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• Bacterial Artificial Chromosomes Establish Replication Timing and Sub-Nuclear Compartment De Novo as Extra-Chromosomal Vectors

  The role of DNA sequence in determining replication timing (RT) and chromatin higher order organization remains elusive. To address this question, we have developed an extra-chromosomal replication system consisting of ~200kb human bacteria artificial chromosomes (BACs) modified with Epstein-Barr virus (EBV) replication origin elements (E-BACs). E-BACs were stably maintained as autonomous mini-chromosomes in both HeLa and human induced pluripotent stem cells (hiPSCs) and established distinct RT patterns. An E-BAC harboring an early replicating chromosomal region replicated early during S phase, while E-BACs derived from RT transition regions (TTRs) and late replicating regions replicated in mid to late S phase. Analysis of E-BAC interactions with cellular chromatin (4C-seq) revealed that the early replicating E-BAC interacted broadly throughout the genome and preferentially with the early replicating compartment of the nucleus. In contrast, mid- to late-replicating E-BACs interacted with more specific late replicating chromosomal segments, some of which were shared between different E-BACs. Together, we describe a versatile system in which to study the structure and function of chromosomal segments that are stably maintained separately from the influence of cellular chromosome context.

  Study phs001520

• Establishing stable brain tumor stem cell lines and translational research for new treatments

  Choroid plexus carcinomas (CPCs) have dismal prognoses with limited clinical options. A lack of characterized cell lines has hindered the development of new treatment strategies. Here, we perform whole genome sequencing analyses of two cell lines established from CPCs. Whole genome sequencing (WGS),was performed in CCHE-45 and NGT131 cell lines. Both cell lines harbored pathogenic TP53 point mutations; CCHE-45 additionally displayed TP53 loss. Furthermore, alterations of the NOTCH and WNT pathways were also detected in both cell lines. Two protein-coding gene fusions, BZW2-URGCP, and CTTNBP2-ERBB4, mutations of two oncodrivers, GBP-4 and KRTAP-12-2, and several copy number alterations were observed in CCHE-45, but not NGT131. The discovered difference's importance and implications highlight the possible diversity of choroid plexus carcinoma and call for additional research to fully understand disease pathogenesis. Whole genome sequencing revealed that the two choroid plexus carcinoma cell lines shared TP53 mutations and other common pathway alterations and activation of NOTCH and WNT pathways. Noticeable differences were also observed. These cell lines can serve as valuable models to propose new treatments in these rare but deadly brain tumors.

  Study JGAS000657

• Gut microbiome dynamics unravelled with metagenomics sequencing

  It has been already several years since we discovered that microbial therapeutics like Faecal Microbiota Transplantation can be used to treat Clostridium difficile infection (CDI) and Inflammatory bowel disease (IBD) with great success. The concept has challenged us to test the limits of our knowledge with the perspective to improve health in the most diverse conditions like Parkinson disease, depression, autism and obesity, just to mention a few. Note: the figure belongs to the original paper and is owned by the authors. Allyson L.Bird and colleagues from Genentech Inc. (San Francisco) recently published an interesting study building up on the key concept that “As microbial therapeutics are increasingly being tested in diverse patient populations, it is essential to understand the host and environmental factors influencing the microbiome.” The authors of this work analysed 1359 gut microbiome samples using shotgun metagenomics sequencing.  The results of the comparison done between microbiota composition across the different groups showed that biological sex is the strongest driver of diversity, while aging (age range studied: 20–69) appears to be the second factor. As smartly outlined in the authors’ own graphical abstract (figure to the left), Bacteroidota species consistently increased with donors' age while Actinobacteriota species, including Bifidobacterium, decreased. This study also integrated data from oncological patients to draw cancer-related evidences. After correcting the biases for technical and geographic differences, they found that cancer patients show significantly altered gut bacterial communities compared with their healthy counterparts. Eg. E.coli was found to be increased in cancer patients together with Bacteroidota/Firmicutes ratios. By comparing sequential samples taken from the same donors (413) within short-distance time points, the authors found that in the short term, intra-individual differences were less than the inter-individual ones, indicating a certain community stability being the norm. One of the pivotal points from this interesting study is that the data proceeds from extremely well-defined and selected donors. Specifically, the data for 949 selected healthy donors came from the Milieu Intérieur (MI) Consortium and extensive metadata, including demographic variables, serological measures, dietary information, and systemic immune profiles, are available. This precise stratification allowed for the robust detection of smaller changes, compared to former works. All sequencing data has been deposited in the EGA archive under the accession number EGAS00001004437. Enjoy this amazing open access paper published in the Experimental Journal of Medicine on January 2021.

