16476 results for "sec+and+unspecified+malignant+neoplasm"

in 51.26 milliseconds.

• 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

• Beyond BRCA deficiency: Clinical and molecular predictors of survival in patients with BRCA-deficient tubo-ovarian high-grade serous carcinoma

  Homologous recombination DNA repair deficient (HRD) tumors account for about 50% of tubo-ovarian high-grade serous carcinomas (HGSC) and are associated with a high response to platinum-based chemotherapy. However, a subset of patients with HRD tumors have unexpected resistance to chemotherapy and experience short survival. Our study compared BRCA-deficient and proficient HGSC among patients with short (<3 years, the lowest quartile of overall survival (OS)) versus longer-term (>3 year OS) to identify prognostic markers and potential therapeutic opportunities. Primary tumors from a cohort of patients with advanced-stage HGSC (n=154) enriched for those with HRD tumors and short survival (n=42) were analyzed using whole-genome sequencing, bulk RNA-sequencing, and DNA methylation profiling. A subset of HRD tumors (n=143) were characterized for immune cell densities by multiplex immunofluorescence. Clinicopathological features were assessed in 1,389 patients with HGSC, including 282 with pathogenic germline BRCA variants (gBRCApv). Findings were validated in two international HGSC cohorts: the Ovarian Tumor Tissue Analysis consortium (n=5,875) and Multisciplinary Ovarian Cancer Outcome Group (n=895). In gBRCApv-carriers, residual disease following surgical cytoreduction was not associated with shorter OS unlike in non-carriers where it was strongly associated. While most patients with gBRCApv had a more favorable OS compared to non-carriers, a survival advantage was not apparent in those with variants located outside of BRCA1 exon 10/23 and BRCA2 exon 11/27. Patient survival correlated with HRD score, such that those with a score ≥63 had significantly longer OS compared to those with HRD scores of 42-63 and <42. While higher HRD scores were associated with better survival outcomes, most gBRCApv carriers with a short survival had tumor HRD scores that exceeded the threshold typically considered predictive of a good response to carboplatin or PARP inhibitors. BRCA2-deficient HGSC with loss of the tumor suppressor NF1 was associated with exceptionally favorable outcome (median OS 17 years), whereas amplification of both PIK3CA and RAD21, was associated with poor outcome in BRCA2-deficient HGSC (median OS 2.9 years). The density of tumor-infiltrating CD8+ PD-1+ T cells was prognostic for OS in gBRCApv-carriers. In summary, rather than simply the presence or absence of a germline BRCA pathological variant influencing patient survival, the co-occurrence of specific somatic gene alterations, the extent of immune cell infiltration, the level of homologous recombination deficiency, and BRCA-variant location may modify clinical outcomes in patients with BRCA-deficient HGSC. Analysis of exceptional outcome patients, in this case gBRCApv-carriers with an atypically short survival, may identify determinants of outcome applicable to the wider HGSC patient population.

