Search Results - EGA European Genome-Phenome Archive

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

DERMATLAS__SG_basal_cell_adenoma_and_adenocarcinoma_WES

Virtually no other tumour type is associated with so many different forms as skin cancer. Histologically, tumours of the skin may arise from epithelium, including epidermis, hair follicle, sebaceous or sweat gland, melanocytes, dermal-associated mesenchymal structures or tissue resident immune cells, making for a diversity of clinical presentations. Importantly, many skin tumour types have an extremely poor prognosis. Many skin tumour subtypes have never undergone molecular profiling, or if they have, targeted sequencing has been used and the number of cases analyzed has been so limited that deriving firm conclusions about the profile of driver genes, DNA mutational signatures and germline alleles has not been possible For 70 key skin tumour subtypes defined by the World Health Organization, that have not undergone extensive genetic analysis previoulsy, we propose to perform whole exome and transcriptome sequencing, from a range of body sites, to build a genomic atlas of dermatological tumours, including detailed maps of SNVs, copy number alterations, genome-wide methylation and expression profiles. The cases in this cohort are SG basal cell adenomas and adenocarcinomas.

Study EGAS00001007745

DERMATLAS__Hidradenoma_papilliferum_WES

Virtually no other tumour type is associated with so many different forms as skin cancer. Histologically, tumours of the skin may arise from epithelium, including epidermis, hair follicle, sebaceous or sweat gland, melanocytes, dermal-associated mesenchymal structures or tissue resident immune cells, making for a diversity of clinical presentations. Importantly, many skin tumour types have an extremely poor prognosis. Many skin tumour subtypes have never undergone molecular profiling, or if they have, targeted sequencing has been used and the number of cases analyzed has been so limited that deriving firm conclusions about the profile of driver genes, DNA mutational signatures and germline alleles has not been possible For 70 key skin tumour subtypes defined by the World Health Organization, that have not undergone extensive genetic analysis previoulsy, we propose to perform whole exome and transcriptome sequencing, from a range of body sites, to build a genomic atlas of dermatological tumours, including detailed maps of SNVs, copy number alterations, genome-wide methylation and expression profiles. The cases in this cohort are hidradenoma papilliferums.

Study EGAS00001005714

DERMATLAS__Porocarcinoma_WES

Virtually no other tumour type is associated with so many different forms as skin cancer. Histologically, tumours of the skin may arise from epithelium, including epidermis, hair follicle, sebaceous or sweat gland, melanocytes, dermal-associated mesenchymal structures or tissue resident immune cells, making for a diversity of clinical presentations. Importantly, many skin tumour types have an extremely poor prognosis. Many skin tumour subtypes have never undergone molecular profiling, or if they have, targeted sequencing has been used and the number of cases analyzed has been so limited that deriving firm conclusions about the profile of driver genes, DNA mutational signatures and germline alleles has not been possible For 70 key skin tumour subtypes defined by the World Health Organization, that have not undergone extensive genetic analysis previoulsy, we propose to perform whole exome and transcriptome sequencing, from a range of body sites, to build a genomic atlas of dermatological tumours, including detailed maps of SNVs, copy number alterations, genome-wide methylation and expression profiles. The cases in this cohort are porocarcinomas.

Study EGAS00001005720

DERMATLAS__Poroma_RNAseq

Virtually no other tumour type is associated with so many different forms as skin cancer. Histologically, tumours of the skin may arise from epithelium, including epidermis, hair follicle, sebaceous or sweat gland, melanocytes, dermal-associated mesenchymal structures or tissue resident immune cells, making for a diversity of clinical presentations. Importantly, many skin tumour types have an extremely poor prognosis. Many skin tumour subtypes have never undergone molecular profiling, or if they have, targeted sequencing has been used and the number of cases analyzed has been so limited that deriving firm conclusions about the profile of driver genes, DNA mutational signatures and germline alleles has not been possible For 70 key skin tumour subtypes defined by the World Health Organization, that have not undergone extensive genetic analysis previoulsy, we propose to perform whole exome and transcriptome sequencing, from a range of body sites, to build a genomic atlas of dermatological tumours, including detailed maps of SNVs, copy number alterations, genome-wide methylation and expression profiles. The cases in this cohort are poromas.

