16758 results for "sec+and+unspecified+malignant+neoplasm"

in 39.07 milliseconds.

• 463 newly diagnosed patients with Multiple Myeloma underwent whole exome sequencing of tumour and peripheral blood DNA.

  463 newly diagnosed patients from the UK Myeloma XI clinical trial (NCT01554852) underwent whole exome sequencing plus targeted capture of the IGH/K/L and MYC loci. 200 ng of DNA were processed using NEBNext DNA library prepartion kit and hybridised to the SureSelect Human All Exon V5 Plus. Four samples were pooled and run on one lane of a HiSeq 2000 using 76-bp paired end reads. DNA from CD138+ selected bone marrow cells (myeloma tumour) as well as peripheral white blood cells were analysed and somatic mutations detected.

  Study EGAS00001001147

• Single cell transcriptomic and genomic profiling of carcinogenesis in patients with familial adenomatous polyposis

  Familial Adenomatous Polyposis (FAP) is characterized by hundreds to thousands of adenocarcinomas at different evolutional stages in the colon and rectum. Much effort has been made to illuminate the key genomic alterations that facilitate the transition from adenoma to carcinoma. However, the strong heterogeneity of the tumors may hamper these efforts. Here, by sequencing matched adjacent normal tissues, adenomas at different stages and carcinomas from the same patient, we precisely traced the process of colorectal carcinogenesis. Our study offers an accurate genomic landscape during the initiation and progression of carcinogenesis, especially for the transition between adenomas and carcinomas.

  Study EGAS00001003598

• Primary breast cancers and paired brain metastases sequencing study

  Improving management of brain metastases (BM) from primary breast cancer (PBC) is a challenge in which targeted therapies play a promising role. However this approach is impaired by miss-knowledge of molecular patterns of the metastatic and drug-resistance processes.We performed a differential analysis of copy-number-alterations (CNAs) and mutations profiles by using pan-genomic array-CGH and targeted next-generation-sequencing of 494 cancer-associated genes, in a series of 14 pairs of matched PBC/BM and assessed if the observed genomic alterations may be used as a druggable agent in a clinical trial.

  Study EGAS00001003173

• Premalignant SOX2 overexpression in the fallopian tubes of ovarian cancer patients: Discovery and validation studies

  To identify early driver mutations in ovarian cancer cells, we used dense whole genome sequencing of micrometastases and microscopic residual disease collected at three time points from a single patient during treatment for high-grade serous ovarian cancer (HGSOC). Laser capture microdissection of tumour islets was performed on samples prior to chemotherapy, after three cycles of chemotherapy and at recurrence. Long frament read whole genome sequencing was performed and mutations were identified. To our knowledge, this is the first longitudinal study that attempts to investigate spatial and temporal micro-heterogeneity in cancer.

  Study EGAS00001001909

• Transcriptome sequencing of intravenous leiomyomatosis and uterine myoma

  Up to now, there are two hypothesis about the pathogenesis of the relationship of intravenous leiomyomatosis and uterine myoma. One theory suggests that the IVL comes from the smooth muscle cell in the vessel wall.The other theory indicates that the IVL derives from the uterine myometrium. However, limited to the technology, few studies have been deeply explore the underlying relation. In this study, we employ the RNA sequencing to explore the molecule relationship between IVL and uterus myoma. In order to identify the molecule relationship between IVl and uterine myoma we conducted transcriptome sequencing and bioinformaitc analysis

  Study EGAS00001002504

• Progression to AML is predictable and distinct from age related clonal hematopoiesis

  To examine the occurrence of somatic mutations prior to the development of acute myeloid leukemia, we undertook deep ECS (estimated limit of detection 1 mutation in 2500 cells) of 261 AML associated genes in 96 pre-AML cases and 420 age and gender-matched healthy controls of an average of 3853 unique DNA molecules covering each of the 1.19M bases spanning the target gene panel. The findings suggest that the development of clonal hematopoiesis and accumulation of somatic mutations is distinct and accelerated in pre-AML cases compared to healthy individuals

  Study EGAS00001002570

• NanoSring of PBMC from bladder cancer and RCC patients

  PBMCs from patients were isolated using 50 mL Leucosep™ tubes (Greiner Bio-One International, Germany) and Ficoll-Paque™ PLUS (GE Healthcare, Sweden). Whole blood drawn into sodium heparin blood collection tubes were diluted 3x with phosphate-buffered saline (PBS) without calcium or magnesium (Lonza, Walkersville, MD). Diluted cell suspensions were carefully layered on Leucosep tubes and centrifuged for 15 minutes at 800 x g at room temperature (RT). Interphase containing PBMCs were harvested and washed with PBS and subsequently centrifuged for 10 minutes at 250 x g at RT before further processing.

  Study EGAS00001004229

• Discovery and capture of novel dynamic DNA methylation in human sperm with preferential links to altered folate metabolism

  The sperm DNA methylation landscape is unique and critical for offspring health. If gamete-derived DNA methylation escapes reprogramming in early embryos, epigenetic defects in sperm may be transmitted to the next generation. Current techniques to assess sperm DNA methylation show bias towards CpG dense regions and do not target areas of dynamic methylation, those predicted to be environmentally sensitive and tunable regulatory elements. Thus, this study aim to assess variation in human sperm DNA methylation and design a targeted capture panel to interrogate the human sperm methylome.

  Study EGAS00001003617

• Subclonal somatic copy number alterations emerge and dominate in recurrent osteosarcoma

  Multiple large-scale genomic profiling efforts have been undertaken in osteosarcoma to define the genomic drivers of tumorigenesis, therapeutic response, and disease recurrence. The spatial and temporal intratumor heterogeneity could also play a role in promoting tumor growth and treatment resistance. Here, we conducted longitudinal whole-genome sequencing of 37 tumor samples from eight patients with osteosarcoma that relapsed or became refractory to initial therapy. We found that the chemoresistant population in recurrent osteosarcoma is subclonal at diagnosis, emerges at the time of primary resection due to selective pressure from neoadjuvant chemotherapy, and is characterized by unique oncogenic amplifications.

  Study EGAS00001007486

• University of North Carolina at Chapel Hill (UNC) Hepatocellular Carcinoma Study by Exome Sequencing (HCCSES)

  Genetic alterations in specific driver genes lead to disruption of cellular pathways and are critical events in the instigation and progression of hepatocellular carcinoma. As a prerequisite for individualized cancer treatment, we sought to characterize the landscape of recurrent somatic mutations in hepatocellular carcinoma. We performed whole exome sequencing on 87 hepatocellular carcinomas and matched normal adjacent tissues to an average coverage of 59x. The overall mutation rate was roughly 2 mutations per Mb, with a median of 45 non-synonymous mutations that altered the amino acid sequence (range 2 to 381). We found recurrent mutations in several genes with high transcript levels: TP53 (18%), CTNNB1 (10%), KEAP1 (8%), C16orf62 (8%), MLL4 (7%) and RAC2 (5%). Significantly affected gene families include the nucleotide-binding domain and leucine rich repeat containing family, calcium channel subunits, and histone methyltransferases. In particular, the MLL family methyltransferases for histone H3 lysine 4 were mutated in 20% of tumors. Conclusion: The NFE2L2-KEAP1 and MLL pathways are recurrently mutated in multiple cohorts of hepatocellular carcinoma.

  Study phs000627

• Role of the Cervico-Vaginal Microbiome in Spontaneous Preterm Birth

  Preterm birth is the leading cause of neonatal morbidity and mortality. A failure to predict and understand the causes of preterm birth have limited effective interventions and therapeutics. From a cohort of 2,000 pregnant women, we performed a nested case control study on 107 well-phenotyped cases of spontaneous preterm birth (sPTB) and 432 women delivering at term. Modern and innovative Bayesian modeling of vaginal microbiota identified features of these communities associated with PTB. Seven bacterial taxa were shown to have relative abundances significantly associated with an increased risk of sPTB, with a stronger effect in African American women. However, higher vaginal levels of β-defensins significantly decreased the risk of sPTB associated with the vaginal microbiota in an ethnicity-dependent manner. These findings hold promise for the development of novel diagnostics that could more accurately identify women at risk for sPTB early in pregnancy and offer new therapeutic strategies that would include immune modulators and microbiome-based therapeutics to reduce this significant health burden.

  Study phs001739

• National Cancer Institute (NCI) Study of Lung Cancer and Smoking Phenotypes in African-American Cases and Controls

  This is a two-stage case-control study designed to evaluate the association between common genetic variants and the risk of lung cancer. The stage 1 studies included 1737 cases and 3602 controls from the following studies: MD Anderson Lung Cancer Epidemiology Study, The Multiethnic Cohort Study (MEC), NCI-MD Lung Cancer-Case Control Study, Northern California Lung Cancer Study, Project CHURCH (Creating a Higher Understanding of Cancer Research δ Community Health), Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO), Southern Community Cohort Study (SCCS), and the Karmanos Cancer Institute at Wayne State University (KCI/WSU). The stage 2 studies included an independent set of 866 cases and 796 controls from the following studies: The Black Women's Health Study (BWHS), The Harvard-MGH Lung Cancer Susceptibility Study (HLCS), MD Anderson Lung Cancer Epidemiology Study, MD Anderson/LBJ Hospital Biorepository, NCI-MD Lung Cancer Case-Control Study, Northern California Lung Cancer Study, Philadelphia Lung Cancer Study on Gene Environment Interactions (Plus-Gene), Southern Community Cohort Study (SCCS), and KCI/WSU.

  Study phs001210

• DCCT/EDIC Epigenetics (DNA Methylation) Study

  Metabolic memory (persistent benefits of early glycemic control on preventing/delaying diabetic complications development) was observed in the Diabetes Control and Complications Trial (DCCT) and follow-up Epidemiology of Diabetes Interventions and Complications (EDIC) study, dbGaP phs000086.v3.p1, but mechanisms are unclear. We investigated the involvement of epigenetic DNA methylation (DNAme) by examining its associations with preceding glycemic history, and subsequent complications development over 18 years in blood DNAs of 499 randomly-selected DCCT/EDIC participants with type 1 diabetes. We found associations between DNAme near DCCT-closeout and mean-DCCT-HbA1c at 186 CpGs (FDR<15%, including 43 at FDR<5%), many located in complications-related genes. These CpGs are enriched in C/EBP motifs, enhancer/transcription regions in blood cells/progenitors, and open chromatin-states in myeloid cells. Remarkably, several CpGs in combination explain 68-97% of the mean-DCCT-HbA1c risk of complications development during EDIC. DNAme at key CpGs appears to mediate the association between hyperglycemia and complications in metabolic memory, through modifying myeloid cell enhancer activity.

  Study phs002024

• Spatiotemporal Evolution of the ccRCC Microenvironment Links Intra-Tumoral Heterogeneity to Immune Escape CINOMA

  We utilize temporal multi-regional multi-omics profiling to uncover the mechanisms of immune escape in clear cell renal cell carcinoma (ccRCC) in 29 patients including 17 patients from a neoadjuvant nivolumab clinical trial. We observe that tumors can be broadly categorized into intra-tumoral heterogeneity (ITH) high and low, which correlates across genomic, transcriptomic, immune and tumor microenvironment (TME) landscapes. We identify several genetic alterations associated with ITH that correlate with a myeloid high and effector T cell low TME. Namely, ITH high tumors are enriched for mutations in SETD2, PBRM1, CDKN2A/B somatic copy number loss and HLA loss of heterozygosity, and they demonstrate the characteristics of immune escape. ITH high tumors demonstrate reduced peripheral blood TCR diversity which is associated with neoantigen depletion. Moreover, we identify a link between neoantigen depletion and immune escape through myeloid activation. A transcriptomic signature associated with neoantigen depletion is strongly associated with response to ICI treatment and targeted therapies in several independent clinical trial cohorts.

