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• Whole-Exome Sequences from Imazighen and non-Imazghen from Algeria

  Study of high-coverage whole-exome sequences from Amazigh (Tamazight-speakers) and non-Amazigh individuals (Arab-speakers) from Algeria to analyze the impact of demography in functional genomic variation in the complex demographic context of North Africa. Amazigh individuals were sampled in Oum El Bouaghi, Batna, Khenchela, and Ghardaïa, and non-Amazigh individuals were sampled in Algiers.

  Study EGAS00001007236

• UKF_Paediatric_Tumours_Behjati_WellcomeCore_RNA_Managed_Access

  Children born with DS have a substantially higher risk of developing childhood leukaemia. Approximately 10% are diagnosed with a preleukemic condition at birth; transient abnormal myelopoiesis (TAM). Of these, 20% - 30% of cases may progress to myeloid leukaemia associated with DS (MLDS) by the age of five. We are interested in directly characterizing the transcriptional changes underlying this stepwise development of TAM and MLDS.

  Study EGAS00001007524

• Three-dimensional patient-derived models of glioblastoma retain intra-tumoral heterogeneity

  The intra- and inter- tumoral heterogeneity of glioblastoma represents a significant therapeutic challenge, as well as difficulty in generating reliable models for in vitro studies. Here, we quantify the tumor cell composition from matched patient-derived neurospheres (PDN) and organoids (PDO) established from the same primary tumor using a series of multi-omic interrogations, relative to primary tissue

  Study EGAS00001008023

• Single cell sequencing of human normal luminal cells

  The dataset includes 12 paired FASTQ files (6 samples) with single cell transcriptome sequencing data of normal breast luminal cells from ducts and TDLUs derived from reduction mammoplasties from three patients. Chromium Single Cell 3’ Reagent Kit v2 or v3 (10x Genomics) were used for processing of cells, whereafter sequencing was performed using the Illumina® NextSeq500/550 High Output Kit v2. Cell Ranger was used for generating FASTQ files and files from different lanes were concatenated prior to uploading the data to EGA. "R1" files include the feature barcodes and UMIs, while "R2" files include the reads.

  Dataset EGAD00001008499

• A next-generation dual guide CRISPR system for genetic interaction library screening

  Raw sgRNA sequencing data from a pilot CRISPR screening library to test the dual guide vector system (8,914 guide pairs), and from a large scale genetic interaction screen (~100,136 guide pairs) in HT-29 cells. This data refers to Burgold et al. Nature Communications 2025.

  Dataset EGAD00001015754

• Single-cell RNA sequencing of breast cancer lung metastasis and adjacent normal tissue

  This dataset contains single-cell RNA sequencing data from two samples: L1 (breast cancer metastasis to lung) and N3 (adjacent normal lung tissue) from a female patient. The samples were processed using 10X Chromium 3' technology and sequenced on Illumina NextSeq 500. This data supports the study "Endocrine therapy reprogramming of breast cancer facilitates metastatic escape via upregulation of P-Rex1/Rac1 signalling" which investigates how endocrine therapy reprograms breast cancer cells, leading to upregulation of P-Rex1/Rac1 signalling pathways that facilitate metastatic escape. The single-cell analysis reveals cellular reprogramming mechanisms in endocrine therapy-resistant breast cancer cells that form metastases in the lung.

  Dataset EGAD00001015769

• A Study to Evaluate Denosumab in Young Patients With Primary Breast Cancer (D-Beyond)

  This is a prospective, single arm phase IIa trial in which patients with early breast cancer will receive pre-operatively two doses of denosumab 120mg subcutaneously one week apart (maximum 12 days) followed by surgery. Tumor, normal breast tissue and blood samples will be collected at baseline and at surgery. Post-operative treatment will be at the discretion of the investigator.Primary objective: to determine if a short course of RANKL inhibition with denosumab can induce a decrease in tumor proliferation rates as determined by Ki67 immunohistochemistry (IHC) in newly diagnosed, early stage breast cancer in pre-menopausal women.

  Dataset EGAD00001004391

• Tumor gene expression profiles for the study "TGF-β attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells"

  RNA was extracted from formalin-fixed and paraffin embedded tumors of a large cohort of bladder cancer patients before treatment with anti-PD-L1. RNA was sequenced using a capture based approach (exome capture, RNA access).

  Dataset EGAD00001003977

• SCLC study George et al. - WGS data set

  Whole genome sequencing was performed with DNA extracted from fresh-frozen tumor and normal material. Short insert DNA libraries were prepared with the TruSeq DNA PCRfree sample preparation kit (Illumina) for paired-end sequencing at a minimum read length of 2x100bp. Human DNA libraries were sequenced to an average coverage of minimum 30x for both tumor and matched normal. Murine DNA libraries of tumor and matched normal were both sequenced to a coverage of 25x.

  Dataset EGAD00001001273

• Multiple Malignancy Familial Comparison

  Patient (who has had multiple malignancies) has previously been found to harbour a pathogenic p53 variant which is probably mosaic. This finding is based on exome sequencing performed elsewhere. In this study we will resequence the locus in question to ascertain whether the variant is indeed mosaic.

  Dataset EGAD00001001062

• Donor InSight III study: Participants typed during UK Biobank version 2 array development phase

  The Donor InSight III study, undertaken by Sanquin research, recruited 3,046 Dutch blood donors between 2015 and 2016. The purpose of the study was to gain more insight into characteristics of donors, their motivations and health. All participants were at the time of recruitment active blood donors. Genotyping data was produced using the Thermo Fisher Scientific Axiom Genotyping platform. The UK Biobank version 2 array design was used, content on this array has been added to allow for accurate DNA based identification of human blood group antigens.

  Dataset EGAD00001005026

• C9orf72 region reads of 3001 samples

  This dataset includes cram files from 3,001 samples. These cram files include all read pairs where at least one of the reads aligns within 1kb of the C9orf72 repeat expansion. Additionally, these cram files also contain reads that are aligned to any of 29 pre-determined off target locations where the aligners are known to mis-align reads associated with this repeat expansion. These samples were sequenced using a combination of 2x100bp reads on an Illumina HiSeq2000 and 2x150bp reads on an Illumina HiSeqX sequencer and aligned using the Isaac aligner.

