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• Pharmacogenomic analysis of patient-derived tumor cells in gynecologic cancers

  Gynecologic malignancy is one of the leading causes of mortality in female adults worldwide. Comprehensive genomic analysis has revealed a list of molecular aberrations that are essential to tumorigenesis, progression, and metastasis of gynecologic tumors. However, targeting such alterations has frequently led to treatment failures due to underlying genomic complexity and activation of various tumor cell survival pathway molecules. A compilation of molecular characterization of tumors with pharmacological drug response is the next step towards clinical application of patient-tailored treatment regimens. Toward this goal, we have established a library of 139 gynecologic tumors including cervical, endometrial, and epithelial ovarian cancers (EOCs) and uterine sarcomas that were genomically and/or pharmacologically annotated and explored dynamic pharmacogenomic associations against 37 molecularly targeted drugs. We discovered lineage-specific drug sensitivities based on subcategorization of gynecologic tumors and identified TP53 mutation as a molecular determinant that elicit therapeutic response to poly (ADP-Ribose) polymerase (PARP) inhibitor. We further identified transcriptome expression of inhibitor of DNA biding 2 (ID2) as a potential predictive biomarker for treatment response to olaparib. Together, our results demonstrate potential utility of rapid drug screening combined with genomic profiling for precision treatment of gynecologic cancers.

  Study EGAS00001003556

• An Atlas of Cells in the Human Tonsil

  Palatine tonsils are secondary lymphoid organs representing the first line of immunological defense against inhaled or ingested pathogens. Here, we provide a comprehensive census of cell types forming the human tonsil by applying single cell transcriptome, epigenome, proteome and adaptive immune repertoire as well as spatial transcriptomics, resulting in an atlas of >350,000 cells. We provide a glossary of over one hundred annotated cell types and states, and disentangle gene regulatory mechanisms that drive cells through specialized lineage trajectories. Exemplarily, we stratify multiple tonsil-resident myeloid slancyte subtypes, establish a distant BCL6 superenhancer as locally active in both follicle-associated T and B cells, and describe SIX5 as a potentially novel transcriptional regulator of plasma cell maturation. Further, our atlas is a reference map to understand alterations observed in disease, here we discover immune-phenotype plasticity in tumoral cells and microenvironment shifts of mantle cell lymphomas (MCL). To facilitate such reference-based analysis, we develop HCATonsilData and SLOcatoR, a computational framework that provides programmatic and modular access to our dataset; and allows the straightforward annotation of future single-cell profiles from secondary lymphoid organs.

  Study EGAS00001006375

• Genome‐wide postnatal changes in immunity following fetal inflammatory response

  The fetal inflammatory response (FIR) increases the risk of perinatal brain injury, particularly in extremely low gestational age newborns (ELGANs, < 28 weeks of gestation). One of the mechanisms contributing to such a risk is a postnatal intermittent or sustained systemic inflammation (ISSI) following FIR. The link between prenatal and postnatal systemic inflammation is supported by the presence of well‐established inflammatory biomarkers in the umbilical cord and peripheral blood. However, the extent of molecular changes contributing to this association is unknown. Using RNA sequencing and mass spectrometry proteomics, we profiled the transcriptome and proteome of archived neonatal dried blood spot (DBS) specimens from 21 ELGANs. Comparing FIR‐affected and unaffected ELGANs, we identified 782 gene and 27 protein expression changes of 50% magnitude or more, and an experiment‐wide significance level below 5% false discovery rate. These expression changes confirm the robust postnatal activation of the innate immune system in FIR‐affected ELGANs and reveal for the first time an impairment of their adaptive immunity. In turn, the altered pathways provide clues about the molecular mechanisms triggering ISSI after FIR, and the onset of perinatal brain injury.