  Study phs003079

• Collaborative Cohort of Cohorts for COVID-19 Research (C4R): Hispanic Community Health Study/Study of Latinos (HCHS/SOL)

  Cohort DescriptionHispanic Community Health Study/Study of Latinos (HCHS/SOL) is an ongoing population-based prospective cohort study of 16,415 community dwelling Hispanic/Latino adults aged 18-74 years at baseline, recruited from four urban field centers with large populations of Hispanics/ Latinos (Bronx, NY; Chicago, IL; Miami, FL; and San Diego, CA). The primary goals of the HCHS/SOL are to describe: (1) the prevalence and incidence of cardiovascular, pulmonary, and other major chronic conditions (2) the risk and/or protective factors associated with these conditions; and (3) the relationships between the initial sociodemographic and health profiles and future health events in the target population. Data Being Submitted Wave 1 questionnaire data includes 397 variables for up to 9817 HCHS/SOL participants in C4R. Wave 2 questionnaire data includes 448 variables for up to 7536 HCHS/SOL participants in C4R. Derived data includes 43 variables for up to 11182 HCHS/SOL participants in C4R. Phenotype data includes 113 variables for up to 11182 HCHS/SOL participants in C4R.

  Study phs002908

• Postmortem Analysis of the Caudate Nucleus in Schizophrenia

  This postmortem study examines genomic signatures (gene, transcript, exon, and exon-exon junction) in the caudate nucleus of individuals with or without psychiatric illnesses. We characterized genetic and epigenetic changes across the lifespan of 443 donor subjects, including 245 individuals without psychiatric illness, 154 individuals with schizophrenia, and 44 individuals with bipolar disorder. The subjects are 210 from African and 233 from European ancestries. Combining expression quantitative trait loci (eQTL) analysis, Mendelian randomization with the latest schizophrenia genome-wide association study (GWAS), transcriptome-wide association study (TWAS) and differential expression analysis, we identified many genes associated with schizophrenia risk, including potentially the dopamine D2 receptor short isoform. We found that antipsychotic medication has an extensive influence on caudate gene expression. We constructed caudate nucleus gene expression networks that highlight interactions involving schizophrenia risk. These analyses provide a resource for the study of schizophrenia and insights into risk mechanisms and potential therapeutic targets. There are 120 subjects in this study which are also present in the study phs000417.

  Study phs003495

• Establishment of an iPSC Repository Derived from Healthy Volunteers

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

  Study phs003649

• Timing and trajectory of BCR-ABL1 driven chronic myeloid leukaemia

  Mutation of some genes provide fitness advantages that drive uncontrolled cell proliferation, leading to clinical manifestations of cancer. The discovery of the Philadelphia chromosome in chronic myeloid leukaemia (CML) provided the very first such genetic link to cancer and the hypothesis that this lesion provided an abnormal growth advantage to cells. However, little is known about the trajectory to CML, the rate of BCR::ABL1 driven clonal expansion, and how this impacts on disease presentation. Here, using whole-genome sequencing of 1013 single-cell-derived colonies from patients with CML, we reconstruct phylogenetic trees of haematopoiesis in 9 patients aged 22 to 81 years at diagnosis. The expected intronic breaks in BCR and ABL1 were not always observed, and out-of-frame exonic breakpoints in BCR, requiring exon skipping to derive BCR::ABL1 fusion transcripts, were noted in several patients. Apart from ASXL1 and RUNX1 mutations, additional somatic mutations in myeloid genes were generally present only in wild-type cells and did not contribute to the CML clone. Using phylogenetic analysis, we infer sustained explosive growth attributed to BCR::ABL1 fusion, with clonal expansions beginning 3-14 years (Cl 2-16 years) before diagnosis and annual growth rates exceeding 70,000% per year in some young patients with the most recent and rapid clonal expansions. Mutation rate was higher in BCR::ABL1-positive cells than in wild-type counterparts, together with markedly shorter telomere lengths, reflecting their excessive cell division history. Clonal expansion rates inferred from phylogenetic trees were in line with mutational signature patterns and telomere attrition, and inversely correlated with the time to diagnosis. Whole genome sequencing of advanced phase CML was characterised by genomic evolution within BCR::ABL1-positive cells. Our findings highlight the oncogenic potency of a single BCR::ABL1 fusion and its capacity to drive fast clonal outgrowth to cancer. These data contrast with the early-in-life, slow, and sequential clonal trajectories typical of most cancers, such as Philadelphia-negative myeloproliferative neoplasms, solid organ malignancies, and patterns of clonal expansion in healthy tissue ageing.

  Dataset EGAD00001015473

• Chromatin remodeler CHD7 regulates the stem cell identity of human neural progenitors

  Multiple congenital disorders often present complex phenotypes, but how the mutation of individual genetic factors can lead to multiple defects remains poorly understood. In the present study, we used human neuroepithelial (NE) cells and CHARGE patient-derived cells as an in vitro model system to identify the function of chromodomain helicase DNA-binding 7 (CHD7) in NE?neural crest bifurcation, thus revealing an etiological link between the central nervous system (CNS) and craniofacial anomalies observed in CHARGE syndrome. We found that CHD7 is required for epigenetic activation of superenhancers and CNS-specific enhancers, which support the maintenance of the NE and CNS lineage identities. Furthermore, we found that BRN2 and SOX21 are downstream effectors of CHD7, which shapes cellular identities by enhancing a CNS-specific cellular program and indirectly repressing non- CNS-specific cellular programs. Based on our results, CHD7, through its interactions with superenhancer elements, acts as a regulatory hub in the orchestration of the spatiotemporal dynamics of transcription factors to regulate NE and CNS lineage identities.

  Study JGAS000131

• Fragmentomics Uncover Non-Mutational HRD Features

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

  Study EGAS00001008190

• Data upcycling, powered by EGA

  In 2012 a collaborative effort headed by the teams of Carlos Caldas in Cambridge, UK and Samuel Aparicio, Canada, produced a pivotal study aimed at defining the mutational landscape of breast cancer. They gathered a collection of over 2000 breast cancer samples (METABRIC) associated with long-term clinical follow-up. They delineated an array of inherited and somatically acquired genetic variants and associated them to gene expression. This led to the identification of putative cancer-driving events and improved stratification of breast cancer patients. The study elicited huge attention and was tackled as herculean effort by fellow researchers. Cristina Curtis and her colleagues deposited the data in the EGA archive (EGAS00000000083). What they probably could not foresee is that their data would be reused more than 100 times, becoming one of the most downloaded datasets at EGA. In 2015, Frederik S. Varn and colleagues accessed the above-mentioned data from the New Hampshire, USA, to correlate it to transcriptional programs of hematopoietic cells infiltrated in breast tumours and found that those can influence patients' prognosis. Their findings, published in Nature Communications, improved the understanding of the interplay between immune system and cancer. Again, in 2017 the dataset was downloaded by an Italian/Polish collaboration and used to corroborate their mechanistic study that demonstrate how a long non-coding RNA (lncRNA) is aberrantly localized into the chromatin, where it modulates oncogenic isoforms expression, thus contributing to breast cancer. To date, the METABRIC dataset has been reused to contribute to 147 publications. Its impact on breast cancer research is incalculable, and it even spread beyond that, with recent contributions to the understanding of pan-cancer mechanisms and features. Some of the publications are translating into improvements in diagnosis and treatment of different types of breast cancer. This is just an example of how data upcycling can amplify the potential of any dataset, well past the scope of its creation, the imagination of its owners and any geographical border. At EGA, we are proud to empower such fruitful worldwide cycles of knowledge, providing a platform that enables safe sharing of sensitive genetic data.

  Blog data-upcycling-powered-by-ega

• Spatial transcriptomics analysis of triple negative breast cancers

  While triple negative breast cancer (TNBC) is known to be heterogeneous at the genomic and transcriptomic levels, spatial information on tumor organization and cell composition is still lacking. Here, we investigated TNBC tumor architecture including its microenvironment using spatial transcriptomics on a series of 92 patients. We performed an in-depth characterization of tumor and stroma organization and composition using an integrative approach combining histomorphological and spatial transcriptomics. Furthermore, a detailed molecular characterization of tertiary lymphoid structures led to identify a gene signature strongly associated to disease outcome and response to immunotherapy in several tumor types beyond TNBC. A stepwise clustering analysis identified nine TNBC ecotypes, further validated in external datasets. Several ecotypes were associated with disease outcome and characterized by potentially actionable features. In this work, we provideThis is the largest TNBC series providing a comprehensive insight into the complexity of TNBC ecosystem with potential clinical relevance, opening avenues for treatment tailoring including immunotherapy. All the processed data needed to replicate the results from the publication (counts, images, clinical data, etc) are available on Zenodo: https://zenodo.org/records/14204217

  Study EGAS50000000475

• CNA differences between RNA-based subtypes of PDAC

  Pancreatic ductal adenocarcinomas (PDAC) have a dismal prognosis with a 5-year survival of <5%. Chemoresistance and recurrences, seen in approximately 70% of PDAC patients, may partly be explained by intratumor heterogeneity (ITH) through which tumors may develop ‘escape routes’. In the Pancreas Multibiopsy (PM)-project we have obtained multiple fragments from pancreatic and other peri-ampullary carcinomas in order to reveal potential ITH and identify genetic aberrations that predict outcome after surgery and response to chemotherapy. CNA-profiles were used to complement the characterization of liabilities in PDAC that we identified previously using RNAseq in the form of epithelial, secretory, compound pancreatic, and mesenchymal subgroups that showed survival outcomes. Comparison of CNA-profiles between these transcriptomics-based subgroups (with 8, 3, 6, and 6 tumors respectively per group) showed differences, ranging from ‘quiet’(i.e. hardly any CNA) to ‘wild’(i.e. lots of CNA), but these were not statistically significant (Chi2 0.09). When differentiating between the classical and basal-like molecular subtypes of PDAC differences in CNA (high or low) were even less statistically significant (Chi2 0.292).

  Study EGAS50000001218

• ScRNA-seq of human kidney immune cells of patients with ANCA-associated glomerulonephritis, Lupus Nephritis against a "healthy" nephrectomy control

  ANCA-associated glomerulonephritis (AGN) associates with a high risk of end-stage kidney disease. The role of kidney immune cells in local inflammation remains unclear. Here, we investigate kidney immune cell diversity and function. Kidney tissue from AGN patients (n=5) and a lupus nephritis (LN) patient (n=1) were aquired during a biopsy procedure for a clinical indication. Needle-core biopsies were obtained for histopathological examination, and an additional pass was performed to retrieve kidney tissue for scRNA-seq. Healthy kidney tissue (n=1) was obtained from a kidney that was surgically removed do tue due to a (non-invasive) papillary urothelial carcinoma. Immediately after collection, kidney tissue was processed into a single-cell suspension and sorted using a 4-color flow cytometry panel to isolate living, CD45+ immune cells. To aid in the multi-omic characterization, surface markers and T and B cell repertoires were sequenced in 2 samples (1 AGN patient and the nephrectomy control). These samples were incubated with an oligo-antibody TotalSeq-C cocktail containing 130 unique cell surface antigens.

  Study EGAS50000000159

• Transcriptomics sequencing analysis of pre-invasive lung adenocarcinoma in never-smokers

  The prevalence of lung adenocarcinoma (LUAD) has increased sharply in East Asia. Early diagnosis leads to better survival rates, but this requires an improved understanding of the molecular changes during early tumorigenesis, particularly in non-smokers. We performed whole exome-sequencing and RNA-sequencing for samples from 94 East Asian patients with precancerous lesions (25 with atypical adenomatous hyperplasia [AAH]; 69 with adenocarcinoma in situ [AIS]) and 73 patients with early invasive lesions (minimally invasive adenocarcinoma [MIA]). Cellular analysis revealed that the activities of endothelial and stromal cells could categorize tumors into molecular subtypes within pathology-defined lesion types. These subtypes were linked with the advanced radiology-defined lesion type and coordinated with immune cell infiltration throughout the progression of LUAD. Characterization of these lesion types identified positively selected mutation patterns, and suggested that angiogenesis of the late-stage AIS type potentially contributes to tissue invasion of the MIA type. Our findings offer a novel resource that may help to improve early diagnosis and patient prognosis, and also suggest possible approaches for early disease interception.