  Dataset EGAD00001004834

• Colon Cancer Organoid Cultures and Tumors Whole Genome Sequencing Data

  Five hundred nanograms of genomic DNA was fragmented by Covaris S2, the fragmented DNAs were performed end-repair, A-tailing at the 3 prime end, adaptors ligation with an IDT dual-indexed UMI adaptor system at the terminal ends. The adapter ligated library with size range 300-750bp were selected by dual-SPRI method. Twenty percent of the size selected PCR-free libraries were enriched by 5 PCR cycles prior to library size assessment by Bioanalyzer Fragment Analyzer. The PCR-free libraries were quantified by qPCR.The PCR-free libraries were denatured and diluted to optimal concentration. Illumina NovaSeq 6000 was used for Pair-End 151bp sequencing.

  Dataset EGAD00001005759

• Chracterising cellur pathways underlying CD3/CD28 activation of human CD4+ cells

  We devised an approach to disentangle the TCR and CD28 pathways upon stimulation in naive and memory primary human CD4+ T cells (Tcons) in response to defined stimulatory signals. Sorted Tcons were activated using a titration of anti-CD3 and anti-CD28 in combination as well as individually. As a control we cultured cells in the same conditions but without the stimuli. In total, we defined seven conditions from four individuals for sequencing. 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/.

  Dataset EGAD00001006610

• Chracterising cellur pathways underlying CD3/CD28 activation of human CD4+ cells

  We devised an approach to disentangle the TCR and CD28 pathways upon stimulation in naive and memory primary human CD4+ T cells (Tcons) in response to defined stimulatory signals. Sorted Tcons were activated using a titration of anti-CD3 and anti-CD28 in combination as well as individually. As a control we cultured cells in the same conditions but without the stimuli. In total, we defined seven conditions from four individuals for sequencing. 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/ .

  Dataset EGAD00001006612

• Dichotomous regulation of lysosomes by MYC and TFEB controls hematopoietic stem cell fate

  We show that lysosomes are antagonistically controlled by TFEB and MYC to balance catabolic and anabolic processes required for activating LT-HSC and guiding their lineage fate. TFEB-mediated induction of the endolysosomal pathway for membrane receptor degradation limits LT-HSC metabolic and mitogenic activation; this promotes quiescence and self-renewal and governs erythroid-myeloid commitment. By contrast, MYC engages biosynthetic processes while repressing lysosomal catabolism to drive LT-HSC activation. Collectively, our study identifies lysosomes as a central regulatory hub for proper and coordinated stem cell fate determination.

  Dataset EGAD00001006884

• Transcriptome sequencing of hepatocellular carcinoma biopsies

  RNA-sequencing of 122 hepatocellular carcinoma biopsies and 15 normal liver biopsies. RNA-seq library prep was performed with 200 ng total RNA using the TruSeq Stranded Total RNA Library Prep Kit with Ribo-Zero Gold (Illumina) according to manufacturer’s specifications. Single-end 126-bp sequencing was performed on an Illumina HiSeq 2500 using v4 SBS chemistry at the Genomics Facility Basel according to the manufacturer’s guidelines. Primary data analysis was performed with the Illumina RTA version 1.18.66.3.

  Dataset EGAD00001008205

• DAC - Department of Periodontology, University of Gothenburg, Sweden

  Data Access Committee to manage external requests. Project: RNA-seq data from soft tissue biopsies harvested from dental implant sites with peri-implantitis

  Dac EGAC50000000241

• SAFIR02_Oncoscan

  Genomics to select patients with metastatic breast cancer for targeted therapy (microarray_oncoscan)

  Dataset EGAD00010002241

• ML modeling data & code

  Rmarkdown code, PDF, and Rdata file to recapitulate the paper's primary figures and machine learning model development.

  Dataset EGAD00001009764

• Esthioneuroblastomas

  This dataset consists on 22 samples linked to 22 bam files from whole genome and whole exome sequencing of Esthioneuroblastomas.

  Dataset EGAD00001004355

• Next Generation Sequencing in an IBD Pedigree Exome Data

  The aim is to find rare variants of intermediate penetrance in those at risk of Crohn's disease

  Dataset EGAD00001000423

• AFB1 Mutation Signature Dataset

  This dataset contains whole exome sequence of six HCC patients from Qidong China who are very likely exposed to aflatoxin.

  Dataset EGAD00001003194

• The Spatio-Temporal Evolution of Multiple Myeloma from Baseline to Relapse-Refractory States

  In multiple myeloma, the spatio-temporal evolution patterns of cancer cells in the bone marrow remain largely unknown. Here, we applied spatial-longitudinal sequencing, including a total of 179 samples collected from 25 patients during a follow-up of up to 14 years. Our study highlights focal bone lesions (FL) as hotspots of tumor evolution and provides possible explanations for their negative prognostic impact. We show a close phylogenetic relationship between baseline FL and relapse clones. In patients with ≥3 FDG-PET-positive FL at diagnosis, relapse was driven by multiple distinct sub-clones, whereas in other patients, a single-cell expansion was typically seen (p<0.01). Applying imaging-guided sampling, we identified a novel evolutionary pattern with unique treatment-resistant sub-clones at distinct locations. We observed multiple selective clonal sweeps, resistant clones that can be hidden over years, and epigenetic modifier mutations as a new class of relapse aberrations. Here we show that imaging can enhance tumor evolution studies and response assessment. The sophisticated evolution mechanisms in myeloma and presence of single cells that can drive relapse even after 10 years of remission suggest that a prerequisite for curative therapies would be to overcome not only tumor heterogeneity but also dormancy.

  Study phs002625

• Exploring the Microbiome-Gut-Brain Axis with Respect to Psychoneurological Symptoms for Children with Solid Tumors

  The human body hosts tens of trillions of microbes, a number 10 times greater than the number of human body cells. The collection of these human-associated microbes and their genomes is called the “human microbiome”. More than 90% of these microbes live in the gastrointestinal (GI) tract, representing 500 species on average. With the development of high-throughput sequencing technology and bioinformatics tools (e.g., 16S ribosomal RNA or 16S rRNA sequencing and shotgun metagenomics analysis), recent progress has been made to elaborate the critical role that the gut microbiome plays in human health and disease. A significant disruption (dysbiosis) of the composition and function of the gut microbiome is associated with carcinogenesis, chemotherapeutic metabolism, and treatment-related symptom toxicities. The current state of science on the gut microbiome in cancer has only recently started in animal models and adults, and has not been well investigated in children diagnosed and treated for cancer, nor with respect to associations with cancer treatment-related toxicities. This proposed study will explore the hypothesis that dysbiosis of the gut microbiome is associated with cancer treatment-related GI and psychoneurological symptoms. We will collect both stool samples (for the gut microbiome) and patient-reported outcomes across chemotherapy.

