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• DIME study: Safety, dose-response and efficacy of treatment with Anaerobutyricum soehgenii on glucose metabolism in human subjects with metabolic syndrome

  The intestinal microbiota has been implicated in insulin resistance, although evidence regarding causality in humans is scarce. We herefore performed a phase I/II dose-finding and safety study on the effect of oral intake of the anaerobic butyrogenic Anaerobutyricum soehgenii on glucose metabolism in subjects with metabolic syndrome. We found that treatment with A. soehgenii was safe and observed an overall significant and dose-dependent increase in insulin sensitivity after 4 weeks in all treated subjects. This was accompanied by an altered microbiota composition and a change in bile acid metabolism. Finally, we show that metabolic response upon administration of A. soehgenii (defined as improved insulin sensitivity 4 weeks after A. soehgenii intake) is dependent on microbiota composition at baseline. These data in humans are promising and additional studies are needed to study long-term effects as well as modes of delivery.

  Study EGAS00001003498

• Structurally Complex Osteosarcoma Genomes Exhibit Limited Heterogeneity within Individual Tumors and across Evolutionary Time

  A key characteristic of osteosarcoma is extensive and complex genomic rearrangements. However, published models explaining how these genomic rearrangements occur disagree about if these rearrangements occur early in tumor progression and then are stable afterwards, or if there is ongoing genomic instability. Previous studies have employed bulk sequencing technologies to characterize genomic alterations. A limitation of this approach is that it averages all changes within the bulk sample, essentially masking intra-sample heterogeneity and making evaluation of ongoing genomic instability difficult. To overcome this limitation and compliment previous work, we utilized single-cell whole genome sequencing to quantify somatic copy number alterations (SCNA). By interrogating individual cells within a sample, we were able to examine intra-sample heterogeneity. We found that the SCNA patterns between cells within a single sample were remarkably consistent, which supports the concept that the genomes of osteosarcoma tumors are relatively stable after early genome fragmentation events.

  Study phs003209

• Genomics and Methylation of Neuroendocrine Prostate Cancer from cfDNA (Cornell/Trento 2019)

  A subset of castration resistant prostate cancers develop small cell neuroendocrine prostate cancer (NEPC) as a mechanism of treatment resistance. Metastatic tissue biopsies to evaluate for NEPC transformation are invasive and challenging to perform serially. We performed whole exome and whole genome bisulfite sequencing of plasma cfDNA and matched tumor biopsy samples from 62 patients with metastatic prostate cancer along the disease spectrum to evaluate for NEPC associated genomic and epigenomic features. Multiple tissue biopsies and/or plasma time points were included for a subset of patients to characterize disease heterogeneity and dynamic changes. Computational analysis of clonality and allele specific quantification allowed for detailed comparison of matched tumor tissue and cfDNA data (CLONET v2). Methylation profiles detected from tissue and plasma data were compared and NEPC specific alterations were evaluated in cfDNA. The study supports the feasibility of a plasma based assay for the detection of NEPC.

  Study phs001752

• Serial assessment of measurable residual disease in medulloblastoma liquid biopsies

  Nearly one-third of children with medulloblastoma, a malignant embryonal tumor of the cerebellum, succumb to their disease. Conventional response monitoring by imaging and cerebrospinal fluid (CSF) cytology remains challenging and a marker for measurable residual disease (MRD) is lacking. Here, we show the clinical utility of CSF-derived cell-free DNA (cfDNA) as a biomarker of MRD in serial samples collected from children with medulloblastoma (123 patients, 476 samples) enrolled on a prospective trial. Using low-coverage whole-genome sequencing, tumor-associated copy-number variations (CNVs) in CSF-derived cfDNA are investigated as an MRD surrogate. MRD is detected at baseline in 85% and 54% of patients with metastatic and localized disease, respectively. The number of MRD-positive patients decline with therapy, yet those with persistent MRD have significantly higher risk of progression. Importantly, MRD detection precedes radiographic progression in half who relapse. Our findings advocate for the prospective assessment of CSF-derived liquid biopsies in future trials for medulloblastoma.

  Study EGAS00001005592

• Phase I Study and Cell-Free DNA Analysis of T-DM1 and Metronomic Temozolomide for Secondary Prevention of HER2-Positive Breast Cancer Brain Metastases

  This study is a phase I trial combining ado-trastuzumab emtansine (T-DM1) with Temozolomide (TMZ) for the prevention of additional brain metastases after previous occurrence and local treatment in HER2+ breast cancer patients. Twelve patients were enrolled in this study. Data includes whole exome sequencing (WES) from patients' cerebrospinal fluid (CSF) and plasma samples. The CSF was collected from each patient at trial entry and after the initial two treatment cycles of TMZ and T-DM1 treatment. Blood was collected through a standard peripheral venipuncture at the following four time points: 1) upon trial entry, 2) after two treatment cycles, 3) the treatment cycle prior to the last follow-up, and 4) most recent follow-up. Whole exome libraries were captured by the SureSelect Human All Exon V8 Kit (Agilent, Santa Clara, CA, USA) and sequenced by NovaSeq 6000 S2 Sequencer in paired-end sequencing mode (Illumina, San Diego, CA, USA). Gene mutations in DNMT3A, ELP1, NOTCH4, KMT2B, CRLF2, and KCNJ18 were observed in patients' CSF.