  Study EGAS50000000439

• Whole exome sequencing of pre-invasive lung adenocarcinoma in non-smokers

  The prevalence of lung adenocarcinoma (LUAD) has increased sharply in East Asia. Early diagnosis leads to better survival rates, but this requires an improved understanding of the molecular changes during early tumorigenesis, particularly in non-smokers. We performed whole exome-sequencing and RNA-sequencing for samples from 94 East Asian patients with precancerous lesions (25 with atypical adenomatous hyperplasia [AAH]; 69 with adenocarcinoma in situ [AIS]) and 73 patients with early invasive lesions (minimally invasive adenocarcinoma [MIA]). Cellular analysis revealed that the activities of endothelial and stromal cells could categorize tumors into molecular subtypes within pathology-defined lesion types. These subtypes were linked with the advanced radiology-defined lesion type and coordinated with immune cell infiltration throughout the progression of LUAD. Characterization of these lesion types identified positively selected mutation patterns, and suggested that angiogenesis of the late-stage AIS type potentially contributes to tissue invasion of the MIA type. Our findings offer a novel resource that may help to improve early diagnosis and patient prognosis, and also suggest possible approaches for early disease interception.

  Study EGAS50000000438

• Anti-myeloperoxidase IgM B cells in anti-neutrophil cytoplasmic antibody-associated vasculitis

  Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a prototypic autoimmune disease, with a subset of AAV patients manifesting anti-myeloperoxidase (MPO) IgG. Patients with AAV respond positively to B cell-targeting and complement-targeting therapies, but disease flares are not uncommon. Here, by comparing samples from healthy individuals and MPO+ AVV patients, we show that B cell autoreactivity against MPO in the circulation of patients is dominated by CD27+IgM+ B cells whereas MPO-specific IgG+ cells are infrequent. Additionally, while naive anti-MPO-IgM B cells are present in both patients and controls and produce anti-MPO IgM upon stimulation, anti-MPO-IgM memory B cells and serum anti-MPO IgM are features of patients. Our results thus hint that defective elimination of B cell reactivity to MPO in the human repertoire, the presence of activated IgM+ anti-MPO B cells in disease, and a dominant role for anti-MPO IgM in complement activation, may all contribute to MPO+ AAV etiology and thereby serve as potential target for therapy.

  Study EGAS50000000753

• Hyperdiploidy impairs fetal hematopoietic progenitor cell fitness and differentiation enabling persistence of rare preleukemic aneuploid clones

  Cells previously cryopreserved in FBS-10%DMSO were thawed and resuspended in 1mL of cold lysis buffer (10 mM Tris-HCl pH 7.4, 154 mM NaCl, 0.2% BSA, 0.1% NP-40, 1 mM CaCl₂, 0.5 mM MgCl₂ in ultra-pure water) to lyse the cell membrane and release intact nuclei. The nuclei were stained with propidium iodide (10 µg/mL) and Hoechst 33258 (10µg/mL) to facilitate sorting based on cell cycle state and viability. Single nuclei from 48 cells per sample were isolated into 96-well plates containing 5µL of freeze buffer (1X PBS, 7.5% DMSO, and 40% ProFreeze freezing medium (Lonza)) using a MoFlo Astrios cell sorter (Beckman Coulter) at the Flow Cytometry Unit of the University Medical Center Groningen (UMCG), Netherlands. The plates were centrifuged at 500 g and stored at -80°C until library preparation. Single-nuclei libraries were prepared using a Bravo Automated Liquid Handling Platform (Agilent Technologies). Nuclei were lysed, and DNA was labelled with unique 10 bp dual barcodes and amplified as previously described. Sequencing was performed on an Illumina NextSeq 2000 platform with 77bp single end reads. The generated data were subsequently demultiplexed using sample-specific barcodes and converted to FASTQ files with bcl2fastq. Sequencing reads were aligned to the GRCh38/hg38 human reference genome using Bowtie2 (v2.2.4), and duplicate reads were marked with BamUtil (v1.0.3). Single-cell karyotypes were determined by performing copy number analysis using AneuFinder (v4.3.3) (https://github.com/ataudt/aneufinder). The analysis included GC-content correction and blacklisting of artifact regions identified from euploid controls. Copy number calling was conducted with the dnacopy and edivisive algorithms, employing a bin size of 1 Mb and a step size of 500 Kb. Libraries with an average of fewer than 10 reads per chromosome copy per bin or less than 95% concordance between the two algorithms were excluded from analysis. Whole-chromosome aneuploidies were identified when over 95% of bins exhibited deviation from the disomic state. Aneuploidy scores were calculated as weighted averages of absolute copy number deviations from the euploid state. 

  Dataset EGAD50000002314

• Long-read sequencing of diagnosis and post-therapy medulloblastoma reveals complex rearrangement patterns and epigenetic signatures

  Cancer genomes harbor a broad spectrum of structural variants (SV) driving tumorigenesis, a relevant subset of which are likely to escape discovery in short reads. We employed Oxford Nanopore Technologies (ONT) sequencing in a paired diagnostic and post-therapy medulloblastoma to unravel the haplotype-resolved somatic genetic and epigenetic landscape. We assemble complex rearrangements and such associated with telomeric sequences, including a 1.55 Megabasepair chromothripsis event. We uncover a complex SV pattern termed "templated insertion thread", characterized by short (mostly less than 1kb) insertions showing prevalent self-concatenation into highly amplified structures of up to 50kbp in size. Templated insertion threads occur in 3% of cancers, with a prevalence ranging to 74% in liposarcoma, and frequent colocalization with chromothripsis. We also perform long-read based methylome profiling and discover allele-specific methylation (ASM) effects, complex rearrangements exhibiting differential methylation, and differential promoter methylation in seven cancer-driver genes. Our study shows the potential of long-read sequencing in cancer.

  Study EGAS00001006576

• DNA methylation atlas of normal human cell types

  DNA methylation is a fundamental epigenetic mark that governs chromatin organization, cell identity, and gene expression. Here we describe a human methylome atlas, based on deep whole-genome bisulfite sequencing allowing fragment-level analysis across thousands of unique markers for 39 cell types sorted from 205 healthy tissue samples. Replicates of the same cell-type are &gt;99.5% identical, demonstrating robustness of cell identity programs to genetic variation and environmental perturbation. Unsupervised clustering of the atlas recapitulates key elements of tissue ontogeny, and identifies methylation patterns retained since gastrulation. Loci uniquely unmethylated in an individual cell type often reside in transcriptional enhancers and contain DNA binding sites for tissue-specific transcriptional regulators. Uniquely hyper-methylated loci are rare and are enriched for CpG islands, polycomb targets, and CTCF binding sites, suggesting a novel role in shaping cell type-specific chromatin looping. The atlas provides an essential resource for interpretation of disease-associated genetic variants, and a wealth of potential tissue-specific biomarkers for use in liquid biopsies.

  Study EGAS00001006791

• Sequencing_Acute_Myeloid_Leukaemia_

  This project will aim at sequencing and analysing three samples from a patient with acute myeloid leukaemia (AML) with t(15;17) translocation (acute promyelocytic leukaemia). The patient was treated with standard chemotherapy and samples (blood and bone marrow) taken for minimal residual disease measured during and after chemotherapy. 2-3years later the patient presented a second AML containing inv (16).In this project we will sequence both AML and normal genomes to find associated mutations This will allow unprecedented insights into the dynamics of appearance of secondary AML, since we will be able to use the MRD samples to track the emergence of the inv(16) leukaemia. We will also be able to distinguish whether the 2 leukaemias are clonally related or not. This project will entail sequencing and analysis of three samples (whole genome 30x coverage) using Hi-Seq. The funds from this grant will cover the cost of sequencing 9 lanes from the AML t(15;17) sample, 9 lanes from AML inv(16) sample and 8 lanes from the normal genome.

  Study EGAS00001000035

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

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

  Study EGAS00001002170

• Genomes of Relapsing Neuroblastoma

  Neuroblastoma is a malignancy of the developing sympathetic nervous system that is often lethal when relapse occurs, but the molecular mechanisms behind this process are poorly defined. We here used whole-exome sequencing, mRNA expression, array CGH and DNA methylation analysis to holistically characterize 16 paired samples from neuroblastoma patients at diagnosis and relapse. The mutational burden significantly increased in relapsing tumors accompanied by altered mutational signatures and reduced subclonal heterogeneity. Global allele frequencies at relapse indicated clonal mutation selection during disease progression. Promoter methylation patterns were consistent over disease course and patient-specific. Recurrent alterations at relapse included mutations in the putative CHD5 neuroblastoma tumor suppressor, chromosome 9p losses, DOCK8 mutations, inactivating mutations in PTPN14 and a relapse-specific activity pattern for the PTPN14 target gene, YAP. Recurrent new mutations in HRAS, KRAS, DOCK8 and genes mediating cell-cell interaction in 13/16 relapse tumors also indicate disturbances in signaling pathways mediating mesenchymal transition. Our data shed first light on genetic alteration frequency, identity and evolution in neuroblastoma.

  Study EGAS00001001387

• MED12L Gene Alterations Define Aggressive BRCA2-Mutant Prostate Cancers

  Germline mutation of BRCA2 increases the lifetime risk of developing prostate cancer (PCa) by over 700%. BRCA2-mutant PCa have poorer prognosis than sporadic PCa, with rapid development of metastatic, castrate-resistant prostate cancer (mCRPC) and 5-year cancer-specific survival rates of ~50-60%1-4. Despite this, unique genomic driver events that explain the aggressiveness of localized BRCA2-mutant PCa are lacking. We used whole-genome sequencing to fully characterize 14 BRCA2-mutant PCa and demonstrate that BRCA2-mutant PCa is associated with increased genetic instability and a mutually exclusive mutational burden when compared to sporadic PCa. Importantly, BRCA2-mutated cancers are defined by unique copy number gains and hypomethylation events, including alterations in the MED12L/MED12 axis, which are found solely in mCRPC and are enriched in PCa tumours harbouring aggressive intraductal carcinoma (IDC-P) pathologic sub-types. Our findings begin to explain the clinical entity of BRCA2-mutated PCa as these tumours have a unique and aggressive genotype de novo, associated with IDC-P and mCRPC, even in the hormone-naive setting.

  Study EGAS00001001615

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

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

  Study EGAS00001001845

• 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

• ALPI deficiency causes refractory Inflammation Bowel Disease

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

  Study EGAS00001003350

• Epigenetic dynamics of monocyte to macrophage differentiation

  Monocyte to macrophage differentiation involves major biochemical and structural changes in non-dividing cells. In order to elucidate the role of gene regulatory changes during this process, we used high-throughput sequencing to analyze the complete transcriptome and epigenome of human monocytes that were isolated by elutriation and differentiated in vitro by addition of MCSF in serum-free medium. We also investigated the effect of loading the macrophages with modified LDL. We found that many mRNAs and miRNAs were significantly up- or downregulated during differentiation. While there was no correlation between gene expression and DNA methylation changes at transcription start sites, we identified a large number of intra- and intergenic regions that rapidly lost DNA methylation, became nucleosome-free and gained histone marks indicative of active enhancers. Loading of macrophages with modified LDL caused gene expression changes, but no chromatin changes. In summary, our results demonstrate that monocyte to macrophage differentiation is associated with rapid, highly targeted epigenetic changes, whereas lipid uptake mainly affects regulatory circuits of soluble factors.

