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• An RCOR1 loss-associated gene expression signature identifies a prognostically significant DLBCL subgroup

  Effective treatment of diffuse large B cell lymphoma (DLBCL) is plagued by heterogeneous responses to standard therapy, and molecular mechanisms underlying unfavorable outcomes in lymphoma patients remain elusive. Here, we profiled 148 genomes with 91 matching transcriptomes in an R-CHOP-treated DLBCL cohort to uncover molecular subgroups linked to treatment failure. Systematic integration of high-resolution genotyping arrays and RNA-seq data revealed novel deletions in RCOR1 to be associated with unfavorable progression free survival (P = 0.001). Integration of expression data from the clinical samples with data from RCOR1 knockdowns in the lymphoma cell lines KM-H2 and Raji yielded an RCOR1 loss-associated gene signature comprising of 233 genes. This signature identified a subgroup of patients with unfavorable overall survival (OS) (P = 0.023). The prognostic significance of the 233-gene signature for OS was reproduced in an independent cohort comprising of 195 R- CHOP treated patients (P = 0.039). Additionally, we discovered that within the IPI low risk group, the gene signature provides additional prognostic value that was independent of the cell-of-origin phenotype. Taken together, we present a novel and reproducible molecular subgroup of DLBCL, impacting risk-stratification of R- CHOP treated DLBCL patients and revealing a new avenue for therapeutic intervention strategies.

  Study EGAS00001001000

• Clonal selection and double hit events involving tumor suppressor genes underlie relapse from total therapy

  In order to gain insights into the mechanisms of disease progression in multiple myeloma (MM) patients treated with multi-agent and high-dose chemotherapy we have performed a longitudinal study of 33 patients entered into Total Therapy protocols using gene expression profiling, high resolution copy number analyses and whole exome sequencing. The results of this study show the importance of acquired mutations in MM driver genes, bi-allelic events affecting tumor suppressor genes and increased proliferation rates in driving relapse, which is enhanced by intra-clonal heterogeneity and Darwinian type clonal evolution. Branching was the most frequent evolution pattern, characterized by clonal loss and appearance of new clones. We found a higher number of lost and acquired copy number aberrations and an excess of bi-allelic inactivation of tumor suppressor genes in GEP70 high risk (HiR) cases, consistent with genomic instability being a key feature of HiR MM. In conclusion, our study further stresses the impact of known prognostic markers and driver genes on the fitness level of MM cells to survive multi-agent chemotherapy. The frequent bi-allelic loss of tumor suppressor genes in HiR cases and the potentially resulting failure of treatment with DNA damaging agents highlight the need for new therapies for HiR MM.

  Study EGAS00001001810

• The Molecular Landscape of Asian Breast Cancers Reveals Clinically Relevant Population-Specific Differences

  Molecular profiles of breast cancer have contributed to an improved understanding of the disease, enabled development of molecular prognostic signatures to guide treatment decisions and unveiled new or more accurate therapeutic options for breast cancer patients. However, the extent to which differences in genetic, environmental and lifestyle factors influence molecular profiles in different populations remains poorly characterised, as relatively few large-scale molecular studies of breast tumours in non-Caucasian populations have hitherto been reported. Here, we present the molecular profiles of 560 Asian breast tumours and a comparative analysis of breast cancers arising in Asian and Caucasian women. Compared to the breast tumours in predominantly Caucasian women reported in TCGA and METABRIC, we show an increased prevalence of Her2-enriched molecular subtypes and higher prevalence of TP53 somatic mutations in ER+ Asian breast tumours. Using gene expression and immunohistochemistry, we observed elevated immune scores in Asian breast tumours, suggesting potential clinical response to immune checkpoint inhibitors. Whilst Her2-subtype and enriched immune score are associated with improved survival, presence of TP53 somatic mutations is associated with poorer survival in ER+ tumours. Taken together, these population differences unveil new opportunities to improve the understanding of this disease and lay the foundation for precision medicine in different populations.

