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• Tumor heterogeneity and acquired drug resistance in FGFR2 fusion-positive cholangiocarcinoma through rapid research autopsy

  Whole exome sequencing was performed on blood and tumor specimens (collected from biopsy or rapid research autopsy) from a patient with FGFR2 fusion positive cholangiocarcinoma.

  Study phs001830

• Clinical and molecular features of early onset pancreatic cancer

  A retrospective cohort study on the clinical and molecular features of early onset pancreatic cancers (i. e. diagnosed at <50 years old) in comparison with later onset tumors.

  Study EGAS50000000362

• Autosomal dominant macular dystrophy associated with THRB: identification of new families and variants 

  This study aims to refine the ophthalmologic phenotype, report a novel THRB variant, and investigate the impact of these splicing variants at the protein level.

  Study EGAS50000000861

• NICOLA QUB Genetic

  Blood-derived DNA was obtained from samples within the NICOLA cohort. Genetic data was generated using the Illumina Infinium CoreExome-24 array (Illumina, USA) and is available for 2,978 participants (551,839 directly genotyped and 18,148,478 imputed single nucleotide polymorphisms following initial quality control). Genetic .bed .bim and .fam files are available.

  Dataset EGAD00010002762

• Single-cell genotype-to-phenotype mapping via co-capture of DNA mutations and mRNA transcripts

  We developed single-cell Genotype-to-Phenotype sequencing (scG2P) for high-throughput, highly-multiplexed, single-cell joint capture of recurrently mutated genomic regions and mRNA phenotypic markers in cells or nuclei isolated from solid tissues. We applied scG2P to aged esophagus samples from five individuals with high alcohol and tobacco exposure.

  Dac EGAC50000000833

• WGS data of paediatric B-other B cell acute lymphoblastic leukemia (set6)

  The dataset includes FASTQ and CRAM files from diagnostic and matched remission (control) samples of one B-other ALL patients (ALLK-138). Sequencing library was made using Novogene NGS DNA Library Prep Set. Both diagnostic (90x) and remission (30x) samples were sequenced using NovaSeqX Plus.

  Dataset EGAD50000002161

• PDAC clinical phenotype data with CA19-9 and Lewis antigen status

  This dataset contains individual-level clinical phenotype data from patients with pancreatic ductal adenocarcinoma, including CA19-9 measurements, Lewis antigen status, and relevant clinicopathological variables. Data were generated as part of an ethically approved study and are available under controlled access.

  Dataset EGAD50000002254

• Combined genetic and transcriptome analysis of patients with Systemic Lupus Erythematosus (SLE)

  A comprehensive profiling of the genomic architecture of Systemic Lupus Erythematosus (SLE) by combining genetic and transscriptomic analysis by RNA-seq.

  Study EGAS00001003662

• SCLC CTC genomic analysis data set

  The data set consists of low-pass whole genome sequence data of single CTCs, pools of CTCs and germline controls for a cohort of 31 SCLC patients at both baseline, and for 5 patients at relapse. In addition 9 CDX models and associated germline controls (where available) are included.

  Dataset EGAD00001002678

• Low-pass whole-genome DNA sequencing of cohesin-mutated and wildtype adult AMLs

  Low-pass whole-genome DNA sequencing of cohesin-mutated (STAG2 or RAD21 mutations) and wildtype (CTRL-AML) adult AMLs generated generated from ultrasound-fragmented genomic DNA. Samples were only sequenced shallow (20-40 Mio reads) Used for digital karyotyping and ChIP-seq background/copy-nuber normalization/correction.

  Dataset EGAD00001011207

• WES data of primary tumors and metastasis corresponding to three patients

  Fastq files of WES data. Primary tumor and/or metastasic samples of three chRCC patients. DNA libraries were produced using the SureSelect XT HumanAllExon V5 kit (Agilent Technologies), and sequencing was performed in a HiSeq instrument (Illumina) using a 100-bp paired-end mode.

  Dataset EGAD00001010173

• Shallow whole genome sequencing from plasma DNA of BC, CRC and NSCLC patients

  This is the raw data obtained from shallow whole-genome sequencing of plasma DNA (plasma-Seq) for calling of somatic copy number alterations as well as focal amplifications and deletions from patients with breast, colorectal and non-small cell lung cancer.

  Dataset EGAD00001006288

• Combined single cell immunophenotyping and genotyping of adult low hypodiploid acute lymphoblastic leukemia

  This dataset includes the Fastq files from sequencing data generate from diagnostic and remission bone marrow mononuclear cell samples using the Mission Bio Tapestri Plateform with both DNA amplicons and protein from antibody-derived tags sequencing libraries.

  Dataset EGAD00001009763

• Whole genome sequencing of Cas9 repaired cystic fibrosis organoids description

  Three SpCas9-ABE (R785X/R785X) and three xCas9-ABE-repaired organoid clones (F508del/R553X) and their respective unrepaired control organoids were paired-end whole genome sequenced using Illumina Novaseq 6000 system. The reads were mapped to hg19 genome assembly and data is provided as BAM files.

  Dataset EGAD00001005427

• subset of 11 samples RRMM (RNA-Seq and WGS) from study EGAS00001005973 used also in study EGAS00001006538

  subset of 11 samples (RNA-Seq and WGS) from study EGAS00001005973, which was published earlier and are linked here to study EGAS00001006538

  Dataset EGAD00001009679

• Genomic (WGS) data for the validation of the glioblastoma progression study (GBMatch).

  43 low-coverage genomes derived from fresh-frozen glioblastoma tumor samples. These genomes have been produced for validation purposes and match the corresponding RRBS and RNA-seq profiles in that DNA and RNA was extracted from the same tumor samples.

  Dataset EGAD00001004077

• Whole genome sequencing of 40 gastric cancer tumours and matched normal samples from Singapore.

  Genomic DNA of tumours and matched normal gastric tissues was extracted (QIAGEN). Libraries were constructed with 300-400 bp insert length, and 101bp or 151bp paired-end sequencing was performed on Illumina Hiseq instruments

  Dataset EGAD00001004279

• Transcriptome (RNA-seq) data for the validation of the glioblastoma progression study (GBMatch).

  37 transcriptomes derived from fresh-frozen glioblastoma tumor samples. These transcriptomes have been produced for validation purposes and match the corresponding RRBS and WGS profiles in that DNA and RNA was extracted from the same tumor samples.

  Dataset EGAD00001004076

• Edinburgh Naevi Cohort (2018-08-03)

  In this project we have sequenced the exome of skin moles (melanocytic naevi) and also normal skin from young and old people. We are interested in looking at the clonality of these lesions and the burden of UV mutations . This dataset contains all the data available for this study on 2018-08-03.

  Dataset EGAD00001004273

• GIS-LUNGTCR1-2016_WES-FASTQ

  This dataset contains FASTQ files for multi-region exome-sequencing of EGFR-mutant lung adenocarcinomas from Asian patient. There are 16 patients and 95 samples in total, including 16 controls and 79 tumors. Multiple runs for each sample, and 368 fastq in total. Please refer to the sample-ID from filename for merging.

  Dataset EGAD00001001978

• Exome data: Histone mutations in human Pre-Leukemic HSC and AML

  Exome sequencing was performed on samples from patients 064, 105, and 8760, including the remission sample for 105. Exomes were captured using the Agilent SureSelect All Exon kit v5 kit and libraries sequenced on HiSeq 2000 or 2500 or 4000.

  Dataset EGAD00001004436

• Whole Exome (WE) sequencing data files for H_NO-JB001

  DNA was derived from the primary tumour, lung metastasis, and peri-aortic lymph node metastasis. DNA from the spleen was used as a normal control.For WE sequencing we user Hybrid capture (Nimblegen version 3.0) of the lymph node and lung metastases, primary tumour and spleen normal; we generated ~100-fold coverage.

  Dataset EGAD00001001252

• Whole genome sequencing data from whole genome amplified single cells and unamplified bulk samples

  The dataset includes paired end fastq files of whole genome sequencing data on the Illumina platfrom. Individual samples are multiple annealing and looping based amplified single fibroblasts and multiple displacement amplified single T lympocytes, including unamplified bulk samples.

  Dataset EGAD00001004195

• The Transcriptome of PLX4032 resistance

  We have collected material from a patient who had BrafV600E mutant melanoma that was treated with PLX4032. We have germline DNA from the patient and DNA and RNA from distinct lesions before and after treatment with PLX4032. We have transcriptome sequenced these samples to obtain a snap shot of the mechanisms of resistance that are operative.

  Dataset EGAD00001000599

• 4C-seq in endometrial healthy and tumor tissues

  4C-seq performed on 10 slices (30um thick) of fresh frozen endometrial tissues. These tissue include 2 healthy tissues and 4 tumor tisseus (post-menopausal patients) in replicate. The library has been performed using DpnII (primary) and NlaIII (secondary) restriction enzymes. Raw single-end fastq.gz files are provided.

