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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.

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.

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.

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 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.

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.

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.

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.

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.

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.

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.

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.

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.

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

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.

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.

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.

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.

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.

Small molecule inhibitors can influence the choice of repair pathways, enhancing nucleotide substitution and gene integration in CRISPR-mediated genome editing. Here the authors introduce CRISPY, a mix of small molecules that can enhance precise editing with Cpf1 and Cas9D10A in hiPSCs.

Fibroblast heterogeneity in the tumor microenvironment can explain their multifaceted role in cancer. Here by single-cell transcriptomic analysis of basal cell carcinoma, squamous cell carcinoma and melanoma samples, the authors explore fibroblast heterogeneity in skin cancer and their potential to modulate the tumor-immune microenvironment.

Perovskite solar cells grown in substrate configuration would open a range of applications, if various challenges could be overcome. Towards that aim, Fu et al. present an architecture allowing inverted semi-transparent planar perovskite solar cells with open-circuit voltage of 1.116 V and 16.1% efficiency.

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

Primary lymphomas of the central nervous system (PCNSL) are defined as diffuse large B-cell lymphomas (DLBCL) confined to the CNS. Here, the authors complete whole genome sequencing and RNA-seq to characterize 51 PCNSLs, and find common mutations in immune pathways and upregulated TERT expression and find distinct pathway differences between DLBCL and other primary CNS lymphomas.

Studies based on correlated operando characterization techniques reveal the coexistence of copper metal, oxide and hydroxide phases during the electrochemical reduction of nitrates to ammonia, providing insights into electrocatalyst evolution during reaction and related catalytic performance.

Cancer is often associated with mutant transcription factors (TFs) but their functional characterization is challenging. Here, the authors describe a recurrent mutation within TF IRF4 in human lymphomas and they show how it causes a complex switch in TF specificity and functionality.

An online approach for the DNA methylation-based classification of central nervous system tumours across all entities and age groups has been developed to help to improve current diagnostic standards.

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.

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.

Sarcomas are morphologically heterogeneous tumours rendering their classification challenging. Here the authors developed a classifier using DNA methylation data from several soft tissue and bone sarcoma subtypes, which has the potential to improve classification for research and clinical purposes.

Dewald et al. show a high Spike-IgG seroprevalence (95%) in a multicenter study with 1,411 participants. They determined a substantially reduced serum neutralization against the SARS-CoV-2 VOCs BA.4/5 and BQ.1.1. and explored predictive factors of neutralizing activity.

Proteomic prediction models developed using a large-scale dataset from the UK Biobank Pharma Proteomics Project were superior to clinical models for assessing the 10-year risk of 67 diseases across different types of pathology, including multiple myeloma, motor neuron disease, pulmonary fibrosis, celiac disease and dilated cardiomyopathy.

A global network of researchers was formed to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity; this paper reports 13 genome-wide significant loci and potentially actionable mechanisms in response to infection.

Nanobodies are normally made from immunized camelids, Ig transgenic mice or synthetic libraries. In this study, the authors introduce the llama Ig heavy chain locus into mice lacking this locus, thereby generating a line in which nanobodies can be made by direct immunization in the absence of an endogenous antibody repertoire.

RNA sequencing data and tumour pathology observations of non-small-cell lung cancers indicate that the immune cell microenvironment exerts strong evolutionary selection pressures that shape the immune-evasion capacity of tumours.

Integrative genomic and transcriptomic analyses reveal molecular events defining Richter transformation from CLL, and highlight the potential of cell-free DNA for early detection.

Juliane Winkelmann and colleagues report that two common variants in the 5′ UTR of PTPRD are independently associated with restless legs syndrome. PTPRD encodes a receptor-like protein tyrosine phosphatase previously implicated in axon guidance and motor neuron development.

Major histocompatibility complex (MHC) loss of heterozygosity, allele-specific mutation and measurement of expression and repression (MHC Hammer) detects disruption to human leukocyte antigens due to mutations, loss of heterogeneity, altered gene expression or alternative splicing. Applied to lung and breast cancer datasets, the tool shows that these aberrations are common across cancer and can have clinical implications.

Sinonasal tumour diagnosis can be complicated by the heterogeneity of disease and classification systems. Here, the authors use machine learning to classify sinonasal undifferentiated carcinomas into 4 molecular classe with differences in differentiation state and clinical outcome.

A significant proportion of individuals with inherited neuromuscular disease do not receive a genetic diagnosis. Here, the authors establish CCG expansions in the 5’ untranslated region of ABCD3 as a cause of oculopharyngodistal myopathy (OPDM) in individuals of European ancestry and identify increased expression of expansion-containing ABCD3 transcripts as a possible disease mechanism underlying muscle degeneration.

Stimulated emission depletion (STED) microscopy allows images to be captured at a subdiffraction resolution. Here optimal transport colocalization is proposed for analyzing macromolecule distributions in high-resolution STED images.