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• Characterization of DLBCL with a PMBL gene expression signature

  Primary mediastinal large B-cell lymphoma (PMBL) is a type of aggressive B-cell lymphoma that typicallyaffects young adults, characterized by presence of a bulky anterior mediastinal mass. Lymphomas withgene expression features of PMBL have been described in non-mediastinal sites, raising questions abouthow these tumors should be classified.Here, we investigated whether these "non-mediastinal PMBLs" are indeed PMBLs or instead represent adistinct group within DLBCL. From a cohort of 325 de novo DLBCL cases, we identified tumors frompatients without evidence of anterior mediastinal involvement that expressed a PMBL expression signature(nm-PMBLsig-pos, n=16, 5%). The majority of these tumors expressed MAL and CD23 – proteins typicallyobserved in bona fide PMBL (bf-PMBL). Evaluation of clinical features of nm-PMBLsig-pos cases revealedclose associations with DLBCL, and the majority displayed a germinal center B-cell-like cell-of-origin(GCB). In contrast to bf-PMBL, nm-PMBLsig-pos patients presented at an older age, did not show pleuraldisease, and bone/bone marrow involvement was observed in three cases. However, while clinicallydistinct from bf-PMBL, nm-PMBL-sig-pos tumors resembled bf-PMBL at the molecular level with upregulationof immune response, JAK-STAT, and NF-kB signatures. Mutational analysis revealed frequent somatic genemutations in SOCS1, IL4R, ITPKB and STAT6, as well as CD83 and BIRC3, with the latter genes beingsignificantly more frequently affected than in GCB-DLBCL and bf-PMBL.Our data establish nm-PMBLsig-pos lymphomas as a group of DLBCL with distinct phenotypic and geneticfeatures, and potential implications for gene expression- and mutation-based subtyping of aggressive Bcell lymphoma and related targeted therapies.

  Study EGAS00001005057

• Whole genome sequencing of tumor samples from advanced pre-treated NSCLC patients recruited in a phase I/II single-arm trial utilising CVA21, an oncolytic coxsackie virus, in combination with pembrolizumab.

  Acquired or de novo resistance to immune checkpoint inhibitors occurs in the majority of advanced non-small cell lung cancers (NSCLC). There is an unmet need to improve outcomes for patients with this condition. Oncolytic viruses represent an attractive treatment approach due to their dual activity in inducing tumor cell lysis directly and potentially augmenting anti-tumor immunity. Here, we present the safety, efficacy and translational findings from a phase I/II single-arm trial utilising CVA21, an oncolytic coxsackie virus, in combination with pembrolizumab in patients with advanced pre-treated NSCLC. We performed paired biopsies pre- and post-treatment in 10 patients who received intravenous CVA21 and pembrolizumab, 8 of whom had prior treatment with immune checkpoint inhibitor (ICI) therapy. Whole genome sequencing and spatial proteomics were performed to comprehensively characterise the response to CVA21. Combination CVA21/pembrolizumab (anti PD-1) therapy was well tolerated with no serious treatment-related adverse events. Partial responses were seen in two patients with prior acquired anti-PD-1 resistance and disease stabilisation in 6 patients, giving a clinical benefit rate of 80%. High baseline tumor mutational burden and PD-L1 expression were observed in patients with better response to treatment. Interestingly, an increase in antigen presentation and CD8+ T cell infiltration was observed on treatment compared with baseline in patients with better progression-free survival. This study demonstrates the potential of CVA21 to modulate the immunogenicity of tumor cells and remodelling the tumor microenvironment, providing novel insights for patient selection for trials involving novel immunotherapeutic approaches.