  Study EGAS00001004518

• A recessive PRDM13 mutation results in congenital hypogonadotropic hypogonadism and cerebellar hypoplasia

  The PRDM13 (PR Domain containing 13) putative chromatin modifier and transcriptional regulator functions downstream of the transcription factor PTF1A, which controls GABAergic fate in the spinal cord and neurogenesis in the hypothalamus. Here, we report a novel, recessive syndrome associated with PRDM13 mutation. Patients exhibited intellectual disability, ataxia with cerebellar hypoplasia, scoliosis and delayed puberty with congenital hypogonadotropic hypogonadism (CHH). Expression studies revealed Prdm13/PRDM13 transcripts in the developing hypothalamus and cerebellum in mouse and human. An analysis of hypothalamus and cerebellum development in mice homozygous for a Prdm13 mutant allele revealed a significant reduction in the number of Kisspeptin (Kiss1) neurons in the hypothalamus and PAX2+ progenitors emerging from the cerebellar ventricular zone. The latter was accompanied by ectopic expression of the glutamatergic lineage marker TLX3. Prdm13-deficient mice displayed cerebellar hypoplasia, normal gonadal structure, but delayed pubertal onset. Together, these findings identify PRDM13 as a critical regulator of GABAergic cell fate in the cerebellum and of hypothalamic kisspeptin neuron development, providing a mechanistic explanation for the co-occurrence of CHH and cerebellar hypoplasia in this syndrome. To our knowledge, this is the first evidence linking disrupted PRDM13-mediated regulation of Kiss1 neurons to CHH in humans.

  Study EGAS00001005878

• T cell landscape definition by multi-omics identifies galectin-9 as novel immunotherapy target in chronic lymphocytic leukemia (CLL)

  Failure of immunotherapy after applying checkpoint inhibitors or CAR-T cells is linked to T cell exhaustion. Here, we explored the T cell landscape in chronic lymphocytic leukemia (CLL) by single-cell omics analyses of blood, bone marrow and lymph node samples of patients and spleen samples of a CLL mouse model. By single-cell RNA- sequencing, mass cytometry (CyTOF), and multiplex image analysis of tissue microarrays, we defined the spectrum of phenotypes and transcriptional programs of T cells and and their differentiation state trajectories. We identified disease-specific accumulation of distinct regulatory T cell subsets and T cells harboring an exhausted phenotype exclusively in the CLL lymph node tissue. Integration of TCR data revealed a clonal expansion of CD8+ precursor exhausted T cells, suggesting their reactivity for CLL cells. Interactome analyses identified the TIM3 ligand Galectin-9 as novel immunoregulatory molecule in CLL. Blocking of Galectin-9 in CLL-bearing mice slowed down disease development and reduced the number of TIM3 expressing T cells. Galectin-9 expression correlated with shorter survival of CLL patients. Thus, Galectin-9 contributes to immune escape in CLL and represents a novel target for immunotherapy.

  Study EGAS00001006864

• Long-term organoid culture of a small intestinal neuroendocrine tumor

  Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are rare and highly heterogeneous neoplasms whose incidence has markedly increased over the last decades. A grading system based on the tumor cells' proliferation index predicts high-risk for G3 NETs. However, low-to-intermediate grade (G1/G2) NETs have an unpredictable clinical course that varies from indolent to highly malignant. Cultures of human cancer cells enable to perform functional perturbation analyses that are instrumental to enhance our understanding of cancer biology. To date, no tractable and reliable long-term culture of G1/G2 NET has been reported to permit disease modeling and pharmacological screens. Here, we report of the first long-term culture of a G2 metastatic small intestinal NET that preserves the main genetic drivers of the tumor and retains expression patterns of the endocrine cell lineage. Replicating the tissue, this long-term culture showed a low proliferation index, and yet it could be propagated continuously without dramatic changes in the karyotype. The model was readily available for pharmacological screens using targeted agents and as expected, showed low tumorigenic capacity in vivo. Overall, this is the first long-term culture of NETs to faithfully recapitulate many aspects of the original neuroendocrine tumor.