  Study phs002960

• Single-cell profiling reveals mechanisms of response to anti-PD-L1 versus anti-PD-L1 combined with anti-CTLA4 in head and neck squamous cell carcinoma

  Cancer patients often receive a combination of PD-(L)1 and CTLA4 inhibitors, but the mechanisms underlying their concerted actions remain unclear. We conducted a neoadjuvant study in head and neck squamous cell carcinoma (HNSCC) involving anti-PD-L1 monotherapy versus anti-PD-L1/anti-CTLA4 combination. Single-cell profiling of on- versus pre-treatment biopsies confirmed T-cell expansion as response biomarker. We identified a type 1 immune response accompanying T-cell expansion on-treatment across treatment arms, and herein characterized co-localized IgG plasma cell expansion as important contributor. In pre-treatment biopsies, similar features correlated with expansion upon anti-PD-L1, but not anti-PD-L1/anti-CTLA4. By profiling tumor-draining lymph nodes, we found the addition of anti-CTLA4 to trigger activation and subsequent trafficking of CD4+ T-cells via the blood, to become T-helper 1 cells in the tumor. anti-PD-L1/anti-CTLA4 indeed facilitated co-localized expansion of CD4+ and CD8+ T-cells in tumors versus mostly CD8+ T-cells with anti-PD-L1 alone. Hence, we identify complimentary mechanisms underlying anti-PD-L1/anti-CTLA4 therapy in HNSCC.

  Study EGAS50000000037

• Inhibiton of the GABPB1L-containing GABP tetramer is sufficient to reverse replicative immortality in TERT promoter mutant glioblastoma cells.

  Over 50 types of cancer acquire TERT promoter mutations. These single point mutations reactivate telomerase, allowing for indefinite maintenance of telomere length and enabling cellular immortalization. The transcription factor binding site created by the point mutations specifically recruit the ETS factor GABP, a multimeric transcription factor composed of the GABPα and GABPβ subunits. GABP can form two functionally independent transcription factor species – a dimer or a tetramer – depending on which of the structurally distinct GABPβ isoforms is incorporated into the complex. In this study, we show that genetic disruption of GABPβ1L, a tetramer forming isoform of GABPβ that is dispensable in normal development, results in TERT silencing in a TERT promoter mutation dependent manner. Failure to activate TERT expression by GABPβ1L culminates in telomere dysfunction, DNA damage, and mitotic cell death exclusively in TERT promoter mutant cells. Furthermore, exogenous expression of TERT is sufficient to prevent telomere degradation and loss of cell viability in GABPβ1L-reduced lines bearing the mutant TERT promoter. Orthotopic injection of tetramer-deficient mutant TERT promoter GBM cells rendered lower tumor burden and prolonged the overall survival of the tumor-bearing mice. These results highlight the potentially widespread role of GABPB1L in enabling replicative immortality of TERT promoter cancers.

  Study EGAS00001002582

• This project aims to study human memory capacity, including short-term memory and long-term memory, systematically via genome-wide association studies

  Development of high-throughput genotyping platforms provides an opportunity to identify new genetic elements related to complex cognitive functions. Taking advantage of multi-level genomic analysis, here we studied the genetic basis of human short-term (STM, n=1,620) and long-term (LTM, n=1,526) memory functions. Heritability estimation based on single nucleotide polymorphism showed moderate heritability of short-term memory but very low heritability of long-term memory. In a two-step genome-wide association study, the markers rs13151012 and rs1558360 passed genome-wide significance (p < 5×10-8) in digit-span STM task and for the first principal component shared by two STM tasks; however, none of them survived the replication. In turn, we selected the ten most significant single nucleotide polymorphisms (SNPs) for replication tests. Among them, a SNP near ZFAT was significantly associated with STM performance in another independent population of 2,789; a polymorphism within BCAT2 was significantly associated with LTM in another independent population of 1,865. Furthermore, we performed a pathway analysis based on the current genomic data and found six pathways significantly associated with STM capacity and one pathway associated with LTM capacity.

  Study EGAS00001002875

• Whole genome, exome and transcriptome analysis to guide individualized cancer interpretation

  Study Design: The Cancer Alliance study was a collaboration of nine academic medical institutions in the New York city area and led by the New York Genome Center. Tumor-normal paired samples were submitted by the institutions for whole genome, whole exome and transcriptome sequencing and bioinformatics analysis at New York Genome Center. Relevant clinical histories were also collected. Raw sequence files were available to all collaborators. Variant call files were analyzed both manually by interpreters at NYGC and by IBM Watson Genome Analytics. This study was approved by a central institutional review board (IRB), Biomedical Research Alliance of New York, and by local IRBs, including Stony Brook University and Northwell Health. The study was supported in part by a grant from the IBM corporation (IBM Watson Health) to the New York Genome Center, New York Genome Center philanthropic funds and Rockefeller University grant # UL1TR000043 from the National Center for Advancing Translational Sciences (NCATS), and the National Institutes of Health (NIH) Clinical and Translational Science Award (CTSA) program. The principal investigator Robert B. Darnell MD, PhD., is a Howard Hughes Medical Institute Investigator. Results: Pending Publication of Analysis of Study Conclusions: Pending Publication of Analysis of Study

  Study EGAS00001004013

• Androgen receptor blockade promotes response to BRAF/MEK-targeted therapy

  We studied a group of melanoma patients treated with neoadjuvant BRAF/MEK-targeted therapy (NCT02231775, n=51), and observed significantly higher rates of major pathologic response (MPR= <10% viable tumor at resection) and improved recurrence-free survival (RFS) in females versus males (MPR-66% versus 14%, p=0.001; RFS-64% versus 32% at 2 years, p=0.021). Findings were validated in a several additional cohorts 2-4 patients with unresectable metastatic melanoma treated with BRAF and/or MEK-targeted therapy (n=664 patients in total), demonstrating improved progression-free survival (PFS) and overall survival (OS) in females versus males in several of these studies. Studies in pre-clinical models demonstrated significantly impaired anti-tumor activity in male versus female BRAF/MEK-treated mice (p=0.006), with significantly higher expression of androgen receptor (AR) in tumors of male and female BRAF/MEK-treated mice versus control (p=0.0006 and 0.0025). Pharmacologic inhibition of AR signaling improved responses to BRAF/MEK-targeted therapy in male and female mice (p=0.018 and p=0.003), whereas induction of AR signaling (via testosterone administration) was associated with significantly impaired response to BRAF/MEK-targeted therapy in males and females (p=0.021 and p<0.0001).