Study EGAS00001005759

DERMATLAS__Leiomyosarcoma_WES

irtually no other tumour type is associated with so many different forms as skin cancer. Histologically, tumours of the skin may arise from epithelium, including epidermis, hair follicle, sebaceous or sweat gland, melanocytes, dermal-associated mesenchymal structures or tissue resident immune cells, making for a diversity of clinical presentations. Importantly, many skin tumour types have an extremely poor prognosis. Many skin tumour subtypes have never undergone molecular profiling, or if they have, targeted sequencing has been used and the number of cases analyzed has been so limited that deriving firm conclusions about the profile of driver genes, DNA mutational signatures and germline alleles has not been possible For 70 key skin tumour subtypes defined by the World Health Organization, that have not undergone extensive genetic analysis previoulsy, we propose to perform whole exome and transcriptome sequencing, from a range of body sites, to build a genomic atlas of dermatological tumours, including detailed maps of SNVs, copy number alterations, genome-wide methylation and expression profiles. The cases in this cohort are leiomyosarcomas.

Study EGAS00001007628

DERMATLAS__Poroma_WES

Virtually no other tumour type is associated with so many different forms as skin cancer. Histologically, tumours of the skin may arise from epithelium, including epidermis, hair follicle, sebaceous or sweat gland, melanocytes, dermal-associated mesenchymal structures or tissue resident immune cells, making for a diversity of clinical presentations. Importantly, many skin tumour types have an extremely poor prognosis. Many skin tumour subtypes have never undergone molecular profiling, or if they have, targeted sequencing has been used and the number of cases analyzed has been so limited that deriving firm conclusions about the profile of driver genes, DNA mutational signatures and germline alleles has not been possible For 70 key skin tumour subtypes defined by the World Health Organization, that have not undergone extensive genetic analysis previoulsy, we propose to perform whole exome and transcriptome sequencing, from a range of body sites, to build a genomic atlas of dermatological tumours, including detailed maps of SNVs, copy number alterations, genome-wide methylation and expression profiles. The cases in this cohort are poromas.

Study EGAS00001007705

DERMATLAS__SG_basal_cell_adenoma_and_adenocarcinoma_RNAseq

Virtually no other tumour type is associated with so many different forms as skin cancer. Histologically, tumours of the skin may arise from epithelium, including epidermis, hair follicle, sebaceous or sweat gland, melanocytes, dermal-associated mesenchymal structures or tissue resident immune cells, making for a diversity of clinical presentations. Importantly, many skin tumour types have an extremely poor prognosis. Many skin tumour subtypes have never undergone molecular profiling, or if they have, targeted sequencing has been used and the number of cases analyzed has been so limited that deriving firm conclusions about the profile of driver genes, DNA mutational signatures and germline alleles has not been possible For 70 key skin tumour subtypes defined by the World Health Organization, that have not undergone extensive genetic analysis previoulsy, we propose to perform whole exome and transcriptome sequencing, from a range of body sites, to build a genomic atlas of dermatological tumours, including detailed maps of SNVs, copy number alterations, genome-wide methylation and expression profiles. The cases in this cohort are SG basal cell adenomas and adenocarcinomas.

Study EGAS00001007746

Using human induced pluripotent stem cells (iPSC) and iPSC-derived neurons to explore cellular phenotypes associated with schizophrenia.