  Study phs003165

• Hominin-specific NOTCH2 paralogs expand human cortical neurogenesis through regulation of Delta/Notch interactions.

  The human cerebral cortex has undergone rapid expansion and increased complexity during recent evolution. Hominid-specific gene duplications represent a major driving force of evolution, but their impact on human brain evolution remains unclear. Using tailored RNA sequencing (RNAseq), we profiled the spatial and temporal expression of Hominid-specific duplicated (HS) genes in the human fetal cortex, leading to the identification of a repertoire of 36 HS genes displaying robust and dynamic patterns during cortical neurogenesis. Among these we focused on NOTCH2NL, previously uncharacterized HS paralogs of NOTCH2. NOTCH2NL promote the clonal expansion of human cortical progenitors by increasing self-renewal, ultimately leading to higher neuronal output. NOTCH2NL function by activating the Notch pathway, through inhibition of Delta/Notch interactions. Our study uncovers a large repertoire of recently evolved genes linking genomic evolution to human brain development, and reveals how hominin-specific NOTCH paralogs may have contributed to the expansion of the human cortex. The dataset contains raw sequences (FASTQ files) from the Illumina 2x150bp paired-end RNA sequencing profiles of 11 fetal human brain samples at 7, 9, 12, 15 and 21 gestational weeks.

  Study EGAS00001002798

• Single cell RNA-seq mapping of nasal and tracheobronchial airways in human healthy volunteers

  The respiratory tract constitutes an elaborated line of defense based on a unique cellular ecosystem. Single-cell profiling methods enable the investigation of cell population distributions and transcriptional changes along the airways. We have explored cellular heterogeneity of the human airway epithelium in 10 healthy living volunteers by single-cell RNA profiling. 77,969 cells were collected by bronchoscopy at 35 distinct locations, from the nose to the 12th division of the airway tree. The resulting atlas is composed of a high percentage of epithelial cells (89.1%), but also immune (6.2%) and stromal (4.7%) cells with peculiar cellular proportions in different sites of the airways. It reveals differential gene expression between identical cell types (suprabasal, secretory, and multiciliated cells) from the nose (MUC4, PI3, SIX3) and tracheobronchial (SCGB1A1, TFF3) airways. By contrast, cell-type specific gene expression was stable across all tracheobronchial samples. Our atlas improves the description of ionocytes, pulmonary neuro-endocrine (PNEC) and brush cells, which are likely derived from a common population of precursor cells. We also report a population of KRT13 positive cells with a high percentage of dividing cells which are reminiscent of “hillock” cells previously described in mouse. Robust characterization of this unprecedented large single-cell cohort establishes an important resource for future investigations. The precise description of the continuum existing from nasal epithelium to successive divisions of lung airways and the stable gene expression profile of these regions better defines conditions under which relevant tracheobronchial proxies of human respiratory diseases can be developed.

  Study EGAS00001004082

• Comprehensive analysis of atypical teratoid rhabdoid tumour (ATRT) using genomic, epigenomic and transcriptomic techniques.

  ATRTs (Atypical teratoid rhabdoid tumours) represent one of the most aggressive pediatric brain cancers, but intriguingly exhibit few other recurrently mutated loci except for SMARCB1/hSNF5. We integrated whole genome (n=15), exome, copy number, gene expression and methylation analyses to comprehensively interrogate 64 ATRTs and observed that structural events were relatively frequent in the ATRT genome (~3 tumour). In addition to SMARCB1, which was targeted by structural events in a majority (49/64) of tumours, recurrent structural alterations targeting the LRP1B, CDH13, BCR and MKL1 loci were observed. We observed novel translocation events, including 2 targeting SMARCB1 which were detected only by NGS analyses. Significantly, integration of gene expression and methylation profiles with genomic analyses revealed ATRT comprise two sub-groups with distinct clinical and genetic features. Group 1 tumours were characterized by supra-tentorial brain location, focal intragenic alterations of SMARCB1 and a pro-neural gene expression signature with evidence of NOTCH pathway activation. While Group 2 ATRTs were characterized by infra-tentorial brain location, broad SMARCB1 alterations and an activation of the BMP signalling pathway. Our findings highlight epigenetic mechanisms as important determinants of ATRT tumour phenotypes, and demonstrate for the first time that ATRTs arising in different anatomical compartments comprise distinct molecular and therapeutic sub-groups.

  Study EGAS00001000506

• Kinomics data

  To ellucidate protein activity in mRCC, Kinomics data was generated as part of the EuroTarget study

  Dataset EGAD50000002293

• Dundee Metformin response GWAS Phenotype 2016

  Variation in the Glucose Transporter gene SLC2A2 is associated with glycaemic response to metformin

  Dataset EGAD00001002277