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• Circulating cell-free and extracellular vesicles-derived microRNA as prognostic biomarkers in patients with early-stage NSCLC: results from RESTING study

  Lung cancer, especially non-small cell lung cancer (NSCLC), has high mortality rates. Early-stage NSCLC shows a 50% relapse rate post-surgery, with most recurrences occurring within two years and a 5-year survival of only 30%. This study focuses on the prognostic value of circulating miRNAs in surgically treated ES-NSCLC patients, aiming to assess their predictive accuracy and compare them to standard prognostic factors.

  Study EGAS50000001032

• Contribution of specific cell types to the development of Barrett’s esophagus and carcinoma via germline genetic risk

  We sought to elucidate how individual cell types in Barrett’s esophagus (BE) and esophageal adenocarcinoma (EAC) contribute to disease development via germline genetic risk.

  Dac EGAC50000000235

• Plasma MicroRNA Signatures of Aging

  Background. MicroRNAs are small non-coding RNAs that regulate gene expression post-transcriptionally and show differential expression in various tissues with aging phenotypes. Detectable in circulation, extracellular microRNAs reflect (patho)physiological processes and hold promise as biomarkers for healthy aging and age-related diseases. This study aimed to explore plasma extracellular microRNAs as biological aging indicator and their associations with health outcomes using population-level data. Methods. We quantified plasma expression levels of 2,083 extracellular microRNAs using targeted RNA-sequencing in 2,684 participants from the population-based Rotterdam Study cohort. The training and test sets included 1,930 participants from the advanced-aged initial and second subcohort (RS-I/RS-II; median age: 70.6), while the validation set comprised 754 participants from the middle-aged fourth subcohort (RS-IV; median age: 53.5). Based on 591 microRNAs well-expressed in plasma, we examined differential expression of microRNAs with chronological age, PhenoAge –a composite score of age and nine multi-system blood biomarkers–, the frailty index, and mortality. Next, elastic net models were employed to construct composite microRNA-based aging biomarkers predicting chronological age (mirAge), PhenoAge (mirPA), frailty index (mirFI), and mortality (mirMort). The association of these aging biomarkers with different age-related health outcomes was assessed using Cox Proportional Hazard, linear regression, and logistic regression models in the test and validation sets. Results. We identified 188 microRNAs differentially expressed with chronological age within the RS-I/RS-II advanced-aged population (ntraining=1158, ntest=772), of which 177 microRNAs (94.1%) were replicated in the middle-aged RS-IV subcohort (nvalidation=754). Moreover, 227 miRNAs showed robust associations with PhenoAge, 61 with FI, and 16 with ten-year mortality independent of chronological age. Subsequently, we constructed four plasma microRNA-based aging biomarkers: mirAge with 108, mirPA with 153, mirFI with 81, and mirMort with 50 miRNAs. Elevated scores on these microRNA-based aging biomarkers were associated with unfavorable health outcomes, including lower subjective physical functioning and self-reported health and increased mortality and frailty risk, but not with first- or multi-morbidity. Overall, larger effect estimates were observed for mirPA, mirFI, and mirMort compared to mirAge. Conclusions. This study describes distinct plasma microRNA-aging signatures and introduces four microRNA-based aging biomarkers with potential to identify accelerated aging and age-related decline, providing insights into the intricate process of human aging.

  Study EGAS00001008117

• MultiOMICS study of a pair of infant monozygotic twins with concordant B-cell ALL (WGS)

  B-cell acute lymphoblastic leukemia (B-cell ALL) is the most common cancer in childhood. Studying identical twins with B-cell ALL provides a unique and tractable model for deciphering the developmental timing of pre- and post-natal mutations contributing to clonal evolution. To date, this has mainly focused on major cytogenetic subgroups of childhood B-cell ALL, including MLL fusions, ETV6-RUNX1, hyperdiploidy, and BCR-ABL1. However, formal demonstration of the prenatal origin and “backtracking” the natural history of the leukemia remains understudied in “B-other”/Normal Karyotype (NK) B-cell ALL. To characterize the genetic landscape of this particular leukemia subtype, we performed whole genome DNA- and B-cell receptor (BCR)- on a pair of 8-month-old monozygotic twins diagnosed with concordant “B-other”/NK B-cell ALL.