  Dataset EGAD00001010897

• Mapping of runs back to samples for snRNASeq data

  Mapping of runs back to samples for PDN, PDO and TIS snRNASeq data. 4 sets of matched PDN, PDO and TIS samples (12 unique samples total) underwent pooled snRNASeq (Parse Biosciences). 2 sublibraries were created from this and sequenced at separate times

  Dataset EGAD00001015609

• Alopecia and Vitiligo

  exome sequencing data captured with agilent v4 (71k) and sequenced on illumina technology. data from a total of 40 samples, of which 14 are vitiligo cases with familial history of vitiligo or immune disease, and the remaining are alopecia areata cases.

  Dataset EGAD00001005289

• Identifying autosomal recessive mutations causing neurological disorders

  The objective of this study is to resequence of targeted intervals containing autosomal recessive variants causing neurological disorders in consanguineous pedigrees. Using homozygosity mapping, three intervals of very different sizes have previously been unambiguously mapped for three different neurological diseases: 2.4Mb, 8Mb and 14.3Mb in size, for Microlissencephaly, Severe Mental Retardation and Complicated hereditary spastic paraplegia respectively. This study is a pilot to assess how well custom targeted resequencing performs across a broad size range of intervals. The study design is to use a different custom capture probe set for each interval, pulldown from a single patient from each family, and sequence 1 lane using Illumina paired-reads for each sample. Candidate variants will be followed up in the families themselves, and in patients with similar phenotypes from outbred populations.

  Study EGAS00001000023

• Recording physiological history of cells with chemical labeling.

  Recordings of the physiological history of cells provide insights into biological processes, yet obtaining such recordings is a challenge. To address this, we introduce a method to record transient cellular events for later analysis. We designed proteins that become labeled in the presence of both a specific cellular activity and a fluorescent substrate. The recording period is set by the presence of the substrate, whereas the cellular activity controls the degree of the labeling. The use of distinguishable substrates enabled the recording of successive periods of activity. We recorded protein-protein interactions, G-protein-coupled receptor activation and elevations in intracellular calcium. Recordings of elevated calcium levels allowed selections of cells from heterogenous populations for transcriptomic analysis and tracking of neuronal activities in flies and zebrafish.

  Study EGAS50000000056

• deCODE Genetics study on genes contributing to nicotine dependence in humans

  A genome-wide association study on smoking behavior and nicotine dependence in Icelandic smokers, assessed by the number of cigarettes smoked per day, smoking initiation and degree of dependence on nicotine. The number of cigarettes smoked per day was ascertained through questionnaires given to individuals participating in multiple disease projects at deCODE Genetics (n=16,483). Smoking initiation was analyzed by comparing those that have ever smoked (n=16,483) versus those that have never smoked (n=21,667). The nicotine dependence analysis included 3,435 nicotine dependent cases (score 4 or higher on Fagerstrom Test for Nicotine Dependence (FTND) or endorsement of at least three of the seven Diagnostic and Statistical Manual of Mental Disorders 4th edition (DSM-IV) criteria) and 3,344 low-quantity smokers as controls.

  Study phs000393

• Human Lung Tissue eQTL Study

  Genetic risks underlying respiratory diseases (e.g. COPD and asthma) are carefully studied by large genome-wide association studies (GWAS), where many loci were identified. In the post-GWAS era, the main challenge is to find the causal genes and pathways in GWAS-nominated chromosomal regions and to characterize etiology mechanism. The Lung eQTL Consortium is an international effort to systematically capture the genetic architecture of gene expression regulation in human lung. By studying lung specimens from 1,103 individuals of mostly European ancestry, we report a large number of genetic variants affecting gene expression in the lung, or lung expression quantitative trait loci (eQTL). These lung eQTLs will serve as an important resource to aid in the understanding of the molecular underpinnings of lung biology and its disruption in disease.

  Study phs001745

• A New High-Throughput Sequencing-Based Technology to Study Heterochromatin Structure

  In this study we report epigenomic and transcriptomics datasets for normal control fibroblasts. The following cell lines were obtained from the NIGMS Human Genetic Cell Repository at the Coriell Institute for Medical Research: AG08498, AG07095, originally collected as part of the NIA Aging Cell Repository study. We applied a high-throughput sequencing-based technique, named Sequential Analysis of MacroMolecules accessibilitY (SAMMY-seq), for the genome-wide mapping of chromatin regions separated by differential accessibility. The method is based on the sequential extraction of multiple chromatin fractions, corresponding to increasingly compacted and less accessible chromatin regions, which are mapped along the genome using high-throughput sequencing. Additionally we carried out ChIP-seq for the H3K9me3 and H3K27me3 histone modifications and RNA-seq for the characterization of transcriptome in control fibroblasts.

  Study phs002202

• Multimodal Mapping of the Immune Landscape in Human Pancreatic Cancer

  Pancreatic ductal adenocarcinoma (PDA) is characterized by an immune-suppressive tumor microenvironment that has rendered it largely refractory to immunotherapy. We used single-cell RNA sequencing on patient tumors and matched blood, and we uncovered a previously unappreciated, complex environment of immune-suppressive cellular interactions. These experiments reveal immune checkpoint expression heterogeneity on individual patient T cells, with corresponding ligands on neoplastic and myeloid cells. TIGIT was upregulated on tumor infiltrating CD8+ T cells and was the only checkpoint receptor consistently expressed by exhausted CD8+ T cells. Clinical annotation of the samples revealed that the exhausted signature is most prominent in patients with advanced stages of disease. Our findings suggest individualized combination therapy, involving anti-TIGIT therapies, may be necessary to extend the benefits of immunotherapy to pancreatic cancer patients.

  Study phs002071

• Prevention of Viral Hepatitis and HIV in Drug Users - A Hepatitis B Model for HIV and an HB Vaccine Model for HIV Vaccine Trials in Drug Users (DASH)

  The goal of the proposed study is to use the Hepatitis B virus (HBV) vaccine as a model for a future Human Immunodeficiency Virus (HIV) vaccine trial, examining the efficacy of community-based outreach intervention as well as an accelerated vaccine schedule as a method for increasing acceptance/adherence with HBV vaccination protocols among not-in-treatment drug users. This study also examined the effect of HBV vaccination coupled with community-based outreach intervention on reducing the incidence of HIV, HBV and Hepatitis C Virus (HCV) infections and the frequency of needle use and sexual risk behaviors related to these viral transmissions. A secondary purpose is to assess the antibody response after HBV vaccination as a measurement of immunological response in drug users.

  Study phs002331

• TCGA WGS Variants Across 18 Cancer Types

  Even though whole genome sequence (WGS) data has been generated and published in many studies, much of this information is not yet processed for use in down-stream analysis. This study's aim is to provide 1342 WGS normal-tumor paired single nucleotide variations (SNP) over 18 different cancer types provided by The Cancer Genome Atlas (TCGA) project. Individual level data for TCGA can be accessed by requesting access for phs000178. This data includes variations within self-reported white and African-American populations. Variations that exist within the tumor tissue but are absent in associated normal organ tissue (as compared to the human reference genome) are reported. Data published includes SNP and small insertions and deletions, which were generated through a pipeline including the VarScan2 variant calling software.

  Study phs003155

• Somatic Mutations in Epilepsy: Whole Genome Sequence Analysis of Single Neurons

  Low-coverage whole-genome sequencing was performed on single-cells from resected brain tissues obtained from an individual with hemimegalencephaly (HMG) along with a somatic copy number variant (sCNV) of chromosome 1q in order to characterize the sCNV at the single cell level. Single neuronal nuclei and non-neuronal nuclei were isolated by fluorescence-activated cell sorting (FACS) using NeuN immunoreactivity to identify neurons. 46 neurons and 30 non-neuronal cells, as well as a batch of 10 and a batch of 100 cells from each group, were genome amplified using multiple displacement amplification (MDA) and sequenced on an Illumina HiSeq 2000 sequencer. Thirty-two samples were multiplexed into each HiSeq lane for single-end 50 bp runs, obtaining ~5 million pass-filter reads per sample.

  Study phs002615

• Clonal heterogeneity leads to secondary resistance in a melanoma patient after adoptive cell therapy with tumor-infiltrating lymphocytes

  Adoptive cell therapy (ACT) with tumor-infiltrating lymphocytes (TIL) is effective in melanoma patients, although long-term responses seem restricted to patients with complete remissions. Many patients develop secondary resistance to TIL-ACT but involved mechanisms are unclear. Here, we describe a case of secondary resistance to TIL-ACT likely due to intratumoral heterogeneity and selection of a resistant tumor cell clone via transferred T cells. This is the first case of clonal selection of a pre-existing non-dominant tumor cell clone and demonstrates a new mechanism involved in secondary resistance to TIL-ACT and could potentially change current clinical practice, because it advocates for T cell collection from different tumor sites and analysis of tumor heterogeneity before the treatment with TIL-ACT.

