Individual donor privacy should be respected at all times. Data cannot be made publicly available under any circumstances. 2) Data cannot be shared nor transferred to a third party without re-applying for eGA access to the DAC. 3) No direct or indirect commercial use of the data can be made 4) No individual medical genetics or disease diagnostics can be performed with the data 5) No medical or legal forensic investigations can be conducted with the data 6) No genealogical research can be conducted with the data (e.g. no paternity nor maternity testing, no genetic identification, no search of relatives using other datasets) 7) Appropriate citation of the article and data set used for any scientific communication using the data 8) Data is destroyed after the completion of the project. Any further re-use of the data is subject to a novel application to the DAC.

  Dac EGAC50000000447

• Tumor-derived cell lines as pharmacogenomic models to predict therapeutic vulnerabilities in hepatocellular carcinoma

  Hepatocellular carcinoma (HCC) is a heterogeneous aggressive malignancy with low efficacy of current therapies at advanced stages. We integrated molecular and pharmacological profiling of a large panel of liver cancer cell lines (LCCL) to assess their clinical relevance as HCC preclinical models and identify new effective therapies and biomarkers of response. We performed multi-omic analysis including whole-exome, RNA and miRNA sequencing and quantification of 126 proteins in a series 34 LCCL coupled with a screening of 29 anti-cancer agents. Molecular profiles of LCCL and primary HCC were compared and we searched for molecular features associated with drug response. Our panel of LCCL faithfully recapitulated the most aggressive molecular "proliferation class" of HCC. Genomic alterations of the RAS-MAPK pathway correlated with trametinib sensitivity that was more potent than FGFR4 inhibitors in tumor cells depending on the FGF19/FGFR4 pathway. Moreover, we showed that FGF19 amplification was only functional in tumor cells that retained a hepatocyte differentiation program with expression of FGFR4, KLB and NR1H4 highlighting the complex interplay between the genomic and transcriptomic context in drug response. We also identified drugs/combination that could target efficiently the transcriptomic "progenitor subclass of HCC", as well as specific genetic contexts such as inactivating mutations in TSC1/TSC2 and TP53 associated with higher sensitivity to the mTOR inhibitor rapamycin and the AURKA inhibitor alisertib, respectively. LCCL represent relevant preclinical models for drug-biomarker discovery in HCC and enabled to identify molecular contexts linked with particular therapeutic vulnerabilities that may be useful to stratify patients in future clinical trials

  Study EGAS00001003536

• MethylationEPIC BeadChip samples of pre- and post-5ZA-treated head and neck cancer patients refractory to anto-PD-1 therapy

  Background Immune checkpoint blockade (ICB) is an effective treatment in a subset of patients diagnosed with head and neck squamous cell carcinoma (HNSCC); however, most patients are refractory. Methods In a non-randomized, open-label phase 1b clinical trial, participants with recurrent and/or metastatic (R/M) HNSCC were treated with low-dose 5’azacytidine (5’aza) daily for either 5- or 10-days in combination with fixed doses of durvalumab and tremelimumab after progression on ICB therapy. The primary objective was to assess the biologically effective dose of 5’aza as determined by molecular changes in paired baseline and on-treatment tumor biopsies; the secondary objective was safety. Results Thirty-eight percent (3/8) of participants with evaluable paired tissue samples had a greater than 2-fold increase from baseline in interferon-gamma (IFN-ɣ) signature and CD274 (programmed cell death protein 1 ligand, PD-L1) expression within the tumor microenvironment (TME), which was associated with increased CD8+ T cell infiltration and decreased infiltration of CD4+ T regulatory cells. The mean neutrophil-to-lymphocyte ratio (NLR) decreased by greater than 50%, from 14.2 (SD 22.6) to 6.9 (SD 5.2). Median overall survival (OS) was 16.3 months (95% CI 1.9, NA) and 2-year OS rate was 24.7% (95% CI: 4.5%, 53.2%) with 58% (7/12) of treated participants demonstrated prolonged OS of greater than 12 months. Conclusion Our findings suggest that low-dose 5’aza can reprogram systemic host immune responses and the local TME to increase IFN-ɣ and PD-L1 expression. The increased expression of these established biomarkers correlated with prolonged OS upon re-challenge with ICB.

  Study EGAS00001007998