  Dataset EGAD00001005017

• MultiOMICS study of a pair of infant monozygotic twins with concordant B-cell ALL (WGBS)

  B-cell acute lymphoblastic leukemia (B-cell ALL) is the most common cancer in childhood. Studying identical twins with B-cell ALL provides a unique and tractable model for deciphering the developmental timing of pre- and post-natal mutations contributing to clonal evolution. To date, this has mainly focused on major cytogenetic subgroups of childhood B-cell ALL, including MLL fusions, ETV6-RUNX1, hyperdiploidy, and BCR-ABL1. However, formal demonstration of the prenatal origin and “backtracking” the natural history of the leukemia remains understudied in “B-other”/Normal Karyotype (NK) B-cell ALL. To characterize the epigenetic landscape of this particular leukemia subtype, we performed DNA bisulfite-sequencing on a pair of 8-month-old monozygotic twins diagnosed with concordant “B-other”/NK B-cell ALL.

  Dataset EGAD00001005018

• BipEx_Landen_SWEBIC

  BipEx: Bipolar Exome Sequencing Broad & Karolinska Institutet. EGAS00001005860. "This research project was a collaboration between the Karolinska Institute and the Stanley Center at the Broad Institute. In this project we sequenced and analyzed the whole exomes of X SWEBIC Bipolar case samples from collaborators in Sweden. Genomic DNA from each samples was sequenced to a mean depth of 20x"

  Dac EGAC50000000142

• BipEx_Pedersen_Karolinska

  "BipEx: Bipolar Exome Sequencing Broad & Karolinska Institutet. EGAS00001005856. ""This research project was a collaboration between the Karolinska Institute BioBank and the Stanley Center at the Broad Institute. In this project we sequenced and analyzed the whole exomes of 4,765 control samples from collaborators in Sweden. Genomic DNA from each samples was sequenced to a mean depth of 20x."" "

  Dac EGAC50000000141

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

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

  Study phs003079

• Mongolia Western HCC

  Mongolia has the world’s highest incidence of hepatocellular carcinoma (HCC), with ~100 cases/105 inhabitants. We molecularly characterize the Mongolian (n=192) compared to Western HCCs (n=187) by RNA-seq and WES. Mongolian patients were predominantly younger, female, with HBV-HDV non-cirrhotic livers. Mongolian HCCs had higher rates of protein-coding mutations (121 vs 70 mut /tumor in West), and mutations in known (i.e. APOB) and putative HCC drivers (TSC2). A novel mutational signature (SBS Mongolia) was identified in 25% of cases associated with the carcinogenic DMS genotoxic signature. Two unique molecular classes enriched in HBV-HDV infection, female gender and inflamed tumors are described.

  Study EGAS00001005364

• Single cell sequences in patients with malignant tumors

  We perfomed single cell RNA and TCR sequencing of 2 lung adenocarcinoma patients and 3 head and neck squamous cell carcinoma to assess the detailed biological mechanisms of resistance to immune checkpoint inhibitors.

  Study JGAS000480

• Nascent transcriptome in T-ALL bone marrow

  Nascent RNA expression profiles were generated with Global Run-On sequencing (GRO-seq) from T-ALL patient samples to measure primary transcription genome-wide and to summarize the transcriptional activity at gene loci and enhancers.

  Study EGAS00001005864

• Single cell atlas of relapsed/refractory large B-cell lymphoma

  Relapsed/refractory large B-cell lymphomas (rrLBCL) are clinically and biologically diverse lymphoid malignancies with intricate microenvironments that play a key role in disease development. In this study, we used single-nucleus multiome profiling along with bulk DNA and RNA sequencing on 120 tumor and control biopsies to comprehensively characterize the various cell types and subsets found in rrLBCL tumors.

  Study EGAS50000001293

• Association of Oxidative Stress Pathway Alterations with Risk of Treatment Failure in RTOG9512: A Randomized Trial of Hyperfractionation Versus Conventional Fractionation in T2 Squamous Cell Carcinoma of the Vocal Cord

  Based on the growing body of retrospectively collected and heterogeneously treated clinical cohorts and preclinical models, we investigated the clinical importance of NRF2 pathway alteration in an independent set of patients treated uniformly in the large prospective phase III trial RTOG 9512. We tested the hypothesis that patients with T2 glottic squamous cell carcinoma (SCC) harboring NRF2 pathway mutations would show radioresistance and have more local failure (LF) and locoregional failure (LRF) compared to those who did not have these mutations, using patients who received radiotherapy alone, thus removing potentially confounding effects of other therapies, like surgery or chemotherapy.