  Study EGAS00001006196

• Swarm Learning to identify COVID-19, tuberculosis and leukemia patients based on blood transcriptomes

  Identification of patients with life-threatening diseases including leukemias or infections such as tuberculosis or COVID-19 is an important goal of modern precision medicine. However, there is an increasing divide between what is technically possible and what is allowed because of privacy legislation. We have recently illustrated that classical machine learning can identify leukemia patients based on their blood transcriptomes. To facilitate integration of any omics data from any data owner world-wide without violating privacy laws, we here introduce Swarm Learning (SL), a decentralized machine learning approach uniting edge computing, artificial intelligence (AI), blockchain and privacy protection without the need for a central coordinator thereby going beyond federated learning. To illustrate its feasibility, using more than 12,000 transcriptomes from peripheral blood mononuclear cells and more than 2,000 peripheral blood transcriptomes we demonstrate that SL of omics data distributed across different individual sites leads to disease classifiers that outperform those developed at individual sites. Yet, SL completely protects local privacy regulations by design. We propose this approach to noticeably accelerate the introduction of precision medicine.

  Dataset EGAD00001006231

• Genetics of Mammographic Density in Ashkenazi Jews

  Mammographic density (MD) is a strong risk factor for breast cancer and is also a highly heritable trait with ~60-70% of the variance due to genetic factors, based on twin studies. MD is also higher in families with a strong history of breast cancer. Genome-wide association studies (GWAS), which focus on common genetic variants, have identified several single nucleotide polymorphisms (SNPs) associated with MD. However, these SNPs explain a very small fraction of the variance of MD, suggesting many other genes are involved. Thus, the vast majority of the heritability of mammographic density remains unexplained and may be explained, at least in part, by rare variants. Ashkenazi Jewish women are a founder population; founder populations frequently have alleles affecting phenotypes which may be unique and/or extremely rare in other populations. Prior reports have identified an association between higher mammographic density and Ashkenazi Jewish ancestry. Therefore, we developed a study of mammographic density in AJ women. We combined datasets from several different cohorts including (a) the California Pacific Medical Center Research Institute (b) the Athena Breast Health Cohort and (c) the Marin Women's study. In each study, we identified women who reported AJ ancestry (determined by self-report or by genetic analysis). We identified mammograms by linking the women to the San Francisco Mammography Registry. We retrieved digital mammographic results and used software to infer volumetric density and percent volumetric density for each woman. We then performed genome-wide genotyping of the samples using the Illumina MEGA array.

  Study phs001857

• Age related Macular Degeneration (AMD)-- Michigan, Mayo, AREDS, Pennsylvania (MMAP) Cohort Study: A Joint Genome Wide Association Study

  Age-related Macular Degeneration (AMD) is a leading cause of incurable blindness in people over the age of 65. AMD is a late-onset multi-factorial neurodegenerative disease and its pathogenesis involves interaction of genetic and environmental factors. Several chromosomal regions have been associated with AMD susceptibility through linkage analysis (Swaroop et al., 2009). More recent studies provide strong evidence that variants within the CFH gene cluster on chromosome 1 and at/near LOC387715/ARMS2 on chromosome 10 are strongly associated with disease. Variants at other genes including C2/BF, C3, CFI and APOE4, also contribute to AMD susceptibility. Our primary goals are to identify genetic variants and haplotypes that are associated with AMD. The underlying hypothesis is that DNA variation(s) in multiple genetic susceptibility loci will predispose individuals to AMD pathogenesis, and comparison of DNA of cases and controls should identify these susceptibility variants. Our studies are focused on the genetic analysis of advanced AMD and should provide novel insights into disease diagnosis, progression and pathology. We have assembled a collaborative group of researchers from the University of Michigan, Mayo Clinic, University of Pennsylvania, and the AREDS group including National Eye Institute intramural investigators, who collected clinical data and DNA from a large number of patients affected with AMD and from unaffected controls. The primary source of funding was National Eye Institute. Through this collaborative effort, we submitted and obtained usable genotyping data on 2184 patients and 1155 controls from the Center for Inherited Disease Research (CIDR).

  Study phs000182

• Population Architecture using Genomics and Epidemiology (PAGE): Causal Variants Across the Life Course (CALiCo): Atherosclerosis Risk in Communities (ARIC)

  CALiCo ARIC The Atherosclerosis Risk in Communities Study (ARIC), sponsored by the National Heart, Lung and Blood Institute (NHLBI), is a prospective epidemiologic study conducted in four U.S. communities. ARIC is designed to investigate the etiology and natural history of atherosclerosis, the etiology of clinical atherosclerotic diseases, and variation in cardiovascular risk factors, medical care and disease by race, gender, location, and date. ARIC includes a Cohort Component and a Community Surveillance Component. Cohort enrollment began in 1987. Each ARIC field center randomly selected and recruited a sample of approximately 4,000 individuals aged 45-64 from a defined population in their community. A total of 15,792 participants received an extensive examination, including medical, social, and demographic data. These participants were reexamined every three years with the first screen (baseline) occurring in 1987-89, the second in 1990-92, the third in 1993-95, and the fourth and last exam wastook place in 1996-98. Follow-up occurs yearly byA fifth cohort examination is underway (2011-2013). Yearly telephone tointerviews maintain contact with participants and to assess health status of the cohort. In the Community Surveillance Component, currently ongoing, these four communities are investigated to determine the community-wide occurrence of hospitalized myocardial infarction and coronary heart disease deaths in men and women aged 35-84 years. Hospitalized stroke is investigated in cohort participants only. The study conducts community surveillance of inpatient heart failure (ages 55 years and older) and cohort surveillance outpatient heart failure events beginning in 2005.