  Study EGAS50000000279

• Inferring causal genes at type 2 diabetes GWAS loci through chromosome interactions in islet cells

  Resolving causal genes for type 2 diabetes at loci implicated by genome-wide association studies (GWAS) requires integrating functional genomic data from relevant cell types. Chromatin features in endocrine cells of the pancreatic islet are particularly informative and recent studies leveraging chromosome conformation capture (3C) with Hi-C based methods have elucidated regulatory mechanisms in human islets. However, these genome-wide approaches are less sensitive and afford lower resolution than methods that target specific loci. Methods: To gauge the extent to which targeted 3C further resolves chromatin-mediated regulatory mechanisms at GWAS loci, we generated interaction profiles at 23 loci using next-generation (NG) capture-C in a human beta cell model (EndoC-βH1) and contrasted these maps with Hi-C maps in EndoC-βH1 cells and human islets and a promoter capture Hi-C map in human islets. Results: We found improvements in assay sensitivity of up to 33-fold and resolved ~3.6X more chromatin interactions. At a subset of 18 loci with 25 co-localised GWAS and eQTL signals, NG Capture-C interactions implicated effector transcripts at five additional genetic signals relative to promoter capture Hi-C through physical contact with gene promoters. Conclusions: High resolution chromatin interaction profiles at selectively targeted loci can complement genome- and promoter-wide maps.

  Dataset EGAD50000000517

• Clinical relevance of TCGA subtypes for gastric cancer patients

  There is a clinical need for the availability of molecular biomarkers in the tratment of gastric cancer (GC), since survival rates remain poor with a 5-year survival rate of only ~`40% for patients with resectable disease. These markers will elad to a more tailored approach in the treatment of GC, which enhances efficacy and reduces toxicity. Recently, The Cancer Genome Atlas (TCGA) classified GC patients into four molecular subgroups: Epstein Barr Virus positive (EBV+), genomically stable (GS), microsatellite instable (MSI), and chromosomal instable (CIN). For this purpose we aim to collect tumor tissue blocks from patients who participated in the Dutch D1/D2 or the CRITICS trial and who gave informed consent for translational studies. Associations between TCGA subtypes and outcomes to these different therapeutic options will be analyzed.

  Study EGAS50000000779

• RNA sequencing data from glioblastoma primary cell lines treated with indisulam

  This study aimed to develop NovumRNA, a bioinformatics pipeline designed to predict non-canonical tumor-specific antigens (ncTSAs) from human tumor RNA-sequencing data, potentially broadening the target pool for cancer neo-epitope-based immunotherapies. The splicing-modulating drug indisulam was investigated for its potential to induce aberrant transcriptomes, potentially increasing ncTSAs, subsequently predicted by NovumRNA. Four glioblastoma primary cell lines were derived from patient Cavitron Ultrasonic Aspirator (CUSA) material, cultured as neurospheres, and treated with indisulam or vehicle control. RNA was extracted at 6 and 16 hours post-treatment and sequenced using the NovaSeq platform. The resulting RNA-seq data was analyzed with NovumRNA, using healthy brain GTEx samples as controls, to identify and validate ncTSAs induced by indisulam treatment. NovumRNA is available at: https://github.com/ComputationalBiomedicineGroup/NovumRNA.

  Study EGAS50000000680

• 3.5KJPNv2, an allele frequency panel of 3,552 Japanese individuals

  In the Tohoku Medical Megabank Project, we have conducted whole-genome sequencing of nearly 4,000 individuals from a Japanese population, and constructed an allele frequency panel of 3,552 individuals (3.5KJPNv2) after removing genetically related individuals. The 3.5KJPNv2 was constructed by using a standard pipeline including the 1KGP and gnomAD algorithms to reduce technical biases and to allow comparisons to other populations. The 3.5KJPNv2 includes variants in chromosome X and mitochondrial genome as well as autosome. The submitter has changed the access level of this study from controlled-access [Type I] to un-restricted access since 11th, January, 2019. The un-restricted access data ?hum0015.v3.3.5kjpnv2.v1? are available at the NBDC site: https://humandbs.biosciencedbc.jp/en/hum0015-v3. This study does not contain any controlled-access dataset.

  Study JGAS000159

• Transcriptomic analysis of B-cell acute lymphoblastic leukaemia (B-ALL) patients treated on the ALL09 clinical trial

  This study provides comprehensive transcriptomic analysis of adolescent and young adult (AYA) patients treated on the Australasian Leukaemia and Lymphoma Group (ALLG) ALL09 clinical trial (ACTRN12618001734257). The ALL09 clinical trial is a Phase II single arm study to assess whether substitution of blinatumomab for conventional multi-agent chemotherapy in phase 2 induction leads to improved minimal residual disease negativity rates when compared to the historical AYA ALL trial cohort. Patients treated on this trial were aged 15-40 years, demonstrated morphological diagnosis of CD19 positive B-lineage acute lymphoblastic leukaemia (B-ALL), and were negative for Philadelphia chromosome-positive disease. Transcriptomic sequencing was performed as a correlative study to determine assess patients’ genomic subtypes and enable comparison of clinical outcome in blinatumomab treated patients.

  Study EGAS50000001109

• Evolutionary Origins of Recurrent Pancreatic Cancer

  Surgery is the only curative option for patients with Stage I/II pancreatic cancer, nonetheless most patients will recur after surgery and die of their disease. To identify novel opportunities for management of recurrent pancreatic cancer we performed whole exome or targeted sequencing of 10 resected primary cancers and their matched intrapancreatic recurrences or distant metastases. We identified that recurrent disease develops from a monophyletic or polyphyletic origin, and this distinction has potential clinical relevance. In all patients, treatment induced genetic bottlenecks led to a modified genetic landscape and subclonal heterogeneity for driver gene alterations in part due to intermetastatic seeding. In one patient what was believed to be recurrent disease was an independent (second) primary tumor. These findings strongly advocate for routine post-treatment sampling in the management of recurrent pancreatic cancer.

  Study EGAS00001004097

• IMCISION RNAseq

  RNA sequencing could be performed on all 32 baseline and 30 on-treatment primary tumor biopsies. Based on gene-set enrichment analysis, the epithelial to mesenchymal transition signature was enriched in baseline tumors of patients without MPR, though its expression was insufficient to predict ICB response. Baseline and on-treatment IFNγ and T-cell signature expression (Z-score) were not significantly higher in patients with an MPR.­­­ Baseline primary tumor hypoxia-associated gene expression in IMCISION did not predict ICB response. However, on-treatment biopsies of MPR tumor samples showed significantly lower hypoxia gene expression when compared to non-MPR samples. Moreover, in a paired analysis of baseline and corresponding on-treatment samples, a significant decrease of hypoxia-related gene expression was observed in MPR biopsies, while this decrease was absent in non-MPR biopsies.

  Study EGAS00001005454

• A genetic compendium of human brains from the UK Medical Research Council brain tissue resource

  Common neurodegenerative diseases have a complex genetic architecture. Highly penetrant diseases alleles are found in a significant minority of cases, and common risk alleles are present in a large proportion. Given the central role of genetic factors in the pathogenesis of these disorders, it is critical that mechanistic studies in human subjects and tissue samples are interpreted in an genetically enlightened context. To address this we performed exome sequencing on 1461 human brains accessible through the Medical Research Council (UK) brain banks network. Our findings confirm the complex genetic landscape of neurodegenerative disease. Clinical, pathological and genetic data for the 1461 brains with corresponding exome sequencing data are available within this dataset, enabling the genetic stratification and selection of post-mortem tissue samples for researchers.

  Study EGAS00001001599

• Most HCCs in Taiwan show the mutational signature of aristolochic acid

  Plants in the genus Aristolochia contain the mutagen aristolochic acid (AA) and have been widely used in traditional medicines and for weight loss. AA binds covalently to genomic DNA and induces a highly distinctive mutational signature. While AA involvement in urinary-tract cancers in Taiwan is known, the possible role of AA in hepatocellular carcinomas (HCCs) in Taiwan has not been examined. Here, we whole-exome sequenced 98 unselected HCCs from Taiwan and analyzed the mutational signatures for evidence of AA mutagenesis. Remarkably, more than 78% of HCCs showed strong evidence of AA mutagenesis, often associated with high mutation burdens. Non-synonymous mutations in genes known to be HCC driver genes were detected. Importantly, we elucidated the potential of immunotherapy in this cohort of liver cancer patients.

  Study EGAS00001002301

• ICGC Oesophageal adenocarcinoma - tumour samples

  The oesophageal project will focus on adenocarcinoma which is increasing in incidence in the UK and other developed countries and has a very poor outcome. The primary aims of this project are to deeply sequence tumour and normal genomic DNA (including the precursor condition Barrett’s oesophagus when material is available) to provide a comprehensive catalogue of somatic mutations. This will be achieved through a UK-wide network of hospitals involved in a research collaboration called the OCCAMS consortium. The goal of this project is to use high quality clinical material with accurately annotated clinic-pathological, treatment and outcome data.

