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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.

Small CRISPR Cas9 proteins have potential in gene therapies but generally have poor editing efficiency or specificity and often recognize sub-optimal PAM sequences. Here the authors characterise four small nucleases and use protein engineering to create effective in vivo editors.

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

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.

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.

Genomic data from over 100 populations of Timema stick insects are used to show the transition from an early phase of speciation involving localized genetic regions to later stages involving genome-wide differentiation.

Renally clearable gold quantum clusters that are stabilized by the milk metalloprotein alpha-lactalbumin and display multicolour fluorescence aid the detection, resection and treatment of breast cancer in mice.

TASK-1 and -3 are members of the two-pore domain K⁺ channel family that play important roles in the regulation of cellular excitability. Here, Wilke et al.demonstrate that the second messenger lipid diacylglycerol (DAG) gates TASK1/3, defining a new role for DAG in controlling the dynamics of cellular excitability.

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.

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.

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.

Mast cells within the tumor microenvironment have controversial roles. Here, the authors show, using genetic mouse models, that in gastric cancer, mast cells at the periphery of the tumors are activated via cancer cell produced-IL33 and promote tumorigenesis by recruiting macrophages within the tumors.

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.

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.

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.

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.

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.

Christopher Newton-Cheh and colleagues report genome-wide association analyses for QT interval, an electrocardiographic measure reflecting myocardial repolarization, in 100,000 individuals. They identify 35 loci associated with QT interval and highlight a role for calcium regulation in myocardial repolarization.

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.

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.

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.

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.

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.

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.

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.

Complexes of iron in high oxidation states play a pivotal role as active intermediates in numerous catalytic processes. Now, using a multimethod approach on a single molecular system, it has been shown that a stable high-valent Fe(VI) nitride can be converted to a reactive, superoxidized, heptavalent Fe(VII) nitride.

Identifying the transcripts and proteins that fluctuate in response to stimuli provides important information for understanding cell physiology. In this study, 52% of theBacillus subtilispredicted proteome is identified following glucose starvation, revealing further insight into protein dynamics at a global scale.

This study reports the correction of pulmonary alveolar proteinosis (PAP) in Csf2rb^–/– mice by a single transfer of either wild-type or gene-corrected macrophages directly to the lungs — the transplanted macrophages persisted for at least 1 year; this transplantation strategy obviated the need for myeloablation and immunosuppression and should be a feasible therapy for humans with hereditary PAP.

As more intersection points between platelets and the immune system are found, the role of platelets for vessel growth in the adult organism remains unclear. The authors demonstrate that platelets negatively modulate revascularization through CXCL4 secretion induced by activation C5aR1 on their surface.

Alternative lengthening of telomeres (ALT) is associated with a poor outcome in neuroblastoma. Here, the authors find that ALT is associated with mutated ATRX and/or reduced protein abundance, frequent telomeric repeat loci and heterochromatic telomeric chromatin.

Heart rate variability (HRV) describes the individual variation in cardiac cycle duration and is a measure of vagal control of heart rate. Here, the authors identify seventeen single-nucleotide polymorphisms associated with HRV, lending new insight into the vagal regulation of heart rhythm.

The structural basis of the interactions between Rubisco and its intrinsically disordered linker protein provides insight into phase separation within the algal pyrenoid, an organelle responsible for around a third of global CO₂ fixation.

Improved electron microscopy methods are used to map a mammalian retinal circuit of close to 1,000 neurons; the work reveals a new type of retinal bipolar neuron and suggests functional mechanisms for known visual computations.

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.

Many proteins exist in various proteoforms but detecting these variants by bottom-up proteomics remains difficult. Here, the authors present a computational approach based on peptide correlation analysis to identify and characterize proteoforms from bottom-up proteomics data.

Integrin internalization through the endosomal pathway can lead either to recycling back to the surface or to lysosomal degradation. Faessler and colleagues now show that, following internalization, β1 integrins are bound by sorting nexin 17 in early endosomes to prevent integrin degradation in lysosomes and to promote surface recycling.

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.

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

SpatialData is a user-friendly computational framework for exploring, analyzing, annotating, aligning and storing spatial omics data that can seamlessly handle large multimodal datasets.