  Study EGAS00001003635

• Pan-neuroblastoma analysis reveals age- and signature-associated driver alterations

  Neuroblastoma is a pediatric malignancy with heterogeneous clinical outcomes depending on age and other factors. To better understand neuroblastoma pathogenesis, here we analyze whole-genome, whole-exome and/or transcriptome sequencing data from 702 neuroblastoma samples, half of which are new data. Over 95% of samples harbor at least one recurrent driver alteration and most aberrations, including MYCN, ATRX, and TERT alterations, differ in frequency by age. MYCN alterations occur at median 2.3 years of age, TERT at 3.8 years, and ATRX at 5.6 years, suggesting age-specific susceptibility to genetic alterations. Mutational signature analysis shows that reactive oxygen-species (ROS)-induced mutations are the most common cause of single nucleotide variant (SNV) drivers in neuroblastoma, including most ALK and Ras pathway SNVs. ROS-induced mutagenesis is both an early event, as it causes truncal variants, and continuous as it also induces relapse-specific mutations. ROS-induced mutations are more abundant in neuroblastomas with MYCN amplification, 17q gains, and increased expression of mitochondrial ribosome genes. We observe recurrent FGFR1 N546K or internal tandem duplication variants in 6 patients and ALK N-terminal structural alterations in 5 samples, identifying additional patients amenable to precision therapy.

  Study EGAS00001003931

• One-step generation of tumor models by base editor multiplexing in adult stem cell-derived organoids

  Recent optimization of CRISPR/Cas9-mediated genome engineering has resulted in the development of base editors that can efficiently mediate C>T and A>G transitions. Combining these genome engineering tools with human adult stem cell (ASC)-derived organoid technology holds promise for disease modeling. Here, we demonstrate the application of base editors for the generation of complex tumor models in human ASC-derived hepatocyte, endometrial and intestinal organoids. First, using conventional and evolved Cas9-variants, we show efficacy of both cytosine and adenine base editors and use them to model four hot-spot point mutations in CTNNB1 in hepatocyte organoids. Next, we apply C>T base editors in endometrial organoids to insert nonsense mutations in PTEN and demonstrate tumorigenicity even in the heterozygous state. Furthermore, we use cytosine base editors for simultaneous oncogene activation (PIK3CA) and tumor-suppressor inactivation (APC and TP53). To increase the flexibility of base editor multiplexing, we then combine SpCas9 and SaCas9 base editors for simultaneous C>T and A>G editing at individual target sites. Finally, we show the power of base editor multiplexing by modeling colorectal tumorigenesis in a single step by simultaneously transfecting sgRNA’s targeting four cancer genes. Seven clonal organoid lines and one bulk wild-type control sample were paired-end whole-genome sequenced using the Illumina Novaseq 6000 system. We sequenced four clonal intestinal organoid lines harbouring engineered TP53 and FBXW7 mutations as well as three lines targeted for oncogenic APC/TP53/PIK3CA/SMAD4 mutations. This WGS showed, as previously reported, a genome-wide increase in C>T mutations due to C>T base editor off-target activity, which is not enriched in predicted off-target regions based on the sgRNA sequences. Furthermore, we confirmed the absence of editing-induced driver mutations and lack of off-target mutational hotspots created by the genomic engineering.

  Study EGAS00001006886

• A single-cell multi-omic atlas of nodal B-cell non-Hodgkin lymphomas

  CITE-Seq (cellular indexing of transcriptomes and epitopes) of 51 lymph node (LN) samples from including mantle cell lymphoma (MCL, n = 8), follicular lymphoma (FL, n = 12), germinal center (GCB, n = 5) or activated B-cell (non-GCB/ABC, n = 7) diffuse large B-cell lymphoma (DLBCL), and marginal zone lymphomas (MZL, n = 11), in addition to non-malignant reactive lymph nodes (rLN, n = 8). Of the malignant LN samples, 20 were collected at the time of initial diagnosis and 23 were from patients who had previously undergone one or more lines of systemic treatment. Relapse samples were collected at least 3 months after cessation of systemic treatment. This dataset also includes 5 prime RNA sequencing and immune receptor sequencing (10X Genomics) for 11 of these samples (2 rLN, 2 MCL, 3 FL, 2 DLBCL (GCB) and 2 MZL).

