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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.

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.

Super-enhancers (SEs) drive specific gene expression programmes underlying different cancer cell states offering opportunities for therapeutic targeting. Here, the authors suggest targeting SE-dependent genes with synthetic ecteinascidins in tumors with heterogeneous transcriptional landscapes.

In this large-scale metagenomics study encompassing 3,483 human host-derived samples from seven body sites, researchers identify 583 unreported single-genome bins and report 314 metagenome-disease as well as 814 biosynthetic gene-disease associations.

Although the precise function of Tryptophan rich antigen multi-gene family (TRAgs) proteins is not known in any Plasmodium species several members of the P. vivax TRAg family have been reported to have red blood cell binding properties. Here, Kundu and Naskar et al. provide the X-ray crystallography structure of a P. vivax TRAg domain of PVP01_0000100. Structural and biochemical assays suggest a lipid binding function for a pan-Plasmodium multi-gene family.

Morin and colleagues develop a data-integration framework capable of performing continuous learning from electronic health records on clinical, social and demographic data collected over a decade to estimate pan-cancer survival prognosis.

Understanding collective behaviour is an important aspect of managing the pandemic response. Here the authors show in a large global study that participants that reported identifying more strongly with their nation reported greater engagement in public health behaviours and support for public health policies in the context of the pandemic.

Cellular state cooccurrence signatures, such as carcinoma ecotypes may serve as potential biomarkers of response to cancer immunotherapy, however, their clinical utility remains unexplored. Here, the authors analyse large real world immunotherapy cohorts and gene expression data and develop a predictive model for response.

Antimicrobial resistance genes that have been mobilized between bacterial species represent a subset of the naturally occurring resistome. Here, the authors compare the abundance, diversity and geographical patterns of acquired resistance genes with latent resistance genes in global sewage metagenomes.

T cells contribute to protection and pathogenesis in tuberculosis. Here the authors sequence T cell receptor repertoires in human skin biopsies from the site of the tuberculin skin test and show enrichment of clonotypes reactive to Mycobacterium tuberculosis using a computational pipeline metaclonotypist to identify distinct TCRs predicted to share peptide-MHC reactivity across participants, as an approach to explore T cell correlates of tuberculosis disease-risk stratification and vaccine efficacy.

Trained on 1.5 million whole-slide images from 100,000 patients, a pathology foundation model is shown to improve performance of specialized models in detection of rare cancers.

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.

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.

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.

Humanity’s Last Exam, a multi-modal benchmark at the frontier of human knowledge, is designed to be an expert-level closed-ended academic benchmark with broad subject coverage.

This study reports that de novo germline missense variants in SF3B1, distinct from the somatic variants frequently observed in cancer, cause a neurodevelopmental disorder and disrupt global RNA splicing.

Arslan et al. present the results of a comprehensive pan-cancer study evaluating deep learning-based multi-omic biomarker profiling using H&E-stained whole slide images. They show that deep learning can predict a wide range of biomarkers across the omics spectrum and in different cancers directly from histomorphology.

RNA sequencing (RNA-seq) is increasingly being integrated into molecular tumour profiling but remains underutilized for clinical decision-making. This Perspective presents a framework for assessing the therapeutic, diagnostic and prognostic actionability of RNA-seq findings as well as an ‘actionable transcriptome’ list to help guide the application of RNA-seq findings in oncology practice.

The authors analyze 162 primary mismatch-repair-deficient gliomas and identify three subgroups underpinned by distinct somatic mutations in replicative DNA polymerases and IDH1.

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.

Insulin signaling plays a crucial role in coordinating skeletal development with whole‑body energy metabolism. Here, the authors use phosphoproteomics to show insulin-signaling rewiring in aged, insulin-resistant bone and identify defective phosphorylation of AFF4 as a key mechanism for regulating gene-specific transcriptional activation.

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.

Whole-genome sequencing suggests that the spread of multidrug-resistant Enterobacter cloacae infections in the UK and Ireland is driven by a diverse community-based pool of strains.

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.

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.

varVAMP is open-source software for designing primers for tiled-amplicon sequencing and qPCR. It simplifies primer design for viral pathogens with high genomic variability by including sequence variations into primer sequences.

The rate and pattern of mutagenesis in cancer genomes are shaped by DNA accessibility and biological processes. Here the authors show that efficient replication initiation sites drive cancer specific mutational processes, increasing the frequency of small mutations and genomic rearrangements at these sites.

Locally elevated cholesterol in colorectal cancer cells with adenomatous polyposis coli truncation was observed to drive Wnt–β-catenin signaling through Dishevelled (Dvl). Inhibitors targeting the cholesterol–Dvl interaction potently suppress tumor growth without adverse side effects.

Genome-scale CRISPR–Cas9-based synthetic lethality screens identify PKMYT1 as a potential therapeutic target in tumours with CCNE1 amplification.

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.

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.

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.

Mutations in RAS oncogenes and related pathways are frequent in lung cancers. Here, the authors derive a RAS gene expression signature and a machine learning classifier to predict drug response and clinical outcomes in lung adenocarcinoma and other solid tumours, with improved performance over KRAS mutations alone.

Ponsioen et al. use a FRET‐based ERK biosensor EKAREN5 in patient‐derived organoids to show that EGFR activity amplifies signal transduction efficiency in KRAS or BRAF mutant MAPK pathways.

De novo assembly of 23 Aspergillus section Nigri and 6 Aspergillus niger genome sequences allows for inter- and intraspecies comparisons and prediction of secondary metabolite gene clusters.

Precise editing of DNA methylation has emerged as a promising tool in disease biology but most applications are limited to in vitro systems. Here, we develop two transgenic mouse lines harboring an inducible dCas9-DNMT3A or dCas9-TET1 editor to enable tissue-specific DNA methylation editing in vivo.

Imaging dozens of proteins in situ and at large scales increases the complexity of data analysis. Here, the authors develop an end-to-end solution for multiplexed image analysis that facilitates data interpretation for clinically relevant insights.

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

Mismatch repair-deficient colorectal cancer clones adapt their mutation landscape by toggling homopolymer sequences in MutS homolog 3 (MSH3) and MutS homolog 6 (MSH6). This increases the subclonal mutation rate and clonal diversity, favoring immune escape and tumor growth.

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.

Dissecting the effects of hypothermic and hypometabolic states on aging processes, the authors show that activation of neurons in the preoptic area induces a torpor-like state in mice that slows epigenetic aging and improves healthspan. These pro-longevity effects are mediated by reduced T_b, reinforcing evidence that T_b is a key mediator of aging processes.

Apoptotic cells often release extracellular vesicles that aid in their clearance and provide molecular information to cellular neighbours. Here, the authors show that some adherent apoptotic cells also create vesicles that remain attached at the site of death.

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.

Truong et al. developed a cell-based reporter system, EXSISERS, that enables non-invasive quantification of the protein expression levels of exon-specific isoforms via intein-mediated protein splicing.

Peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) is a heterogeneous and aggressive type of T-cell lymphoma. Here, the authors perform single-cell analyses of human and murine PTCL-NOS tumors, and identify a subtype defined by the loss of SMARCB1 that could be targeted with HDAC-inhibitor combination therapies.

A population-genomic analysis of more than 800 isolates of Staphylococcus aureus, representing the breadth of host-species diversity, reveals details of the pathogen’s evolutionary trajectory, including how this has been influenced by animal domestication and antibiotic use.

Intestinal tuft cell subtypes represent successive stages of differentiation that is driven by crypt-villus signaling gradients. Here, the authors show that applying these gradients to organoids generates mature immune-related chemosensory tuft cells suitable for experimental studies.