  Study EGAS00001007093

• Lysosomal Disease Network (LDN6719) Immune Response to Intrathecal Enzyme Therapy in Mucopolysaccharidosis 1 Patients

  In this study we characterized the immune response to intrathecal (IT) recombinant human alpha-L-iduronidase (rhIDU) in mucopolysaccharidosis I (MPS I) subjects with spinal cord compression who had been previously treated with intravenous rhIDU. Concentrations of specific antibodies and cytokines were measured in serum and cerebrospinal fluid (CSF) collected before monthly IT rhIDU infusions. These serologic findings were compared with clinical adverse event (AE) reports to establish temporal correlations with clinical symptoms. We found that IT rhIDU was generally well tolerated in the subjects studied although one subject had moderate to severe clinical symptoms and serologic abnormalities consistent with an immune response.

  Study phs000862

• Whole Exome Sequencing and RNA Sequencing of High Grade Serous Ovarian Cancer in Black and White Patients

  In this study, we generated new RNA and whole exome sequencing data from high-grade serous ovarian cancer tumor samples of self-identified Black and White individuals. Our RNA-Seq analysis revealed that, while the prevalence of subtypes varied across racial groups, the cluster-specific gene expression patterns were consistent. Despite these differences in subtype prevalence, the subtype-specific survival rates were similar across racial groups. Additionally, we used the WES-Seq data to characterize mutational signatures and their underlying causes in Black high-grade serous ovarian cancer (HGSC) cases, and compared the prevalence and distribution of these signatures with those in White TCGA cases.

  Study phs003632

• HuBMAP: High Resolution 3D Mapping of Cellular Heterogeneity Within Multiple Types of Mineralized Tissues

  The overall goal of the study was to generate 3D single cell maps of healthy human knee cartilage. Articular cartilage from the weightbearing and non-weightbearing regions of the femoral condyles in healthy knees from young donors (n=12) was analyzed by bulk RNA-sequencing (RNA-Seq), single nuclei RNA (snRNA-seq) and ATAC-sequencing and by spatial transcriptomic methods (GeoMx, MERFISH and Xenium). These multimodal data and additional single cell RNA-sequencing (scRNA-seq) data were integrated to generate a comprehensive molecular, genomic and function annotation of chondrocyte populations. Regulatory mechanisms were derived by linking motifs in expressed genes, transcription factors and chromatin organization.

  Study phs003721

• ISCAPE V(D)J libraries from HA-specific single memory B cells and personalized IGM, IGK, IGL V(D)J repertoire sequencing of four Influenza A exposed individuals

  Peripheral blood mononuclear cells were used to produce paired, full-length IGM, IGK and IGL V(D)J libraries from HA-binding single memory B cells using the ISCAPE (Individualized Single Cell Analysis of Paired Expressed antigen receptors) technique. Locus-specific multiplexed nested PCR with 5’ leader IGHV/IGKV/IGLV and 3’ constant IGG/IGK/IGL primer mixtures was performed before well and plate indexing and paired chain sequencing with an Illumina MiSeq instrument. Expressed total IGM, IGK and IGL V(D)J libraries from each donor were generated to define personalized IG allele content.

  Study EGAS50000001390

• PRADO trial - Personalized response-directed surgery and adjuvant therapy after neoadjuvant ipilimumab plus nivolumab in stage III melanoma

  The PRADO trial tested a personalized response-directed treatment approach based on the pathologic response after neoadjuvant ipilimumab plus nivolumab in stage III melanoma patients. In patients achieving a major pathologic response, in their index lymph node (the largest lymph node metastasis at baseline), therapeutic lymph node dissection (TLND) and adjuvant therapy were omitted. Patients with partial response underwent TLND only, whereas patients with pathologic non-response underwent TLND and adjuvant systemic therapy ± synchronous radiotherapy. Biomarker analyses based on baseline RNA sequencing data were performed in order to find features that are associated with major pathologic response.