  Blog gut-microbiome-dynamics-unravelled

• Error-corrected flow-based sequencing at whole genome scale and its application to circulating cell-free DNA profiling

  Differentiating sequencing errors from true variants is a central genomics challenge calling for error suppression strategies that balance costs when sparse material or ultra-rare variants require high-accuracy methods. For example, circulating cell-free DNA (ccfDNA) sequencing for cancer monitoring is limited by sparsity of circulating tumor DNA (ctDNA), abundance of genomic material in samples, library preparation error rates and sequencing errors. Whole-genome sequencing (WGS) can overcome the low abundance of ccfDNA by integrating signal across the mutation landscape, but higher cost limits adoption compared with targeted panels, where ccfDNA abundance limits maximal coverage depths. Here we applied deep (~120x) lower-cost WGS (Ultima Genomics) with analytic error correction for tumor-informed ctDNA detection within the part-per-million range. We further developed high-coverage duplex error-corrected WGS of ccfDNA, achieving 7.7x10-8 error rates, to assess disease burden in melanoma and urothelial cancer patients without matched tumor sequencing. Together, we show that deeply sequenced error-corrected WGS accurately calls somatic variants, demonstrating the feasibility of WGS for tumor-informed and tumor-agnostic ctDNA detection.

  Study EGAS50000000844

• MATISSE WES and bulk RNA-sequencing data

  High-risk cutaneous squamous cell carcinoma is frequently seen in frail, elderly patients and often requires mutilating surgical treatment and adjuvant radiotherapy (RT). The MATISSE trial (NCT04620200) was conducted to improve clinical prospects in CSCC patients eligible for extensive curative surgery, and evaluated early treatment response and immune dynamics following ultra-short neoadjuvant immunotherapy prior to standard of care surgery with or without radiotherapy. Fifty patients were randomized to receive two courses of nivolumab 3 mg/kg (NIVO, weeks 0&2) or nivolumab 3 mg/kg (weeks 0&2) and one course of ipilimumab 1 mg/kg (week 0 only, NIVO/IPI before surgery at week 4, with the primary objective being histopathological response based on residual viable tumor cells in the surgical specimen. Ten patients choose not to undergo surgery, of whom nine reached a clinical complete response during follow up, and were disease-free at median 34 months follow up. Serial tumor and blood samples at baseline, week 1, week 2 and week 4, enabled to investigate dynamical changes through bulk WES and RNA sequencing to potentially aid future de-escalation trials.

  Study EGAS50000001003

• Final results and ctDNA analyses from the randomized phase 3 IMpassion031 trial evaluating peri-operative atezolizumab for early-stage triple-negative breast cancer

  In IMpassion031, adding atezolizumab to neoadjuvant chemotherapy significantly improved pathologic complete response (pCR) rate (primary endpoint) for stage II/III triple-negative breast cancer (TNBC). Patients with stage II/III TNBC were randomized 1:1 to neoadjuvant chemotherapy plus peri-operative atezolizumab or pre-operative placebo. Descriptive secondary endpoints included event-free, disease-free, and overall survival. Long-term outcomes favored the atezolizumab group (event-free survival HR 0.76, 95% CI: 0.47–1.21). Among patients without pCR, 14/70 (20%) atezolizumab-treated and 33/99 (33%) placebo-treated patients received additional adjuvant therapy, frequently capecitabine. In exploratory analyses, pCR was prognostic for long-term outcome. Patients with baseline ctDNA-negative status (6%) had excellent long-term outcomes. Most patients (87%) had cleared ctDNA at surgery. ctDNA-positive status at surgery identified a subset of non-pCR patients with poorest prognosis. Long-term safety was consistent with primary results. Adding atezolizumab to chemotherapy for stage II/III TNBC is associated with more favorable long-term outcomes. ctDNA dynamics provide prognostic value beyond pCR. ClinicalTrials.gov identifier: NCT03197935