  Study EGAS00001001595

• Liverpool Preterm Birth Biomarker Study

  Preterm birth is a multifactorial condition defined as birth less than 37 weeks of gestation. This study aimed to identify early pregnancy biomarkers from maternal genome-wide and transcriptome-wide data of women experiencing two types of spontaneous PTB (sPTB): spontaneous preterm birth (SPTB) and preterm premature rupture of membranes (PPROM). Whole blood samples were obtained from women with singleton pregnancies (N=567) recruited at the Liverpool Women’s Hospital at 16 and 20 weeks of gestation. Women with a previous history of sPTB pregnancies &lt;34 weeks were categorised on their index pregnancy outcome as spontaneous preterm birth (SPTB) and preterm premature rupture of membranes (PPROM) or high-risk term control (HTERM, ≥37 weeks). Women with no history of SPTB/PPROM and delivered at term were LTERM (≥39 weeks of gestation). DNA was genotyped on the UK Biobank Axiom™ array (Applied Biosystems™, Thermo Fisher Scientific) and RNA who processed using the Clariom™ D Human assay (Thermo Fisher Scientific). Genome-wide association analysis, differential expression analysis and expression quantitative trait loci (eQTL) were completed.

  Study EGAS00001005076

• HCA_Placental_Infection_Atlas

  HCA Placental Infection Atlas Self-renewing human trophoblast stem cells (hTSC) can give rise to major trophoblast lineages, including syncytiotrophoblast (SCT) and extravillous trophoblast (EVT). hTSC has facilitated the study of placental development and function in vitro. Here, we aim to utilise the hTSC line (HMDMC 20/0005) to study human placental infection and inflammation. This study will provide the opportunity to better understand the pathogenesis of human placenta in the event of infection and inflammation. In brief, differentiated hTSC will be infected with relevant pathogens and stimulated with a panel of inflammatory cytokines. We will use single-cell genomic and spatial approaches to characterise cellular heterogeneity in response to infection or cytokines stimulus. In parallel, we will investigate the interaction between iPSC-derived macrophages with different trophoblast lineages during the course of infection using single-cell genomic and spatial methods. This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/

  Study EGAS00001004722

• Reference exome data for Australian Aboriginal populations to support health-based research

  Whole exome sequencing (WES) is a popular and successful technology which is widely used in both research and clinical settings. However, there is a paucity of reference data for Aboriginal Australians to underpin the translation of health-based genomic research. Here we provide a catalogue of variants called after sequencing the exomes of 50 Aboriginal individuals from the Northern Territory (NT) of Australia and compare these to 72 previously published exomes from a Western Australian (WA) population of Martu origin. Sequence data for both NT and WA samples were processed using an ‘intersect-then-combine’ (ITC) approach, using GATK and SAMtools to call variants. A total of 289,829 variants were identified in at least one individual in the NT cohort and 248,374 variants in at least one individual in the WA cohort. Of these, 166,719 variants were present in both cohorts, whilst 123,110 variants were private to the NT cohort and 81,655 were private to the WA cohort. Our data set provides a useful reference point for genomic studies on Aboriginal Australians.

  Study EGAS00001003745

• Automated image-based profiling of complex drug induced phenotypes in patient-derived organoids

  We established a platform for high-throughput confocal fluorescence microscopy and automated image analysis to perform large-scale drug response profiling with patient derived organoids (PDOs). Using PDO lines newly established from colorectal cancer patients with a standardized workflow, we performed chemical perturbations with more than 500 experimental and clinically used compounds. Subsequently, we captured approx. six million images by confocal microscopy. To analyze drug-induced PDO re-organization on a single organoid level we developed SCOPE, a software framework for automated PDO high-throughput image analysis. We observed a rich variety of divergent and reoccurring compound induced phenotypes in organoids. Perturbation of cellular processes, including signaling by MEK, GSK3β, cyclin dependent kinases (CDKs) and others, led to recurring and distinct architectural changes. Highlighting the clinical relevance, PDO viability was heterogeneous after perturbation with anticancer drugs and matched clinical response of corresponding colorectal cancer patients. Our work opens new avenues for image-based profiling for accelerated drug discovery and clinical decision-making.

  Study EGAS00001003140

• Molecular stratification of endometrioid ovarian carcinoma predicts clinical outcome

  Endometrioid ovarian carcinoma (EnOC) is an under-investigated type of ovarian carcinoma. Here, we report the largest genomic study of EnOCs to date, performing whole exome sequencing of 112 cases following rigorous pathological assessment. High frequencies of mutation were detected in CTNNB1(43%), PIK3CA(43%), ARID1A(36%), PTEN(29%), TP53(26%) and SOX8(19%), a novel target of recurrent mutation in EnOC. POLE and mismatch repair protein-encoding genes were mutated at lower frequency (6%, 18%) with significant co-occurrence. A molecular taxonomy was constructed using a novel algorithm (PRISTINE), identifying clinically distinct EnOC subtypes: TP53m cases demonstrated greater genomic complexity, were frequently FIGO stage III/IV at diagnosis (48%) and incompletely debulked (44%), and demonstrated inferior survival; conversely, CTNNB1m cases demonstrated low complexity and excellent clinical outcome, were predominantly stage I/II at diagnosis (89%) and completely resected (87%). Tumour complexity provides further resolution within the TP53wt/CTNNB1wt group. Moreover, we identify the WNT, MAPK/RAS and PI3K pathways as good candidate targets for molecular therapeutics in EnOC.

  Study EGAS00001004366

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

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

  Study EGAS00001004508

• 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

• Genomic analysis and evolutionary modeling of breast and larynx cancer, based on specimens from Polish population

  We explore the genomic characteristics of the original dataset of breast and larynx cancer specimens of several cell types from the collection of the Department of Applied Radiology of the Maria Sklodowska-Curie National Research Institute of Oncology, Krakow (Poland) Branch and Institute of Human Genetics Polish Academy of Sciences. DNA from paired tissue samples from primary tumor locations and concurrent metastasis to regional lymph nodes was sequenced and matched to controls. A range of genomic analyses was carried out, such as estimation of variant allele frequencies (VAF) and copy number variation (CNV). They show that subsets of variants from primary tumors are present in metastatic lymph nodes and that the CNV pattern is similar, but not identical to that known in the literature. In addition to that, we fit the VAF data to theoretical site frequency spectra predicted by multiple models found in the literature. Analysis suggests existence of secondary advantageous subclones arising on the clonal background as well as of a number of neutral or slightly deleterious passenger mutations.

  Study EGAS00001006456

• Effective reprogramming of patient-derived M2-polarized glioblastoma-associated microglia/macrophages by treatment with GW2580

  Purpose: Targeting immunosuppressive and pro-tumorigenic glioblastoma-associated macrophages and microglial cells (GAMs) has great potential to improve patient outcomes. Colony stimulating factor-1 receptor (CSF1R) has emerged as a promising target for reprogramming anti-inflammatory M2-like GAMs. However, treatment data on patient-derived, tumor-educated GAMs and their influence on the adaptive immunity are lacking. Experimental Design: CD11b+-GAMs freshly isolated from patient tumors were treated with CSF1R-targeting drugs PLX3397, BLZ945, and GW2580. Phenotypical changes upon treatment were assessed using RNAseq. Changes in GAM activation were confirmed in a complex patient-derived 3D tumor organoid model serving as a tumor avatar. Results: The most effective reprogramming of GAMs was observed upon GW2580 treatment, which led to the downregulation of M2-related markers, IL-6, and IL-10, ERK1/2 and MAPK signaling pathways, while M1-like markers and gene set enrichment indicating activated MHC-II presentation were substantially increased. Moreover, treatment of patient-derived glioblastoma organoids with GW2580 confirmed successful reprogramming.

  Study EGAS00001007466

• Sequential Antigen-loss and Branching Evolution in Lymphoma after Anti-CD19 and Anti-CD20 Targeted T Cell Engaging Immunotherapy

  CD19 CAR T cells and CD20 targeting T cell engaging bispecific antibodies have been approved in B-cell Non-Hodgkin lymphoma lately, heralding a new clinical setting where patients are treated with both approaches, sequentially. The aim of our study was to investigate the selective pressure of CD19 and CD20 directed therapy on the clonal architecture in lymphoma. Using a broad analytical pipeline, we identified truncating mutations in the gene encoding CD20 conferring antigen loss in 80% of patients relapsing from CD20 bispecs. Pronounced T cell exhaustion was identified in cases with progressive disease and retained CD20 expression. We also confirmed CD19 loss after CAR T cell therapy and report the case of sequential CD19 and CD20 loss. We observed branching evolution with re-emergence of CD20 positive subclones at later time points and spatial heterogeneity for CD20 expression in response to targeted therapy. Our results highlight immunotherapy as an evolutionary bottleneck selecting for antigen-loss variants but also complex evolutionary pathways underlying disease progression from these novel therapies.

  Study EGAS00001007561

• Genes and Blood Clotting Study (GABC)

  Objectives: Use genome-wide approaches to identify genetic variants that influence common thrombosis and hemostasis factors, as well as selected common human traits. Design/Methods: The GABC study was a prospective sibling cohort design. Siblings were recruited by targeted email to the undergraduate and graduate student email lists at the University of Michigan. Healthy persons between 14 and 35 years old who had healthy siblings within the same age restriction were able to participate. Study participants agreed to an online informed consent and subsequently completed a 52-question online survey describing their specific bleeding traits as well as many common human traits. Fifty milliliters of blood was collected into a citrate-dextrose solution (ACD) from each participant. An aliquot of whole blood was used for an automated complete blood count analysis and the remainder was processed into platelet poor plasma and buffy coat portions. Plasma and buffy coat aliquots were snap frozen and stored in liquid nitrogen for future studies. 1189 individuals representing 507 sibships were collected between 06/26/2006 and 01/30/2009. Phenotyping Survey Details: To characterize individual bruising and bleeding history, the online survey recorded answers to questions based on a modified von Willebrand Disease (VWD) screening questionnaire. To characterize a collection of participant&#39;s common human traits, the survey recorded answers to questions about height, weight, presence of skin tags, history of acne, eye color, hair color, hair line characteristics, skin sunburn sensitivity, skin tanning ability, natural skin color, freckling, cheek dimpling, earlobe shape, shoe size, foot arch characteristics, hand fifth digit morphology, history of dyslexia, history of migraine headaches, history of seasonal allergies, history of apthous ulcers, tendency to sneeze while walking into a bright sunny place, history of dental caries, need for corrective eye lenses, handedness and like or dislike of strongly flavored foods. Biochemical phenotyping: Assays for plasma Von Willebrand Factor (VWF) antigen were performed using ELISA and "Alphalisa" techniques. Automated complete blood count analysis was performed on a Bayer Advia 120 on all participants (including WBC differential, RBC indices, and platelet count.) For the dbGaP v2 update, new biochemical phenotypes have been submitted and include von Willebrand Factor, von Willebrand Factor propeptide, plasminogen, gamma prime fibrinogen, ADAMTS 13, antithrombin III, protein C, and protein S. All new phenotypes were obtained using "Alphalisa" techniques. Genotyping Details: SNP genotyping was performed using genomic DNA extracted from peripheral blood at the Broad Institute, (MIT/Harvard). Genotyping was performed on the Illumina Omni-1 quad chip at the Broad Institute. For the dbGaP v2 update, genotyping data from the Illumina Human Exome was deposited. 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 blood clotting through large-scale genome-wide association studies of siblings. Genotyping was performed at the Broad Institute of MIT and Harvard, a GENEVA genotyping center. Data cleaning and harmonization was performed by the primary investigators at the University of Michigan, Ann Arbor, and at the GEI-funded GENEVA Coordinating Center at the University of Washington. This study serves as a resource for investigators who are interested in the genetic determinants of specific plasma proteins in a healthy population. The sibling cohort design allows for linkage analysis in addition to association studies. Analysis of thrombosis and hemostasis related traits should help elucidate specific biochemical and genetic networks that maintain hemostasis. We hope to identify specific genetic determinants of VWF levels in order to better understand the factors that influence the development of VWD.

