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Similarities in cancers can be studied to interrogate their etiology. Here, the authors use genome-wide association study summary statistics from six cancer types based on 296,215 cases and 301,319 controls of European ancestry, showing that solid tumours arising from different tissues share a degree of common germline genetic basis.

Large-scale data on human mobility metrics have been used to gain insights into COVID-19 transmission dynamics, but best practices for use of these datasets have not been established. Here, the authors perform a systematic review to describe the sources of mobility data and methods used for analysis in the early COVID-19 pandemic.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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

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.

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.

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.

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.

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.

Notch signaling is known to control neuroendocrine fate in the lungs. Shue and colleagues further identify the REST and YAP transcriptional regulators as key components of the Notch signaling pathway in the control of the neuroendocrine cell fate in lung development, lung injury response, and small-cell lung cancer.

O’Donnell and colleagues report that activation of the integrated stress response in non-small cell lung cancer cells by impairing heme production leads to enhanced PD-L1 translation in an eIF5B-dependent manner.

Dimethyl fumarate (DMF) is an anti-inflammatory drug proposed as a treatment for COVID19. Here the results are reported from a randomised trial testing DMF treatment in 713 patients hospitalised with COVID-19. DMF was not associated with any improvement in day 5 outcomes.

Pyrrolysine (Pyl) exists in nature as the 22^nd proteinogenic amino acid, but studies of Pyl have been hindered by the difficulty and inefficiency of both its chemical and biological syntheses. Here, the authors developed an improved PANCE approach to evolve the pylBCD pathway for increased production of Pyl proteins in E. coli.

Openshaw and colleagues find myeloid inflammation and complement activation signatures in patients with long COVID who were previously hospitalized.

The effect of vitamin C deprivation on mouse germline development is analysed, revealing that maternal vitamin C is required for proper DNA demethylation and the development of fetal oocytes, whereas the lack of vitamin C during pregnancy leads to reduced female fecundity in the offspring.

Souza et al. determine the genomic characteristics of Escherichia coli implicated in bloodstream infection and the spread of antimicrobial resistance. The spread of genes encoding different variants of β-lactamases, including extended-spectrum β-lactamases, is driven by genetically distinct lineages of E. coli.

A peptide display method was developed, revealing that a kinase important for infection by Salmonella and related pathogens detects specific human antimicrobial peptides, possibly reflecting bacterial adaptation to distinct host locations.

In this study the authors identify a possible link between the gene FAM222A and brain atrophy. The protein it encodes is found to accumulate in plaques seen in Alzheimer’s disease, and functional analysis suggests it interacts with amyloid-beta.

Opioid receptors are important modulators of nociceptive pain. Here the authors show that opioid receptor activation recruits peroxiredoxin 6 (PRDX6) to the receptor-Gαi complex by c-Jun N-terminal kinase, resulting in Gαi depalmitoylation and enhanced receptor-Gαi association.

The crystal structure of the GP1–GP2 complex of the prototypical arenavirus LCMV in prefusion form sheds light on the conformational changes that the arenavirus glycoprotein undergoes to cause fusion.

Callosal projection neurons located in the hemisphere contralateral to primary glioblastoma promote progression and widespread infiltration, and screening of axon guidance genes identified SEMA4F as a key regulator of tumourigenesis and activity-dependent progression.

Metabolomics data from germ-free and specific-pathogen-free mice reveal effects of the microbiome on host chemistry, identifying conjugations of bile acids that are also enriched in patients with inflammatory bowel disease or cystic fibrosis.

Holger Lerche, Camila Esguerra and colleagues report the identification of inactivating mutations in STX1B in individuals with various seizure-related disorders, including febrile seizures and epilepsy. Functional studies indicate that STX1B acts in the presynaptic release machinery.

Lassa virus infections in humans can result in severe disease, including hemorrhagic fever. Here the authors describe an mRNA-based Lassa virus vaccine that shows protection without requirement for neutralizing antibody in a guinea pig model of infection.

A discovery pipeline integrating time-resolved HT-SAXS and fragment screening identifies chemical leads targeting exemplary allosteric states of mitochondrial oxidoreductase apoptosis-inducing factor (AIF).

Naoki Irie and colleagues report the draft genomes of the soft-shell and green sea turtles. Their genome-wide phylogenetic analysis supports the hypothesis that turtles are a sister group of crocodilians and birds.

In vivo human neuroimaging shows that locus coeruleus (LC) integrity changes precede medial temporal tau accumulation, and jointly predict future lower cognition in older people at risk for Alzheimer’s disease. A common transcriptomic profile underlies LC’s early vulnerability to tau.

Patient derived tumor xenografts (PDXs) are important models for pre-clinical testing in cancer research and personalized medicine. PDXs often represent patient tumors with high similarity in terms of histology and driver mutations. However, certain limitations exist that warrant a detailed understanding of PDX heterogeneity and evolution. Hynds et al. demonstrate the relevance of primary tumor heterogeneity in PDX model establishment and explore multi-region sampling to determine the extent to which PDXs represent primary tumors.

Habib and colleagues show that type 1 IFN signaling is triggered by EGFR inhibition in nonsmall cell lung cancer models and propose EGFR inhibition and IFN-neutralizing antibody as a potential combination therapy approach.

Dynamin promotes membrane fission by constricting the neck of invaginating membranes; however, it was recently shown that dynamin also regulates membrane fusion. Here the authors show that this fusogenic activity is mediated by interaction with the Qa SNARE, thereby promoting trans-SNARE formation.

Analysis of whole-genome sequencing data across 2,658 tumors spanning 38 cancer types shows that chromothripsis is pervasive, with a frequency of more than 50% in several cancer types, contributing to oncogene amplification, gene inactivation and cancer genome evolution.

Analysis of mitochondrial genomes (mtDNA) by using whole-genome sequencing data from 2,658 cancer samples across 38 cancer types identifies hypermutated mtDNA cases, frequent somatic nuclear transfer of mtDNA and high variability of mtDNA copy number in many cancers.