  Study phs003274

• Research Study into The Molecular Genetics of Hereditary Neuropathies

  Identification of genes implicated in inherited neuropathy through collecting and sequencing multiple generation families with inherited neuropathy. Patients in this study have been evaluated for demyelinating peripheral neuropathy as determined by decreased motor nerve conduction velocities in the sural nerve. Patients have also been screened for mutations in all genes implicated in demyelinating peripheral neuropathy and are expected to have previously unidentified mutations. Exome (WES) sequencing for two patients affected with inherited neuropathy. VCF files with called variants for each de-identified patient have been submitted.

  Study phs001351

• Data Access Committee of CiRA Foundation

  The iPS Cell Stock Project promoted by the CiRA Foundation is intended to generate and distribute iPS cells for medical use so they can be effectively utilized for research and development of cell transplantation therapy and contribute to the advancement of regenerative medicine that may become a novel treatment for patients suffering from intractable diseases or trauma who are not expected to improve with conventional therapies. In order to achieve this objective, CiRA Foundation establish the DAC based on the basic policies and rules for handling analysis information including iPS cell stocks for the purpose of proper sharing of samples and analyzed data collected directly or indirectly from the donors of iPS cell stocks.

  Dac EGAC50000000128

• Collaborative Cohort of Cohorts for COVID-19 Research (C4R): Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS)

  Cohort Description The Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS) is a multi-center, observational, longitudinal case-control study designed to guide future development of therapies for COPD. SPIROMICS has recruited 2,983 COPD cases and controls, 40-80 years old with 20+ pack-years of smoking at 12 US sites in 2010–2015.

  Study phs002909

• Whole-exome sequencing data of ovarian clear cell carcinoma in East Asia

  This is a genomic study to uncover the molecular landscape of ovarian clear cell carcinoma (OCCC) in East Asia. This dataset contains normal-tumor paired samples of 104 patients with OCCC diagnosed in two branches of Chang Gung Memorial Hospital, Taiwan. These are paired-end, whole-exome sequencing data, sequenced by Illumina NovaSeq with target depth of 150X.

  Study EGAS50000000031

• Deciphering RBP - alternative splicing networks in ALS iPSC-MN: NOVA1 gain and loss of function systems

  We produced NOVA1 and EGFP over-expression RNA-seq datasets in three healthy control individuals using lentivirus-mediated gene transfer to model NOVA1 gain of function. Additionally, we produced a NOVA1 loss of function RNA-seq dataset by generating iPSC-MN with NOVA1 knock out produced by CRISPR/Cas9 in the CV-B iPSC line.

  Study EGAS00001005881

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

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

  Dataset EGAD00001004391

• Whole genome study of Hurthle cell thyroid carcinoma

  Oncocytic thyroid carcinoma, also known as Hürthle cell thyroid carcinoma, accounts for only a small percentage of all thyroid cancers. However, this malignancy often presents at an advanced stage and poses unique challenges to patients and clinicians. Surgical resection of the tumor accompanied in some cases by radioactive iodine treatment, radiation and chemotherapy are the established modes of therapy. Knowledge of the perturbed oncogenic pathways can provide better understanding of the mechanism of disease and thus opportunities for more effective clinical management. Initially, two oncocytic thyroid carcinomas and their matched normal tissues were profiled using whole genome sequencing. Subsequently, 72 oncocytic thyroid carcinomas, one cell line and 5 Hürthle cell adenomas were examined by targeted sequencing for the presence of mutations in multiple endocrine neoplasia I (MEN1) gene. We report the identification of MEN1 loss-of-function mutations in approximately 7% of patients diagnosed with oncocytic thyroid carcinoma. Whole genome sequence data also revealed large regions of copy number variation encompassing nearly the entire genomes of these tumours. Menin, a ubiquitously expressed nuclear protein, is a well-characterized tumor suppressor whose loss is the cause of multiple endocrine neoplasia type 1 syndrome. Menin is involved in several major cellular pathways such as regulation of transcription, control of cell cycle, apoptosis and DNA damage repair pathways. Mutations of this gene in a subset of Hürthle cell tumors point to a potential role for this protein and its associated pathways in thyroid tumorigenesis.