  Study EGAS00001000725

• Whole Genome Sequencing of Liver Cancers

  Genomic alterations driving tumorigenesis result from the interaction of environmental exposures and endogeneous cellular processes. With a diversity of risk factors including viral infection, carcinogenic exposures and metabolic diseases, liver cancer is an ideal model to study these interactions. Whole genome sequencing of liver tumors identified 10 mutational signatures showing distinct relationships with environmental exposures, replication and transcription. Transcription-coupled damage was specifically associated with the liver-specific signature 16 and alcohol intake. Flood of indels were identified in very highly expressed hepato-specific genes, likely resulting from replication-transcription collisions. Reconstruction of sub-clonal architecture revealed mutational signature evolution during tumor development exemplified by the vanishing of aflatoxin-B1 signature in African migrants. These findings shed new light on the natural history of liver cancers

  Study EGAS00001002408

• WGS of liver cancer in the Japanese population

  Hepatocellular carcinoma (HCC) is the third leading cancer-related cause of death and the seventh most common form of cancer worldwide, with an estimate of more than 700,000 new cases each year. The most established risk factors of HCC are chronic HBV and HCV infection. HBV infection is responsible for over 50% of the worldwide attributable risk of HCC, especially in East Asia and Africa, while in Japan and several Western countries HCV infection is the most common risk factor for HCC. To gain insights into the molecular alterations of virus-associated HCC, we performed whole genome sequencing (WGS) of 321 HCC tumors from 159 patients. This work was performed as a part of the ICGC (International Cancer Genome Consortium) project.

  Study EGAS00001000678

• Frequent somatic transfer of mitochondrial DNA into the nuclear genome of human cancer cells

  Mitochondrial genomes are separated from the nuclear genome for most of the cell cycle by the nuclear double membrane, intervening cytoplasm and the mitochondrial double membrane. Despite these physical barriers we show that somatically acquired mitochondrial-nuclear genome fusion sequences are present in cancer cells. Most occur in conjunction with intranuclear genomic rearrangements and the features of the fusion fragments indicate that non-homologous end joining and/or replication-dependent DNA double strand break repair are the dominant mechanism involved. This study includes 12 pairs of whole-genome sequences (tumour and paired-normal), which present somatic mitochondrial DNA integrations in tumour genomes. Reference: Young Seok Ju et al., Frequent somatic transfer of mitochondrial DNA into the nuclear genome of human cancer cells, Genome Research (2015).

  Study EGAS00001001234

• Loss-of-activity-mutation in the cardiac chloride-bicarbonate exchanger AE3 causes short QT syndrome

  Patients with short QT syndrome (SQTS) may present with syncope, ventricular fibrillation or sudden cardiac death. Six SQTS susceptibility genes, encoding cation channels, explain less than 25% of SQTS cases. Here we identify a missense mutation in the anion exchanger (AE3)-encoding SLC4A3 gene in two unrelated families with SQTS. The mutation causes reduced surface expression of AE3 and reduced membrane bicarbonate transport. Slc4a3 knockdown in zebrafish causes increased cardiac pHi, short QTc, and reduced systolic duration, which is rescued by wildtype but not mutated SLC4A3. Mechanistic analyses suggest that an increase in pHi and decrease in [Cl-]i shortened the action potential duration. However, other mechanisms may also play a role. Altered anion transport represents a mechanism for development of arrhythmia and may provide new therapeutic possibilities.

  Study EGAS00001002632

• A benchmarking resource for NGS testing of cancer predisposition genes

  A benchmarking resource of 639 individuals, to assess the analytical sensitivity of cancer predisposition gene (CPG) testing.The dataset includes sequencing data generated using the TruSight Cancer Panel (TSCP) a targeted NGS assay for analysis of CPGs and orthogonally generated data supporting at least one pathogenic variant in a CPG for a total of 645 pathogenic CPG variants.The set of pathogenic CPG variants includes strong representation of some of the most challenging types of pathogenic variants, with 339 indels, including 16 complex indels and 24 insertions or deletions with length greater than 5bp, and 74 exon CNVs, including 23 single exon CNVs. There are 502 pathogenic variants in BRCA1 or BRCA2, making this an important first-line validation dataset for laboratories performing NGS testing of BRCA1 and BRCA2.

  Study EGAS00001002993

• Patient-derived organoids as a novel tool to study cervical cancer

  Cervical cancer is the most prevalent gynecological malignancy worldwide, often caused by infection with a high-risk human papillomavirus. Currently, there are only limited number of human-derived culture systems available that enable to study the viral infection for short-term. Here, we report on establishment of long-term human-derived organoid cultures from both healthy ecto- and endocervical epithelia that closely recapitulate the tissues of origin by maintaining the authentic histological and tissue-specific gene expression profiles. Additionally, using material from patients’ Pap-brush material, a successful panel of long-term patient-derived cancer organoids was established that maintain the causative viral infection in vitro and show differential response to common chemotherapy regimens. This study provides a promising platform for cervical cancer research and studying direct virus-host interactions.

  Study EGAS00001004439

• Characterization of genomic landscape of Peripheral T-cell Lymphomas, not otherwise specified (PTCL-NOS) (2018-10-30)

  Peripheral T-cell lymphomas not otherwise specified (PTCL-NOS) represent a heterogeneous group of nodal and extra-nodal mature T-cell lymphomas, with a low prevalence in Western countries. PTCL-NOSs account for about 25% of all PTCLs and are currently diagnosed based on exclusion criteria, as this lymphomas lack unifying morphological, phenotypic and genomic features. Cytogenetic and FISH analysis of PTCL-NOS samples have not revealed recurrent pathogenetic abnormalities, while gene expression profiling has shown only partial ability to segregate cases representing homogeneous clinic-pathological entities. This underscores the need to look at PTCL-NOS with innovative and high-throughput approaches to identify recurrent genetic lesions that could further our understanding of the biology of this heterogeneous group of diseases, provide better diagnostic tools and perhaps new targets for innovative treatments. Our aim is to study ~15 patients affected by PTCL-NOS. Out study will be funded by a private, non-profit Italian cancer research fund (Associazione Italiana per la Ricerca sul Cancro, www.airc.it) based on a grant owned by Anna Dodero and Cristiana Carniti, hematologists at INT. Samples will be analysed by whole genome sequencing using Illumina X10 machines, on a 150bp-PE protocol. Data will be analysed using the pipeline available in Team 78, under the supervision of Peter Campbell, the WTSI faculty who will oversee the project, and by Francesco Maura, visiting scientist at the WTSI. . This dataset contains all the data available for this study on 2018-10-30.

  Dataset EGAD00001004428

• Disease Variant Landscape of a Large Multiethnic Population of Moyamoya Patients by Exome Sequencing

  We report a significant advance in Moyamoya disease (MMD) research through our unique access to a large MMD patient population combined with high depth exome sequencing and bioinformatics. We confirm a reported RNF213 founder mutation (FM), provide evidence for its ethnic specificity and identify novel variants in other genes that associate with Caucasian and non-RNF213 FM MMD. This work has a broader impact in vascular research by highlighting novel genetic aspects of cerebrovascular disease. Moyamoya Disease (MMD) is a rare cerebrovascular disorder characterized by unilateral or bilateral progressive stenosis or occlusion of the internal carotid artery, with frequent involvement of the anterior cerebral artery and the middle cerebral artery (MCA). Fragile collateral vessels subsequently develop and are particularly prone to hemorrhage. MMD patients are usually diagnosed angiographically following presentation of developmental delays, seizures, migraines, ischemia, and/or hemorrhage. The most common approach to re-establish normal blood flow is bypass surgery. While some progress has been made in identifying disease-associated genes, the underlying disease biology is not well understood. Moyamoya disease (MMD) is a rare cerebrovascular disease. Our unique access to a large MMD patient population combined with high depth exome sequencing and bioinformatics has led to a significant advance in the field. We confirm a reported RNF213 founder mutation (FM), provide evidence for its ethnic specificity and identify novel variants in other genes that associate with Caucasian and non-RNF213 FM MMD. This work has a broader impact in vascular research by highlighting novel genetic aspects of cerebrovascular disease. The 125 ethnically diverse, unrelated MMD patients were matched based on sex and broad ethnic category to 125 controls. Control DNA from the 1000 Genomes project was used to design a control Library by Personalis. 125 controls were selected from this Personalis Control DNA Library for our study. (The 1000 Genomes Project Consortium 2012). Genomic DNA was extracted using the Gentra Puregene kit (Qiagen, Valencia, CA). Libraries were prepared from approximately 3 &#181;g of high quality genomic DNA (50-200 ng/&#181;l) using Illumina TruSeq Genomic DNA High throughput Sample Prep Kits (Illumina, San Diego, CA) and exome enrichment (targeting 62Mb) was accomplished using the TruSeq Exome Target Enrichment kit (Illumina, San Diego, CA), all according to manufacturer&#39;s protocols. Target enrichment validation was confirmed by determining the concentration of the library by PicoGreen-based quantitation. Library yields ranged from 100-1000ng of DNA, a portion of which was run on the Bioanalyzer HS DNA chip (Agilent, Santa Clara, CA), with an average size of 300-550nt for DNA fragments. Exome Sequencing. Sequencing was performed using Illumina Hiseq2000 or HiSeq2500 sequencers with single lane, paired-end 2X100bp reads. DNA fragments were generated and amplified using Clonal Single Molecule Array technology (Illumina, San Diego, CA). The sequences were determined using the Clonal Single Molecule Array and Sequencing-by-Synthesis using Illumina&#39;s instrumentation and Reversible Terminator Chemistry. Each sequencing lane interrogated the DNA sequences of a pool of 3 individual sample libraries each carrying a unique index. Sequencing reads of at least 2x100bp in length for a total of approximately 8 Gb of sequence data were generated for each sample.