  Study phs000304

• Smith-Lemli-Opitz Syndrome: A Longitudinal Clinical Study of Patients Receiving Cholesterol Supplementation

  Smith-Lemli-Opitz syndrome (SLOS) is a disorder of cholesterol production by the body. It is caused by changes in the DHCR7 gene, which is the blueprint for an enzyme called 7-dehydrocholesterol- delta7-reductase. This enzyme is necessary for the production of cholesterol by all cells in the body. People with SLOS often have malformations of major organs, slow growth, feeding difficulties and intellectual disability or learning problems. Because patients with SLOS cannot make enough cholesterol, it has been proposed that cholesterol supplementation (either with egg yolk or liquid suspensions of cholesterol) could help improve the symptoms of the disease. However, despite the widespread use of cholesterol supplementation, it is still not known whether it works or not. The study will try to provide an answer to this question by studying the disease and its progression while patients are receiving cholesterol. The clinical features of SLOS are thought to be related to low cholesterol and buildup of toxic cholesterol precursors (substances from which cholesterol is formed). But how exactly low cholesterol and toxic precursors contribute to the disease is poorly understood. This knowledge is critically important because it should help discover new therapeutic targets and develop treatments of the disease in the long run. The study will try to fill this gap with a comprehensive clinical and biochemical testing of the study participants over the course of several years. Last, a limitation of previous SLOS research studies has been their low number of participants. This is understandable because SLOS is a rare diseases and few research groups are working on it. However, in order to fully understand the disease, researchers need to study as many patients as possible. This study is unique in that it is run by a network of several highly specialized clinical research sites across the country. Having several sites involved increases the researcher&#39;s ability to recruit and study large number of patients, and centralize patients&#39; information in a comprehensive SLOS clinical registry. This registry will be key to identify markers for diagnostic testing, screening and measuring outcomes in future studies of treatment. The purpose of this study is to learn as much as possible about Smith-Lemli-Opitz Syndrome (SLOS) by following a large group of affected children and adults over time. In this study, we will measure cholesterol and other similar chemicals in blood and urine, evaluate development and behavior, do limited medical evaluation, and carry out brain imaging studies.This study will help researchers: learn more about what causes SLOS and how SLOS changes with age, note differences in features of SLOS among those affected, evaluate the effect of giving extra cholesterol in this condition, and develop ways to evaluate whether treatments developed in the future will be helpful.

  Study phs001430

• Minority Health Genomics and Translational Research Bio-Repository Database

  The Minority Health Genomics and Translational Research Bio-repository Database (MHGRID) Network infrastructure facilitated the collection of biospecimens and related multidimensional data elements within a consortium of minority-serving clinics. This initiative expands the diversity of ancestral groups in national genomic medicine datasets and promises to accelerate the translation of personalized medicine into minority communities. MHGRID has an observational case-control design with severe hypertension as primary outcome.

  Study phs001815

• Maintenance of Genome Sequence Integrity in Long- and Short-lived Rodent Species

  In this study, we compared somatic mutation frequencies and spectra of bleomycin-treated and control fibroblasts of 5 species, i.e., mouse, guinea pig, blind mole-rat, naked mole-rat and humans, by using single-cell whole-genome sequencing. Sequencing data of the human cells are deposited here in the dbGaP. Sequencing data of the rodent cells are in the SRA database, under accession ID: PRJNA753541.

  Study phs002610

• Advanced Genetic and Molecular Analysis of Solid Tumors

  This study is designed to understand the role of immunosuppressive regulatory B cells (Breg) in pancreatic cancer. Breg and conventional B cells (Bcon) from patients are compared by RNA sequencing analysis. Bregs and Bcon were isolated from freshly isolated PBMCs in peripheral blood. These data represent the examination of differentially expressed genes in these two blood-derived B cell subsets from both healthy and pancreatic cancer patients.

  Study phs001999

• Cellular Origins and Genetic Landscape of Cutaneous GD T Cell Lymphoma

  Cutaneous gamma-delta T cell lymphomas are a rare and aggressive subtype of cutaneous lymphoma. In the present study, we analyzed these cancers by DNA and RNA sequencing in order to illuminate the genetic landscape for this rare disease. We obtained tumor samples from multiple institutions, including Northwestern University (Chicago, IL), University of Chicago (Chicago, IL), University of Virginia (Charlottesville, VA), and Massachusetts General Hospital (Boston, MA).

  Study phs001969

• Integrated Genetic and Pharmacologic Interrogation of Rare Cancers

  Due to the paucity of patient derived models in rare cancers, identification of therapeutic targets remains challenging. We developed a patient derived model, CLF-PED-015-T, from a patient with an undifferentiated sarcoma. From this model, we performed pooled RNAi and CRISPR-Cas9 negative selection screens and integrated that with a small molecule screen. Integration of these data identified CDK4 and XPO1 as potential therapeutic targets.

  Study phs001121

• Project for Development of Innovative Research on Cancer Therapeutics;Shuttle system between petient-derived xenograft and ex vivo culture for innovative platform of evaluating drug sensitivity.

  We developed CTOS (cancer tissue-originated spheroid) panel covering diversity among patients for colorectal cancer, lung cancer and cervical small cell carcinoma. We then carried out exome sequence analysis of tumor tissues, cell lines and CTOS derived from patients to validate qualitative changes in preparation, culture, cell line, transplantation and passage of CTOS pathologically, biochemically, molecular biologically.

  Study JGAS000089

• Identification Of Pathogenic Mutations And Application Of Polygenic Risk Scores In Early-Onset Diabetes Patients

  Maturity-onset Diabetes of the Young (MODY) presents a diagnostic challenge. In this study we investigate the genetic background of Latvian early-onset diabetes patients, using whole-genome sequencing data. Additionally, we investigate the utility of previously published and available type 1 diabetes (T1D) and type 2 diabetes (T2D) polygenic risk scores in differentiating monogenic diabetes (MODY) from T1D and T2D cases.

  Study EGAS50000000991

• RNASeq from PPGL-derived PC12 cell lines cultivated in normoxia and hypoxia conditions.

  PC12 cells derived from rat PPGL were then either continued cultivated in the same normoxia condition (37˚C, 5% CO2 and 21% O2 balanced with N2) or were placed in a hypoxic incubator, that maintained a constant hypoxic environment (37˚C, 5% CO2 and 1% O2 balanced with N2), for different short (12h, 24h, and 48h) or prolonged time (36 days, approximately 860h).

  Study EGAS50000000814

• Molecular underpinnings of dedifferentiation and aggressiveness in chromophobe renal cell carcinoma

  This study expands our understanding of aggressive chromophobe renal cell carcinoma (ChRCC), provides insight into molecular mechanisms of tumor progression, and informs pathologic classification and diagnostics. Tumor and adjacent normal samples were collected from 11 patients treated in affiliated hospitals of the University of Texas Southwestern Medical Center (UTSW), including Parkland Hospital. Seven of the eleven patients consented to depositing their genomic data to public repository.

  Study EGAS50000000287

• Comprehensive molecular portrait reveals genetic diversity and distinct molecular subtypes of small intestinal neuroendocrine tumors

  This study aims to characterize neuroendocrine tumors of the small intestine (siNETs) from genomic, transcriptomic, epigenomic, and clinical perspectives. Involving 122 patients and 219 samples, we generated whole-genome sequencing data, RNA sequencing data, genotyping arrays, and methylation arrays to conduct an integrative analysis of this rare tumor type. Our findings identify distinct molecular subtypes that correlate with siNET clinical features.

  Study EGAS50000000642

• Bulk RNAseq FASTQ files of WNT7B reporter PDAC organoids (P28 and P40) sorted by mNeonGreen high and low

  This dataset contains raw FASTQ files from bulk RNA sequencing of two patient-derived PDAC organoid lines (P28 and P40) carrying a WNT7B reporter knock-in. Organoids were sorted into mNeonGreen high (WNT-high) and low (WNT-low) populations, with three biological replicates per sorted population. RNA was extracted using the Qiagen QiaSymphony SP system, and libraries were prepared with the Illumina Truseq stranded polyA kit. Sequencing was performed on an Illumina NextSeq2000 platform using single-end 50bp reads. Quality control was conducted with FastQC, and reads were trimmed with TrimGalore as appropriate. Data are controlled-access and intended for transcriptomic analysis of WNT7B expression-dependent transcriptional programs in PDAC organoids.

  Dataset EGAD50000002218

• WES analysis of tumor samples from ER+ breast cancer patients treated with CDK4/6 inhibitor

  We performed whole exome sequencing of paired fresh frozen tumor from 4 ER+ advanced breast cancer patients. Samples were obtained for each patient prior to combined CDK4/6 inhibitor and endocrine therapy and at disease progression (N=8). DNA was extracted using the Maxwell® RSC FFPE and Tissue DNA Kit (Promega). WES was performed at the Department of Molecular Medicine, Aarhus University Hospital on matched tumor DNA (derived from primary fresh frozen and FFPE tissue) and buffy coat DNA. Libraries of tumors and matching germline DNA were prepared using 50 ng DNA and captured by Twist Comprehensive Exome with custom spike-ins, sequenced on the Illumina NovaSeq 6000 platform to an average coverage of 413x (range: 148-515x). The dataset include the analysis data files (vcf files).

  Dataset EGAD50000000622

• Transcriptomic subgroups in soft tissue tumors correlate with morphologic subtype, genomic features, and outcome

  We assessed gene expression (GGE) profiles and gene fusions as detected by transcriptome sequencing (RNA-seq) of 704 soft tissue tumors (STT) representing 56 different tumor types. Comparison with follow-up data identified transcriptional subclusters among sarcomas with complex genomes and among adipocytic tumors that correlated with metastasis-free survival and local recurrences, respectively. Thus, RNA-seq analysis of STT provides clinically important information.

  Study EGAS50000001472

• Novel manifestations of immune dysregulation and granule defects in gray platelet syndrome

  Gray Platelet Syndrome (GPS) is a rare recessive bleeding disorder resulting from biallelic variants in NBEAL2. As part of a comprehensive evaluation of the phenotype and genotype in 47 patients with GPS, four different blood cell-types (platelets, neutrophils, monocytes, and CD4-lymphocytes) were evaluated using bulk RNA-seq in five patients and five controls. These data are deposited in this archive in FASTQ format.

  Study EGAS00001004216

• HipSci HumanExome BeadChip analysis - Usher syndrome and congenital eye defects

  The HipSci project brings together diverse constituents in genomics, proteomics, cell biology and clinical genetics to create a UK national iPS cell resource and use it to carry out cellular genetic studies. In this sub-study we performed Genotyping analysis using the Infinium HumanExome BeadChip on iPS cells generated from skin biopsies or blood samples from rare disease patients diagnosed with Usher syndrome and congenital eye defects.

  Study EGAS00001002008

• HipSci HumanExome BeadChip analysis - Bleeding and Platelet disorders

  The HipSci project brings together diverse constituents in genomics, proteomics, cell biology and clinical genetics to create a UK national iPS cell resource and use it to carry out cellular genetic studies. In this sub-study we performed Genotyping analysis using the Infinium HumanExome BeadChip on iPS cells generated from skin biopsies or blood samples from rare disease patients diagnosed with Bleeding and Platelet disorders.

  Study EGAS00001002013

• HipSci___Whole_Exome_sequencing___Usher syndrome and congenital eye defects

  The HipSci project brings together diverse constituents in genomics, proteomics, cell biology and clinical genetics to create a UK national iPS cell resource and use it to carry out cellular genetic studies. In this sub-study we perform whole exome sequencing using Agilent whole exome pulldown method on iPS cells generated from skin biopsies or blood samples from rare disease patients diagnosed with Usher syndrome and congenital eye defects.

  Study EGAS00001001985

• RNA sequencing data from visceral and abdominal subcutaneous adipose tissue from morbidly obese women with normal glucose tolerance or type 2 diabetes

  The study group consisted of 17 obese women with normal glucose tolerance and 15 obese women with T2DM. Adipose tissue specimens were taken from the epigastric region of the abdominal wall (SAT) and from the major omentum (VAT). RNA was isolated and RNA sequencing was used to analyse the transcriptome. Dharuri H et al, Diabetologia. 2014;57(11):2384-92.

