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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

• Molecular and functional profiling of plasmablastic lymphoma

  Plasmablastic lymphoma (PBL) represents a rare and aggressive lymphoma subtype frequently associated with immunosuppression. Clinically, patients with PBL are characterized by poor outcome. The current understanding of the molecular pathogenesis is limited. A hallmark of PBL represents its plasmacytic differentiation with loss of B-cell markers and, in 60% of cases, its association with Epstein-Barr virus (EBV). Roughly 50% of PBLs harbor a MYC translocation. Here, we provide a comprehensive integrated genomic analysis using whole exome sequencing (WES) and genome-wide copy number determination in a large cohort of 96 primary PBL samples. We identify alterations activating the RAS-RAF, JAK-STAT, and NOTCH pathways as well as frequent high-level amplifications in MCL1 and IRF4. The functional impact of these alterations is assessed using an unbiased shRNA screen in a PBL model. These analyses identify the IRF4 and JAK-STAT pathways as promising molecular targets to improve outcome of PBL patients.

  Study EGAS00001004659

• A comprehensive characterization of the cell-free transcriptome reveals tissue- and subtype-specific biomarkers for cancer detection

  Cell-free RNA (cfRNA) is a promising analyte for cancer detection. However, a comprehensive assessment of cfRNA in individuals with and without cancer has not been conducted. We performed the first transcriptome-wide characterization of cfRNA in cancer (stage III breast [n=46], lung [n=30]) and non-cancer (n=89) participants from the Circulating Cell-free Genome Atlas (NCT02889978). Of 57,820 annotated genes, 39,564 (68%) were not detected in cfRNA from non-cancer individuals. Within these low-noise regions, we identified tissue- and cancer-specific genes, defined as "dark channel biomarker" (DCB) genes, that were recurrently detected in individuals with cancer. DCB levels in plasma were correlated with tumor shedding rate and RNA expression in matched tissue, suggesting that DCBs with high expression in tumor tissue could enhance cancer detection in patients with low levels of circulating tumor DNA. Overall, cfRNA provides a unique opportunity to detect cancer, predict the tumor tissue of origin, and determine the cancer subtype.

  Study EGAS00001004704

• Genomic analysis of a hypermutated gliosarcoma

  Gliosarcoma is a variant of glioblastoma with equally poor prognosis and characterized by mixed glial and mesenchymal pathology. Metastasis is not uncommon but involvement of the spinal cord is rare, and comprehensive genetic characterization of spinal gliosarcoma is lacking. We describe a patient initially diagnosed with a low-grade brain glioma via biopsy, followed by adjuvant radiation and temozolomide treatment. Nearly two years after diagnosis, she developed neurological deficits from an intradural, extramedullary tumor anterior to the spinal cord at T4, which was resected and diagnosed as gliosarcoma. Whole-exome sequencing (WES) of this tumor revealed a hypermutated phenotype, characterized by somatic mutations in key DNA mismatch repair (MMR) pathway genes, an abundance of C>T transitions within the identified somatic SNVs, and microsatellite stability, together consistent with temozolomide-mediated hypermutagenesis. This is the first report of a hypermutator phenotype in gliosarcoma, which may represent a novel genomic mechanism of progression from lower-grade glioma.

  Study EGAS00001004864

• RNA-seq on patient-derived, stage II, CRC cell lines

  The gut microbiome is a key player in the immunomodulatory and pro-tumorigenic microenvironment in colorectal cancer (CRC). It is well established that Fusobacterium’s virulence factors are responsible for its pro-tumorigenic properties, however the role of its metabolic cross-talk with the tumor remains unexplored. Here we use in vitro, in vivo, and in silico methods to describe a novel microbe-host interaction keystone: formate. Omics data reveals molecular signatures, linking a metabolically driven CRC phenotype with Fusobacteria. We observed a metabolic shift towards increased F. nucleatum formate secretion in gut-on-chip model co-cultures with patient-derived CRC cells, along with an accelerated cancer glutamine metabolism. We show that high formate levels trigger AhR signaling, increase cancer stemness and cellular invasion. Finally, we observed an expansion of Th17 cells accompanying F. nucleatum-induced tumorigenesis. Moving beyond observational studies, we applied new experimental approaches for gaining ecosystem-level mechanistic understanding of F. nucleatum’s role in cancer pathogenesis.