  Study phs001700

• Data access committee (DAC) in the Graduate School of Medical Science and Engineering (GSMSE) at Korea Advanced Institute of Science and Technology (KAIST)

  Dac EGAC00001001643

• DAC of The polarity and specificity of antiviral T lymphocyte responses determine susceptibility to SARS-CoV-2 infection in cancer patients and healthy individuals

  Dac EGAC00001002517

• Gastric and Esophageal tumour rearrangement screen

  Gastric and Esophageal tumour rearrangement screen

  Dataset EGAD00001000075

• Circulating tumor DNA, pathological and immunologic responses to neoadjuvant nivolumab or nivolumab plus relatlimab and chemoradiotherapy in resectable esophageal/gastroesophageal junction cancer

  Study EGAS00001007299

• WES in Angolan and Cape Verdean triple-negative breast cancer samples

  WES in 23 Angolan and 7 Cape Verdean triple-negative breast cancer samples

  Dac EGAC50000000486

• Ovarian subtypes tumor methylation data

  This dataset contains ovarian endometriod and ovarian, stomach, pancreatic and colorectal mucinous tumor tissue samples

  Dataset EGAD00010002773

• endogene.bio

  The Endogene Bio Data Access Committee oversees and manages access to controlled genomic and clinical datasets deposited by the Endogene Bio research team.

  Dac EGAC50000000786

• Breast_Heterogeneity_Validation

  Validation of subs and indels called in breast whole genome studies

  Study EGAS00001001972

• Nasal brushes analysis

  scRNA-seq samples from healthy and asthma donors part 1.

  Study EGAS00001006657

• Metadata file

  "Master" file of patient clinical characteristics and outcomes, samples, and the results of certain analyses, including immunohistochemistry.

  Dataset EGAD00001008792

• Genetic_variation_in_Kuusamo

  The aim of this study is to characterize as completely as possible the genetic variation and structure of Kuusamo and surrounding regions. We will perform low coverage, whole genome sequencing in a relatively limited number (approximately 200) of individuals from the FINRISK study both of whose parents are born in Kuusamo, Posio or Taivalkoski. Sequencing will be performed at the Wellcome Trust Sanger Institute (WTSI). We have previously shown using simulations and genome wide SNP data that the genetic characteristics agree with known genealogical data, and that approximately 200 individuals suffice to capture the majority of the genetic variation in this population.We have also developed methods for long-range haplotyping and long-range imputation, which are more accurate than traditional methods. This will allow us to identify a majority of the founder haplotypes in this population. The information from the haplotypes identified in this study can be used in other studies to impute from genome-wide SNP data the full genome sequence of samples ascertained for specific phenotypes.

  Study EGAS00001000020

• Clonal Evolution in Patients with Chronic Lymphocytic Leukemia

  We analyzed clonal evolution in serial samples from five CLL patients who became resistant to the Bruton&#39;s tyrosine kinase (BTK) inhibitor ibrutinib, using whole-exome and deep targeted sequencing. We observe a BTK-C481S mutation in one of five patients, and multiple PLCG2 mutations in a second patient. The other patients had an expansion of clones harboring del(8p) carrying additional driver mutations (EP300, MLL2, EIF2A), with one patient developing trans-differentiation into CD19-negative histiocytic sarcoma. We calculated the growth kinetics of ibrutinib-resistant subclones and estimated the size of the resistant clones at treatment initiation, which we validated by droplet-microfluidic technology. Haplo-insufficiency of TRAIL-R, a consequence of del(8p), led to TRAIL insensitivity which may contribute to development of ibrutinib resistance. These findings demonstrate that ibrutinib therapy has the potential to lead to clonal selection and expansion of rare cell populations already present at the time of treatment initiation. They also provide insight into the heterogeneity of genetic changes associated with ibrutinib resistance, previously attributed solely to mutations in BTK and related pathway molecules.

  Study phs001091

• A Multi-Gene Mutation Classification of 468 Colorectal Cancers Reveals a Prognostic Role for APC

  Colorectal cancer (CRC) is a highly heterogeneous disease, for which prognosis has been relegated to clinic-pathologic staging for decades. There is a need to molecularly stratify subpopulations of CRC to better predict outcome and assign therapies. Here we report targeted exome sequencing of 1,321 cancer-related genes on 468 tumor specimens, which identified a subset of 17 genes that best classify CRC, with APC (Gene ID: 324) playing a central role in predicting overall survival. APC may assume 0, 1, or 2 truncating mutations, each with a striking differential impact on survival. Tumors lacking any APC mutation carry a worse prognosis than single APC mutation tumors, but tumors with two APC mutations and KRAS (Gene ID: 3845) and TP53 (Gene ID: 7157) mutations confer the poorest survival among all the subgroups examined. Our study demonstrates a substantial prognostic role for APC and suggests that sequencing of APC may have clinical utility in the routine staging and potential therapeutic assignment for CRC.

  Study phs001111

• Next Generation Mendelian Genetics: Congenital Hyperinsulinism

  The NHGRI Next Generation Mendelian Genetics project uses exome resequencing to identify variants in unsolved Mendelian diseases. Congenital Hyperinsulinism (CHI) is the most common cause of hypoglycemia in the newborn and it is due to mutations in 8 different genes (ABCC8, KCNJ11, GLUD1, GCK, HADH, SLC16A1, HNF4A and UCP2). It is a heterogeneous disease with variable onset (birth to adulthood) and a persistent, intermittent, or transient course with possible later conversion to non-autoimmune diabetes. Although mutations in the two subunits of the KATP channel (ABCC8 and KCNJ11) account for 50% of the cases, the other half is still genetically unexplained. CHI can be inherited in a dominant or recessive and can also present as a &#39;de novo&#39; mutation. We became part of this study when we submitted 8 DNA samples for exome sequencing, from patients with CHI of Caucasian ancestry, which had no mutations identified in ABCC8 or KCNJ1, with the goal to identify new mutations in known genes or new mutations in new genes or genetic variants.

  Study phs000539

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

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

  Study phs000387

• Estrogen Receptor Positive Breast Cancer: Aromatase Inhibitor Response Study

  Highly variable outcomes are observed in patients with estrogen receptor positive (ER+) breast cancer who undergo preoperative estrogen deprivation therapy with aromatase inhibitors (AI). In this study, 46 baseline tumor and normal genomes and 31 baseline tumor/normal exomes of participants selected from two clinical trials of neoadjuvant AI therapy on ER+ breast cancer were sequenced to identify somatic alterations that correlate with response to AI, to screen for therapeutic targets and to elucidate the genetic landscape of ER+ breast cancer. From the same set of patients we later performed deep genomic characterization of a subset of matched primary tumors after four months of AI therapy, generating comprehensive information about the range of changes that occur when ER+ breast cancers are subjected to estrogen deprivation. This data includes whole genome sequence and transcriptome data. To better understand tumor heterogeneity and the evolution of resistance to estrogen-deprivation therapy, a subset of these tumours, along with 38 additional cases were sequenced to greater depth using targeted capture with a gene panel.

  Study phs000472

• Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) - OncoArray Genotypes

  The data come from 40 studies participating in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). CIMBA recruits individuals with pathogenic mutations in BRCA1 or BRCA2. The majority of carriers were recruited through cancer genetics clinics offering genetic testing, and were enrolled into national or regional studies. The remainder were identified by population-based sampling of cases, or community recruitment. Eligibility to participate is restricted to carriers of pathogenic BRCA1/2 mutations who were 18 years or older at recruitment. Information collected included amongst other variables: age at recruitment; ages at breast and ovarian cancer diagnosis; and estrogen receptor (ER) status. Samples were genotyped using the Illumina OncoArray beadchip 500K SNP custom array. Details of the genotyping process and sample selection are included in Phelan et al, Identification of twelve new susceptibility loci for different histotypes of epithelial ovarian cancer, Nat Genet. 2017 May;49(5):680-691 (PMID:28346442), and Milne et al, Identification of ten variants associated with risk of estrogen receptor negative breast cancer, Nat Genet (in press).

  Study phs001321

• The Cardiopulmonary Effects of Particulate Exposure

  The study was initially designed as a longitudinal cohort study of cardiovascular effects of particulate exposure. Participants were boilermaker construction workers who were exposed to particulate matter (PM) component (e.g. a focus on metal constituents) while performing welding, grinding or cutting work in the welding plants. Participants were followed up approximately half a year for a non-work day and a work day from 1999 to 2012, and blood, urine, blood pressure, as well as real-time PM2.5 samples were collected from each participant. In this specific study, we conducted epigenome-wide DNA methylation profiling through Center for Inherited Disease Research (CIDR) services using Illumina Infinium HumanMethylation450, which will give us more compete epigenome-wide coverage. Genome-wide DNA methylation was carried out on paired samples pre- and post-work shift at a welding apprentice school. With transcriptomic and metabolomic data already generated from the same panel study, we will be able to conduct integrative analysis to gain insights into mechanisms of gene-metal interactions and maximize the probability of finding genes functionally relevant to PM-induced adverse cardiovascular outcomes.