  Study phs000223

• Bayesian-Based Noninvasive Prenatal Diagnosis of Single-Gene Disorders

  In the last decade, non-invasive prenatal diagnosis (NIPD) has emerged as an effective procedure for early detection of inherited diseases during pregnancy. This technique is based on using cell-free DNA (cfDNA) and fetal cfDNA (cffDNA) in maternal blood, and hence, has minimal risk for the mother and fetus compared with invasive techniques. NIPD is used today for identifying chromosomal abnormalities (in some instances) and for single-gene disorders (SGDs) of paternal origin. However, for SGDs of maternal origin, sensitivity poses a challenge that limits the testing to one genetic disorder at a time. Here we present a Bayesian method for the NIPD of monogenic diseases that is independent of the mode of inheritance and parental origin. Furthermore, we show that accounting for differences in the fragment length distribution of fetal- and maternal-derived cfDNA results in increased accuracy. Our model is the first to predict inherited insertions-deletions (indels). The method described can serve as a general framework for the NIPD of SGDs; this will facilitate easy integration of further improvements. One such improvement that is presented in the current study is a machine learning model that corrects errors based on patterns found in previously processed data. Overall, we show that next generation sequencing (NGS) can be used for the NIPD of a wide range of monogenic diseases, simultaneously. We believe that our study will lead to the achievement of a comprehensive NIPD for monogenic diseases. (Reprinted from Bayesian-based noninvasive prenatal diagnosis of single-gene disorders, with permission from Genome Research)

  Study phs001659

• Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations

  It is well established that autism spectrum disorders (ASD) have a strong genetic component; however, for at least 70% of cases, the underlying genetic cause is unknown. Under the hypothesis that de novo mutations underlie a substantial fraction of the risk for developing ASD in families with no previous history of ASD or related phenotypes-so-called sporadic or simplex families-we sequenced all coding regions of the genome (the exome) for parent-child trios exhibiting sporadic ASD, including 189 new trios and 20 that were previously reported. Additionally, we also sequenced the exomes of 50 unaffected siblings corresponding to these new (n = 31) and previously reported trios (n = 19), for a total of 617 individual exomes from 209 families deposited in dbGaP. Here we show that de novo point mutations are overwhelmingly paternal in origin (4:1 bias) and positively correlated with paternal age, consistent with the modest increased risk for children of older fathers to develop ASD. Moreover, 39% (49 of 126) of the most severe or disruptive de novo mutations map to a highly interconnected beta-catenin/chromatin remodelling protein network ranked significantly for autism candidate genes. In proband exomes, recurrent protein-altering mutations were observed in two genes: CHD8 and NTNG1. Mutation screening of six candidate genes in 1,703 ASD probands identified additional de novo, protein-altering mutations in GRIN2B, LAMC3 and SCN1A. Combined with copy number variant (CNV) data, these results indicate extreme locus heterogeneity but also provide a target for future discovery, diagnostics and therapeutics.

  Study phs000482

• Genetic Markers of Lipids in Indians: A Validation Study of Most Relevant Findings of Genome-Wide Association Studies

  We aimed to validate the GWAS loci (identified in European populations) related to serum lipid levels (total cholesterol, triglycerides, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and very low-density lipoprotein cholesterol (VLDL-C)) in the Indian population originally recruited to examine the 20-year trend of cardiometabolic risk factors in rural and urban areas around National Capital region in India. Isolated DNA was processed for genotyping of 12 established GWAS variants using multiplex Sequenom Mass ARRAY technology. We examined the association of these genetic variants with different lipid levels and found association of eight variants for lipid levels. We also derived weighted genetic risk scores (wGRAS) using the validated variants. The wGRS for triglycerides and VLDL-C was derived based on four associated variants (rs174546 at FADS1, rs17482753 at LPL, rs2293889 at TRPS1, rs4148005 at ABCA8, rs4420638 at APOC1) which was associated with 36.31 mg/dL elevated triglycerides and VLDL-C (β=0.95, SE=0.16, pTRPS1 and rs4147536 at ADH1B) was associated with 40.62 mg/dL higher total cholesterol (β=1.01, SE=0.23, pTRPS1, rs4147536 at ADH1B, rs4420638 at APOC1 and rs660240 at CELSR2). The wGRS derived from five associated variants (rs174546 and FADS1, rs17482753 at LPL, rs4148005 at ABCA8, rs4420638 at APOC1 and rs7832643 at PLEC) was associated with 10.64 mg/dL lower HDL-C (β= -0.87, SE =0.14, pThe phenotypic and genotypic data will be made available on the dbGaP portal for access.

  Study phs003469

• PCPT and SELECT Cohorts: Core Infrastructure Support for Cancer Research

  SELECT study: SELECT was a phase III, double-blind, placebo-controlled 4-arm study of selenium, vitamin E, selenium and vitamin E together, and placebo designed to assess the effect of these supplements on the incidence of prostate cancer. Funded by the National Cancer Institute and conducted by SWOG, the study opened in August 2001 and quickly exceeded its accrual goal of 35,533 men.In the fall of 2008, the trial's Data Safety and Monitoring Committee recommended that participants discontinue taking study supplements due to convincing evidence (planned interim futility analysis) that neither vitamin E nor selenium supplements were associated with the prevention of prostate cancer. A subsequent analysis in 2011 showed a significant 17% increase in prostate cancer incidence in participants who were on the vitamin E only arm. Approximately 17,000 participants from the original trial recently completed an additional four years of centralized follow-up. This follow-up ended on May 31, 2014 and SELECT is now closed. PCPT study: The Prostate Cancer Prevention Trial (PCPT) was a SWOG Cancer Research Network-coordinated study designed to test whether the drug finasteride (Proscar®) would prevent prostate cancer in men ages 55 and older. This study was closed on June 24, 2003 because the study objective had been reached. The results of the study, which did find a preventive benefit for the drug, were published as "The Influence of Finasteride on the Development of Prostate Cancer," in the New England Journal of Medicine on July 17, 2003.

  Study phs003382

• Study on the Genetics of Alcoholism (COGA): Smoke Screen and Exome Sequencing

  This is a family study of alcoholism, in which the subjects have been drawn from the Collaborative Study on the Genetics of Alcoholism (COGA), a large, ongoing family-based study that includes subjects from seven sites around the US. COGA has gathered detailed, standardized data on study participants, including diagnostic and neurophysiological assessments. This project has already proved successful in identifying several genes that influence the risk for alcoholism and neurophysiological endophenotypes, which have been independently replicated. COGA data were included as part of two Genetic Analysis Workshops, and the phenotypes are familiar to the genetics community. Alcoholic probands were recruited from treatment facilities, assessed by personal interview, and after securing permission, other family members were also assessed. A set of comparison families was drawn from the same communities as the families recruited through an alcoholic proband. Assessment involved a detailed personal interview developed for this project, the Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA), which gathers detailed information on alcoholism related symptoms along with other drugs and psychiatric symptoms. Many participants also came to the laboratories for electroencephalographic studies. Neurophysiological features that have been shown to be useful endophenotypes for which we have linkage and in some cases association results are included on a subset of the case-control sample: the beta power of the resting electroencephalogram (EEG), the P3(00) amplitude of the visual event-related potential (ERP), and the theta and delta event-related oscillations (EROs) underlying the P3.

