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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.

Nimbus, a deep learning model, uses a large multiplexed imaging dataset to predict the likelihood of marker positivity in single cells.

The tolerogenic activity of type 1 conventional dendritic cells (cDC1s) is determined by EPOR, which is preferentially expressed in cDC1s and induces antigen-specific FOXP3-expressing regulatory T cells.

Global Burden of Disease estimates show that between 1990 and 2023, the prevalence and burden of drug use disorders, inclusive of amphetamine, cannabis, cocaine and opioid use, have been increasing in high-income countries, particularly in the USA.

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.

Methods for the systematic synthesis and evaluation of large numbers of transition metal complexes at a time are still limited. Here, the authors report a high-throughput method to create and test hundreds of metal complexes, revealing potent new metalloantibiotics and a highly active iridium catalyst.

Biomarkers predictive of response to T cell therapy remain to be better defined. This study identifies potential predictive and pharmacodynamic markers of response to NY-ESO-1 T-cell therapy in a solid tumor that may inform lymphodepletion, cell dose, and strategies to enhance anticancer efficacy.

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.

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.

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 interaction between the host immune response and the component organisms forming the microbiota is critical during homeostatic but all pathological contexts. Here the authors use a multi-omics spatial approach to dissect and characterise host and microbiome in a murine model of intestinal inflammation.

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 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.

Inventory data from more than 1 million trees across African, Amazonian and Southeast Asian tropical forests suggests that, despite their high diversity, just 1,053 species, representing a consistent ~2.2% of tropical tree species in each region, constitute half of Earth’s 800 billion tropical trees.

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.

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.

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

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.

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.

Oh and colleagues demonstrate that the DUSP6–RSK1 axis is involved in the transformation of myeloproliferative neoplasms to secondary acute myeloid leukemia and that DUSP6 mediates the response to JAK2 inhibition.

An integrated analysis of glioma samples from patients with neurofibromatosis 1 annotates their mutational, epigenetic, transcriptional, and immunological features and uncovers similitudes with a subset of sporadic gliomas.

Secondary acute myeloid leukemias (sAMLs) evolving from myeloproliferative neoplasms (MPNs) associate with poor prognosis. Here authors identify RSK1 as a vulnerability for MPN and sAML and show the efficacy of a first-in-class RSK inhibitor, PMD-026, against these types of myeloid malignancies.

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.

The advantage of living in cities compared with rural areas with respect to height and BMI in children and adolescents has generally become smaller globally from 1990 to 2020, except in sub-Saharan Africa.

In this Resource paper, the authors use MIBI spatial proteomics to map microglial cell states in brains from cognitively normal humans and those with Alzheimer’s disease.

Cancer driver mutations can occur within noncoding genomic sequences. Here, the authors develop a statistical approach to identify candidate noncoding driver mutations in DNase I hypersensitive sites in breast cancer and experimentally demonstrate they are regulatory elements of known cancer genes.

Studies using human pluripotent stem cells and a mouse model of Down syndrome identify HMGN1 as a key contributor to congenital heart defects in individuals with Down syndrome.

A Pitx1 enhancer shows activity in forelimbs and hindlimbs but only interacts with Pitx1 in hindlimbs because of its three-dimensional configuration. Structural variants that affect three-dimensional conformation induce Pitx1 expression in forelimbs and cause partial arm-to-leg transformation in mice and humans.

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.

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.

Myeloid cells are the predominant cell type in the tumor microenvironment of human and murine glioblastoma (GBM). By generating a mouse model deficient for all monocyte chemoattractant proteins, here the authors show that blocking monocyte recruitment promotes a compensatory neutrophil influx and that concomitant neutrophil inhibition is required to improve survival in GBM preclinical models.

Analyses of single-cell transcriptomic data from patients with VEXAS syndrome combined with xenotransplantation experiments in a mouse model of the disease provide insights on the mechanisms of clonal dominance of mutated cells leading to bone marrow failure

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.

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.

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.

Alterations in the tumour microenvironment (TME) can contribute to prostate cancer progression, but it is unclear how tumours mediate those changes. Here, analysis of human prostate cancer tissues and key stages of prostate cancer progression in a genetically engineered mouse model using single-cell RNA-sequencing reveals the central role of MYC signalling in reprogramming the TME.

FHFs are known to regulate voltage-gated sodium channels (NaVs). Here, the authors compare the role of FHFs in cerebellar granule cell propagation, and find NaVs in the distal axon function independently of FHFs, allowing for faster inactivation rates and reducing energy demands during repetitive spiking.

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.

The activity of PD-1 blockade in patients with sarcoma has been modest so far. Here, the authors report the results of a pilot clinical trial to assess the efficacy and safety of bempegaldesleukin, a CD122-preferential interleukin-2 (IL-2) pathway agonist, in combination with the PD1 blockade (nivolumab) in patients with locally advanced or metastatic high-grade sarcoma.

Here, the authors show that combining γ9δ2 TCR-mediated metabolic and co-stimulatory stress targeting by chimeric NKG2D or anti-CD277 co-receptors shapes transcriptomic heterogeneity of engineered T cells and is associated with improved control of solid tumors.

Inspired by the primate visual system, this work implements an event-driven, bio-inspired architecture for figure-ground segmentation on the neuromorphic robot iCub, bridging neuromorphic algorithms and software. Its performance is benchmarked on the Berkeley Segmentation Data Set and validated in real-world scenarios.