  Study EGAS00001008059

• Privacy Notice for Helpdesk service

  Privacy Notice for EGA Helpdesk service This Privacy Notice explains what personal data is collected by the specific service you are requesting, for what purposes, how it is processed, and how we keep it secure. Note that this service collects personal data directly provided by the user, and also collects personal data from users that is provided by other organisations. 1. Who controls your personal data and how to contact us? European Genome- Phenome Archive - EGA offers a service for permanent archiving and sharing of all types of personally identifiable genetic and phenotypic data resulting from biomedical research projects, jointly managed by European Molecular Biology Laboratory – European Bioinformatics Institute (EMBL-EBI) and Fundació Centre de Regulació Genòmica - Centre for Genomic Regulation (CRG). EMBL-EBI and CRG represent joint Data Controllers’ of processing of your personal data. They and their Data protection officers may be contacted for data protection queries and for exercising your rights under Section 8. You may contact EMBL-EBI, represented by dr. Thomas Keane, by: email at: tk2@ebi.ac.uk or post at EMBL-EBI, Wellcome Genome Campus, CB10 1SD Hinxton, Cambridgeshire, UK. EMBL’s Data Protection Officer may be contacted by: telephone at +49 6221 387-8590, email at dpo@embl.org , or post at EMBL Heidelberg, Data protection officer, Meyerhofstraße 1, 69117 Heidelberg, Germany. You may contact CRG, whose EGA team is represented by dr. Jordi Rambla de Argila, by: email at jordi.rambla@crg.eu, or post at Fundació Centre de Regulació Genòmica - Centre for Genomic Regulation (CRG), Dr.Aiguader 88, PRBB Building, 08003 Barcelona, Spain. CRG Data protection officer may be contacted by: email at dpo@crg.eu post at Fundació Centre de Regulació Genòmica - Centre for Genomic Regulation (CRG), C/ Dr. Aiguader, 88, PRBB Building, 08003 Barcelona, Spain. 2. Which is the lawful basis for processing personal data? We process your personal data on the grounds of important public interest. For monitoring your activities on the website, we process your personal data on the grounds of important public interest. Such legal basis is found in Article 5(1)(a) of EMBL Internal Policy No 68 on General Data Protection (hereinafter IP 68), which is equivalent to Article 6 (1)(e) of the EU General Data Protection Regulation (hereinafter GDPR) and upon which personal data are processed for the achievement of the aims laid down in 1973 agreement establishing EMBL, such as the promotion of the cooperation in the fundamental research, in the development of advanced instrumentation and in advanced teaching in molecular biology and dissemination of information. 3. What personal data is collected from users of the service? How do we use this personal data? We collect the following personal data from users of the service: Name Email address Job title Date and time when the support request was sent We will use your personal data for the following purposes: To provide uninterrupted user access to the service To better understand the needs of the users and guide future improvements of the service To create anonymous usage statistics 4. Who will have access to your personal data? The personal data will be disclosed to: Authorised staff in the data controller’s institutions acting on data controller`s behalf and instructions. 5. Will your personal data be transferred to third countries (i.e. countries not part of EU/EEA) and/or international organisations? There are no personal data transfers to third countries or international organizations. 6. How long do we keep your personal data? Any personal data directly obtained from you will be retained as long as the service is live. Such duration serves the purpose of enabling scientific research and ensures legal compliance and facilitates internal and external audits if they arise. By contrast, the log files for the data categories related to anonymous usage statistics (raw web service logs) are processed only for 30 days and thereafter erased. 7. The joint Data Controllers provide these rights regarding your personal data You have the right to: Not be subject to decisions based solely on an automated processing of data (i.e. without human intervention) without you having your views taken into consideration. Request at reasonable intervals and without excessive delay or expense, information about the personal data processed about you. Under your request we will inform you in writing about, for example, the origin of the personal data or the preservation period. Request information to understand data processing activities when the results of these activities are applied to you. It must be clarified that rights under points 4 and 5 are only available whenever you need support whilst using our website. For other processing based on the grounds of important public interest you cannot exercise your rights to object, rectify or erase your personal data according to the Article 13(2)(a)(b) of IP 68 (equivalent to Article 17(3)(b)(d) and Article 21(6) of the GDPR). 8. Supervisory authority If you wish to complain against the processing of your personal data, you may do so by post at: EMBL Heidelberg, Data Protection Committee, Meyerhofstraße 1, 69117 Heidelberg, Germany, or Autoritat Catalana de Protecció de Dades (Catalan Data Protection Authority), C/Rosselló 214, Esc A, 1r 1a, Barcelona 08008, Spain. Published at: February 6, 2019

  Documentation data-protection/privacy-notice/ega-helpdesk

• 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'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 'de novo' 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 "microscaled" proteogenomics approach for tumor-rich frozen core needle biopsies. Tissue-sparing specimen processing ("Biopsy Trifecta EXTraction", BioTExt) and microscaled proteomics (MiProt) generated deep-scale proteogenomics datasets. As a proofof- concept, biopsies were accrued from ERBB2 positive (ERBB2+) 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+ 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' Alda Scale > 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

• 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

• 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

• Impact of germline pathogenic variants in 27 cancer-predisposing genes on the risk of lymphoma

  The application of advanced molecular technology has significantly expanded lymphoma classification, allowing risk stratification and treatment optimization. Limited evidence suggests the presence of a genetic predisposition in lymphoma, indicating the potential for better individualized clinical management based on a novel lymphoma classification. Herein, we examined the impact of germline pathogenic variants in 27 cancer-predisposing genes with lymphoma risk and explored the clinical characteristics of pathogenic variant carriers. This study included 2,066 lymphoma patients and 38,153 cancer-free controls from the Japanese population. Following quality control of sequencing data, samples from 1,982 lymphoma patients and 37,592 controls were further analyzed. Sequencing data of controls were obtained from JGAD000721. Germline pathogenic variants in some cancer-predisposing genes were associated with a high risk of lymphoma. Furthermore, germline pathogenic variants in these genes were especially associated with the higher risk of a certain subtype. These results would provide novel insights concerning monogenic form into lymphoma classification. Some lymphoma patients may benefit from surveillance and targeted treatment like other neoplasms.

  Study JGAS000347

• 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

• Broad utility of ultrasensitive analysis of ctDNA dynamics across solid tumors treated with immunotherapy

  Prior studies have suggested the biomarker potential of plasma circulating tumor DNA (ctDNA) in cancer patients treated with immune checkpoint inhibitors (ICIs). In order to characterize the potential role of ultrasensitive ctDNA detection in the management of these patients we have performed tumor whole-genome-informed, ultrasensitive ctDNA analysis—tracking approximately 1,800 tumor-specific mutations per patient—in a retrospective cohort (n=136) and a prospective validation cohort (n=66) across 24 cancer types treated with ICIs alone or in combination with bispecific antibodies or immune cell engagers. Analyzing 1,455 longitudinal samples, we found that ctDNA molecular response measured as early as 3 weeks after treatment initiation correlated with improved progression-free and overall survival, while ctDNA clearance at any time strongly correlated with radiological response and prolonged survival. Additionally, ctDNA dynamics distinguished true progression from pseudoprogression and predicted outcomes in patients receiving continued immunotherapy beyond initial progression. This study highlights the broader applicability of ultrasensitive ctDNA as a biomarker across cancer types and immunotherapy modalities.