  Study phs001208

• Comprehensive genomic analysis of colorectal cancer with microsatellite instability

  Microsatellite instability-high (MSI-H) colorectal cancers (CRCs) account for 10?15% of all CRCs. MSI-H CRC is characterized by a large number of somatic insertions/deletions (indels) resulting from either mutations within or the silencing of genes involved in the DNA mismatch repair (MMR) system. A subset of MSI-H CRCs is associated with Lynch syndrome (LS), which is caused by germline MMR gene mutations, leading to hereditary cancer predisposition. Other than frequent somatic mutations in BRAF, the transformation mechanisms underlying MSI-H CRC are largely unknown. Here, genomic DNA from 149 MSI-H CRC specimens was analyzed using whole-exome sequencing, and 93 of these samples were subjected to genome-wide DNA methylation analysis. Furthermore, transcriptome sequencing was conducted on 111 samples. Genomic/epigenomic analyses identified three subgroups within our cohort: (1) MSI-H CRCs with silenced MLH1 that share frequent indels, a specific mutation/copy number alteration profile and promoter DNA methylation; (2) LS-associated MSI-H CRCs with MMR genes containing germline mutations; and (3) the remaining MSI-H CRCs with frequent somatic disruptive mutations of MLH1 or MSH2. Unexpectedly, only the first group was found to frequently carry fusion-type protein kinases (15% of this group and 9.9% of all MSI-H CRCs) that are promising therapeutic targets. Thus, MSI-H CRCs can be classified into three subgroups with distinctive genomic as well as epigenomic statuses, probably reflecting the oncogenic processes of these cancers. Fusion-type kinases are enriched in MSI-H CRCs, shedding new light on potential treatment strategies.

  Study JGAS000113

• Sequence analysis of colorectal serrated lesions

  Recent studies have shown that colorectal serrated lesions, which include sessile serrated adenomas (SSAs) and traditional serrated adenomas (TSAs), are precursors of colorectal cancer. However, the molecular mechanisms underlying the carcinogenesis, particularly in TSAs, remain largely uncharacterized. To clarify their molecular and clinicopathological characteristics, we performed mutation and methylation analyses of cancer-associated genes in 78 serrated lesions, including TSAs, SSAs and microvesicular hyperplastic polyps. Target exon sequence analysis was performed with 39 genes, including genes known to be frequently mutated in colorectal cancers and/or serrated lesions. We also used bisulfite pyrosequencing to assess the methylation status of various cancer-associated genes and marker genes of the CpG island methylator phenotype (CIMP). The prevalence of mutations in genes associated with Wnt signaling was significantly higher in TSAs than SSAs (65% vs. 28%, p < 0.01). Among those, RNF43 mutations were observed in 38% of TSAs and 17% of SSAs. In immunohistochemical studies of 39 serrated lesions, the prevalence of abnormal nuclear ?-catenin accumulation was significantly higher in TSAs (57%) than SSAs (8%) (P = 0.01). SMOC1 methylation was detected in 54% of TSAs but in no SSAs (p < 0.01). Additionally, SMOC1 methylation was more prevalent among TSAs with KRAS mutation (82%) than with BRAF mutation (38%, p = 0.03). Lesions with CIMP-high or RNF43 mutations were detected only in TSAs with BRAF mutation, suggesting two distinct carcinogenic pathways in TSAs. Mutations in genes associated with Wnt signaling play a greater role in the carcinogenesis of TSAs than SSAs.

  Study JGAS000217

• Impact of Glycolysis Inhibition on the Epigenome of Synovial Fluid T Cells in Juvenile Idiopathic Arthritis

  Juvenile Idiopathic Arthritis (JIA) encompasses a group of childhood-onset autoimmune conditions characterized by joint inflammation and mononuclear cell infiltration, especially of activated CD4+ memory/effector T (Tmem/Teff) cells in synovial fluid (SF). JIA CD4+ T cells exhibit a distinct inflammation-associated epigenomic profile, though the underlying molecular mechanisms remain unclear. This study investigates the role of glycolysis in shaping the epigenomic landscape of JIA SF CD4+ T cells, with a focus on H3K27ac histone modifications. Using an ex vivo model of antigen stimulation, CD4+ T cells were isolated from peripheral blood (PB) of healthy controls (HC) and synovial fluid from JIA patients. Cells were activated in vitro with anti-CD3/CD28 for 24 hours, and changes in H3K27ac were assessed by chromatin immunoprecipitation followed by sequencing (ChIP-seq). To explore the specific role of glycolysis, cells were also treated with 2-deoxyglucose (2DG), an inhibitor of glucose-6-phosphate production. This inhibition impacted both H3K27ac acetylation patterns and gene expression associated with the activated epigenomic regions. Additionally, HC CD4+ T cells were activated in vitro in the presence of 30% SF or 30% plasma from JIA patients. RNA sequencing (RNA-seq) was performed to examine SF-induced transcriptional changes, providing insight into the metabolic dysregulation and epigenomic alterations observed in JIA SF CD4+ T cells. This dataset includes ChIP-seq and RNA-seq data that collectively advance our understanding of how glycolysis and the SF environment contribute to the epigenetic and transcriptional regulation in JIA CD4+ T cells.

  Study EGAS50000000808

• Surgery in combination with immune checkpoint therapy as an effective treatment for patients with metastatic cancer.

  Abstract Surgical removal of primary tumors was shown to reverse tumor-mediated immune suppression in pre-clinical models with metastatic disease. However, how cytoreductive surgery in the metastatic setting modulates the immune responses in patients, especially in the context of immune checkpoint therapy (ICT)-containing treatments is not understood. Here, we report the first prospective, non-comparative clinical trial (N=104) using three different ICT-containing strategies plus cytoreductive or “debulking” surgery to remove the primary tumor-bearing kidney or a metastatic lesion as a treatment for patients (N=43) with metastatic clear cell renal cell carcinoma (mccRCC). For those patients (N=61) who were not candidates for cytoreductive surgery, a biopsy was obtained instead for correlative biological studies. Our data demonstrated that the combination of ICT with cytoreductive surgery was safe and feasible in patients with mccRCC. The 2-year overall survival was 84% with a median OS of 54.7 months for patients who received ICT containing regimens plus surgery. Immune-monitoring studies with co-detection by indexing (CODEX) identified distinct tumor spatial conformation of cellular subsets as a novel and improved predictor of response to ICT. Importantly, single-cell RNA-sequencing data demonstrated that surgical removal of the tumor increased antigen-presenting dendritic cell population with a concurrent reduction in KDM6B expressing immune-suppressive myeloid cells in the peripheral blood. Together, this study highlighted the feasibility of combining ICT with cytoreductive surgery in a metastatic setting and demonstrated potential enhancement of immune responses following ICT plus cytoreductive surgery in patients with metastatic disease.