  Study phs000968

• CPTAC: Microscaled Proteogenomic Methods for Precision Oncology

  Cancer proteogenomics combines genomics, transcriptomics and mass spectrometry-based proteomics to gain insights into cancer biology and treatment outcomes. To promote clinical investigation, we developed a &#34;microscaled&#34; proteogenomics approach for tumor-rich frozen core needle biopsies. Tissue-sparing specimen processing (&#34;Biopsy Trifecta EXTraction&#34;, BioTExt) and microscaled proteomics (MiProt) generated deep-scale proteogenomics datasets. As a proofof- concept, biopsies were accrued from ERBB2 positive (ERBB2&#43;) breast cancers before and 48 to 72 hours after the first dose of neoadjuvant trastuzumab-based chemotherapy. Multi-omics comparisons were conducted between samples associated with residual disease versus complete pathological response (pCR). Integrated analyses diagnosed diverse molecular causes of treatmentresistance including: 1) absence of ERBB2 amplification (false-ERBB2&#43); 2) insufficient ERBB2 activity for therapeutic sensitivity despite ERBB2 amplification (pseudo-ERBB2&#43); 3) resistance features in true-ERBB2&#43; cases including androgen receptor signaling, mucin expression and an inactive immune microenvironment; 4) lack of acute phospho-ERBB2 down-regulation in nonpCR cases. We conclude microscaled cancer proteogenomics could improve diagnostic precision.

  Study phs001907

• Kidney Two-Hit Mapping

  Germ-line genetic variants identified thus far generally account for only part of the genetic risk predicted for most cancers. A component of the remaining risk may be explained by functionally consequent genetic variants that are individually very rare (or private to that individual's family). While their identification may be highly informative for cancer etiology and biological knowledge, strategies that allow for agnostic (genome-wide) identification of such genes are not straight forward. This is particularly true for rare cancers where sufficient numbers of patients may simply not be available for appropriate statistically powered studies. In this project we have explored a study design based around the concept of "two-hit mapping" using the co-occurrence of germ-line and somatic mutations in the same gene to assist in the identification of susceptibility genes. The dataset includes 54 kidney cancer patients selected for enrichment of genetic disease, that is patients with: early age of onset and/or family history and/or bilateral disease. Germ-line and somatic (kidney cancer) tumor sequencing was carried out. These data may improve our understanding of kidney cancer.

  Study phs001971

• A Pharmcogenetic Study of Bipolar Disorder in a Taiwanese Han Chinese Population (TWBP)

  Objective: To identify genetic variants associated with response to lithium prophylaxis treatment. Materials: 294 bipolar I (BPI) patients receiving lithium treatment, a subset of 1761 bipolar I (BPI) patients recruited by the Taiwan Bipolar Consortium. Lithium response was assessed based on the Alda Scale. Methods: Responders to lithium treatment were defined if the patients&#39; Alda Scale &gt; 4, 5, 6, and 7. Genome-wide association (GWA) analysis was carried out on the 294 BPI patients for the 4 definitions of responders. The SNPs showing strongest association in the GWAS were then tested for association in a replication sample of 100 patients and further tested in a prospective follow-up series of 24 patients. Results: Two SNPs on GADL1 showed the strongest associations in the four GWA analyses and in the replication set of 100 patients. These two SNPs had a sensitivity of 0.93 for predicting lithium response and differentiated between the good and poor responders in the follow-up cohort. Summary: These genetic variants are associated with response to lithium prophylaxis treatment for BPI.

  Study phs000692

• Epigenetic Landscape of Human Parathyroids

  The goal of this study is to produce a comprehensive map of the chromatin landscape of human parathyroids. Data from 20 subjects with parathyroid adenoma causing primary hyperparathyroidism were used. For the sequencing platform, Illumina HiSeq 2000 with V3 high-output kits were used. For the data processing pipeline, reads were aligned to hg19 using Bowtie or BWA. For RNA-seq data, transcript levels were estimated per gene to RPKM using Cufflink. For ChIP-seq and ATAC-seq data, enrichment peaks were estimated compared to inputs or background using MACS2 after merging reads from replicates. For DNase-seq, significant peaks compared to background distribution were computed using Hotspot. For Hi-C data, significant interactions were detected using Juicer HiCCUPS and 5 kb resolution for the merged data from replicates. Chromatin states for parathyroids were computed using ChromHMM based on ChIP-seq profiles in parathyroids of H3K4me3, H3K4me1, H3K27ac, H3K36me3, H3K27me3 and H3K9me3 and the emission matrix from 18 states pre-trained in the Roadmap Epigenomics. Gene expression, binding positions of transcription factor, open chromatin regions, 3D-chromatin interaction, and chromatin states are submitted.

  Study phs003302

• WES in HCCOs with varying Doxorubicin resistance

  We aimed to identify somatic mutations that could explain the resistance to Doxorubicin. Therefor, we purified Exomes from liver biopsies and HCC organoids using Agilent SureSelectXT (clinical research exome, HS2 V8, or Human all Exon V6 Cosmic) and performed WES. Matched non-tumoral liver biopsies served as the control for germline mutations. 12 of these samples were previously reported. Sequence reads were aligned to the reference human genome GRCh38 using Burrows-Wheeler Aligner (BWA, v0.7.17). Duplicate removal, base quality adjustment, mutation calling (Mutect2, intervals: SureSelectXT_HS_V8_S33266340, germline-recourse: gnomad.exomes.r2.1.1.sites.liftover_grch38, Panel-of-Normal: 1000g_pon.hg38), filtering of Mutect calls, and functional annotation (Funcotator, funcotator_dataSources.v1.7.20200521g) were performed using the Genome Analysis Toolkit (GATK, v4.4) according to the Broad Institute best practices in Somatic short variant discovery workflows. Mutations with a functional annotation of Deletion, Insertion, Non-stop, Splice-Site, Start-Codon and Missense mutations were kept. A list of 43 commonly mutated genes in HCC was analyzed in the HCC organoids [TCGA, Comprehensive and Integrative Genomic Characterization of Hepatocellular Carcinoma. Cell, 2017. 169(7): p. 1327-1341.e23].

  Study EGAS50000000043

• An isoform quantitative trait locus in SBNO2 links genetic susceptibility to Crohn’s disease with defective antimicrobial activity

  Despite major advances in linking single genetic variants to single causal genes, the significance of genetic variation on transcript-level regulation of expression, transcript-specific functions, and relevance to human disease has been poorly investigated. Strawberry notch homolog 2 (SBNO2) is a candidate gene in a susceptibility locus with different variants associated with Crohn’s disease and bone mineral density. The SBNO2 locus is also differentially methylated in Crohn’s disease but the functional mechanisms are unknown. Here we show that the isoforms of SBNO2 are differentially regulated by lipopolysaccharide and IL-10. We identify Crohn’s disease associated isoform quantitative trait loci that negatively regulate the expression of the noncanonical isoform 2 corresponding with the methylation signals at the isoform 2 promoter in IBD and CD. The two isoforms of SBNO2 drive differential gene networks with isoform 2 dominantly impacting antimicrobial activity in macrophages. Our data highlight the role of isoform quantitative trait loci to understand disease susceptibility and resolve underlying mechanisms of disease.

  Study EGAS50000000183

• IL-27 promotes tumour control by enhancing cytotoxic T cell function

  Cytotoxic CD8+ T lymphocytes (CTL) are essential for anti-tumour immunity but are frequently dysfunctional in established tumours. Here, we show that expression of a CTL signature is strongly associated with IL-27 expression in diverse human and murine tumours. In mice, IL-27 acts directly on tumour-specific CTL to promote their persistence and effector function in the tumor microenvironment. Moreover, treatment with inducible IL-27 overexpression or a half-life-extended IL-27 protein in vivo is well tolerated, induces regression of large established tumours, drives an enhanced cytotoxic program in anti-tumour CTL, and synergizes with PD-L1 blockade. In cancer patients treated with anti-PD-1 or anti-PD-L1 therapy, high expression of IL-27 is associated with improved clinical response. Finally, IL-27 increases cytotoxicity and limits terminal differentiation of human CD8+ T cells during chronic antigen exposure. Our data demonstrate that endogenous IL-27 is essential for anti-tumour immunity and that IL-27 receptor agonism can safely improve anti-tumor T cell responses alone or in combination with PD-L1 blockade.

  Study EGAS50000000694

• CALGB 40601: Randomized Phase III Trial of Paclitaxel Combined With Trastuzumab, Lapatinib, or Both As Neoadjuvant Treatment of HER2-Positive Primary Breast Cancer

  This randomized phase III trial studies paclitaxel and trastuzumab with or without lapatinib to see how well they work in treating patients with stage II or stage III breast cancer that can be removed by surgery. Drugs used in chemotherapy, such as paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Monoclonal antibodies, such as trastuzumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Lapatinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving paclitaxel with trastuzumab and/or lapatinib before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. It is not yet known which regimen is more effective in treating patients with breast cancer.

