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The ZFTA–RELA fusion, an oncogene for ependymomas, promotes the production of itaconate, and its dependence on this metabolite represents a new therapeutic target for this cancer.

The APOE-ε4 allele is the strongest genetic risk factor for late-onset Alzheimer’s disease, but it is not deterministic. Here, the authors show that common genetic variation changes how APOE-ε4 influences cognition.

Engineered mucus-tethering bispecific nanobodies neutralize and entrap viruses to enhance mucosal immunity, preventing influenza infection and limiting SARS-CoV-2 transmission.

Intranasal inoculation of BALB/c and C57BL/6J mice with the bovine H5N1 clade 2.3.4.4b virus  results in rapid fatal disease characterized with high viral titers in lung and brain. Interestingly, only the C57BL/6J mice develop neurologic disease.

Integrative analyses of transcriptome and whole-genome sequencing data for 1,188 tumours across 27 types of cancer are used to provide a comprehensive catalogue of RNA-level alterations in cancer.

The hormone prolactin is a known modulator of mammalian lactation and hair growth. Here, the authors describe two dominant mutations in bovine prolactin and its receptor, demonstrating antagonistic effects on these traits and highlighting a role for this pathway in sweat gland function and thermoregulation.

In this study the authors consider the structural variants (SVs) present within cancer cases of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium. They report hundreds of genes, including known cancer-associated genes for which the nearby presence of a SV breakpoint is associated with altered expression.

The functions of small nucleolar RNAs (snoRNAs) in cancer remain to be studied. Here the authors show that the snoRNA Snord67 promotes lymph node metastasis of breast cancer cells through guiding modifications of the spliceosome and regulating the splicing landscape.

Tumor draining lymph nodes are essential for immunotherapy efficacy in head and neck squamous cell carcinoma (HNSCC). Here, the authors show that sequential tumor-directed radiotherapy and PD-1 inhibition and migratory CCR7+ dendritic cells are required for complete and durable tumor responses in HNSCC.

The flagship paper of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Consortium describes the generation of the integrative analyses of 2,658 cancer whole genomes and their matching normal tissues across 38 tumour types, the structures for international data sharing and standardized analyses, and the main scientific findings from across the consortium studies.

The largest harmonized proteomic dataset of plasma, serum and cerebrospinal fluid samples across major neurodegenerative diseases reveals both disease-specific and transdiagnostic proteomic signatures, including a robust plasma profile associated with the APOEε4 genotype.

Genome-wide association and fine-mapping analyses in ancestrally diverse populations implicate candidate causal genes and mechanisms underlying type 2 diabetes. Trans-ancestry genetic risk scores enhance transferability across populations.

Tumour profiling with next-generation sequencing is challenging due to the low amounts of diagnostic material in cytology samples that are obtained through non-invasive procedures. Here, the authors report on the optimization of this process across 4,871 cancer cytology samples profiled by MSK-IMPACT, with emphasis on the successful use of supernatant cell-free DNA.

Jamaican fruit bats support disseminated infection of Ebola but not Marburg virus. The differences in infection dynamics are partially attributable to Marburg’s less efficient entry and impaired antagonism of type I interferon signaling.

Analyses of 2,658 whole genomes across 38 types of cancer identify the contribution of non-coding point mutations and structural variants to driving cancer.

Targeted sequencing panels such as MSK-IMPACT have been successfully used to profile solid tumours in clinical settings. Here, the authors develop and implement the MSK-IMPACT Heme sequencing panel and platform to profile haematologic malignancies using paired tumor and normal tissues.

Following spinal cord injury, gamified physical therapy that incorporates closed-loop vagus nerve stimulation can aid restoration of arm and hand function.

Understanding the molecular basis of leukaemia predisposition is essential for intervention. The authors here investigate germline genetic leukaemia predisposition by studying Shwachman-Diamond syndrome and report compensatory inactivating mutations in EIF6 and transforming biallelic TP53 alterations.

Ribosomal DNA transcription is essential for cell growth and division. Here, the authors show that EMT is accompanied by Snail binding to rDNA operons and Rictor association with nucleoli to fuel an induction of ribosome biogenesis during G1/S cell cycle arrest and inhibition of ribosome biogenesis hampers EMT, differentiates primary tumors and reduces metastasis.

Understanding deregulation of biological pathways in cancer can provide insight into disease etiology and potential therapies. Here, as part of the PanCancer Analysis of Whole Genomes (PCAWG) consortium, the authors present pathway and network analysis of 2583 whole cancer genomes from 27 tumour types.

Multi-omics datasets pose major challenges to data interpretation and hypothesis generation owing to their high-dimensional molecular profiles. Here, the authors develop ActivePathways method, which uses data fusion techniques for integrative pathway analysis of multi-omics data and candidate gene discovery.

Analysis of cancer genome sequencing data has enabled the discovery of driver mutations. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium the authors present DriverPower, a software package that identifies coding and non-coding driver mutations within cancer whole genomes via consideration of mutational burden and functional impact evidence.

Dynamics of type I interferon (IFN) following infection with SARS-CoV-2 are critical in determining disease severity in humans but have been difficult to model in mice. Here, infection of genetically diverse mice reveals how delayed or immediate IFN signaling coordinates antiviral immunity.