  Study EGAS00001005948

• Human genome-wide variations in the Massim region

  The Massim, a cultural region encompassing the southeastern tip of mainland Papua New Guinea (PNG) and nearby islands, is famous for the Kula trading network, in which different valuables circulate in different directions among the islands. To explore Massim genetic history, we generated genome-wide data from across the region and found variable levels of Papuan-related (indigenous) ancestry, including a novel ancestry associated with Rossel Island, and Austronesian-related ancestry that arrived later. We find genetic evidence for different patterns of contact across PNG, the Massim, and the Bismarck and Solomon Archipelagoes for Austronesian-related vs. Papuan-related ancestry, with more geographic restriction for the latter. Moreover, Kula-practicing groups share more genetic similarity than do other groups, and this likely predates the origin of Kula, suggesting that high between-group contact facilitated the formation of Kula. Our study provides the first comprehensive genome-wide assessment of Massim inhabitants and new insights into the fascinating Kula system.

  Study EGAS00001006010

• 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

• Molecular Profiling Reveals Unique Immune and Metabolic Features of Melanoma Brain Metastases

  There is a critical need to improve our understanding of the pathogenesis of -melanoma brain metastases (MBM). Thus, we performed RNA sequencing on 88 resected MBMs and 42 patient-matched extracranial metastases; tumors with sufficient tissue also underwent whole-exome sequencing, T-cell receptor sequencing, and IHC. MBMs demonstrated heterogeneity of immune infiltrates that correlated with prior radiation and post-craniotomy survival. Comparison with patient-matched extracranial metastases identified significant immunosuppression and enrichment of oxidative phosphorylation (OXPHOS) in MBMs. Gene-expression analysis of intracranial and subcutaneous xenografts, and a spontaneous MBM model, confirmed increased OXPHOS gene expression in MBMs, which was also detected by direct metabolite profiling and [U-13C]-glucose tracing in vivo IACS-010759, an OXPHOS inhibitor currently in early-phase clinical trials, improved survival of mice bearing MAPK inhibitor-resistant intracranial melanoma xenografts and inhibited MBM formation in the spontaneous MBM model. The results provide new insights into the pathogenesis and therapeutic resistance of MBMs.

  Study EGAS00001003672

• Multimodal Epigenetic Sequencing Analysis (MESA) of Cell-free DNA for Non-invasive Cancer Detection

  Multimodal characterization of cell-free DNA (cfDNA) in the blood can enable the sensitive and non-invasive detection of human cancers but remains technically challenging and costly. Here, we developed Multimodal Epigenetic Sequencing Analysis (MESA), a flexible and sensitive method of capturing and integrating multimodal epigenetic information of cfDNA using a single experimental assay, i.e., non-disruptive bisulfite-free methylation sequencing, such as Enzymatic Methyl-seq (EM-seq) and TET-assisted pyridine borane sequencing (TAPS). MESA can simultaneously infer cfDNA methylation, nucleosome occupancy, nucleosome fuzziness, and fragmentation profile for regions surrounding the promoters and polyadenylation sites (PASs). MESA’s integrated analysis of multimodal epigenetic features significantly improved the performance of cancer detection models compared to the usage of any single modality alone. MESA captures additional and highly complementary epigenetic information from cfDNA without additional experimental assays, highlighting the importance and clinical prospect of using multimodal epigenetic features for non-invasive cancer detection

  Study EGAS00001006462

• Adult human kidney organoids originate from CD24+ cells and represent an advanced model for adult polycystic kidney disease

  Adult kidney organoids have been described as strictly tubular epithelial and termed tubuloids. While the cellular origin of tubuloids has remained elusive, here we report that they originate from a distinct CD24+ epithelial subpopulation. Long-term-cultured CD24+-derived tubuloids represent a functional human kidney tubule. We show that kidney tubuloids can be used to model the most common inherited kidney disease, namely autosomal dominant polycystic kidney disease (ADPKD), reconstituting the phenotypic hallmark of this disease with cyst formation. Single-cell RNA sequencing of CRISPR/Cas9 gene-edited PKD1 and PKD2 knockout tubuloids and human ADPKD and control tissue show similarities in upregulation of disease-driving genes. Furthermore, in a proof of concept, we demonstrate that tolvaptan, the only approved drug for ADPKD, shows a significant effect on cyst size in tubuloids but no effect in a pluripotent-stem-cell-derived model. Thus, tubuloids derive from a tubular epithelial subpopulation and represent an advanced model for ADPKD disease modeling.

  Study EGAS00001006551