  Study EGAS00001005667

• Tumor Evolution Analysis Uncovered Immune-Escape Related Mutations in Relapsed Diffuse Large B-Cell Lymphoma

  More than 60% of patients with primary diffuse large B-cell lymphoma (DLBCL) achieve durable remissions upon the chemoimmunotherapy with R-CHOP. However, the outcome of the relapse patients is extremely poor. To characterize the molecular features that underlie treatment resistance, we performed whole-exome sequencing (n=44) and deep targeted sequencing (n=27) of 44 diagnosis-relapse DLBCL pairs. We found that the overall landscape of genetic alterations was concordant between diagnosis and relapse DLBCL. By a deep comparison of the longitudinal sequencings, we identified relapse-enriched mutations that involved in evasion of immune surveillance (CD58, TNFRSF14, PKD1, FAS), resistance to DNA damaging agents (ATM, TP53), and critical tumor suppressor gene (ZFHX3). Knockdown of ATM and ZFHX3 resulted in increased drug resistance in both germinal center B cell like (GCB) and activated B cell like (ABC) DLBCL cell lines in vitro, while the knockdown of TNFRSF14 and FAS conferred resistance specifically in GCB cell lines. Furthermore, we summarized two evolutionary patterns of DLBCL relapse as the “durable retention” model with stable clone structure, and the “selective sweep” model which exhibited significant clonal switch. Of note, genetic alterations leading to attenuated immune responses usually presented as trunk mutations in the “durable retention” model (7/12) while were newly acquired or expanded upon relapse in the “selective sweep” model (9/16). Overall, our study demonstrated that relapse DLBCL derives from distinct clonal evolutionary patterns, and highlighted immune escape as an important contributor of tumor relapse.

  Study EGAS50000000032

• Sequencing data from triple-negative breast cancer tumors

  Autoimmunity and anti-cancer immunity lie on the same biological continuum1,2, but their link remains obscure. The paraneoplastic neurological syndrome anti-NMDA receptor (NMDAR) encephalitis (ANRE) is a paradigm for their connectivity3 given that intratumoral NMDAR expression correlates with the generation of anti-NMDAR antibodies4,5. Here, we verify ectopic expression of GluN1 and GluN2B NMDAR sub-units in triple-negative breast cancer (TNBC)6 and model this using orthotopic TNBC tumors with inducible expression of GluN1-GluN2B NMDARs. We show that NMDAR expression is sufficient to induce B cell recruitment and their affinity maturation, consistent with an integrated adaptive immune response. Reconstruction of extended intratumoral B cell phylogenies and cryo-EM structural analyses demonstrated that affinity-matured hypermutated and class-switched antibodies emerged from pre-existing germline-configuration lower-affinity anti-NMDAR antibodies. Distinct matured antibodies targeted specific epitopes and induced conformational rearrangements within the NMDAR amino-terminal domain, predictive of their functional effects, ranging from inhibition to potentiation. Passive transfer of an NMDAR-potentiating antibody caused autonomic dysregulation and lowered the seizure threshold in healthy female mice, recapitulating key diagnostic criteria of ANRE4,5. We further identify a correlation between intratumoral NMDAR expression and anti-NMDAR antibody titers in TNBC patients. Taken together, our data establish a direct connection between intratumoral NMDAR expression, antibody maturation, and the onset of autoimmunity. These findings suggest that germline-encoded anti-NMDAR antibodies contribute to immune surveillance but can also trigger autoimmune disease upon maturation, revealing a mechanistic tradeoff between cancer immunity and neurotoxicity.

  Study EGAS50000001585

• Sequencing data from triple-negative breast cancer tumors

  Autoimmunity and anti-cancer immunity lie on the same biological continuum1,2, but their link remains obscure. The paraneoplastic neurological syndrome anti-NMDA receptor (NMDAR) encephalitis (ANRE) is a paradigm for their connectivity3 given that intratumoral NMDAR expression correlates with the generation of anti-NMDAR antibodies4,5. Here, we verify ectopic expression of GluN1 and GluN2B NMDAR sub-units in triple-negative breast cancer (TNBC)6 and model this using orthotopic TNBC tumors with inducible expression of GluN1-GluN2B NMDARs. We show that NMDAR expression is sufficient to induce B cell recruitment and their affinity maturation, consistent with an integrated adaptive immune response. Reconstruction of extended intratumoral B cell phylogenies and cryo-EM structural analyses demonstrated that affinity-matured hypermutated and class-switched antibodies emerged from pre-existing germline-configuration lower-affinity anti-NMDAR antibodies. Distinct matured antibodies targeted specific epitopes and induced conformational rearrangements within the NMDAR amino-terminal domain, predictive of their functional effects, ranging from inhibition to potentiation. Passive transfer of an NMDAR-potentiating antibody caused autonomic dysregulation and lowered the seizure threshold in healthy female mice, recapitulating key diagnostic criteria of ANRE4,5. We further identify a correlation between intratumoral NMDAR expression and anti-NMDAR antibody titers in TNBC patients. Taken together, our data establish a direct connection between intratumoral NMDAR expression, antibody maturation, and the onset of autoimmunity. These findings suggest that germline-encoded anti-NMDAR antibodies contribute to immune surveillance but can also trigger autoimmune disease upon maturation, revealing a mechanistic tradeoff between cancer immunity and neurotoxicity.

