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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.

A pan-haematologic cancer approach, involving analysis of data from 256 patients across 5 cancer types and 13 clinical trials, revealed predictive biomarkers for understanding the response or non-response of patients to CAR-T therapy.

Multimodal machine learning reveals that tumour microenvironments can be decomposed into spatially organized multicellular ecosystems, termed spatial ecotypes, that can be accessed non-invasively via liquid biopsy and used to profile individual cancers and target treatments.

Eggplants are important vegetables worldwide. Here, the authors report 40 genome assemblies of Solanum melongena, its progenitor S. insanum and the allied species S. incanum to construct two pangenomes, and identify loci associated with multiple traits via pangenome-wide association analysis.

Effective response to immune checkpoint inhibitors depends on the proliferation and expansion of tumor-reactive CD8⁺ T cells. By combining analysis of CD8⁺ T cell clones in a preclinical multi-site tumor model with clinical datasets, the authors track the expansion dynamics of hundreds of T cell clones over time and define a signature to predict intratumoral CD8⁺ T cell expansion in response to immunotherapies.

Using a multi-OMICS approach, Haas et al identify 54 human genes and 16 host-targeting chemical compounds that regulate influenza A virus infection in lung epithelial cells, including AHNAK and COBP1 which are also essential for SARS-CoV-2 infection.

A large-scale proteomics analysis of the dark proteome by the TransCODE Consortium reveals many translated non-canonical open reading frames to encode microproteins and peptideins.

Available wheat genomes are annotated by projecting Chinese Spring gene models across the new assemblies. Here, the authors generate de novo gene annotations for the 9 wheat genomes, identify core and dispensable transcriptome, and reveal conservation and divergence of gene expression balance across homoeologous subgenomes.

Mutations may be enriched in tumor samples because they promote carcinogenesis or because they promote clonal expansions in healthy tissue. This study mathematically disentangles these two possibilities by analyzing tumor and normal tissue sequencing datasets.

Profiling alternative splicing in single cells is challenging due to technical limitations. Here the authors use deep single-cell sequencing to identify alternative splicing in single neurons, revealing widespread differential intron retention and pan-neuronal genes harboring cell-specific isoforms.

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.

DNA damage burden and inadequate repair in CUX2⁺ cortical layer 2/3 excitatory neurons contributes to selective vulnerability in neuroinflammatory injury.

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.

Currently, the biological and clinical implications of copy number alteration (CNA) size heterogeneity and co-occurrence are incompletely understood. Here, the authors use 691 meningiomas and 29 cancer types from The Cancer Genome Atlas to develop size-dependent CNA and CNA co-occurrence models to optimize individualized pan-cancer risk stratification.

The transcription factor ATF4 is shown to regulate double-stranded DNA repair within vulnerable CUX2⁺ upper-layer 2/3 cortical neurons, enabling their survival during development.

The neuraminidase-targeting monoclonal antibody FNI9 potently inhibits the enzymatic activity of influenza A and B viruses via receptor mimicry.

Cox and colleagues develop PXS-5505, a first-in-class selective pan-lysyl oxidase inhibitor and show that it reduces chemotherapy-induced desmoplasia and stiffness, thereby improving chemotherapy response and survival in pancreatic cancer models.

LINE-1 activity was quantified in a large, pan-cancer dataset, finding locus-specific heterogeneity and new associations using a computational pipeline. A mathematical mediation model of p53 and L1 interactions was inferred. Somatic retrotransposition was seen in Li-Fraumeni Syndrome with heritable TP53 mutations.

An analysis of diet-induced obesity using MouseMapper—a suite of foundation-model-based deep-learning algorithms—identifies structural alterations of the infraorbital branch of the trigeminal ganglia.

Global analysis of obesity trends from 1980 to 2024 in 200 countries and territories using data from 4,050 population-based studies reveals that framing obesity as a single global epidemic masks the highly varied dynamics across countries and age groups.

PDL1 expression is a common biomarker for immunotherapy response in cancer, and it is usually quantified using immunohistochemistry. Here, the authors develop a weakly supervised learning approach combining multiple instance learning and a teacher-student framework to predict PDL1 expression from histopathological imaging.

Comparative genomics and high-resolution mass spectrometry reveal the biosynthetic gene clusters, and vast chemical diversity of natural products that they encode, in Photorhabdus and Xenorhabdus, bacteria that interact with hosts as symbionts and entomopathogens.

Tropical land ecosystems contain vast carbon reservoirs, but their influence on atmospheric CO₂ is poorly understood. Here the authors use new carbon-observing satellites to reveal a large emission source over northern tropical Africa, where there are large soil carbon stores and substantial land use changes.