  Study EGAS00001007601

• Somatic Mutation in Normal Bladder Study

  Adult human somatic tissues are landscapes of mutant clones, but little is known about how these landscapes are shaped by known cancer risk factors. The goal of this study was to determine how the main bladder cancer risk factors (sex and smoking) change the mutational landscape of the normal urothelium. We collected normal urothelium from 45 donors at autopsy by brushing ~2cm² of the surface epithelium in the upper part (dome) and lower part (trigone) of the bladder (79 samples total). To identify mutations with high sensitivity we employed ultradeep (~5000x) DNA error-correcting duplex-sequencing on a panel of 15 protein coding genes and the TERT promoter, previously described to be under positive selection in normal urothelium or relevant to bladder cancer. We identified thousands of clonal driver mutations, which demonstrate pervasive positive selection in the normal urothelium. Males showed a significantly higher number of driver truncating mutations in RBM10, CDKN1A and ARID1A, despite similar rates of non-coding mutations, indicating stronger positive selection and clonal expansion in the male urothelium. We also discovered clonal expansions driven by activating TERT promoter mutations in the normal bladder, which were strongly associated with age and smoking. These results demonstrate that sex and smoking shape the clonal landscape of the normal bladder and indicate that the high mutational content of normal tissues might be leveraged to study the effect of mutations in vivo (i.e. natural saturation mutagenesis). We will deposit in dbGaP de-identified relevant clinical information from the 45 donors and the fastq files derived from duplex sequencing of the 79 samples in the study. We will also deposit fastq files derived from duplex sequencing of 3 control cord blood samples.

  Study phs004105

• Development and validation of multivariate predictors of primary endocrine resistance to tamoxifen and aromatase inhibitors in luminal breast cancer reveal drug-specific differences

  Background: Endocrine therapy is highly effective in blocking the estrogen receptor pathway in HR+/HER2- early breast cancer (EBC). However, up to 40% of patients experience relapse during or after adjuvant endocrine therapy. Here, we investigate molecular mechanisms associated with primary resistance to endocrine therapy and develop predictive models. Results: TP53 mutations were prominently associated with primary resistance to both tamoxifen (TAM) and aromatase inhibitors (AI), with AI non-responders exhibiting resistance in up to 32% of cases. Additionally, we identified distinct DNA methylation patterns in TAM and AI non-responders, with TAM non-responders showing global DNA methylation loss, associated with KRAS signaling, apical junctions and epithelial-mesenchymal transition (EMT). Conversely, we observed methylation gain in AI non-responders affecting developmental transcription factors, hypoxia and estrogen signaling. TAM or AI resistance was associated with increased methylation-inferred proportions of immune cells and decreased proportions of endothelial cells. Based on these findings and patient age, we developed the Predictive Endocrine ResistanCe Index (PERCI). PERCI stratified NR and R cases in both treatment groups and cohorts with high accuracy (ROC AUC TAM discovery 93.9%, validation 83%; AI discovery 98.6%, validation 76.9%). A simplified PERCI efficiently predicted progression-free survival in the TCGA-BRCA sub-cohort (Kaplan-Meier log-rank p-value = 0.03 between low and high PERCI groups). Conclusions: We identified genomic and epigenomic features associated with primary resistance to TMA and AI. By combining information on genomic alterations, patient age, differential methylation and tumor microenvironment (TME) composition, we developed PERCI TAM and PERCI AI as novel predictors of primary resistance, with potential additional prognostic value. Applying PERCI in a clinical setting may allow patient-specific drug selection to overcome resistance.

  Study EGAS50000001102

• ICARUS-LUNG01-ExomeSeq

  Whole exome sequencing (WES) on frozen tumor biopsies at BL to identify genomic alterations associated with response/resistance. Non- synonymous point mutations, indels, homozygous deletions, loss of heterozygosity (LOH) and low, medium, and high-level amplifications were assessed.

  Study EGAS50000000733

• MEMORI WES bams

  This project stores bam files from deep whole exome sequencing from oesophageal adenocarcinoma at different timepoints during neoadjuvant treatment (prior, during, post treatment), which were used to analyse evolutionary and phenotype dynamics in oesophageal adenocarcinoma during neoadjuvant treatment.