  Dataset EGAD50000000497

• RNA sequencing from patient-derived intestinal organoids

  uman duodenal tissues for establishing organoid cultures used in this study were sourced from de-identified surgical specimens (n = 3) of the duodenum obtained from patients who had undergone biopsy procedures unrelated to CeD at Tampere University Hospital. The protocol was approved by the Ethics Committee of Tampere University Hospital, Tampere, Finland (ETL code R18082). RNA from the duodenal organoids was isolated using an RNeasy Kit (Qiagen, Hilden, Germany) following the manufacturer’s instructions. RNA purity and concentration were measured using a NanoDrop One spectrophotometer (NanoDrop Technologies, Wilmington, Delaware, USA). Preparation of the RNA library and transcriptome sequencing was conducted by Novogene Co., LTD (Cambridge, UK). Messenger RNA was purified from total RNA using polyA selection and subjected to library construction. Sequencing was performed on an Illumina platform, and 150 bp paired-end reads were generated.

  Dataset EGAD50000000492

• Single nuclei ATAC-Seq data from the human ganglionic eminences

  Data generated through single nuclei ATAC sequencing on whole ganglionic eminences from 3 human fetuses (two of 16 and one of 17 gestational weeks). Tissue was acquired from the MRC-Wellcome Trust Human Developmental Biology Resource with ethical approval. snATAC-Seq libraries were prepared from ~8,000 nuclei per sample using Chromium Next GEM Single Cell ATAC (v1.1) reagents (10X Genomics). Quality control of libraries was performed using the Agilent 5200 Fragment Analyzer before sequencing on an Illumina NovaSeq 6000 to a depth of at least 617 million read pairs per library. Raw sequencing data were converted into FASTQ files. For a full description of data generation, please see Cameron et al, Schizophrenia Bulletin 2024, https://doi.org/10.1093/schbul/sbae083. Please note that 10X generated BAM files, rather than FASTQ files, have been uploded. FASTQ files can be regenerated using the 10X Genomics bamtofastq tool. https://support.10xgenomics.com/docs/bamtofastq

  Dataset EGAD50000000601

• Longitudinal single-cell transcriptomic study in patient-derived xenografts of pediatric T-ALL

  In this study, we conducted single cell full length total RNA sequencing (VASA-seq) on 13 matched pediatric T-ALL PDX samples at initial diagnosis and relapse, along with 5 non-relapsing PDX samples collected at initial diagnosis. We identified a subpopulation of T-ALL cells with stem-like cell features that expands substantially at relapse indicating resistance to first-line therapy. Chemotherapy resistance was further validated through functional testing: Two samples were subjected to in-vitro drug testing, treated with Cytarabine for three days, followed by single-cell transcriptomic analysis using 10x Genomics. Additionally, in-vivo drug testing was conducted on one sample, involving re-engraftment into mice and treatment with a combination of Vincristine, Doxorubicin, and Dexamethasone. Single-cell transcriptomic analysis using 10x Genomics was performed after 0, 15 and 30 days of treatment.

  Dataset EGAD50000000831

• EOSC4Cancer Longitudinal Synthetic Colorectal Cancer Genomic data developed at BSC

  The synthetic genomes have been created trying to mimic real cancer data of 4 patients (Named 185,186,187 and 188). Mutations are based on real CRC patients from the PCAWG dataset. For each patient, two tumor samples at different time points and one healthy sample have been simulated. The cancer intra-tumor heterogeneity and evolution in the patients is depicted by simulating reads from tumor subclones separately and then mixing them according to their clonal proportions in each sample. For rapid use and transfer only selected chromosomes have been generated for each patient. Chromosomes per patient: -185: chr4, chr5, chr7, chr17 -186: chr1, chr7, chr12, chr17 -187: chr1, chr2, chr5, chr12, chr17 -188: chr2, chr5, chr12, chr13, chr17 Worflows used to create BAM/BAI, VCF and MAF files from FASTQ (Alignment with GRCh38): - https://usegalaxy.eu/published/workflow?id=2c3d05023c02113e - https://usegalaxy.eu/published/workflow?id=1da86d74f8535f4e

  Dataset EGAD50000000276