  Study EGAS50000000974

• scRNA-seq of HSPC treated with gemcitabine and carbplatin

  The study used cryopreserved hematopoietic stem and progenitor cells (HSPCs) harvested from one patient with chronic myelogenous leukemia (CML). The cells were thawed and acclimatized for 48 hours in StemMACS HSC Expansion Media XF (Miltenyi Biotec) supplemented with StemMACS HSC Expansion Cocktail (Miltenyi Biotec) at 37°C in a humidified atmosphere containing 5% CO2. 4 samples of 2000000 HSPCs in 2 ml media each were then prepared and treated for 24 hours: carboplatin-high: 150 µg/ml carboplatin carboplatin-low: 18.75 µg/ml carboplatin gemcitabine: 25 ng/ml gemcitabine control: no drug Single-cells were subsequently extracted using the ddSEQ™ Single-Cell Isolator (Bio-Rad) and later sequenced using the SureCell™ Whole Transcriptome Analysis 3' Library Prep Kit (Illumina) on the NextSeq 500 System (Illumina) using the NextSeq 500/550 High Output Kit v2.5 150 Cycles (Illumina) all following the manufacturer's instructions. FASTQ-files were then processed following the ddSeeker (Romagnoli, D., et al., BMC Genomics 2018, doi:10.1186/s12864-018-5249-x) and Drop-seq (Macosko, E.Z., et al., Cell 2015, doi:10.1016/j.cell.2015.05.002) protocols for processing scRNA-seq data to yield the final digital gene expression for each cell.

  Study EGAS00001004381

• Functional single-cell characterization of immune aplastic anemia shows convergence of NK and NK-like CD8+ T cells with disease-associated TCR signature

  Immune aplastic anemia (AA) is a life-threatening bone marrow (BM) failure disorder driven by an autoimmune T cell attack against the hematopoietic stem and progenitor cells (HSPCs). However, the autoantigen targets and the role of other immune cells are unknown. Here, by analyzing an international cohort of 156 AA patients with scRNA+TCRαβ-seq, TCRβ-seq, flow cytometry, and plasma cytokine profiling with comparisons to healthy controls and patients with other hematological disorders, we identify NK cells and CD8+ TEMRA cells expressing NK receptors with AA-associated TCRβ-seq motifs as the most dysregulated immune cell populations in AA BM. Functional co-culture experiments with scRNA-TCRαβ-seq readout utilizing primary HSPCs and immune cells provide evidence that NK cellscannot kill HSPCs alone, but sensitize them to CD8+ T cell-mediated killing. Furthermore, HSPCs induce strong activation of T cell clones with CD8+ TEMRA NK-like phenotype and AA-associated TCR motifs. Our results reveal the convergent evolution of innate and adaptive immune cells in AA, where NK cells support CD8+ T cell-mediated autoimmunity.

  Study EGAS00001007602

• Single-nucleus transcriptomic profiling of aging Down Syndrome brains

  Down syndrome (DS) – trisomy of human chromosome 21 (HSA21) – is characterized by lifelong cognitive impairments and development of neuropathological hallmarks of Alzheimer’s disease (AD). The cellular and molecular modifications responsible for these effects are not understood. Here we performed single-nucleus RNA-sequencing (snRNA-seq) employing both short (Illumina) and long-read (Pacific Biosciences) sequencing technologies on a total of 29 DS and non-DS control prefrontal cortex samples. In DS, the ratio of inhibitory-to-excitatory neurons was significantly increased, which was not observed in previous reports examining sporadic AD. DS microglial transcriptomes displayed AD-related aging and activation signatures in advance of AD neuropathology, with increased microglial expression of C1q complement genes (associated with dendritic pruning) and the HSA21 transcription factor gene RUNX1. Long-read sequencing detected vast RNA isoform diversity within and amongst specific cell types including numerous novel sequences that differed between DS and normal brains. Notably, over 8,000 genes produced RNAs containing intra-exonic junctions (IEJs), including APP that had previously been associated with somatic gene recombination. These and related results illuminate large-scale cellular and transcriptomic alterations as novel features of the aging DS brain.

  Study EGAS00001005691

• The identification of genetic vulnerabilities in head and neck cancers for the development of novel treatments.

  The global cancer burden is expected to double by the year 2030 and this will disproportionately affect the Asian continent. Head and neck squamous cell carcinoma (HNSCC) is endemic in Asia. It is the sixth most common cancer worldwide and the second most common in Malaysia, with approximately 600,000 new cases per year globally. Longterm survival remains less than 50%, underscoring the need for better therapeutic strategies. In this proposal we aim to bring new technological advancements in the identification of critical genes in HNSCC and the identification of compounds for the development of new therapies in HNSCC. We propose to genomically characterise 16 unique Asian H&N cancer cell lines, to classify sub groups where identification of essential genes that can be targeted for tumor control can be applied in a more rational way. Further, we propose to use zebrafish, an established drug discovery platform to identify promising pathway-specific compounds that could be further studied using CRISPR/Cas9 lethality screens and biological models to better identify novel therapeutic strategies to combat this major health problem in Asia.

  Study EGAS00001002682