  Study EGAS50000000240

• 10Xchromium 3' RNA-seq of 21 samples from human embryonic heart

  21 samples were taken from human embryonic heart of PCW 5.5-14 of a total of 13 fetuses. Samples were subject to 10Xgenomics chromium single cell 3' sequencing version 2 or 3. Data was analyzed using STARSolo version 2.7.10a, using human genome GRCh38.p12 and transcript annotations from ENSEMBL release 93 from reference package GRCh38-3.0.0 as available from 10Xgenomics.

  Dataset EGAD50000001499

• Genomic Profiling Reveals Heterogeneous Populations of Ductal Carcinoma In Situ

  Whole Exome Sequencing(WES) and copy number variation(CNV) analysis were performed using breast samples collected from non-invasive breast cancer patients in order to analysis of somatic mutations related to breast tumor phenotypes.

  Study JGAS000202

• ChIP-seq data of Hodgkin lymphoma cell line L-428

  ChIP-seq data (H3K4Me3, H3K27Ac histone modifications) of Hodgkin lymphoma cell line L-428. Samples were processed as previously described (Sud et al., 2018). The files are in bam format, aligned to build 37.

  Study EGAS00001003033

• (h)MeDIP-Seq of high-risk prostate cancer

  Immunoprecipitation of methylated and hydroxymethylated DNA was performed on DNA isolated from tumoral and non-tumoral prostate tissue of patients with high-risk disease. Samples were sequenced on the Illumina HiSeq as 50 bp single end.

  Study EGAS00001001019

• Microbial signatures and innate immune gene expression in lamina propria phagocytes of inflammatory bowel diseases patients

  The microbial populations associated with the lamina propria phagocyte population in CD and UC patients was examined. Specifically, the differences between phagocyte-associated microbiota (PAM) and mucosa-associated microbiota were determined.

  Study EGAS00001003105

• GWAS in bullous pemphigoid in Germans

  Genome-wide association study of bullous pemphigoid in Germans, using 446 BP patients and 433 age- and sex- matched controls. 6 SNPs in the HLA locus were found to be of genome-wide significance.

  Study EGAS00001004627

• BCSA_Exome+SmartSeq3

  Multiple regions were cut out of each tumor extracted form breast cancer patients and two experiments were run: - Whole exome sequencing on each of the regions plus an adjacent normal tissue sample - Smart-Seq3 Single cell RNA sequencing on EPCAM+ CD45- sorted cells from different tumor regions

  Dataset EGAD00001009781

• BulkTCR-sequencing data from different human intestinal CD8 T cell subsets.

  5000 cells of each subset of CD8 T cells (CD103-KLRG1+, CD103-KLRG1- and CD103+ from LP and CD103+ IELs) were sorted into tubes. A modified SMART protocol was used in first-strand cDNA synthesis, and TCRalpha / TCRbeta genes were amplified in two rounds of semi-nested PCR reaction, following the method described in detail in Risnes et al., 2018.

  Dataset EGAD00001005049

• Next Generation Sequencing Characterization of Tregs in Human Peripheral Blood during Autoimmunity

  Tregs were sorted as CD4+CD25+CD127- cells from peripheral blood of 14 healthy individuals, 8 patients with systemic lupus erythematosus, 9 patients with rheumatoid arthritis, and 11 patients with multiple sclerosis. RNA was extracted and polyA libraries were prepared using the Illumina Truseq sample preparation kit v.2. Single-end sequencing was performed on NextSeq500.

  Dataset EGAD00001006193

• Morphological and gene expression changes in SCA1 cerebral organoids suggest neurodevelopmental disease characteristics

  Cerebral organoids were generated from controls, individuals with SCA1 and gene-edited SCA1 hiPS cells. At day 31 and day 60, RNA sequencing was performed showing differential of several genes involved in neural development.

  Study EGAS50000001720