  Study EGAS00001008258

• RNA-Seq of Whole Blood from Patients with Intracranial Aneurysms

  Rupture of intracranial aneurysms (IAs) causes intracranial hemorrhaging that leads to high rates of neurological deficits and death. Although rupture rates are low, clinicians must decide whether to treat or monitor these potentially dangerous lesions. In the current clinical practice, the most common metric to measure risk of rupture is aneurysm size. However, clinical data show that small aneurysms can also rupture. As a result, alternative clinical stratification scores have been proposed, including the PHASES (Population, Hypertension, Age, Size, Earlier subarachnoid hemorrhage, and Site) score based on patient demographics and IA characteristics to stratify ruptured and unruptured IAs, and the Rupture Resemblance Score (RRS) that stratifies ruptured and unruptured IAs based on hemodynamic and morphological properties. However, all metrics require imaging on digital subtraction angiography (DSA), which is invasive, expensive, requires the use of X-rays, and is associated with transient or permanent neurological and non-neurological complications. We hypothesize that individuals with dangerous IAs have detectable gene expression differences in their blood that could be used as biomarkers to determine rupture risk. We propose to use whole blood transcriptomes to develop a "one-stop" diagnostic test that can detect the presence of IAs and determine the risk of rupture based on circulating RNA expression biomarkers using our prototype AneuScreenTM platform. We aim to develop and validate biomarkers to predict risk, as calculated by the currently-used metric of aneurysm size, the clinical PHASES score, and the RRS. Here, we collected blood samples from consented individuals who were receiving cerebral imaging at the Gates Vascular Institute (Buffalo, NY) for intracranial aneurysm. RNA extracted from blood samples (n=43) was subjected to RNA-sequencing and added to our existing database (n=44). When combined with our previous data, we had transcriptome data from 68 aneurysms (after additional sample filtering). This dataset was stratified into low- and high-risk according to IA size, PHASES score, and RRS score. Differentially expressed genes were identified and used to construct predictive models. Fastq files and basic demographic information for the 43 newly-sequenced intracranial aneurysm samples on this project will be available through dbGaP.

  Study phs003072

• Longitudinal Studies of Patients with Familial Platelet Disorder with Associated Myeloid Malignancy (FPDMM)

  FPDMM (OMIM #601399) is a rare autosomal dominant disease characterized by defective megakaryocytic development, thrombocytopenia, platelet functional defects, and a life-long risk of developing hematological malignancies. FPDMM is caused by germline mutations in the RUNX1 gene, which encodes a master regulator of hematopoiesis. The overall lifetime risk of hematological malignancies in FPDMM patients is 35 - 45%. It is hypothesized that mutations in other genes cooperate with the germline RUNX1 mutations for leukemia development. However, it is not clear which genes need to be mutated for leukemia to develop and which biomarkers or clinical tests can be used to predict which patients will progress to leukemia. Likewise, there are no treatments and/or preventative measures that can reduce or stop disease progression except for stem cell transplantation, which is not available for all patients and may be associated with significant complications. To address these questions, we launched a longitudinal natural history study of patients associated with RUNX1 germline mutations at the NIH Clinical Center in early 2019 (Trial Registration ID: NCT03854318). The goals of this study are to: (1) perform comprehensive longitudinal phenotyping of FPDMM patients to document the full spectrum of both hematopoietic and non-hematopoietic manifestations of the disease; and (2) perform extensive genomic analyses of FPDMM patient samples to identify cooperating genomic variants, which may confer growth advantage that leads to clonal expansion of affected hematopoietic cells that may serve as the precursor to malignancies. The data available through dbGaP include exome sequencing and RNA-seq data from these patients. Diverse germline mutation types were identified in the RUNX1 gene, including splice site mutations and large deletions, in addition to nucleotide substitutions and small indels. Somatic mutations, especially in genes associated with clonal hematopoiesis of indeterminate potential (CHIP), were found in a substantial proportion of FPDMM patients who were leukemia-free. The findings suggest that the genomes in these patients are prone to somatic mutations and monitoring the dynamic changes of these somatic mutations prospectively may provide a way to predict progression to malignancies.