Schizophrenia and major mental illness are common devastating conditions. Whilst partially effective treatments are available, none are disease-modifying. Notwithstanding important insights provided by animal models there is a need for novel models of mental illness to develop more effective therapies. A study of sporadic schizophrenia-derived human induced pluripotent stem cells (hiPS) has demonstrated a neuronal phenotype representing a powerful proof of concept of in vitro disease modeling, even for diseases with complex causation such as schizophrenia. These techniques have been used here to examine the behaviour of neural stem cells and neurons derived from fibroblasts from subjects carrying NDE1 copy number variations (CNVs) associated with increased risk of major mental illness. Using hiPS from individuals with and without disease-associated CNVs we have investigated how disease risk is conferred at a cellular and molecular level through detailed comparative studies of neural progenitor proliferation, neuronal morphology, physiology, cytoskeletal organization, synaptic function, glutamate (NMDA) receptor expression and also RNA sequencing and proteomic studies of these patient-derived cells.

Study EGAS00001002895

Pheno-Seq, linking 3D phenotypes of clonal tumor spheroids to gene expression

3D-culture systems have advanced cancer modeling by reflecting physiological characteristics of in-vivo tissues, but our understanding of functional intratumor heterogeneity including visual phenotypes and underlying gene expression is still limited. Transcriptional heterogeneity can be dissected by single-cell RNA-sequencing, but these technologies suffer from low RNA-input and fail to directly correlate gene expression with contextual cellular phenotypes. Here we present pheno-seq for integrated high-throughput imaging and transcriptomic profiling of clonal tumor spheroids derived from 3D models of breast and colorectal cancer. Specifically, we identify characteristic expression signatures that are associated with heterogeneous invasive and proliferative behavior including a rare cell subtype. Furthermore, we identify functionally relevant transcriptional regulators missed by single-cell RNA-seq, link visual phenotypes defined by heterogenous expression to inhibitor response and infer single-cell regulatory states by deconvolution. We anticipate that directly linking molecular features with patho-phenotypes of cancer cells will improve the understanding of intratumor heterogeneity and consequently prove to be useful for translational research.

Study EGAS00001002999

Dissecting intratumor heterogeneity of nodal B cell lymphoma on the transcriptional, genetic, and drug response level

Tumor heterogeneity encompasses both the malignant cells and their microenvironment. While heterogeneity between individual patients is well-known to affect the efficacy of anti-cancer, most personalized treatment approaches do not account for intratumor heterogeneity. We addressed this issue by studying the heterogeneity of lymph node-derived B cell non-Hodgkin lymphoma (B-NHL) by single cell RNA-sequencing (scRNA-seq) and transcriptome-informed flow cytometry. We identified transcriptionally distinct malignant subclones and compared their drug response and genomic profiles. Malignant subclones of the same patient responded strikingly different to anti-cancer drugs ex vivo, which recapitulated subclone-specific drug sensitivity during in vivo treatment. Tumor infiltrating T cells represented the majority of non-malignant cells, whose gene expression signatures were similar across all donors, whereas the frequencies of T cell subsets varied significantly between the donors. Our data provide new insights into the heterogeneity of B-NHL and highlight the relevance of intratumor heterogeneity for personalized cancer therapies.

Study EGAS00001004335

DERMATLAS__Hidradenoma_papilliferum_RNAseq

Virtually no other tumour type is associated with so many different forms as skin cancer. Histologically, tumours of the skin may arise from epithelium, including epidermis, hair follicle, sebaceous or sweat gland, melanocytes, dermal-associated mesenchymal structures or tissue resident immune cells, making for a diversity of clinical presentations. Importantly, many skin tumour types have an extremely poor prognosis. Many skin tumour subtypes have never undergone molecular profiling, or if they have, targeted sequencing has been used and the number of cases analyzed has been so limited that deriving firm conclusions about the profile of driver genes, DNA mutational signatures and germline alleles has not been possible For 70 key skin tumour subtypes defined by the World Health Organization, that have not undergone extensive genetic analysis previoulsy, we propose to perform whole exome and transcriptome sequencing, from a range of body sites, to build a genomic atlas of dermatological tumours, including detailed maps of SNVs, copy number alterations, genome-wide methylation and expression profiles. The cases in this cohort are hidradenoma papilliferums.