  Study phs001570

• Gene expression adaptation of metastases to their host tissue

  The adaptation of metastatic cells to their host tissue critically determines the pathogenicity of a cancer and therefore patient survival. Yet, it remains elusive to what extent the host environment drives gene expression programs in metastatic cells. Here we identify adaptive mechanisms that enable metastases to establish themselves in a novel tissue context. We performed single-cell RNA-sequencing on malignant and benign tissue samples from untreated donors with colorectal adenocarcinoma and liver metastasis to deduce tissue adaptive expression patterns. A novel computational approach identified genes and pathways that consistently adapted to the host tissue at the transition from the primary tumor to the paired metastasis across donors. This analysis revealed that the majority of expression changes in the metastasis reflect an expression signature reminiscent of benign liver epithelial cells. Cellular processes adapting to the liver environment include basic cellular functions such as energy metabolism, as well as tissue-specific pathways such as the regulation of lipid metabolism by PPAR-α. These adaptations potentially increase the pathogenicity of the metastatic cells and may provide new therapeutic strategies.

  Study EGAS50000000817

• Genomic Analysis of Relapsed/Refractory DLBCL

  Molecular phenotyping techniques have established a landscape of genomic variants in diagnostic Diffuse Large B Cell Lymphoma (DLBCL), however these have not yet been applied in large scale studies of relapsed/refractory DLBCL resulting in incomplete characterization of mechanisms driving tumor progression and treatment resistance. Here, we performed an integrated multiomic analysis on relapsed/refractory DLBCL samples. Tumors from 87 relapsed/refractory DLBCL patients were included in this study and were available for data deposition [Tumor whole exome sequencing (WES): n=75, Germline WES: n=73, RNA sequencing (RNA-Seq): n=72]. Tumor DNA was extracted from formalin-fixed, paraffin embedded (FFPE) tissue sections, germline DNA was extracted from blood, and WES of all samples was performed using the Agilent SureSelect XT All Exon v6 kit and sequencing was carried out on an Illumina NovaSeq, 100 x 2 paired end reads. Tumor RNA was extracted from FFPE tissue sections and RNA-Seq was performed using the Illumina TruSeq RNA Exome Kit (Illumina) for library preparation, sequencing platform HiSeq 4000, 100 x 2 paired end reads.

  Study phs003868

• Response​ to Tagraxofusp in Blastic Plasmacytoid Dendritic Cell Neoplasm

  Tagraxofusp is a CD123-targeted therapy comprised of a recombinant human interleukin-3 (IL-3) fused to a truncated diphtheria toxin (DT) payload. It is the first approved treatment specifically for patients with Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN). In order to identify biomarkers of response, bone marrow samples from 12 BPDCN patients who were treated with tagraxofusp in the pivotal phase II trial (NCT02113982) were profiled longitudinally using gene panel and/or single-cell RNA sequencing. Durable responders had either wildtype or missense TET2 mutations while transient and non-responders had at least one truncating TET2 mutation. Those who had progression at any one point during the treatment course (transient responders) and non-responders had enrichment of the chemokines CCL3, CCL4, and CCL5. Residual tumor cells following tagraxofusp treatment were identified in all patients, whose resistance may be due to their lower levels of TXNRD1 possibly preventing the potentiation of tagraxofusp. Thus, response to tagraxofusp may be related to culmination of intrinsic TET2 mutations, levels of TXNRD1, and extrinsic effects of chemokines within bone marrow.

  Study phs003895

• Human liver cholangiocyte organoids capture the heterogeneity of in vivo human liver ductal epithelium

  Human liver ductal epithelium is morphologically, functionally and transcriptionally heterogeneous. However, understanding the dynamics within human biliary/ductal epithelium has been hampered by the absence of an in vitro system that fully mimics its complex cellular heterogeneity. Here, we found that the human liver cholangiocyte (ductal-cell) organoids we previously published (Huch et al., 2015) are fairly homogenous and do not retain the cellular heterogeneity of the in vivo human biliary/ductal epithelium. Inspired by the knowledge of the in vivo niche, we refined our previous organoid culture medium to fully capture the cellular heterogeneity of the human ductal epithelium. We employed this refined system to analyse the interactions and relationships between the different human biliary epithelial cell states and discovered that acquiring a bipotent ductal cell state is necessary for differentiating the human ductal epithelium into functional hepatocyte-like cells. Our improved cholangiocyte organoid model represents a new platform to investigate cell plasticity and duct-to-hepatocyte differentiation in human liver.

  Study EGAS50000001000

• Whole genome sequencing data of pediatric B-other subtype acute lymphoblastic leukemia

  For a long time, approximately 70% of childhood B-ALL cases could be classified routinely, and the remaining 30% were classified into the “B-other” group lacking the known genetic features. However, more recently, new genomic tools have uncovered new subtypes among the B-other groups. Approximately 10% of B-ALL cases lack the recurrent genetic abnormalities, and are referred as "B-other". They are typically more heterogeneous than other subtypes of B-ALL, and their prognoses are more variable. In a more recent update of the B-ALL classification, 27 subtypes were identified (Arber et al., 2022). The identification of some of these subtypes is dependent on NGS methods, such as RNA sequencing, which are not routinely used in all clinical laboratories. For example, ETV6::RUNX1-like and DUX4-rearranged subtypes have been identified using RNA sequencing. For this study, subtype predictions for some of the cases is acquired from ALLIUM (Krali et al., NPJ Precis Oncol., 2023) and ALLCatchR (Beder et al., Blood, 2022) based on the RNA-seq profiles.

  Study EGAS50000001497

• High MAPK Activity Leading to Reduced WNT Signaling Drives Metastasis in Colorectal Cancer

  Colorectal cancer, a leading cause of cancer-related mortality due to distant metastases, is driven by activating mutations in the Wnt and MAPK pathways. Understanding the interplay between these crucial pathways during metastatic progression is essential for developing effective treatments. Here we developed an immunocompetent mouse model of metastatic colorectal cancer using in vivo orthotopic passaging. We demonstrate that highly metastatic tumor cells exhibit chromosomal amplifications in MAPK pathway genes, leading to increased MAPK activity, which in turn suppresses Wnt-associated transcriptional programs, including stem cell-associated genes. Inhibiting mutant KrasG12D effectively reversed this metastatic transcriptional state, reducing MAPK-driven gene expression and restoring Wnt activity. Notably, this treatment significantly curtailed lung metastases and reduced liver metastases during early seeding stages. Analysis of CRC patient data revealed that high MAPK activity and the associated metastatic gene signature correlated with poorer survival outcomes. These findings underscore that the plasticity of metastasis-initiating cells in CRC arises from the opposing roles of MAPK and Wnt signaling, despite their synergistic importance in colon tumor initiation.

  Study EGAS50000001231

• Spatial predictors of response to immunotherapy in microsatellite stable metastatic colorectal cancer

  Microsatellite stable (MSS) colorectal cancers (CRC) are largely unresponsive to immune checkpoint inhibition (ICI), prompting investigation into strategies to enhance sensitivity. The MAYA trial, which utilized temozolomide (TMZ) in MGMT-silenced MSS mCRC, hypothesized that TMZ-induced hypermutation could sensitize tumors to ICI. This phase II trial met its primary endpoint, demonstrating durable clinical responses with TMZ combined with ipilimumab and nivolumab. To elucidate factors influencing response heterogeneity, we conducted multi-omic spatial profiling of samples from patients who participated in the MAYA trial, including baseline and on-treatment tissue and blood specimens. While increased neoantigen load following TMZ exposure did not consistently predict for deep responses, spatial profiling revealed key determinants. Lymphocyte proportions, particularly CD8+KI67+ cells, within stromal and tumor compartments, along with macrophage composition (CD68+CD163+ cells) at the tumor-stromal interface, were predictive of response. Treatment pressures dynamically altered the tumor microenvironment composition and activated peripheral immune cells. This study is the first to identify spatial predictors of response to this promising novel treatment approach for MSS CRC.

  Study EGAS50000001567

• Djerroudi et al., E-cadherin inactivation shapes tumor microenvironment specificities in invasive lobular carcinoma

  Invasive lobular breast carcinoma (ILC) shows specific stromal features, T lymphocyte infiltration (TIL) being associated with poor prognosis. Here, we reveal the involved mechanism by performing single cell RNA sequencing, combined immunohistochemistry, deconvolution of bulk RNA sequencing from large retrospective ILC series, and functional assays using primary cells. We show that ILC accumulate FAP+ inflammatory cancer-associated fibroblasts (iCAF) through a previously undescribed mechanism mediated by E-cadherin/CDH1 on CAF plasticity. Indeed, CDH1 inactivation in ILC cancer cells prevents differentiation of iCAF into myofibroblastic CAF (myCAF), leading to iCAF accumulation. In turn, iCAF increase TIL infiltration and shape their spatial organization in ILC. Subsequently, CDH1-inactivated ILC cancer cells promote immune escape by lack of retention and activation of ITGAE-expressing resident memory CD8+ T lymphocytes (TRM). Hence, our study uncovers reciprocal interactions between CDH1-inactivated cancer cells, iCAF and CD8+ TRM, revealing why and how TILs have a poor prognosis in ILC patients, a mechanism extrapolated to other CDH1-mutated cancer types.