There are no robust methods for systematically identifying mutation-specific synthetic lethal (SL) partners in cancer. Here, the authors develop a computational algorithm that uses pan-cancer data to detect mutation-andcancer-specific SL partners and they validate a novel SL interaction between mutant IDH and loss of ACACA in leukaemia.

Pan-genomes provide useful resources for evolutionary studies, functional genomics and breeding of cultivated plants. Here, the authors report a new rice pan-genome including 73 Asian rice and two wild relatives (Oryza rufipogon and O. punctata), and reveal the prevalence and scale of large inversions across the pan-genome.

NatD is an acetyltransferase responsible for N-α-terminal acetylation of the histone H4 and H2A and has been linked to cell growth. Here the authors show that NatD-mediated acetylation of histone H4 serine 1 competes with the phosphorylation by CK2α at the same residue thus leading to the upregulation of Slug and tumor progression.

Studies of histidine phosphorylation have been limited owing to a lack of appropriate tools. The synthesis of a stable phosphohistidine mimic now leads to a pan antibody, enabling detection and further functional investigations of this little-known post-translational modification.

A meta-analysis of studies on chimpanzees and bonobos across Africa shows that their conspecific aggression is the normal and expected product of adaptive strategies to obtain resources or mates and has no connection with the impacts of human activities.

A sorghum pan-genome generated from 16 genomes representing cultivated and wild sorghum shows extensive variation, with 64% of the gene families exhibiting presence/absence variations, some of which confer phenotypic outcomes and contribute to domestication and improvement.

Epigenetic reprogramming is a hallmark of cancer. Here the authors find that resetting primed human embryonic stem cells to naïve state results in the acquisition of a DNA methylation landscape that mirrors the cancer DNA methylome and provides evidence that the transition to naïve pluripotency and oncogenic transformation share common epigenetic trajectories.

Kozlova et al. report a functional role for NDRG1 in regulating R-loops and DNA repair, thereby linking cancer-associated fibroblast-derived extracellular matrix to chemotherapy responses in pancreatic cancer.

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.

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.

The role of differential gene content in the evolution and function of eukaryotic genomes remains poorly explored. Here the authors assemble and annotate the Brachypodium distachyon pan-genome consisting of 54 diverse lines and reveal the differential present genes as a major driver of phenotypic variation.

A small-molecule inhibitor of TMPRSS2 is effective against SARS-CoV-2 variants of concern in human lung cells and in donor-derived colonoids, and also shows prophylactic and therapeutic benefits in a mouse model of COVID-19.

AGO-CLIP permits the identification of miRNA target genes. Here, Hamilton et al. compile publicly available AGO-CLIP data and combine this information with miRNA analysis from The Cancer Genome Atlas, permitting the identification of an oncogenic miRNA superfamily that targets tumour suppressor genes.

Walsh and colleagues use prospective sequencing in a large cohort of pediatric patients with solid tumors to detect mutations in cancer predisposition genes and guide downstream clinical care.

Plant community properties affect ecosystem functioning via energy fluxes in food webs, with the leaf and root resource economics of dominant tree species controlling soil food web multifunctionality.

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.

Existing plant pan-genomic studies usually report considerable intraspecific whole gene presence-absence variation. Here, the authors use pan-genomic approach to reveal gradual polyploid genome evolution by analyzing of Brachypodium hybridum and its diploid progenitors.

The Amazon faces worsening droughts, yet little is known about large-scale variation in the physiological limits of Amazon trees. Here, the authors reveal family-level conservatism in embolism resistance and estimate that Brazilian and Guiana shield forests are more resistant than Western Amazonia forests.

Integrating independent large-scale pharmacogenomic screens can enable unprecedented characterization of genetic vulnerabilities in cancers. Here, the authors show that the two largest independent CRISPR-Cas9 gene-dependency screens are concordant, paving the way for joint analysis of the data sets.

The authors resolve 63 structurally diverse haplotype structures for the 22q11.2 deletion syndrome region. Deletion risk differs depending on structure; individuals of African ancestry are enriched for inverted repeats that predispose to inversion.

DNA-sequencing data from primary tumours and paired metastases from participants in the TRACERx lung study and PEACE autopsy programme are used to analyse the metastatic diversity of advanced non-small cell lung cancer and the seeding patterns that underpin it.

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.

Imidazolopiperazines (IZPs) are a class of compounds under clinical development for malaria, but their mechanism of action is unclear. Here, the authors show that IZPs inhibit the parasite’s secretory pathway, affecting protein trafficking and export.