Study EGAS00001005715

DERMATLAS__Porocarcinoma_RNAseq

Virtually no other tumour type is associated with so many different forms as skin cancer. Histologically, tumours of the skin may arise from epithelium, including epidermis, hair follicle, sebaceous or sweat gland, melanocytes, dermal-associated mesenchymal structures or tissue resident immune cells, making for a diversity of clinical presentations. Importantly, many skin tumour types have an extremely poor prognosis. Many skin tumour subtypes have never undergone molecular profiling, or if they have, targeted sequencing has been used and the number of cases analyzed has been so limited that deriving firm conclusions about the profile of driver genes, DNA mutational signatures and germline alleles has not been possible For 70 key skin tumour subtypes defined by the World Health Organization, that have not undergone extensive genetic analysis previoulsy, we propose to perform whole exome and transcriptome sequencing, from a range of body sites, to build a genomic atlas of dermatological tumours, including detailed maps of SNVs, copy number alterations, genome-wide methylation and expression profiles. The cases in this cohort are porocarcinomas.

Study EGAS00001005721

Serum proteomics of aortic diseases

Aortic diseases are a rare but potentially life-threatening condition. We present a serum proteomic study for a spectrum of aortic diseases including thoracic aortic aneurysms (n = 11), chronic dissections (n = 9), acute aortic dissections (n = 11), and surgically treated dissections (n = 19) as well as healthy controls (n = 10) and patients of coronary heart disease (n = 10) to represent non-aortic cardiovascular disease. In total, we identified and quantified 425 proteins across all 70 samples. The different aortic diseases represented distinguishable proteome profiles. We identified protein clusters that positively or negatively correlate with disease severity, including increase of cytosolic tissue leakage proteins and decrease of components of the coagulation and complement system. Further, we identified a serum proteome fingerprint of acute aortic dissections, consisting, among others, of enriched inflammatory markers such as C-reactive protein and members of the S100 protein family. The study underlines the applicability of serum proteomics for the investigation of aortic diseases and highlights the possibility to establish disease-specific prognostic markers.

Study EGAS00001006201

DERMATLAS__Tubular_adenoma

IVirtually no other tumour type is associated with so many different forms as skin cancer. Histologically, tumours of the skin may arise from epithelium, including epidermis, hair follicle, sebaceous or sweat gland, melanocytes, dermal-associated mesenchymal structures or tissue resident immune cells, making for a diversity of clinical presentations. Importantly, many skin tumour types have an extremely poor prognosis. Many skin tumour subtypes have never undergone molecular profiling, or if they have, targeted sequencing has been used and the number of cases analyzed has been so limited that deriving firm conclusions about the profile of driver genes, DNA mutational signatures and germline alleles has not been possible For 70 key skin tumour subtypes defined by the World Health Organization, that have not undergone extensive genetic analysis previoulsy, we propose to perform whole exome and transcriptome sequencing, from a range of body sites, to build a genomic atlas of dermatological tumours, including detailed maps of SNVs, copy number alterations, genome-wide methylation and expression profiles. The cases in this cohort are tubular adenomas.

Study EGAS00001006686

DERMATLAS__Tubular_adenoma_RNAseq

IVirtually no other tumour type is associated with so many different forms as skin cancer. Histologically, tumours of the skin may arise from epithelium, including epidermis, hair follicle, sebaceous or sweat gland, melanocytes, dermal-associated mesenchymal structures or tissue resident immune cells, making for a diversity of clinical presentations. Importantly, many skin tumour types have an extremely poor prognosis. Many skin tumour subtypes have never undergone molecular profiling, or if they have, targeted sequencing has been used and the number of cases analyzed has been so limited that deriving firm conclusions about the profile of driver genes, DNA mutational signatures and germline alleles has not been possible For 70 key skin tumour subtypes defined by the World Health Organization, that have not undergone extensive genetic analysis previoulsy, we propose to perform whole exome and transcriptome sequencing, from a range of body sites, to build a genomic atlas of dermatological tumours, including detailed maps of SNVs, copy number alterations, genome-wide methylation and expression profiles. The cases in this cohort are tubular adenomas.