  Study EGAS50000001598

• Organoid cultures of early-onset colorectal cancers reveal distinct and rare genetic profiles

  Sporadic early-onset colorectal cancer (EOCRC) has bad prognosis, yet is poorly represented by cell line models. We examine the key mutational and transcriptomic alterations in an organoid biobank enriched in EOCRCs. We established paired cancer (n=32) and normal organoids (n=18) from 20 patients enriched in microsatellite-stable EOCRC. Exome and transcriptome analysis was performed. We observed a striking diversity of molecular phenotypes, including PTPRK-RSPO3 fusions. Transcriptionally, RSPO fusion organoids resembled normal colon organoids and were distinct from APC mutant organoids, with high BMP2 and low PTK7 expression. Single cell transcriptome analysis confirmed the similarity between RSPO fusion organoids and normal organoids, with a propensity for maturation on Wnt withdrawal, whereas the APC mutant organoids were locked in progenitor stages. CRISPR/Cas9 engineered mutation of APC in normal human colon organoids led to upregulation of PTK7 protein and suppression of BMP2, but less so with an engineered RNF43 mutation. The frequent co-occurrence of RSPO fusions with SMAD4 or BMPR1A mutation was confirmed in TCGA database searches. RNF43 mutation was found in organoid from a leukaemia survivor with a novel mutational signature; and organoids with POLE proofreading mutation displayed ultramutation. The cancer organoid genomes were stable over long culture periods, while normal human colon organoids tended to be subject to clonal dominance over time. These organoid models enriched in EOCRCs with linked genomic data fill a gap in existing CRC models and reveal distinct genetic profiles and novel pathway cooperativity.

  Study EGAS00001004063

• Pediatric Papillary Thyroid Carcinoma Whole Exome Sequencing

  BACKGROUND: Pediatric papillary thyroid carcinoma (PPTC) is distinct from adult-onset disease. Despite higher rates of regional and distal metastases and more frequent recurrence, there is, paradoxically, a highly favourable prognosis. Historically, only 40-50% of childhood PTC are driven by genomic variants common to adult PTC, while the oncogenic drivers in the remainder are unknown. METHODS: Fifty-two PPTCs were genotyped by candidate gene testing, followed, in a subset (n=32), by whole exome (WES) and transcriptome sequencing (RNASeq) to identify oncogenic variants in driver-unknown tumors and to explore gene expression patterns. FINDINGS: Thirty-one tumors (60%) carried variants identified by candidate gene testing, specifically: BRAFV600E(22%), NRASQ61R(2%), RET-CCDC6(19%), RET-NCOA4(15%) and PAX8-PPARG. Among the 21 remaining tumors with negative first-line genotyping, oncogenic variants were identified in 19 (90%). These were enriched with oncogenic fusions, with 11 non-recurrent fusion transcripts identified, including two that had not been previously described: STRN-RET and TG-PBF. Most fusions were associated with 3’ receptor tyrosine kinase (RTK) moieties: RET, MET, ALK and NTRK3. Gene expression analysis defined three distinct clusters, which demonstrated differing expression of genes involved in thyroid differentiation and MAPK signaling. INTERPRETATION: Exome and transcriptome-wide sequencing identify genomic drivers of PPTC in 98% of tumors, whereas conventional genotyping leaves many tumors genetically unexplained. PPTC is driven, in the majority of cases, by oncogenic fusion transcripts involving one of a limited number of RTKs. These observations have broad implications for diagnostic testing and for therapeutic options in children with advanced disease.

  Study EGAS00001005187

• shallow WGS and deep targeted panel on ctDNA in rhabdomyosarcomas

  The genomic spectrum of rhabdomyosarcoma (RMS) progression from primary to relapse is not fully understood. In this study we investigate 35 patients with relapsed RMS from two contributing institutions, 18 fusion-positive (FP-RMS) and 17 fusion-negative RMS (FN-RMS). Targeted DNA or whole exome sequencing (WES) was used to detect alterations in paired primary/relapsed samples. In 10 cases, circulating tumor DNA (ctDNA) from multiple timepoints through clinical care and progression was analyzed for feasibility of liquid biopsy in monitoring treatment response/relapse. ctDNA alterations were evaluated using a targeted custom RMS panel (36 genes) at high coverage for single nucleotide variation and fusion detection, and a shallow whole genome sequencing for copy number variation. FP-RMS had a stable genome with relapse, with the most common secondary alterations : CDKN2A/B, MYCN and CDK4 alterations, being already present at diagnosis and impacting overall survival. FP-RMS lacking major secondary events at baseline acquired recurrent MYCN and AKT1 alterations. FN-RMS acquired a higher number of new alterations, most commonly SMARCA2 missense mutations. ctDNA analyses detected pathognomonic variants in all RMS patients at diagnosis, regardless of FP/FN or type of alterations, while at relapse selected alterations were confirmed in 86% of FP-RMS and 100% FN-RMS. Moreover, a higher number of fusion reads was detected with increased disease burden and at relapse in patients following a fatal outcome. These results underscore patterns of tumor progression within a relatively stable genomic landscape and provide rationale for using liquid biopsy to monitor treatment response.

  Study EGAS00001007399

• These are from Korean HCC samples with exome sequencing

  Hepatic resection is the most curative treatment option for early-stage hepatocellular carcinoma, but is associated with a high recurrence rate, which exceeds 50% at 5 years after surgery. Understanding the genetic basis of hepatocellular carcinoma at surgically curable stages may enable the identification of new molecular biomarkers that accurately identify patients in need of additional early therapeutic interventions. Whole exome sequencing and copy number analysis was performed on 231 hepatocellular carcinomas (72% with hepatitis B viral infection) that were classified as early-stage hepatocellular carcinomas, candidates for surgical resection. Recurrent mutations were validated by Sanger sequencing. Unsupervised genomic analyses identified an association between specific genetic aberrations and postoperative clinical outcomes. Recurrent somatic mutations were identified in 9 genes, including TP53, CTNNB1, AXIN1, RPS6KA3, and RB1. Recurrent homozygous deletions in FAM123A, RB1, and CDKN2A, and high-copy amplifications in MYC, RSPO2, CCND1, and FGF19 were detected. Pathway analyses of these genes revealed aberrations in the p53, Wnt, PIK3/Ras, cell cycle, and chromatin remodelling pathways. RB1 mutations were significantly associated with cancer-specific and recurrence-free survival after resection (p = 0.016 and p = 0.001, respectively). FGF19 amplifications, known to activate Wnt signalling, were mutually exclusive with CTNNB1 and AXIN1 mutations, and significantly associated with cirrhosis (p = 0.017). RB1 mutations can be used as a prognostic molecular biomarker for resectable hepatocellular carcinoma. Further study is required to investigate the potential role of FGF19 amplification in driving hepatocarcinogenesis in patients with liver cirrhosis and to investigate the potential of anti-FGF19 treatment in these patients.

  Study EGAS00001000604