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• A Proteogenomic Analysis of Clear Cell Renal Cell Carcinoma in a Chinese Population

  Clear cell renal cell carcinoma (ccRCC) is a common and aggressive subtype of renal cancer. Here we conduct a comprehensive proteogenomic analysis of 232 tumor and adjacent non-tumor tissue pairs from Chinese ccRCC patients. By comparing with tumor adjacent tissues, we find that ccRCC shows extensive metabolic dysregulation and an enhanced immune response. Molecular subtyping classifies ccRCC tumors into three subtypes (GP1–3), among which the most aggressive GP1 exhibits the strongest immune phenotype, increased metastasis, and metabolic imbalance, linking the multi-omics-derived phenotypes to clinical outcomes of ccRCC. Nicotinamide N-methyltransferase (NNMT), a one-carbon 38 metabolic enzyme, is identified as a potential marker of ccRCC and a drug target for GP1. We demonstrate that NNMT induces DNA-dependent protein kinase catalytic subunit (DNA-PKcs) homocysteinylation, increases DNA repair, and promotes ccRCC tumor growth. This study provides insights into the biological underpinnings and prognosis assessment of ccRCC, revealing targetable metabolic vulnerabilities.

  Study EGAS00001006005

• Comprehensive genomic and transcriptomic analysis of three synchronous primary tumours and a recurrence from a head and neck cancer patient

  Synchronous primary malignancies occur in a small proportion of head and neck squamous cell carcinoma patients. Here, we analysed three synchronous primaries and a recurrence from one patient, by comparing the genomic and transcriptomic profiles among the tumour samples and determining the recurrence origin. We found remarkable levels of heterogeneity among the primary tumours, and through the patterns of shared mutations, we traced the origin of the recurrence. Interestingly, the patient carried germline variants which might have predisposed him to carcinogenesis, together with a history of alcohol and tobacco consumption. Mutational signature analysis confirmed the impact of alcohol exposure, with Signature 16 present in all tumour samples. Characterisation of immune cell infiltration highlighted an immunosuppressive environment in all samples, which exceeded the potential activity of T cells. Studies such as the one described here have important clinical value and contribute to personalised treatment decisions for patients with synchronous primaries and matched recurrences.

  Study EGAS00001004857

• Combined gene expression and digital pathology identifies molecular mediators of T cell exclusion and immune suppression in ovarian cancer

  Close proximity between cytotoxic T lymphocytes and tumour cells is required for effective immunotherapy. However, what determines the spatial distribution of T cells in the tumour microenvironment is not well understood. Coupling digital pathology and transcriptome analysis on a large ovarian tumour cohort, we develop a machine learning approach to molecularly classify and characterize tumour-immune phenotypes. Our study identifies two important hallmarks characterizing T cell excluded tumours: 1) loss of antigen presentation on tumour cells and 2) upregulation of TGFb and activated stroma. Furthermore, we identify TGFb as a key mediator of T cell exclusion. TGFb reduces MHC-I expression in ovarian cancer cells in vitro; TGFb also activates fibroblasts and induced extracellular matrix (ECM) production as a potential physical barrier to hinder T cell infiltration. Our findings indicate that targeting TGFb may represent a promising strategy to overcome T cell exclusion and improve clinical benefits of cancer immunotherapy.

  Study EGAS00001003487

• Phase 1 CX-5461 Trial (Canadian Cancer Trials Group Trial IND.231)

  CX-5461 is a G-quadruplex stabilizer that exhibits synthetic lethality in homologous recombination (HR) deficient models. In this multicentre Phase Ib trial in patients with solid tumors, 40 patients were treated across 10 dose levels (50 - 650 mg/m2) to determine the recommended phase II dose (RP2D), and evaluate safety, tolerability, pharmacokinetics. Defective HR was explored as a predictive biomarker. CX-5461 was generally well tolerated, with a RP2D of 475 mg/m2 d1, 8 and 15 every 4 weeks, and dose limiting toxicities of phototoxicity. Responses were observed in 10% of patients, primarily in patients with defective HR (ORR 14%). Reversion mutations in PALB2 and BRCA2 were detected on progression following initial response in germline carriers, confirming the underlying synthetic lethal mechanism. In vitro characterization of UV sensitization showed this toxicity is related to the CX-5461 chemotype, independent of G4 synthetic lethality. These results establish clinical proof-of-concept for this first-in class G4 stabilizer.

  Study EGAS00001006173

• Atypical teratoid/rhabdoid tumoroids reveal subgroup-specific drug vulnerabilities

  Atypical teratoid/rhabdoid tumors (ATRTs) represent a rare, but aggressive pediatric brain tumor entity. They are genetically defined by mutations in SWI/SNF chromatin remodeling complex members SMARCB1 or SMARCA4. ATRTs can be subdivided in different molecular subgroups based on their epigenetic profiles. Although recent studies suggest that the different subgroups have distinct clinical features, subgroup-specific treatment regimens have not been developed thus far. This is hampered by the lack of pre-clinical in vitro models representative of the different molecular subgroups. Here, we describe the establishment of ATRT tumoroid models from the ATRT-MYC and ATRT-SHH subgroups. We demonstrate that ATRT tumoroids retain subtype-specific epigenetic and gene expression profiles. High throughput drug screens on our ATRT tumoroids revealed distinct drug sensitivities between and within ATRT subgroups. Our ATRT tumoroids represent the first pediatric brain tumor organoid model, providing representative pre-clinical models allowing for the development of subtype-specific therapies.