Study EGAS00001006685

DERMATLAS__Leiomyoma_WES

Virtually no other tumour type is associated with so many different forms as skin cancer. Histologically, tumours of the skin may arise from epithelium, including epidermis, hair follicle, sebaceous or sweat gland, melanocytes, dermal-associated mesenchymal structures or tissue resident immune cells, making for a diversity of clinical presentations. Importantly, many skin tumour types have an extremely poor prognosis. Many skin tumour subtypes have never undergone molecular profiling, or if they have, targeted sequencing has been used and the number of cases analyzed has been so limited that deriving firm conclusions about the profile of driver genes, DNA mutational signatures and germline alleles has not been possible For 70 key skin tumour subtypes defined by the World Health Organization, that have not undergone extensive genetic analysis previoulsy, we propose to perform whole exome and transcriptome sequencing, from a range of body sites, to build a genomic atlas of dermatological tumours, including detailed maps of SNVs, copy number alterations, genome-wide methylation and expression profiles. The cases in this cohort are leiomyomas.

Study EGAS00001007629

DERMATLAS__Leiomyoma_RNAseq

Virtually no other tumour type is associated with so many different forms as skin cancer. Histologically, tumours of the skin may arise from epithelium, including epidermis, hair follicle, sebaceous or sweat gland, melanocytes, dermal-associated mesenchymal structures or tissue resident immune cells, making for a diversity of clinical presentations. Importantly, many skin tumour types have an extremely poor prognosis. Many skin tumour subtypes have never undergone molecular profiling, or if they have, targeted sequencing has been used and the number of cases analyzed has been so limited that deriving firm conclusions about the profile of driver genes, DNA mutational signatures and germline alleles has not been possible For 70 key skin tumour subtypes defined by the World Health Organization, that have not undergone extensive genetic analysis previoulsy, we propose to perform whole exome and transcriptome sequencing, from a range of body sites, to build a genomic atlas of dermatological tumours, including detailed maps of SNVs, copy number alterations, genome-wide methylation and expression profiles. The cases in this cohort are leiomyomas.

Study EGAS00001007630

DERMATLAS__Leiomyosarcoma_RNAseq

Virtually no other tumour type is associated with so many different forms as skin cancer. Histologically, tumours of the skin may arise from epithelium, including epidermis, hair follicle, sebaceous or sweat gland, melanocytes, dermal-associated mesenchymal structures or tissue resident immune cells, making for a diversity of clinical presentations. Importantly, many skin tumour types have an extremely poor prognosis. Many skin tumour subtypes have never undergone molecular profiling, or if they have, targeted sequencing has been used and the number of cases analyzed has been so limited that deriving firm conclusions about the profile of driver genes, DNA mutational signatures and germline alleles has not been possible For 70 key skin tumour subtypes defined by the World Health Organization, that have not undergone extensive genetic analysis previoulsy, we propose to perform whole exome and transcriptome sequencing, from a range of body sites, to build a genomic atlas of dermatological tumours, including detailed maps of SNVs, copy number alterations, genome-wide methylation and expression profiles. The cases in this cohort are leiomyosarcomas.

Study EGAS00001007631

Development, maturation and maintenance of human prostate inferred from somatic mutations

Stem cells within prostate epithelium frequently undergo malignant transformation, but there is limited information on their clonal dynamics and mutation burden in healthy human prostates. We sequenced whole genomes from 409 microdissections of prostate epithelium across 8 donors, using phylogenetic reconstruction with spatial mapping in a 59-year-old man’s prostate to provide high-resolution reconstruction of tissue dynamics across the lifespan. Somatic mutation burden increases linearly with age, at ~16 mutations/year/clone, and is higher in peripheral than peri-urethral regions. The 24-30 independent glandular subunits are established as rudimentary ductal structures during fetal development by 5-10 embryonic cells each. Puberty induces formation of further side branches and terminal acini by local stem cells disseminated through the rudimentary ducts during development. During adult tissue maintenance, clonal expansions are small, with limited geographic scope and minimal migration. Driver mutations are rare in normal ageing prostate epithelium, but the one canonical driver we did observe generated a sizable intraepithelial clonal expansion. By resolving unbiased, continuously occurring lineage-marking mutations, we define stem cell dynamics through embryogenesis, puberty and ageing, with relevance for prostate cancer.