  Study phs003075

• NHLBI GO-ESP: Heart Cohorts Exome Sequencing Project (Ischemic Stroke Genetic Study, ISGS)

  The NHLBI "Grand Opportunity" Exome Sequencing Project (GO-ESP), a signature project of the NHLBI Recovery Act investment, was designed to identify genetic variants in coding regions (exons) of the human genome (the "exome") that are associated with heart, lung and blood diseases. These and related diseases that are of high impact to public health and individuals from diverse racial and ethnic groups will be studied. These data may help researchers understand the causes of disease, contributing to better ways to prevent, diagnose, and treat diseases, as well as determine whether to tailor prevention and treatments to specific populations. This could lead to more effective treatments and reduce the likelihood of side effects. GO-ESP is comprised of five collaborative components: 3 cohort consortia - HeartGO, LungGO, and WHISP - and 2 sequencing centers - BroadGO and SeattleGO. The Ischemic Stroke Genetics Study (ISGS) is a study of newly onset cases (~600) with ischemic stroke (a stroke due to sudden interruption of blood flow to a part of the brain) compared with sex- and age-matched non-stroke participants. The study was conducted to determine the genes and their variants that contribute to an individual's risk of developing an ischemic stroke. The coordination of the recruitment and flow of the samples occurred at the Mayo Clinic, Jacksonville, FL, under the direction of James F. Meschia, MD. The University of Virginia (Stephen S. Rich, PhD) served as the analytic site for the genetic data. All GWAS data on ISGS participants have been deposited into dbGaP. As part of the NHLBI Exome Sequencing Project, DNA from a subset of ISGS participants will undergo exome sequencing. For the NHLBI ESP, a subset of 92 individuals with lacunar (small vessel) or atherosclerotic (large vessel) TOAST subtypes were selected from among all ISGS participants, excluding those individuals with TOAST subtypes of stroke of other etiology or of stroke with undetermined etiology. All 92 samples pass initial quality control metrics and 89 samples completed exome sequencing. A total of 75 participants with appropriate consent and variant calls had their genetic and phenotypic data deposited into dbGaP.

  Study phs000546

• Longitudinal Studies of Brain Structure and Function in MPS Disorders

  Mucopolysaccharidosis (MPS) types I, II, IV, VI and VII, are inherited diseases that result from the bodies inability to break down large sugar molecules that are by-products of metabolism. MPS affects most organs of the body and causes abnormalities in the liver, spleen, bones, and brain. We are studying the central nervous system (primarily the brain) so we can better understand the nature of the problems individuals with MPS I, II, IV, VI and VII have so we can find ways of better treating these problems. We would like to find out about the changes in the brain of individuals with MPS I, II, IV, VI and VII using data from MRI and neuropsychological tests. This is a longitudinal study so patients who enroll will need to be seen 3 times over 5 years. The longitudinal nature of the study allows us to make conclusions about how changes in some structures of the brain and changes in cognitive ability are related. The research objectives are: To identify abnormalities of brain (and central nervous system) structure and function in patients with MPS I, II, IV, VI and VII, regardless of how they are being treated or have been treated in the past; and to track disease progression over time. To examine the degree to which independent variables (e.g., age at first treatment, severity of disease, types of medical abnormalities, mutation, medical events, and sensory abnormalities) have an impact on both functional and structural outcomes as well as on quality-of-life. To identify, through longitudinal study, those measures that most accurately reflect the current disease state. This is a longitudinal study of 75-100 individuals with either MPS I, II, IV, VI and VII. Those participating in the study will be evaluated 3 times over 5 years. The primary site for this study is the University of Minnesota but there are an additional 6 centers in the United States and Canada that are also participating and will provide data for analysis. You will need to be able to travel to Minnesota or one of the participating centers in order to be a part of this study.