  Study EGAS00001000940

• The molecular basis of T-PLL is an actionable perturbation of TCL1/ATM- and epigenetically instructed damage responses

  T-cell prolymphocytic leukemia (T-PLL) is a rare and poor-prognostic mature T-cell malignancy. To address its incomplete molecular concept, we integrated large-scale profiling data of alterations in gene expression, allelic copy number (CN), and nucleotide sequences in 111 well-characterized patients. Besides prominent signatures of T-cell activation and prevalent clonal variants, we also identified novel hot-spots for CN variability, fusion molecules, alternative transcripts, and progression-associated dynamics. The overall lesional spectrum of T-PLL is mainly annotated to axes of DNA damage responses, T-cell receptor/cytokine signaling, and histone modulation. We formulate a multi-dimensional model of T-PLL pathogenesis centered around a unique combination of TCL1 overexpression with damaging ATM aberrations as initiating core lesions. The effects imposed by TCL1 cooperate with compromised ATM towards a leukemogenic phenotype of impaired DNA damage processing. Dysfunctional ATM appears inefficient in alleviating elevated redox burdens and telomere attrition and in evoking a p53-dependent apoptotic response to genotoxic insults. As non-genotoxic strategies, synergistic combinations of p53 reactivators and deacetylase inhibitors reinstate such cell death execution.

  Study EGAS00001002744

• SU2C-MARK Lung Cancer Consortium - Checkpoint Blockade Response Project

  Immune checkpoint inhibitors have become a critical part of the armamentarium against advanced Non-Small Cell Lung Cancer (NSCLC). While early studies have identified Tumor Mutation Burden (TMB) and PD-L1 staining as important biomarkers of response, they remain imperfect predictors. Here we describe a multi-institutional effort as part of the SU2C-MARK Lung Cancer Consortium in which Whole Exome Sequencing (WES) - and in select cases, RNA sequencing – was performed on a large collection of NSCLC samples prior to immune checkpoint blockade therapy, along with matched clinical response data following therapy. (Profiling of a small number of on- or post-treatment samples was also performed.) We anticipate this dataset to be of high value for the development of a deep understanding of the molecular determinants of immune checkpoint blockade response as well as the discovery of novel biomarkers.

  Study phs002822

• TenK10K Phase 1:  Single Cell

  Understanding the genetic basis of gene expression can shed light on the regulatory mechanisms underlying complex traits and diseases. Single-cell resolved measures of RNA levels and single-cell expression quantitative trait loci (sc-eQTLs) have revealed genetic regulation that drives sub-tissue cell states and types across diverse human tissues. Here, we describe the first phase of TenK10K, the largest- to-date dataset of matched whole-genome sequencing (WGS) and single-cell RNA-sequencing (scRNA-seq). We leverage scRNA-seq data from over 5 million cells across 28 immune cell types and matched WGS from 1,925 individuals. This provides power to detect associations between rare and low-frequency genetic variants that have largely been uncharacterised in their impact on cell-specific gene expression. We map the effects of both common and rare variants in a cell type specific manner using SAIGE-QTL.

  Study EGAS50000001653

• CUT&RUN of AML1-ETO binding occupancy following miR-130a KD in Kasumi-1 cells

  We performed CUT&RUN assay with control Ig , anti-Flag and anti-ETO antibodies in Flag-tag AML1-ETO Kasumi-1 cells to determine binding occupancy of AML1-ETO following miR-130a KD. Kasumi-1 cells were transduced in 3 independent replicates for control and miR-130a KD samples with lentiviruses containing GFP reporter gene. GFP+ cells were sorted 3 days post-transduction and the cells were used in the CUT&RUN assay. Three antibodies were used for each biological sample.

  Study EGAS00001005867

• PGRN-Leducq: Identification of the KCNE1 D85N Polymorphism as a Possible Modulator of Drug-Induced Torsades de Pointes

  The goal of this study was to search for genetic variants that could be responsible for modifying the risk of drug-induced long QT syndrome (diLQTS). diLQTS is a relatively common adverse drug event and has been a leading cause for drug relabeling and withdrawal from the market. Our hypothesis, that variants in genes which regulate electrical properties in the heart modify the risk of diLQTS, was tested by genotyping patients of European descent at 1424 single nucleotide polymorphisms (SNPs) in 18 candidate genes. We found that the SNP KCNE1 D85N was highly predictive of diLQTS with an odds ratio of 9.0 (95% confidence interval: 3.5-22.9).

  Study phs000617