  Study EGAS50000001333

• 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

• 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 >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 >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

• Proteogenomics reveals two distinct biological pilocytic astrocytoma subgroups

  Pilocytic astrocytoma (PA) is the most common pediatric brain tumor and driven by aberrant MAPK signaling, typically mediated by BRAF alterations. While five-year overall survival rates exceed 95%, tumor recurrence constitutes a major clinical challenge in incompletely resected tumors despite chemotherapeutic or radiation based therapies. Therefore, we used proteogenomics to discern the biological heterogeneity of PA to improve classification of this tumor entity and identify novel therapeutic targets. Our proteogenomics approach integrates RNA sequencing and LC/MS-based proteomic profiling data from a cohort of 58 confirmed, primary PA samples. An integrative genomics approach was conducted to discern the biological heterogeneity of PA and to identify aberrant pathway activation in these biological subgroups. In summary, Pilocytic astrocytomas segregate into two groups where younger patients are significantly associated with Group 1. Importantly, we validate the two distinct biological subgroups in two non-overlapping cohorts. The biological heterogeneity seen here may improve biological classification and reveal novel therapeutic targets specifically useful for non-resectable tumors with high risk of recurrent or progressive disease.

  Study EGAS00001006402

• Upper cortical layer-driven network impairment in schizophrenia

  Schizophrenia is one of the most wide-spread and complex mental disorders. To characterize the impact of schizophrenia, we performed single nucleus RNA sequencing (snRNA-seq) of >220,000 neurons from the dorsolateral prefrontal cortex of patients with schizophrenia and matched controls. Additionally, >115,000 neurons were analyzed topographically by immunohistochemistry. Compositional analysis of snRNA-seq data revealed a reduction in abundance of GABAergic neurons and a concomitant increase in principal neurons, most pronounced for upper cortical layer subtypes, which was substantiated by histological analysis. Many neuronal subtypes showed extensive transcriptomic changes, the most dramatic - in upper layer GABAergic neurons, including downregulation in energy metabolism and upregulation in neurotransmission. Transcription factor network analysis demonstrated a developmental origin of transcriptomic changes. Finally, Visium spatial transcriptomics further corroborated upper layer neuron vulnerability in schizophrenia. Overall, our results point towards general network impairment within upper cortical layers as a core substrate associated with schizophrenia symptomatology. Study is available on bioRxiv (https://doi.org/10.1101/2020.11.17.386458) and in upcoming publication.

  Study EGAS00001006495

• Proteogenomic analysis reveals RNA as a source for tumor-agnostic neoantigen identification (H021)

  Systemic pan-tumor analyses may reveal the significance of common features implicated in cancer immunogenicity and patient survival. Here, we provide a comprehensive multi-omics data set for 32 patients across 25 tumor types for proteogenomic-based discovery of neoantigens. By using an optimized computational approach, we discover a large number of tumor-specific and tumor-associated antigens. To create a pipeline for the identification of neoantigens in our cohort, we combine DNA and RNA sequencing with MS-based immunopeptidomics of tumor specimens, followed by the assessment of their immunogenicity and an in-depth validation process. We detect a broad variety of non-canonical HLA-binding peptides in the majority of patients demonstrating partially immunogenicity. Our validation process allows for the selection of 32 potential neoantigen candidates. The majority of neoantigen candidates originates from variants identified in the RNA data set, illustrating the relevance of RNA as a still understudied source of cancer antigens. This study underlines the importance of RNA-centered variant detection for the identification of shared biomarkers and potentially relevant neoantigen candidates.

  Study EGAS00001006706

• ETMR_Meth

  77 ETMR samples were profiled using methylation array. DNA from frozen tissue and formalin-fixed, paraffin-embedded (FFPE) materials were analyzed with the Illumina Infinium HumanMethylation450 (450k) and MethylationEPIC (EPIC) array according to manufacturer’s instructions and with a modified method that was previously described (Torchia et al. Cancer Cell. 2016; Triche et al. Nucleic Acids Res. 2013).

  Dataset EGAD00010001669

• Prediction of plasma ctDNA fraction and prognostic implications of liquid biopsy in advanced prostate cancer

  Targeted cfDNA and WBC sequencing data from patients profiled in the study "Prediction of plasma ctDNA fraction and prognostic implications of liquid biopsy in advanced prostate cancer". Note that 'Exome sequencing' is listed under Dataset Type since there is no option for targeted panel sequencing.

  Dataset EGAD50000000303

• Somatic Mutations in Variant and IGHV4-34 Expressing Hairy Cell Leukemia

  To understand the genetic mechanisms driving variant and IGHV4-34 expressing hairy-cell leukemia, we performed whole exome sequencing of tumor/normal pairs from ten patients.

  Study phs000671