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The protein stability of KRAS mutants can influence tumor promotion. Here, the authors identify that deubiquitinase JOSD2 stabilizes KRAS mutants and JOSD2 depletion inhibits KRAS-mutant colorectal cancer growth in part due to mutant KRAS degradation.

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.

Liang et al. study the impact of ERα antagonist/degraders against different Esr1 mutations in murine models and find that inhibition of mutant ERα induces lineage plasticity, which is also observed in Esr1-wild-type mice with long-term estrogen deprivation.

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.

Metabolic enzymes of the tricarboxylic acid cycle, such as 2-oxoglutarate dehydrogenase, are differentially expressed in absorptive and secretory lineages, guiding cell fate establishment and offering insights for targeted regenerative therapies.

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.

This study provides a de novo resequencing of 802 Camellia accessions and a genome-wide variation map. Genome-wide association study (GWAS) and metabolite GWAS identify genes responsible for crucial agronomic and flavor traits.

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.

Independent of antigen presentation, migratory CCR7⁺ dendritic cells orchestrate the influx, proliferation and cytotoxic action of natural killer cells to control cancer cell growth in the leptomeninges.

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.

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.

The authors achieve configurable ferroelectric switching kinetics in CuInP₂S₆ through precisely tuning the Cu ions interlayer hopping, paving the way for development of advanced multifunctional ferroelectric devices.

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.

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 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.

The authors achieve nonvolatile manipulation of atomically thin topological polar textures in twisted boron nitride, enabling a tunable platform for exploring topological phenomena and high-density nanoelectronic devices.

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.

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.

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.

There have been great advances in the treatment of patients with breast cancer, with novel targeted agents having a great impact on treatment at all stages of the disease trajectory. In this Review, the treatment options for patients with metastatic disease are discussed—focussing on agents that target breast cancer cells, breast cancer stem cells and the breast microenvironment.

Recent studies of mRNA distribution and translation show that, in addition to serving as the site of protein translocation into the endoplasmic reticulum (ER), ER-bound ribosomes translate a large fraction of mRNAs that encode cytosolic proteins. This, along with the discovery of many mechanisms for recruiting translation to the ER, suggests an expansive role for the ER in post-transcriptional gene expression.

Resistance to first line treatment is a major hurdle in cancer treatment, that can be overcome with drug combinations. Here, the authors provide a large drug combination screen across cancer cell lines to benchmark crowdsourced methods and to computationally predict drug synergies.

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.

Here the authors identify age-associated changes in the epithelial cell compartment of the thymus that form high-density nonproductive microenvironmental niches that contribute toward thymic involution and inhibit its repair following injury.

The unfolded protein response (UPR) is an important pro-survival pathway that is often activated in tumour cells owing to endoplasmic reticulum stress that is caused by both intrinsic and extrinsic factors. Wang and Kaufman discuss the mechanisms of UPR activation in tumour cells, the importance of this pathway to cancer development and targeting strategies for therapeutic intervention.

A refreshable memristor leveraging dynamic ferro-ionic phase allocation enables neural reuse, improving classification accuracy, reducing consumption, and accelerating training speed compared to randomly initialized models, enhancing efficiency and adaptability in neuromorphic hardware.

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 tumour-specific circular RNA FAM53B is highly immunogenic and can induce anti-tumour responses in mouse models of breast cancer and melanoma, expanding the repertoire of anticancer targets for development.

Circulating Ly6C^lo monocytes are thought to be derived from Ly6C^hi subset. Here the authors show that Notch signalling is activated in Ly6C^locells and is required for their differentiation, and that Notch ligands that initiate this signalling are provided by a subset of endothelial cells.

Cancer cells can be dependent on mitochondrial respiration to survive. Here, in pancreatic cancer cells, the authors show that monounsaturated fatty acids-linked ether lipids maintain mitochondrial redox homeostasis and modulate sensitivity to inhibition to electron transport chain complex I.

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.

In recent years a new concept of immunogenic cell death (ICD) has emerged. In this Review, the authors discuss the role of endoplasmic reticulum (ER) stress and reactive oxygen species (ROS) in regulating the immunogenicity of dying cancer cells and how this might relate to therapeutic intervention.

Barriga et al. develop MACHETE, a genome engineering strategy enabling the flexible modeling of megabase-sized deletions and show that the concomitant loss of the interferon cluster with CDKN2A/B deletions on 9p21.3 enhances immune evasion.

Efficient, large-scale genomic analysis is facilitated on the cloud by a computational tool with error-diagnosing and self-healing capabilities.

Danko and colleagues develop BayesPrism, a bulk RNA sequencing deconvolution tool to infer cell type composition and cell-specific expression levels across clinical cancer datasets.

Single-cell aggregation with archetypes provides intermediate granularity for downstream analyses.

Identification of causal drivers behind expression is essential for understanding gene function. Here authors develop a method for the large-scale inference of gene–gene interactions in observational population genomics data and characterize a network of trans-effects for 6600 genes.

DNA methylation is critically involved in X chromosome inactivation (XCI) and dosage compensation, yet some X-chromosomal genes escape XCI. Here, Lujik et al. identify three autosomal genetic loci that associate with differential DNA methylation near genes that variably escape XCI in females.