  Study EGAS00001001872

• HipSci HumanHT 12 Expression BeadChip analysis - Bleeding and Platelet disorders

  The HipSci project brings together diverse constituents in genomics, proteomics, cell biology and clinical genetics to create a UK national iPS cell resource and use it to carry out cellular genetic studies. In this sub-study we performed Expression analysis using the Illumina HumanHT -12 Expression BeadChip on iPS cells generated from skin biopsies or blood samples from rare disease patients diagnosed with Bleeding and Platelet disorders.

  Study EGAS00001002028

• Whole-genome sequencing identifies ADGRG6 enhancer mutations and FRS2 duplications as angiogenesis-related drivers in bladder cancer

  Bladder cancer is one of the most common and highly vascularized cancers. To better understand its genomic structure and underlying etiology, we conducted whole-genome sequencing in 65 urothelial bladder carcinomas (the most common type of bladder cancer) and identified recurrent genetic alterations in a set of angiogenesis genes, facilitating the understanding of molecular mechanisms underlying pathological angiogenesis in this type of cancer.

  Study EGAS00001003388

• Gene regulation of human stimulated and cultured CD4+ Treg cells

  This dataset maps gene expression regulation in human primary regulatory CD4+ T cells (Tregs) stimulated using PMA and ionomycin or cultured without stimulus for 18 hours. It includes whole genome sequence data for ChM-seq (18 H3K4me3, 20 H3K27ac and 3 inputs), ATAC-seq (42 samples) and whole transcriptome (39 samples). All individuals were genotyped using coreExome Illumina SNP chip array (included in EGAS00001003516).

  Study EGAS00001003515

• Shallow whole genome sequencing and targeted capture sequencing data of PCNSL and PTL primary and relapse pairs

  Shallow whole genome sequencing for copy number analysis and targeted capture sequencing data for translocation and mutation anslysis of paired primary and relapse PCNSL and PTL samples

  Dataset EGAD00001008387

• Single-cell Transcriptomic and TCR Repertoire Profiling of DENV-specific CD8+ T Cells Across Dengue Disease Severities

  This dataset contains single-cell RNA sequencing (Smart-seq2) and paired TCR repertoire data of sorted dengue virus (DENV)-specific CD8⁺ T cells from individuals with differing clinical outcomes: asymptomatic dengue (AD), dengue fever (DF), and dengue hemorrhagic fever (DHF). Samples were obtained from HLA-A11⁺ and HLA-A24⁺ individuals during acute and convalescent phases, with antigen-specific CD8⁺ T cells isolated using HLA tetramers loaded with immunodominant DENV epitopes. The study identifies phenotypically distinct T cell subsets associated with disease severity, TCR avidity, and antigen reactivity to current or prior DENV serotypes. The dataset supports the understanding of CD8⁺ T cell heterogeneity, TCR features, and potential mechanisms of CD8⁺ T cell-mediated protection versus immunopathogenesis in dengue infection.

  Dataset EGAD00001015637

• Expanding the SPTBN1 Spectrum: A Case of Neurodevelopmental Disorder with GI and Musculoskeletal Involvement

  Background: Mutations in the SPTBN1 gene, which encodes the βII-spectrin protein, are associated with a recently described neurodevelopmental syndrome characterized by developmental delay, intellectual disability, autistic traits, seizures, and dysmorphic features. While the phenotypic spectrum continues to evolve, gastrointestinal (GI) involvement and vertical transmission remain rarely reported features. Case Presentation: We describe a 13-year-old male from Georgia with a heterozygous missense mutation in SPTBN1 (c.3799C>G, p.Leu1267Val), inherited from his clinically unaffected mother. The patient presented with cognitive and motor delays, autistic traits, behavioral challenges, feeding difficulties, growth delay, musculoskeletal anomalies (pectus excavatum, pes planus), and persistent GI symptoms including abdominal pain and gallbladder sludge. Despite therapy with ursodeoxycholic acid and nutritional counseling, the gallbladder abnormalities persisted over a 12-month follow-up. Feeding therapy could not be initiated due to access barriers, although parental efforts led to modest dietary improvement. Upon recent visit pes planus was also confirmed. Conclusion: This case contributes to the growing body of literature on SPTBN1-related neurodevelopmental disorders, highlighting the potential for a broader phenotypic spectrum than currently recognized. In addition to the well-documented behavioral, cognitive, and musculoskeletal features, our patient presented with notable gastrointestinal involvement—specifically, gallbladder sludge and feeding disorder—which are not commonly reported in association with SPTBN1 mutations. Although causality cannot be established from a single case, the observed GI manifestations may be indirectly related to underlying neurobehavioral features such as ASD and associated eating disorders. The identification of a vertically transmitted missense variant (c.3799C>G, p.Leu1267Val) adds to the limited but growing evidence of inherited SPTBN1 mutations, expanding our understanding of transmission patterns. Given the novelty of the findings, we emphasize the need for multidisciplinary management, including feeding and behavioral therapy, as well as longitudinal follow-up to assess developmental, nutritional, and hepatobiliary outcomes. Future studies and case series are warranted to determine whether pes planus, pectus excavatum, gastrointestinal symptoms, including biliary tract involvement, represent an underrecognized component of the SPTBN1 phenotypic spectrum.

  Study EGAS50000001213

• Neoadjuvant atezolizumab plus chemotherapy in gastric and gastroesophageal junction adenocarcinoma: the phase 2 PANDA trial

  Gastric and gastroesophageal junction (G/GEJ) cancers carry a poor prognosis, and despite recent advancements most patients die of their disease. While immune checkpoint blockade has become part of the standard of care for patients with metastatic G/GEJ cancers, its efficacy and impact on the tumor microenvironment in the early disease setting remain largely unknown. We hypothesized a higher efficacy of neoadjuvant immunotherapy plus chemotherapy in patients with non-metastatic G/GEJ cancer. In the phase 2 PANDA trial, patients with previously untreated resectable G/GEJ tumors (n=21) received neoadjuvant treatment with one cycle of atezolizumab monotherapy followed by 4 cycles of atezolizumab plus docetaxel, oxaliplatin and capecitabine. Treatment was well-tolerated, and all patients underwent resection without treatment-related delays, meeting the primary endpoint of safety and feasibility. Tissue was obtained at multiple time points, allowing analysis of the effects of single-agent PD-L1 blockade and the subsequent combination with chemotherapy on the tumor microenvironment. A total of 21 patients were included, of whom 20 patients underwent surgery and were evaluable for the secondary pathologic response and survival endpoints, while 19 were evaluable for exploratory translational analyses. A major pathologic response (MPR, ≤10% residual viable tumor) was observed in 14/20 (70%; 95% CI 46-88%) patients, including 9 (45%; 95% CI 23-68%) pathologic complete responses. At a median follow-up of 47 months, 13/14 responders were alive and disease-free, while 5/6 nonresponders had died due to disease recurrence. Notably, baseline PD-1+CD8+ T cell infiltration was significantly higher in responders than in nonresponders, and comparison of the tumor microenvironment alterations following anti-PD-L1 monotherapy versus the subsequent combination with chemotherapy revealed that increased immune activity was achieved upon single-agent PD-1/L1 axis blockade. Based on these data, anti-PD-L1 plus chemotherapy warrants further exploration in patients with non-metastatic G/GEJ cancer, and these results call for validation in a larger cohort.

  Study EGAS50000000168

• Evolution and clinical impact of genetic epistasis within EGFR-mutant lung cancers

  The current understanding of tumorigenesis is largely centered on a monogenic driver oncogene model. This paradigm is incompatible with the prevailing clinical experience in most solid malignancies: monotherapy with a drug directed against an individual oncogenic driver typically results in incomplete clinical responses and eventual tumor progression1-7. By profiling the somatic genetic alterations present in over 2,000 cases of lung cancer, the leading cause of cancer mortality worldwide, we show that combinations of functional genetic alterations, i.e. genetic collectives dominate the landscape of advanced-stage disease. We highlight this polygenic landscape and evolution of advanced-stage non-small cell lung cancer (NSCLC) through the spatial-temporal genomic profiling of 7 distinct tumor biopsy specimens and 6 plasma specimens obtained from an EGFR-mutant NSCLC patient at (1) initial diagnosis of early-stage disease, (2) metastatic progression, (3) sequential treatment and resistance to 2 EGFR inhibitors, (4) death. The comprehensive genomic analysis of this case, coupled with circulating free (cf) tumor DNA profiling of additional advanced-stage EGFR-mutant NSCLC clinical cohorts with associated treatment responses uncovered features of evolutionary selection for multiple concurrent gene alterations: including the presence of EGFR inhibitor-sensitive (EGFRL858R;EGFRexon19del) or inhibitor-resistant (EGFRT790M;EGFRC797S) forms of oncogenic EGFR along with cell cycle gene alterations (e.g. in CDK4/6, CCNE1, RB1) and activating alterations in WNT/β-catenin and PI3K pathway genes, which our data suggest can cooperatively impart non-redundant functions to limit EGFR targeted therapy response and/or promote tumor progression. Moreover, evidence of an unanticipated parallel evolution of both EGFR T790M and two distinct forms of oncogenic PIK3CA was observed. Our study provides a large-scale clinical and genetic dataset of advanced-stage EGFR-mutant NSCLC, a rationale for specific polytherapy strategies such as EGFR and CDK4/6 inhibitor co-treatment to potentially enhance clinical outcomes, and prompts a re-evaluation of the prevailing paradigm of monogenic-based molecular stratification for targeted therapy. Instead, our findings highlight an alternative model of genetic collectives that operate through epistasis to drive lung cancer progression and therapy resistance.

  Study EGAS00001002604

• Identifying transcriptional programs underlying anti-EGFR small molecule response and resistance with TraCe-seq

  Genetic and non-genetic heterogeneity within cancer cell populations represents a major challenge to anti-cancer therapies. We currently lack robust methods to determine how pre-existing and adaptive features affect cellular responses to therapies. Here, by conducting clonal fitness mapping and transcriptional characterization using expressed barcodes and single-cell RNA-sequencing, we have developed TraCe-seq, a method that captures at clonal resolution the origin, fate, and differential early adaptive transcriptional programs of cells in a complex population in response to distinct treatments. We used TraCe-seq to benchmark how next-generation dual EGFR inhibitors-degraders compare to standard EGFR kinase inhibitors in EGFR-mutant lung cancer cells. To QC the TraCe-seq strategy, single-cell RNA-seq libraries were generated from a variety of human cancer cell lines transduced with the TraCe-seq library to validate the TraCe-seq strategy. Specifically, 5 different cell lines (PC9, MCF-10A, MDA-MB-231, NCI-H358, and NCI-H1373) were each transduced with a unique TraCe-seq barcode. The transduced cells were selected with puromycin only, dissociated to single cell suspensions, and then mixed together. The complex mixture of the 5 cell lines was profiled by 10X scRNA-seq. Furthermore, transduced NCI-H1373 cells were sorted by FACS to enrich for the top 50% of eGFP positive cells, and sorted cells were cultured briefly and used to construct scRNA-seq libraries and profiled by 10x scRNA-seq. To carry out the full TraCe-seq experiment, ~600 PC9 cells carrying unique TraCe-seq barcodes were expanded over 12 doublings to establish the barcoded population. A subset of the barcoded PC9 population was used to generate scRNA-seq libraries and profiled by 10x scRNA-seq prior to treatment to establish a baseline transcription profile for each barcoded clone. The rest of the cells were then treated for four days with 1 µM erlotinib, 1 µM GNE-069, or 1 µM GNE-104 respectively. scRNA-seq libraries were then generated form the treated cells and profiled by 10x scRNA-seq.