  Study EGAS50000000761

• Population_dynamics_in_abnormal_haematopoiesis

  Background: Our recent study has made direct insight into the clonal dynamics of blood cell production in an unperturbed setting in a human. Using whole genome sequencing to track acquired somatic mutations, we were able to construct a phylogenetic tree of different stem and progenitor cells and used this tree to determine the dynamics of mature blood cell production in longitudinal samples. These data set the baseline for understanding population dynamics in abnormal haematopoiesis, and how malignant clones outcompete their normal counterparts to drive haematological malignancies. Aim: This study will measure population dynamics in abnormal human haematopoiesis in patients with clonal blood stem cell disorders. Methods: From patient bone marrow or peripheral blood, we have isolated colonies grown from single blood stem cells/progenitors. Colony DNA will be analysed by whole-genome sequencing to build (or populate) a phylogenetic tree to determine clonal relationships and track stem cell contribution to mature blood cell production. These data will also reveal disease-associated genomic features (mutational burden and mutational signatures) in haematopoietic cells.

  Study EGAS00001003181

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

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

  Study EGAS00001004116

• DERMATLAS__SG_basal_cell_adenoma_and_adenocarcinoma_WES

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

  Study EGAS00001007745

• Pancreatic islets PISA RNA-seq samples

  GWAS have identified more than 700 genetic signals associated with type 2 diabetes (T2D). To gain insight into the underlying molecular mechanisms, we created the Translational human pancreatic Islet Genotype tissue-Expression Resource (TIGER), aggregating &gt;500 human islet RNA-seq and genotyping datasets. We imputed genotypes using 4 reference panels and meta-analyzed cohorts to improve coverage of expression quantitative trait loci (eQTL) and developed a method to combine allele-specific expression across samples (cASE). We identified &gt;1 million islet eQTLs (56% novel), of which 53 colocalize with T2D signals (60% novel). Among them, a low-frequency allele that reduces T2D risk by half increases CCND2 expression. We identified 8 novel cASE colocalizations, among which an SLC30A8 T2D associated variant. We make all the data available through the open-access TIGER portal (http://tiger.bsc.es), which represents a comprehensive human islet genomic data resource to elucidate how genetic variation affects islet function and translate this into therapeutic insight and precision medicine for T2D.

  Study EGAS00001005535

• CD36 defines CML cells less sensitive to imatinib

  Tyrosine kinase inhibitors (TKIs) are highly effective for treatment of chronic myeloid leukemia (CML), but very few patients are cured. Major drawbacks with TKIs are their low efficacy in eradicating the leukemic stem cells responsible for disease maintenance and relapse upon TKI cessation. Here, we performed RNA-sequencing of flow-sorted primitive (CD34+CD38low) and progenitor (CD34+CD38+) chronic phase CML cells and identified transcriptional upregulation of 32 cell surface molecules relative to corresponding normal bone marrow cells. Focusing on novel markers with increased expression on primitive CML cells, we confirmed upregulation of the scavenger receptor CD36 and the leptin receptor (LEPR) by flow cytometry. We also delineate a subpopulation of primitive CML cells expressing CD36 that is less sensitive to imatinib treatment. Using CD36 targeting antibodies, we show that the CD36 positive cells can be targeted and killed by antibody dependent cellular cytotoxicity (ADCC). In summary, CD36 defines a subpopulation of primitive CML cells with decreased imatinib sensitivity that can be effectively targeted by ADCC using an anti-CD36 antibody.

  Study EGAS00001002421

• Biallelic HMBS Inactivation Defines a Homogenous Clinico-Molecular Subtype of Hepatocellular Carcinoma

  Acute intermittent porphyria (AIP), caused by heterozygous germline mutations of the heme synthesis pathway enzyme HMBS (hydroxymethylbilane synthase), confers high risk of hepatocellular carcinoma (HCC) development. Yet, the role of HMBS in liver tumorigenesis remains unclear. Here we explore HMBS alterations in a large series of 758 HCC. We identify recurrent bi-allelic HMBS inactivation, both in AIP patients acquiring a second somatic HMBS mutation and in sporadic HCC with two somatic hits. HMBS alterations are enriched in truncative mutations, in particular in splice regions, leading to abnormal transcript structures. Bi-allelic HMBS inactivation results in a massive accumulation of its toxic substrate porphobilinogen and synergizes with CTNNB1 activating mutations, leading to the development of well differentiated tumors with a transcriptomic signature of Wnt/ß-catenin pathway activation and a DNA methylation signature related to ageing. HMBS-inactivated HCC mostly affect females, in absence of fibrosis and classical HCC risk factors. These data identify HMBS as a tumor suppressor gene whose bi-allelic inactivation defines a homogenous clinical and molecular HCC subtype.

  Study EGAS00001005986

• Illumina HumanCoreExome genotyping data from the British Society for Surgery of the Hand Genetics of Dupuytren’s Disease consortium (BSSH-GODD consortium) collection

  Dupuytren's Disease (DD - OMIM126900) is the most common heritable disorder of connective tissue. It is a fibroproliferative disorder of the palmer fascia, causing flexion contractures of affected digits. DD affects men more commonly than women. DD is an archetypal complex disease, with multiple genetic and environmental factors affecting the final expression of the disease phenotype. The incidence increases with age, and the prevalence of DD is therefore increasing as the UK population ages. Half of all patients present before age 60. DD causes significant functional impairment, and severe contractures can lead to permanent disability. The mainstay of current treatment is surgery, but recurrence and complications are both high. For severe contractures, the only suitable treatment option is amputation. The direct costs to the NHS are high, and underestimate the true economic costs to society. We collected salivary samples from adults in the UK who have had surgery for DD. We have genotyped these samples using the Illumina HumanCoreExome Beadchips. https://research.ndorms.ox.ac.uk/public/dupuytrens/what-is-dupuytrens-disease/

  Study EGAS00001001206

• DERMATLAS__SG_basal_cell_adenoma_and_adenocarcinoma_RNAseq

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

  Study EGAS00001007746

• Integration of human pancreatic islet genomic data refines regulatory mechanisms at Type 2 Diabetes susceptibility loci

  Human genetic studies have emphasised the dominant contribution of pancreatic islet dysfunction to development of Type 2 Diabetes (T2D). However, limited annotation of the islet epigenome has constrained efforts to define the molecular mechanisms mediating the, largely regulatory, signals revealed by Genome-Wide Association Studies (GWAS). We characterised patterns of chromatin accessibility (ATAC-seq, n=17) and DNA methylation (whole-genome bisulphite sequencing, n=10) in human islets, generating high-resolution chromatin state maps through integration with established ChIP-seq marks. We found enrichment of GWAS signals for T2D and fasting glucose was concentrated in subsets of islet enhancers characterised by open chromatin and hypomethylation, with the former annotation predominant. At several loci (including CDC123, ADCY5, KLHDC5) the combination of fine-mapping genetic data and chromatin state enrichment maps, supplemented by allelic imbalance in chromatin accessibility pinpointed likely causal variants. The combination of increasingly-precise genetic and islet epigenomic information accelerates definition of causal mechanisms implicated in T2D pathogenesis.

  Study EGAS00001002592

• Tumor-intrinsic expression of the autophagy gene Atg16l1 suppresses anti-tumor immunity in colorectal cancer

  The vast majority of colorectal cancer (CRC) patients fail to respond to immune checkpoint inhibitors (ICI). Understanding tumor-intrinsic determinants of immunotherapy resistance is critical to improve CRC patient outcomes. Here, we demonstrate that transcript levels of the core autophagy gene ATG16L1 are prognostic of poor outcome and predictive of ICI resistance in late-stage CRC. Deletion of Atg16l1 in murine CRC organoids markedly inhibited tumor growth in primary and metastatic niches in syngeneic hosts. ATG16L1 deficiency rendered CRC organoids more responsive to interferon (IFN) signaling and enhanced programmed cell death while decreasing tumor stem-like populations. IFN hypersensitivity consequently promoted cytotoxic anti-tumor immunity in vivo. In IMblaze370, a large phase III clinical trial of anti-PD-L1 in advanced metastatic CRC, low ATG16L1 levels identified patients with increased lymphocyte infiltration and improved outcome in a KRAS mutant setting. This work reveals autophagy as a clinically relevant immunosuppressive mechanism in CRC and provides a rationale for autophagy inhibition to boost immunotherapy responses in the clinic.

  Study EGAS00001005952

• Functional screening on patient-derived organoids identifies a therapeutic bispecific antibody that triggers EGFR degradation in LGR5+ tumor cells

  Patient-derived organoids (PDOs) have demonstrated predictive value in prospective clinical trials supporting selection of personalized treatments. Because PDOs retain the organization and physiological functions of their source tissue, PDO biobanks could also be an ideal substrate to screen for novel therapeutic interventions. Here we describe a large-scale functional screen of dual targeting bispecific antibodies (bAbs) on a colorectal cancer (CRC) PDO biobank to target their dependency on cancer stem cells. A novel drug discovery pipeline was assembled where therapeutic bAb panels generated against WNT and receptor tyrosine kinases (RTK) targets were functionally evaluated by high content imaging to capture the complexity of PDO responses across a wide range of different CRCs and paired normal colonic mucosa samples. Our strategy resulted in a bAb that specifically triggers EGFR degradation in LGR5+ CSCs and that exhibits unique therapeutic properties such as potent growth inhibition of KRAS mutant CRCs, blockade of metastasis initiation in preclinical models and minimal toxicity towards normal LGR5+ colon stem cells.

  Study EGAS00001004584