Dataset EGAD00001006591

P647 Targeted resequencing project

In collaboration with Dr Robert Semple we have identified a family harbouring an autosomal dominant variant, which leads to severe insulin resistance (SIR), short stature and facial dysmorphism. This family is unique within the SIR cohort in having normal lipid profiles, preserved adiponectin and normal INSR expression and phosphorylation. DNA is available for 7 affected and 7 unaffected family members across 3 generations. All 14 samples have been genotyped using microsatellites and the Affymetrix 6.0 SNP chip. Linkage analysis identified an 18.8Mb haplotype on chromosome 19 as a possible location of the causative variant. However, Exome sequencing of 3 affected and 1 unaffected family members has not identified the causative variant suggesting the possibility of an intronic or intergenic variant in this region or elsewhere in the genome. We propose to conduct whole genome sequencing of 5 members of the pedigree at a depth of 20X. The chosen samples are two sets of parents plus one member of an unaffected branch of the pedigree who shares the risk haplotype on chromosome 19. Sequencing of the two sets of parents will be used along with the genome-wide SNP data to impute 4 affected children giving an effect sample size of 6 affected individuals.

Dataset EGAD00001000383

SS18-SSX-mediated hijacking of BAF complexes drives synovial sarcoma

Synovial sarcoma (SS) is defined by a recurrent t(x;18) chromosomal translocation, which produces the hallmark SS18-SSX oncogenic fusion. Incorporation of SS18-SSX into BAF complexes renders BAF complexes aberrant in two distinct manners: the addition of 78aa of SSX onto SS18, and concomitant loss of BAF47 assembly. However, the importance and functional contributions of each of these perturbations on BAF complex targeting and gene expression regulation remain unclear. Here we use an integrative set of genomic approaches in human cancer cell lines and primary tumor samples to define the mechanistic consequences of the SS18-SSX fusion oncoprotein. We find that SS18-SSX hijacks BAF complexes to broad polycomb domains to activate bivalent genes, driving a unique gene expression program distinct from other loss-of-function BAF complex malignancies. Importantly, restoration of BAF47 rescues enhancer activation but is dispensable for proliferative arrest in cell lines. These results demonstrate that gain-of-function SS18-SSX-mediated BAF complex targeting and gene activation is the driving event in SS, and present a mechanism by which distinct functions of BAF complexes can be co-opted to drive oncogenesis.

Dataset EGAD00001004135

CSER: Genomic Sequencing to Aid Diagnosis in Pediatric and Prenatal Practice: Examining Clinical Utility, Ethical Implications, Payer Coverage, and Data Integration in a Diverse Population