  Study EGAS00001005405

• Molecular Biomarkers in Glioma (Mechanisms and Therapeutic Implications of Hypermutation in Gliomas)

  This study seeks to genomically and mechanistically examine the basis for resistance of glioblastoma to chemotherapy, radiation therapy, and targeted therapy including immunotherapies. The study design addresses two Aims. In Aim 1, we will test the hypothesis that treatment with radiation and temozolomide or other therapies leads to consistent genetic changes in human tumors using whole exome sequencing of paired pre- and post-treatment tumor samples to determine large-scale changes in population structures and single cell whole genome sequencing to evaluate the effects of these treatments on microheterogeneity. In Aim 2, we will test the hypothesis that genetic changes identified in post-treatment glioblastomas (GBMs) functionally contribute to various forms of resistance in GBM using patient derived cell lines (PDCL) and patient derived xenografts (PDX). These studies will create a comprehensive understanding of genetic evolution during standard-of-care therapy for GBM. They will inform diagnostic approaches for assignment of targeted therapeutics in the recurrent setting and identify genetic changes driving resistance. Therapeutic targeting of these novel resistance drivers could represent a rational approach to substantially improve our existing standard of care for GBM patients.

  Study phs001967

• Nicotine dependence GWAS meta-analysis across European and African American ancestries

  Cigarette smoking is the leading cause of preventable morbidity and mortality. Knowledge is evolving on genetics underlying initiation, regular smoking, nicotine dependence (ND), and cessation. We performed a genome-wide association study using the Fagerstr&#246;m Test for ND (FTND) in 58,000 smokers of European or African ancestry. Five genome-wide significant loci, including two novel loci MAGI2/GNAI1 (rs2714700) and TENM2 (rs1862416) were identified, and loci reported for other smoking traits were extended to ND. Using the heaviness of smoking index (HSI) in the UK Biobank (N=33,791), rs2714700 was consistently associated, but rs1862416 was not associated, likely reflecting ND features not captured by the HSI. Both variants were cis-eQTLs (rs2714700 for MAGI2-AS3 in hippocampus, rs1862416 for TENM2 in lung), and expression of genes spanning ND-associated variants was enriched in cerebellum. SNP-based heritability of ND was 8.6%, and ND was genetically correlated with 13 other smoking traits (rg=0.40-0.95) and co-morbid diseases. Our results emphasize the FTND as a composite phenotype that expands genetic knowledge of smoking, including loci specific to ND.

  Study phs001532

• Youth Drug Abuse, ADHD and Related Disorders

  There are two major aims with this study. 1. To describe the developmental trajectory of (a) a community-based sample of youth with a childhood diagnosis of ADHD that has been prospectively followed from childhood into adulthood (approximately a 17-year span), and (b) a clinical sample of youth that received drug abuse treatment during adolescence (variable time span). 2. To examine the association of phenotypes of drug involvement severity and risk alleles that prior research has suggested to be associated with drug abuse and externalizing disorders. The sample (N=607) consists of three groups based on youth status: Treatment, High Risk, and Control. These groups are defined as follows: Treatment - attended treatment or a brief intervention for a substance use disorder during adolescence (n=402); High Risk - elevated scores on standardized measures of disruptive behaviors during childhood based on teacher and parent reports (n=142); Control - normative scores during childhood on standardized measures of disruptive behaviors based on teacher and parent reports, and absent of any DSM-based behavioral/mental disorder when assessed during childhood based on parent report (n=66). Among the 610 participants who provided DNA, 607 are usable samples.

  Study phs001734

• Nivolumab and Tumor Infiltrating Lymphocytes (TIL) in Advanced Non-Small Cell Lung Cancer

  We performed a trial of adoptive cell therapy using tumor infiltrating lymphocytes (TIL) in metastatic non-small cell lung cancer (NSCLC). We conducted a single-arm open- label phase 1 trial (NCT03215810) of TIL administered with nivolumab in 20 patients with advanced NSCLC. Patients had tumor metastases resected for TIL, and the sequencing data from these tumors is included herein. The primary endpoint was safety, and secondary endpoints included objective response rate, duration of response, and T-cell persistence. Autologous TIL was expanded ex vivo from minced tumors cultured with IL-2. Patients received initial nivolumab for 4 cycles. If they had subsequent evidence of progression, then they proceeded to receive cyclophosphamide and fludarabine lymphodepletion, TIL infusion, and interleukin-2, followed by maintenance nivolumab. The endpoint of safety was met according to pre-specified criteria. Of 13 evaluable patients, 3 had confirmed responses and 11 had reduction in tumor burden, with a median best change of 35%. Two patients achieved complete responses ongoing 1.5 years later. In exploratory analyses, we found T cells recognizing multiple types of cancer mutations were detected after TIL treatment, and were enriched in responding patients.

  Study phs002486

• Non-small cell lung cancer molecular subtypes and vulnerability to immunotherapy treatment combinations

  The phase 3 IMpower150 trial in treatment-naïve patients with metastatic non-small-cell lung cancer (NSCLC) demonstrated significantly longer progression-free (PFS) and overall survival (OS) with first-line atezolizumab (anti-PD-L1)-bevacizumab (anti-VEGF)-carboplatin-paclitaxel (ABCP) than with bevacizumab-carboplatin-paclitaxel (BCP). We characterised four molecular NSCLC subtypes identified by unsupervised clustering of transcriptomes of 564 pre-treatment primary tumour samples from IMpower150 using non-negative matrix factorization (NMF1-4). Each subtype had distinct tumour PD-L1 expression levels, epithelial characteristics, immune composition, and treatment outcomes. Both NMF2 (enriched in tumour proliferation signal, macrophages, and monocytes) and NMF4 (enriched in B-cells and T cells) had elevated tumour PD-L1 expression. Of these two, only NMF4 demonstrated PFS and OS benefits with ABCP versus either BCP or atezolizumab-carboplatin-paclitaxel (ACP). Patients with NMF1 (enriched in basal and squamous-like cells) had improved outcomes on ABCP compared with ACP or BCP; those with NMF3 (enriched in adenocarcinoma signatures) showed similar outcomes among treatments. These insights could help inform individualised first-line treatment for metastatic NSCLC.

  Study EGAS50000001272

• Proteomic predictors of individualized nutrient-specific insulin secretion in health and disease

  Population level variation and molecular mechanisms behind insulin secretion in response to carbohydrate, protein, and fat remain uncharacterized despite ramifications for personalized nutrition. We now define prototypical insulin secretion dynamics in response to the three macronutrients in islets from 140 cadaveric donors, including those diagnosed with type 2 diabetes. We leverage the insulin response heterogeneity and use transcriptomics and proteomics to identify molecular pathways of specific nutrient responsiveness. Surprisingly, we find robust insulin secretion to fatty acid stimulus in ~8% of donors, challenging the idea that fat has negligible effects on insulin release. Distinct islet proteomes with differences in metabolic signalling networks convey this hyper-responsiveness to fat relative to carbohydrate. By comparing human islets to human embryonic stem cell-derived islet clusters, we show that, unlike glucose-responsiveness, fat hyper-responsiveness is equivalent and may be a hallmark of functionally immature cells. Our study represents the first comparison of dynamic responses to nutrients and multi-omics analysis in human insulin secreting cells. Responses of different people’s islets to carbohydrate, protein, and fat lay the groundwork for personalized nutrition.

  Study EGAS00001007241

• Atezolizumab Plus Chemotherapy With or Without Bevacizumab in Advanced Biliary Tract Cancer: Clinical and Biomarker Data From the Randomized Phase II IMbrave151 Trial

  PURPOSE Biliary tract cancers (BTCs) harbor an immunosuppressed tumor microenvironment (TME) and respond poorly to PD-1/PD-L1 inhibitors. Bevacizumab (anti-VEGF) plus chemotherapy can promote anticancer immunity, augmenting response to PD-L1 inhibition. PATIENTS AND METHODS This randomized, double-blind, proof-of-concept Phase II study enrolled patients (n=162) with previously untreated advanced BTC (IMbrave151; NCT04677504). Patients were randomized 1:1 to receive 3-weekly cycles of atezolizumab (1200 mg) plus bevacizumab (15 mg/kg) or atezolizumab plus placebo until disease progression or unacceptable toxicity. All patients received cisplatin (25 mg/m2) plus gemcitabine (1000 mg/m2; CisGem) on Days 1 and 8 every 3 weeks for up to 8 cycles. Stratification of patients was by disease status, geographic region, and primary tumor location. The primary endpoint was progression-free survival (PFS). No formal hypothesis testing was performed. Exploratory correlative biomarker analysis was undertaken using transcriptome analysis (n=95) and mutation profiling (n=102) on baseline tumor samples. RESULTS Between February and September 2021, 162 patients were enrolled. Median PFS was 8.3 months in the bevacizumab arm and 7.9 months in the placebo

  Study EGAS50000000387

• FLT3-targeting and places FLT3 as an ideal therapeutic target to selectively eradicate LSCs, while sparing HSC.

  CRISPR/Cas9 FLT3 knock-out (FLT3-KO) in human HSCs and LSCs followed by functional xenograft assays to test their ability to regenerate human hematopoiesis and leukemia, respectively. FLT3-KO in HSCs from human fetal liver, cord blood and adult bone marrow showed no impairment in multilineage hematopoiesis in primary and secondary xenografts. By contrast, FLT3-KO LSCs from 6 of 7 FLT3-ITD mutated AMLs were able to generate short-term engraftment but were completely exhausted by 12 weeks. Thus, FLT3 is essential for LSC long-term propagation. This dependency was unique to FLT3-ITD AML samples as non-FLT3-ITD AML samples generated leukemic grafts upon FLT3-KO. Transcriptomic analysis revealed that FLT3-KO induced downregulation of DNA repair and cell cycle checkpoints, uniquely in FLT3-ITD AML, but not in healthy HSCs or other AMLs. Our research highlights a critical distinction between healthy HSCs and LSCs: whereas healthy hematopoiesis proceeds unperturbed upon FLT3-KO, FLT3-ITD leukemogenesis is impaired through elimination of LSCs. This evidence underscores the necessity for more potent FLT3-targeting and places FLT3 as an ideal therapeutic target to selectively eradicate LSCs, while sparing HSC.

  Study EGAS50000000437

• Targeted therapy of advanced parathyroid carcinoma guided by genomic and transcriptomic profiling (hipo_021)

  Parathyroid carcinoma (PC) is an orphan malignancy with a high risk of recurrence after surgery. Tumor-directed systemic treatments for PC are not established. We used whole-genome and RNA sequencing in four patients with advanced PC to identify molecular alterations that could guide clinical management. In two cases, the genomic and transcriptomic profiles provided targets for experimental therapies that resulted in biochemical response and prolonged disease stabilization: (i) immune checkpoint inhibition with pembrolizumab based on high tumor mutational burden and a single-base substitution signature associated with APOBEC (apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like) overactivation; (ii) multi-receptor tyrosine kinase inhibition with lenvatinib due to overexpression of FGFR1 and RET and, later in the course of disease, PARP inhibition with olaparib prompted by signs of defective homologous recombination DNA repair. In addition, our data provided new insights into the molecular landscape of PC with respect to the genome-wide footprints of specific mutational processes and pathogenic germline alterations. These data underscore the potential of comprehensive molecular analyses to improve care for patients with ultra-rare cancers based on insight into disease biology.

  Study EGAS00001006747

• The impact of BNT162b2 mRNA vaccine against SARS-CoV-2 on adaptive and innate immune responses

  The mRNA-based BNT162b2 protects against severe disease and mortality caused by SARS-CoV-2 through induction of specific antibody and T-cell responses. Much less is known about its broad effects on immune responses against other pathogens. In the present study, we investigated the specific adaptive immune responses induced by BNT162b2 vaccination against various SARS-CoV-2 variants, as well as its effects on the responsiveness of human immune cells upon stimulation with heterologous viral, bacterial, and fungal pathogens. BNT162b2 vaccination induced effective humoral and cellular immunity against SARS-CoV-2 that started to wane after six months. We also observed long-term transcriptional changes in immune cells after vaccination, as assessed by RNA sequencing. Additionally, vaccination with BNT162b2 modulated innate immune responses as measured by the production of inflammatory cytokines when stimulated with various microbial stimuli other than SARS-CoV-2, including higher IL-1/IL-6 release and decreased production of IFN-α. Altogether, these data expand our knowledge regarding the overall immunological effects of this new class of vaccines and underline the need of additional studies to elucidate their effects on both innate and adaptive immune responses.