  Study EGAS00001006422

• Arriba: accurate and efficient detection of gene fusions from RNA-Seq (H021)

  The identification of gene fusions from RNA sequencing data is a routine task in cancer research and precision oncology. However, despite the availability of many computational tools, fusion detection remains challenging. Existing methods suffer from poor prediction accuracy and are computationally demanding. We developed Arriba, a novel fusion detection algorithm with high sensitivity and short runtime. When applied to a large collection of published pancreatic cancer samples (n=803), Arriba identified a variety of driver fusions, many of which affected druggable proteins, including ALK, BRAF, FGFR2, NRG1, NTRK1, NTRK3, RET, and ROS1. The fusions were significantly associated with KRAS wild-type tumors and involved proteins stimulating the MAPK signaling pathway, suggesting that they substitute for activating mutations in KRAS. In addition, we confirmed the transforming potential of two novel fusions, RRBP1-RAF1 and RASGRP1-ATP1A1, in cellular assays. These results demonstrate Arriba’s utility in both basic cancer research and clinical translation.

  Study EGAS00001003554

• Massively parallel single-cell B-cell receptor sequencing enables rapid discovery of diverse antigen-reactive antibodies

  Using high-throughput single-cell B-cell receptor sequencing (scBCR-seq) we obtained accurately paired full-length heavy- and light-chain variable regions from thousands of individual B cells in a massively parallel fashion. We sequenced more than 250,000 B cells from rat, mouse and human repertoires to characterize their lineages and expansion. In addition, we immunized rats with chicken ovalbumin and profiled antigen-reactive B cells from lymph nodes of immunized animals. The scBCR-seq data recovered 81% (n = 56/69) of B-cell lineages identified from hybridomas generated from the same set of B cells that were subjected to scBCR-seq. Importantly, scBCR-seq identified an additional 710 candidate lineages that were not recovered as hybridomas. We synthesized, expressed and tested 93 clones from the identified lineages and found that 99% (n = 92/93) of the clones were antigen-reactive. Our results establish scBCR-seq as a powerful tool for antibody discovery.

  Study EGAS00001003663

• Multi-omics identify falling LRRC15 as a COVID-19 severity marker and persistent pro-thrombotic signals in convalescence

  Patients with end-stage kidney disease (ESKD) are at high risk of severe COVID-19. Here, we perform longitudinal blood sampling of ESKD haemodialysis patients with COVID-19, collecting samples pre-infection, serially during infection, and after clinical recovery. Using plasma proteomics, and RNA-sequencing and flow cytometry of immune cells, we identify transcriptomic and proteomic signatures of COVID-19 severity, and find distinct temporal molecular profiles in patients with severe disease. Supervised learning reveals that the plasma proteome is a superior indicator of clinical severity than the PBMC transcriptome. We show that a decreasing trajectory of plasma LRRC15, a proposed co-receptor for SARS-CoV-2, is associated with a more severe clinical course. Strikingly, we observe that two months after the acute infection, patients still display dysregulated gene expression related to vascular, platelet and coagulation pathways, including PF4 (platelet factor 4), which may explain the prolonged thrombotic risk following COVID-19.

  Study EGAS00001006778

• Malignant progression of an ancestral bone marrow clone harboring a CIC-NUTM2A fusion in isolated myeloid sarcoma

  Myeloid sarcoma is a rare condition consisting of extramedullary myeloid blasts found in association with acute myeloid leukemia (AML) or, in the absence of bone marrow involvement. We identified an infant with isolated myeloid sarcoma whose bone marrow was negative for involvement by flow cytometry. Sequencing revealed the fusion oncogene CIC-NUTM2A and identified the sarcoma to be clonally evolved from the bone marrow which carried the fusion despite the absence of pathology. Murine modeling confirmed the ability of the fusion to transform hematopoietic cells and identified receptor tyrosine kinase signaling activation consistent with disruption of the CIC transcriptional repressor. These findings extend the definition of CIC-rearranged malignancies to include hematologic disease, provide insight into the mechanism of oncogenesis, and demonstrate the importance of molecular analysis and tracking of bone marrow involvement over the course of treatment in myeloid sarcoma, including patients that lack flow cytometric evidence of leukemia at diagnosis.

  Study EGAS00001006833

• Epigenetic landscape of mixed phenotype leukemias

  Leukemias with ambiguous lineage comprise a number of loosely defined entities, often without a clear mechanistic basis. Here, we investigated a group of such leukemias with a CpG Island Methylator Phenotype (CIMP), previously identified as CEBPA-silenced AML. Transcriptomics and epigenomics analyses revealed a hybrid myeloid/lymphoid epigenetic landscape, whereas genetic alterations were heterogenous. This suggests that CIMP leukemias are defined by their shared epigenetic profile rather than a common genetic lesion. Gene expression enrichment showed strong similarity with ETP-ALL and an early lymphoid progenitor cell of origin. Accordingly, integration of differential methylation and expression revealed widespread silencing of myeloid transcription factors (TFs), among which CEBPA was key for differentiation arrest. Hypermethylation also resulted in loss of CTCF binding, accompanied by a few changes in chromatin interactions involving critical TFs like KLF4. In conclusion, epigenetic dysregulation, and not genetic lesions, explain the mixed phenotype of a group of CIMP leukemias resembling ETP-ALL.

  Study EGAS00001007094