  Study phs001328

• Nurminen et al ("GP2Men") Study Primary and Metastatic Prostate Cancer Whole Genome Sequence Data

  We used novel processing techniques to obtain whole genome data together with 3D anatomic and histomorphologic analysis in two men (GP5 and GP12) with high risk PrCa undergoing radical prostatectomy. A total of 22 whole genome-sequenced sites (16 primary cancer foci and 6 lymph node metastatic) were analyzed using evolutionary reconstruction tools and spatio-evolutionary models. Probability models were used to trace spatial and chronological origins of the primary tumor and metastases, chart their genetic drivers, and distinguish metastatic and non-metastatic subclones.

  Study EGAS50000000005

• SUM-seq data for spontaneously differentiated iPSCs to EBs

  Clonal CRISPRi/a hiPS cell lines were plated to induce spontaneous differentiation in KSR medium (KSR medium: knockout DMEM/F12 (Gibco, 12660012), 2 mM GlutaMAX, 1× NEAAs, 20% knockout serum replacement (Gibco, 10828010) and 0.1 mM β-mercaptoethanol (Merck-Millipore)). non-TC plates and dishes were used. At the day of plating, KSR medium was supplemented with Y-27632 (10 µM). The next day, medium was replaced with fresh KSR medium. Medium changes were performed every other day. EBs were transferred to 15 ml conical tubes and allowed to sediment at room temperature for 5 min. The supernatant was replaced with fresh KSR medium and cells were transferred onto non-TC treated plates and maintained at 37 °C, 5% CO2. On day 12 of differentiation, the KSR medium was replaced with Essential 6 medium (Gibco, A1516401). EBs were collected and subjected to SUM-seq library preparation as described in Lobato-Moreno et al. 2025 Nature Methods.

  Dataset EGAD50000001589

• Single-cell RNA sequencing of control and Notch inhibitor treated HCC PDX model

  We generated single-cell RNA-seq data for anti-Notch2 (n=3), anti-JAG1 (n=1) and anti-gD (n=4) treated LIV78 tumors. NCR nude mice bearing similarly sized LIV78 tumors (volumes between 300-900mm3) were injected intravenously with 30mg/kg body weight of either anti-Notch2, anti-Jag1 or anti-gD control antibody 72hrs prior to tumor harvest and tumor cell isolation. Following the depletion of CD45+ and Ter119+ cells, the samples were processed for single-cell RNA-seq (scRNAseq) as described previously (Long et al., 2019) using the Chromium Single Cell 3’ Library and Gel bead kit v2, following the manufacturer’s manual. cDNAs and libraries were prepared following the manufacturer’s manual (10X Genomics). Libraries were profiled by Bioanalyzer High Sensitivity DNA kit (Agilent Technologies) and quantified using Kapa Library Quantification Kit (Kapa Biosystems, Wilmington, MA). Each library was sequenced in one lane of HiSeq 2500 (Illumina) following the manufacturer’s sequencing specification (10X Genomics) to produce the resulting FASTQ files.

  Dataset EGAD50000000738

• Targeted Myeloid DNA-Panelsequencing, DKFZ

  Targeted myeloid DNA-Panelsequencing from purified bone marrow blasts of 104 treatment naive AML patients from the discovery cohort. For more details, we refere to Jayavelu, Wolf, Buettner et al. Libraries were prepared from 40 ng DNA using the QIASeq Human Myeloid Neoplasms Panel (Qiagen) according to the manufacturer’s protocol. Samples were tagged with the QIAseq 96-Unique Dual Index Set A for Illumina platforms (Qiagen) to yield unique combinations of i5 and i7 barcodes for each sample. Sample fragment size distribution and concentration was estimated using the Agilent High Sensitivity DNA kit on a 2100 Bioanalyzer (Agilent). Samples were pooled in an equimolar fashion, denatured, and diluted to 1.5 pM according to Illumina’s recommendations. The diluted library was sequenced on a NextSeq 500 benchtop sequencer (Illumina) using NextSeq High Output cartridges. Demultiplexing was performed using the BaseSpace cloud platform (Illumina).

  Dataset EGAD00001008501