  Study EGAS00001006818

• Resuscitation Outcomes Consortium (ROC) Trauma Epidemiologic Registry (Trauma Epistry) (ROC-Trauma Epistry-BioLINCC)

  Data Access NOTE: Please refer to the "Authorized Access" section below for information about how access to the data from this accession differs from many other dbGaP accessions.Available Data: This dataset only includes traumatic injury participants. For ROC cardiac arrest Epistry data please see: ROC-Cardiac Epistry 1 and 2 and ROC-Cardiac Epistry 3.Objectives: To build a prospective population-based registry of participants with out-of-hospital traumatic injury responded to by Emergency Medical Services (EMS). Specific aims included: to establish whether the results of Resuscitation Outcomes Consortium (ROC) trials can be generalized to the larger population of people that experience traumatic injury; to more fully establish the burden of traumatic injury; and to examine the relationships between variation in EMS structure and process, regional and periodic factors, and participant outcomes.Background: Traumatic injury is a major public health problem generating substantial morbidity, mortality, and economic burden on society. The majority of seriously injured persons are initially evaluated and cared for by prehospital providers, however the effect of EMS systems, EMS clinical care, and EMS interventions on trauma patient outcomes is largely unknown. EMS factors such as service level, number of responding providers, use of procedures or drugs in the field, training, quality assurance/feedback, and response time intervals also vary significantly by region.The Resuscitation Outcomes Consortium (ROC) was established in 2004 to conduct clinical research in the areas of cardiopulmonary arrest and life-threatening traumatic injury with the overall goal of improving resuscitation outcomes. Previous trauma registries have generally focused primarily on hospitalized patients with limited prehospital information. Registries may also exclude trauma cases at far ends of the spectrum, such as those who die in the field or in a non-trauma center and/or patients that are treated and released. These limitations do not allow for detailed, outcome-based assessments of EMS system factors necessary to define prehospital resuscitation best practices. Therefore there was a need for standardized data collection of out-of-hospital traumatic injuries matched to hospital-based outcomes in diverse geographic locations in order to identify the independent effects of prognostic or treatment factors accounting for variations in survival. Participants: The registry included 13,830 traumatic events from 264 EMS agencies transporting to 287 acute care hospitals from the following regional centers: Birmingham, Alabama; Dallas, Texas; Iowa City, Iowa; Milwaukee, Wisconsin; Pittsburgh, Pennsylvania; Portland, Oregon; San Diego, California; Seattle/King County, Washington; Ottawa, Ontario; Toronto, Ontario; and Vancouver, British Columbia.Design: ROC Epistry collected standardized data regarding episode-specific factors, participant demographics, clinical information, pre-hospital interventions and disposition, hospital information, and participant outcome for all out-of-hospital traumatic injuries in the ROC regions. Cases were identified through review of emergency response system records including dispatch centers, EMS ground agencies, and air medical services. Out-of-hospital data were extracted from existing databases whenever possible and augmented with targeted review of EMS reports. Hospital data were abstracted directly from the hospital file in most cases. Sites submitted data using a web-based interface or batch uploads (Newgard, et al., 2008, PMID: 18482792).

  Study phs003809

• Immune Profiles Study

  This study assesses glioma patient blood methylation longitudinally beginning pre-surgery through other clinically important timepoints. Progression and survival are studied in relation to methylation derived immunologic profiles and other characteristics. For this study, patients scheduled for surgery at University of California San Francisco (UCSF) for a possible newly diagnosed glioma (grades 2-4) or recurrent grade 2/3 glioma were consented and enrolled. Patients had blood collected pre-surgery and, if the pathology results confirm a glioma, every few weeks or months during their treatment (up to 30 total timepoints). Blood immunomethylomic profiles were measured at these timepoints to assess associations with glioma patient outcomes, clinical measures, other known prognostic markers, and imaging characteristics.

  Study phs002998

• Neurogenetic Investigations of Obsessive-Compulsive Disorder

  Obsessive-compulsive disorder (OCD) is a disabling early-onset neuropsychiatric disorder with a clear genetic contribution to risk but unclear underlying pathophysiology, which has hindered the development of new treatments and interventions. This study uses high-throughput sequencing approaches to identify OCD risk genes, detect gene expression differences in OCD, and determine epigenetic signatures driving gene expression in OCD brain. These studies will improve our understanding of the underlying mechanisms of OCD and identify points of traction for mechanistic studies in model systems, ultimately leading to novel therapeutics, and reducing the significant morbidity and mortality associated with this disabling illness. Furthermore, insights gained in these studies can inform gene discovery approaches to other complex neuropsychiatric disorders.

  Study phs001929

• Longitudinal Study of the Porphyrias

  This is an observational, longitudinal study of approximately 800 individuals with various types of porphyria. Those participants will be evaluated annually for 5 years, or longer if they agree. Participation in this project will include: Participating in annual visits or contacts. Providing samples, including blood, buccal cells (cells from inside of the mouth), saliva, and urine. The type of samples and amounts may vary from person to person, depending on the type of porphyria. Giving permission for samples to be stored and used for porphyrias research. Granting permission to obtain your medical records. Providing information about your medical history and family history. Completing a questionnaire about your porphyria symptoms and quality of life.

  Study phs001278

• The Epigenomic Atlas of Early Human Craniofacial Development

  Parallel profiling of six distinct histone modifications via ChIP-Seq in craniofacial tissue samples from individual human embryos was performed. Epigenomic marks imputed with ChromImpute and a 25-state chromatin state model of uniformly processed epigenomic data was produced through ChromHMM. Samples were obtained from the MRC-Wellcome Trust Human Developmental Biology Resource (HDBR) tissue bank. HDBR provided karyotypically and developmentally normal pharyngeal arch or craniofacial tissue from embryos between 4.5 and 10 post-conception weeks. This repository contains raw data (fastq) files from ChIP-seq and RNA-seq experiments associated with this project. Processed ChIP-seq data and imputed data for additional histone marks are available at GEO (Series GSE97752).

  Study phs002008

• Multiethnic Cohort Adiposity Phenotype Study (MEC-APS)

  A total of 1,861 healthy men and postmenopausal women aged 60-77 years with body mass indexes (BMIs) of 17.1-46.2 kg/m2 were enrolled into the study. Stratified sampling was conducted based on sex, race/ethnicity, and six BMI categories (18.5-21.9, 22-24.9, 25-26.9, 27-29.9, 30-34.9, and 35-40 kg/m2) to balance the sample size across the wide range of BMI and optimize adjustment for total adiposity in populations with different BMI distributions. Study participants underwent body composition assessment, in person interview, blood collection, and completed a self-administered questionnaire. A genome-wide association study of obesity phenotypes was conducted among five racial/ethnic groups of the Multiethnic Cohort Study.

  Study phs001689

• Early progression to active tuberculosis is a highly heritable trait driven by 3q23 in Peruvians

  In a genome-wide genetic study of early progression to active tuberculosis (TB), we genotyped 4,002 active TB cases and their household contacts in Lima, Peru. We first established TB progression has a strong genetic basis, and is comparable to traits with well-established genetic bases (h2g=0.212). We identified a novel association between early TB progression and variants located in a putative enhancer region on chromosome 3q23 (rs73226617, OR = 1.18; P = 3.93 x 10-8). With in silico and in vitro analyses we identified genetic variant rs73226617 or rs148722713 as the likely functional variant and ATP1B3 as a potential causal target gene with monocyte specific function.

  Study phs002025

• NHLBI TOPMed - NHGRI CCDG: UCSF Atrial Fibrillation Study

  The University of California San Francisco (UCSF) Cardiovascular Research Institute (CVRI) Resource in Arteriosclerosis and Metabolic Disease is an ongoing multi-ethnic study of adults &#8805; 18 years of age which was started in 1989 and now includes 28,000 participants recruited from the UCSF medical system. Within the Resource lies data and biospecimens from nearly 1,000 patients presenting to the electrophysiology laboratory for electrophysiology procedures that were densely phenotyped for electrophysiologic characteristics with biospecimens collected from various intra and extra-cardiac chambers. Phenotyping of all participants was achieved via interview and review of medical records. A subset of 113 participants with early-onset atrial fibrillation underwent WGS as a part of the TOPMed Program.

  Study phs001933

• Genetic contributions of lupus nephritis in a multi-ethnic cohort of systemic lupus erythematosus (SLE)

  Lupus nephritis (LN) is a severe manifestation of systemic lupus erythematosus (SLE) and it occurs at a much higher rate in patients that are not of European descent. The purpose of this study is to identify genetic variants contributing to the risk of LN in a multi-ethnic cohort of SLE patients. We used a comprehensive genome-wide screen and 1244 SLE patients from 5 different ethnic groups. In genome-wide gene-based and candidate SNP analyses, we found distinct genes and pathways, and established risk SNPs associated with lupus nephritis for each ethnic group. This study represents progress in elucidating the genetic underpinnings driving LN among SLE patients of different ethnic groups.

  Study phs001609

• Precision Diagnosis of Neurodevelopmental Disorders in Middle Eastern Populations

  We constructed de novo genome assemblies for six family trios from diverse Middle Eastern ancestries (Sudan, Jordan, Syria, Qatar, and Afghanistan), involving probands with various unresolved neurodevelopmental conditions. We generated high-quality, nearly complete genome assemblies for trios, revealing extended novel sequence impacting known genes, novel HLA/KIR alleles, and strong signals of inbreeding, with runs of homozygosity covering large parts of individual chromosomes. We also identified potential disease variants underlying the unresolved symptoms. Also, the assemblies uncovered unique variation relative to existing references, showing enhanced mapping and variant calling of Middle Eastern genomes. The dataset available through dbGaP includes raw short (Illumina) and long (PacBio) sequencing reads and assembled haplotypes.

  Study phs003917

• CSER: North Carolina Clinical Genomic Evaluation by Next-Gen Exome Sequencing 2

  The North Carolina Clinical Genomic Evaluation by Next-gen Exome Sequencing, 2 (NCGENES 2) study is part of a larger consortium project investigating the clinical utility, or net benefit of an intervention on patient and family well-being as well as diagnostic efficacy, management planning, and medical outcomes. A clinical trial will be implemented to compare (1) first-line exome sequencing to usual care and (2) participant pre-visit preparation to no pre-visit preparation. The study will use a randomized controlled design, with 2x2 factorial design, coupled with patient-reported outcomes and comprehensive clinical data collection addressing key outcomes, to determine the net impact of diagnostic results and secondary findings.

  Study phs002110

• Re-evaluation of human mitochondrial DNA methylation reveals signals consistent with technical artifacts

  The existence and functional relevance of mitochondrial DNA (mtDNA) methylation remain controversial. We assessed 5mC and 5hmC in human brain, blood, and related cancers using both enzymatic and native DNA sequencing. While nuclear DNA exhibited expected methylation patterns, mtDNA consistently showed negligible methylation levels, indistinguishable from technical noise. Elevated methylation in nuclear-embedded mitochondrial sequences demonstrates a clear potential to confound mtDNA methylation measurements. Furthermore, technical discrepancies in mtDNA methylation were observed, underscoring the need for careful evaluation when interpreting data generated using earlier sequencing workflows. Our findings provide evidence against the presence of 5mC or 5hmC in mtDNA under the physiological and pathological conditions studied.

  Study EGAS50000001186

• Transcriptomic profiling of granulosa cells from IVF patients at different ages

  Two major factors contributing to reduced fertility is use of exogenous hormones and old age. Here, we sequenced RNA from granulosa cell samples from human patients undergoing in vitro fertilization to test how hormonally stimulated cells' transcriptional profiles change with age. All patients were normal responders referred for male infertility and were grouped into two age groups. The gene expression differences in aging were compared to mouse data (previous experiments, see ArrayExpress E-MTAB-13479) and the results are published in the article "Granulosa cell transcription is similarly impacted by superovulation and aging and predicts early embryonic trajectories". Corresponding count tables are available in ArrayExpress (E-MTAB-13496).

  Study EGAS50000000824