Congenital abnormalities and developmental disorders affect 3-5% of live born infants and children. Despite advances in both pre- and post-natal treatment, the utility of genetic testing in diagnosing the etiology underlying such conditions in order to guide management has been frustratingly limited. Traditional genetic testing with specific gene tests, or even gene panels, is diagnostic in only a small percentage of cases. Recent technological advances in next generation sequencing (NGS) have led to the ability to sequence and interpret the entire exome relatively quickly, allowing a diagnosis in 25-30% or more of cases of developmental disorders when other genetic tests have not yielded a result. Although whole exome sequencing (WES) holds great promise for improved diagnosis leading to better clinical outcomes, challenges remain in determining how best to apply and utilize sequence data. Fulfilling the promise of WES also requires investigation of ELSI (ethical, legal, social) concerns, given skepticism in some communities that research will benefit them; economic considerations that ultimately determine access to and equitable use of WES; and a need to share clinical genetic results with families and across health care systems to enable better prognostication and management of rare conditions in community settings. We propose a Program in Prenatal and Pediatric Genomic Sequencing (P3EGS) at UCSF to examine the diagnostic and clinical utility of WES. P3EGS will recruit and study affected individuals and their parents, including pregnancies in which the fetus has a confirmed structural anomaly and children with previously undiagnosed developmental disorders that are likely of genetic etiology. Following consent and collection of standardized phenotypic data, the families will undergo WES as part of clinical care. To achieve diversity, patient ascertainment and recruitment will occur at four UCSF sites that serve a broad range of underrepresented minorities (target of 75%) and span the full socio-economic spectrum, including the underserved. Our specific aims will: 1) examine the clinical utility of WES, including assessment of a variety of health-related and reproductive outcomes, in undiagnosed individuals; 2) address ethical, social and economic issues in the delivery of genomic sequencing results to ancestrally and economically diverse populations through (2.1) a mixed methods, longitudinal empirical study of clinical interactions and experiences, (2.2) an economic analysis of insurance coverage, price and reimbursement of multigene tests, and (2.3) creation of an Ethics Advisory Board to respond to emerging issues and establishment of authentic stakeholder engagement; and 3) pilot a user-friendly web-based patient/provider application integrating genomic and clinical data as a shared evidence base to support result communication, interpretation and clinical decision making; the application will be based on the “Bioscreen” model created and successfully implemented at UCSF.

Study phs002324

The Dutch Microbiome Project: Defining the (un)healthy gut microbiome

The Dutch Microbiome Project (DMP) data includes raw data generated by shotgun metagenomic sequencing of faecal samples of 8,208 Dutch individuals, processed microbiome data analysed using Biobakery2 tools (including taxonomy, pathway, virulence factors and antibiotic resistance gene profiles), and basic phenotypes (age and sex, BMI). Data is made available in two randomly assigned batches to facilitate the data access and maintenance. Access to this dataset requires a minimal access procedure (data access form at https://forms.gle/eHeBdXJMXbVvCJRc8 or email request to the data access committee (DAC) of this study, listed at DAC EGAC00001001996, https://ega-archive.org/dacs/EGAC00001001996). This access procedure is to ensure that the data is being requested for research/scientific purposes only and thus complies with the informed consent signed by Lifelines participants, which specifies that the collected data will not be used for commercial purposes. Submitted data access forms will be evaluated by the DAC and Lifelines, and a response to requests will be given within two weeks. For requests from verified academic parties, access will be given without further delay. For requests from commercial parties, Lifelines will perform a pre-DPIA (Data Privacy Impact Assessment) to assess the risks of the proposed processing of personal data (e.g. purpose, storage, access, archiving, etc.) with respect to the GDPR (EU privacy laws) subject rights. Based on the outcome of the pre-DPIA, Lifelines will decide whether sharing data with the commercial entity is allowed and/or whether additional measures have to be taken.

Study EGAS00001005027

Synthetic - FEGA Sweden Heilsa synthetic dataset December 2023

Synthetic - This submission contains a subset of a synthetic dataset derived from the project Heilsa Tryggvedottir - a Nordic collaboration on sharing sensitive human data. Heilsa Tryggvedottir is funded by the Nordic e-Infrastructure Collaboration (NeIC), the ELIXIR nodes of Finland, Norway, and Sweden, Computerome in Denmark, and the Estonian Scientific Computing Infrastructure (ETAIS). In the synthetic data creation process, it was attempted to strike a fine balance between the usability of the datasets (e.g. technical FEGA development, testing, user training, and basic bioinformatics) and compliance with GDPR. File names and file content (e.g. headers in fastq) are anonymized. Moreover, the X, Y, and mitochondrial sequences have been discarded from the original data since these data can be used for maternal, paternal, or ethnic origin tracing. The dataset does not follow natural haplotype distribution (inherent to imputation panels). The only inputs derived from real sequence data are variant distribution density per chromosome and learning sequencing error models. The synthetic dataset consists of two fastq files, a cram file, a vcf file, and two index files.

Dataset EGAD50000000119

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