This paper reports integrative molecular analyses of urothelial bladder carcinoma at the DNA, RNA, and protein levels performed as part of The Cancer Genome Atlas project; recurrent mutations were found in 32 genes, including those involved in cell-cycle regulation, chromatin regulation and kinase signalling pathways; chromatin regulatory genes were more frequently mutated in urothelial carcinoma than in any other common cancer studied so far.

Antibody responses to SARS-CoV-2 may be important biomarkers for assessing the risk for viral transmission. Here the authors present serological antibody profiling results of COVID-19 patients using a new multiplex assay to show distinct kinetics and dynamics of IgG, IgM and IgA responses in patients with different disease severity.

Some cancer patients first present with metastases where the location of the primary is unidentified; these are difficult to treat. In this study, using machine learning, the authors develop a method to determine the tissue of origin of a cancer based on whole sequencing data.

An analysis of 2,954 genomes from 38 cancer subtypes identified 19,166 retrotransposition events in 35% of samples. Aberrant LINE-1 retrotranspositions can lead to the deletion of tumor-suppressor genes as well as the amplification of oncogenes.

The authors present SVclone, a computational method for inferring the cancer cell fraction of structural variants from whole-genome sequencing data.

The role of interferon-γ (IFNγ) in anti-viral immunity has been unclear. Here the authors show that bacterial-induced or intranasally administered IFNγ effectively restricts SARS-CoV-2 infection in mice through effects on non-hematopoietic cells.

Whole-genome sequencing data from more than 2,500 cancers of 38 tumour types reveal 16 signatures that can be used to classify somatic structural variants, highlighting the diversity of genomic rearrangements in cancer.

A pan-cancer genomic analysis reports the effects of structural variations on chromatin domains (TADs). Most TAD disruptions do not result in appreciable changes in expression of nearby genes.

Cancers evolve as they progress under differing selective pressures. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, the authors present the method TrackSig the estimates evolutionary trajectories of somatic mutational processes from single bulk tumour data.

Zhang et al. show that the poly(GA) proteins produced in patients with C9ORF72 repeat expansions cause neurodegeneration and behavioral abnormalities when expressed in mice. The emergence of these phenotypes requires poly(GA) aggregation, and poly(GA) inclusions sequester HR23 proteins involved in proteasomal degradation, as well as proteins involved in nucleocytoplasmic transport.

With the generation of large pan-cancer whole-exome and whole-genome sequencing projects, a question remains about how comparable these datasets are. Here, using The Cancer Genome Atlas samples analysed as part of the Pan-Cancer Analysis of Whole Genomes project, the authors explore the concordance of mutations called by whole exome sequencing and whole genome sequencing techniques.

Viral pathogen load in cancer genomes is estimated through analysis of sequencing data from 2,656 tumors across 35 cancer types using multiple pathogen-detection pipelines, identifying viruses in 382 genomic and 68 transcriptome datasets.

The prognosis of cancer patients with lymph node (LN) metastasis is worse than those without. Here, the authors report that while histone deacetylase 11 (HDAC11) inhibition suppresses tumor growth within the LN, it also promotes cancer cell migration out of the LN to form distant metastasis, and therefore suggest caution with HDAC inhibitors.

In somatic cells the mechanisms maintaining the chromosome ends are normally inactivated; however, cancer cells can re-activate these pathways to support continuous growth. Here, the authors characterize the telomeric landscapes across tumour types and identify genomic alterations associated with different telomere maintenance mechanisms.

Whole-genome sequencing data for 2,778 cancer samples from 2,658 unique donors across 38 cancer types is used to reconstruct the evolutionary history of cancer, revealing that driver mutations can precede diagnosis by several years to decades.

Many tumours exhibit hypoxia (low oxygen) and hypoxic tumours often respond poorly to therapy. Here, the authors quantify hypoxia in 1188 tumours from 27 cancer types, showing elevated hypoxia links to increased mutational load, directing evolutionary trajectories.

The characterization of 4,645 whole-genome and 19,184 exome sequences, covering most types of cancer, identifies 81 single-base substitution, doublet-base substitution and small-insertion-and-deletion mutational signatures, providing a systematic overview of the mutational processes that contribute to cancer development.

There’s an emerging body of evidence to show how biological sex impacts cancer incidence, treatment and underlying biology. Here, using a large pan-cancer dataset, the authors further highlight how sex differences shape the cancer genome.

Amalio Telenti, Craig Venter and colleagues report common, low-frequency and rare variants associated with blood metabolite levels using whole-genome sequencing and comprehensive metabolite profiling in 1,960 individuals. They identify 246 metabolites whose levels are associated with genetic variation at 101 loci.

Pediatric brain cancers are lethal malignancies driven by less-differentiated stem-like cells. Here the authors show that these cells exhibit distinct mitochondrial metabolism programs with targetable vulnerabilities.

The alternative sigma factor RpoS of Borrelia burgdorferi regulates a pathway implicated in tick transmission, mammalian infectivity and persistent infection. Here, the authors characterise the role of the RpoS negative regulator bbd18 and show that RpoS also controls induction of endogenous prophage.