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PROTAC development has surged in popularity, however our ability to characterize PROTAC specificity in living cells has lagged behind. Here, the authors develop ProtacID, a flexible proximity-dependent biotinylation (BioID)-based approach to identify PROTAC-protein interactions in living cells.

Somatic small variants in cancer genomes are identified in both short-read and long-read data.

Basal cells, rather than neuroendocrine cells, have been identified as the probable origin of small cell lung cancer and other neuroendocrine–tuft cancers, explaining neuroendocrine–tuft heterogeneity and offering new perspectives for targeting lineage plasticity.

MHC class I and II molecules generally present endogenous and exogenous peptides, respectively, through distinct mechanisms. Here, the authors show that the class II molecule HLA-DP^84Glyuses both class I and II mechanisms to constitutively present peptides.

Thomas, Egan et al. report that hexokinase 2 localizes to the nucleus of leukaemic and normal haematopoietic cells to maintain stemness by interacting with nuclear proteins and modulating chromatin accessibility independently of its kinase activity.

Type I PRMT inhibition elicits potent antitumor activity associated with increased interferon response and intron-retained dsRNA accumulation, suggesting its potential combination with immune checkpoint inhibitors for cancer treatment.

Previous work shows that a small population of quiescent SOX2⁺ medulloblastoma (MB) stem cells can drive tumour growth in early tumorigenesis and relapse. Here, the authors identify OLIG2 as a transcriptional mediator of the transition from quiescent to rapidly proliferating progenitor states and therapeutically target this axis in preclinical models of MB.

A study of several longitudinal birth cohorts and cross-sectional cohorts finds only moderate overlap in genetic variants between autism that is diagnosed earlier and that diagnosed later, so they may represent aetiologically different conditions.

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.

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.

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.

An analysis of 24,202 critical cases of COVID-19 identifies potentially druggable targets in inflammatory signalling (JAK1), monocyte–macrophage activation and endothelial permeability (PDE4A), immunometabolism (SLC2A5 and AK5), and host factors required for viral entry and replication (TMPRSS2 and RAB2A).

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.

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.

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 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.

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.

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.

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.

Zheng et al. show that ChAT-expressing cholinergic T cells suppress the development of liver cancer via their cholinergic activity, which constrains calcium/NFAT signaling induced by TCR engagement.

The Microprocessor executes the first step in microRNA biogenesis. Here, the authors identify a protein motif in DGCR8/Pasha that is essential for proper Microprocessor assembly, which in turn regulates its subcellular localization.

Neutrophil extracellular traps (NETs) are known to promote metastasis in mouse models. Here the authors show plasma redox imbalance caused by albumin oxidation to induce inflammation-independent NETosis and lung metastasis, and albumin oxidation and reduced plasma free thiol to be associated with lung metastasis in a cohort of head and neck cancer patients.

N⁶-methyladenosine (m⁶A) modification of mRNA regulates gene expression in eukaryotes. Here, Zeng et al. show that m⁶A modification of mRNAs contributes to protection against the pathogen Helicobacter pylori by downregulating a host protein that acts as receptor for the pathogen.

The PEAK family of pseudokinases is known to play oncogenic roles in poor-prognosis triple negative breast cancer (TNBC). Here this group identifies the role of calcium/calmodulin-dependent protein kinase 2 (CAMK2) in targeting downstream of PEAK1 thereby utilizing RA306 (CAMK2 inhibitor) to effectively attenuate TNBC xenograft growth and block metastasis as well.

Clonal hematopoiesis is driven by the selective advantage of mutant hematopoietic stem cells. Here, authors discover that elevated mitochondrial activity is a targetable mechanism by which mutant hematopoietic stem cells gain a selective advantage.

Functional characterization of genetic alterations is a prerequisite for pancreatic cancer precision medicine. Here, using in vivo CRISPR screens, the authors integrate human cancer genomics and mouse models, identifying that loss of USP15 or SCAF1 accelerates tumor development and leads to reduced inflammatory responses and increased sensitivity to PARP inhibition and Gemcitabine.

Here, the authors show that PRMT1 targeting inhibits clear cell renal cell carcinoma cells through perturbation of RNA metabolism and down-regulation of DNA repair pathways, resulting in the accumulation of unresolved R-loops and DNA damage.

CD4⁺ T cells are readily detected with class II MHC dimers.

The origin and source of mammary gland progenitors and how they interact with the adipose‐rich stroma is unclear. Here, the authors identify PDGFRα⁺ adipocyte progenitors in the murine mammary stroma as a mesenchymal cell lineage recruited into the expanding epithelium during development, hormone exposure and pregnancy.

Reduced expression of DICER—responsible for the processing of microRNA precursors—was previously linked to poor clinical outcomes in cancer patients. Here, the authors uncover an epigenetic mechanism by which hypoxia suppresses DICER expression and deregulates the miR-200-Zeb1 circuit in breast cancer to promote the tumour phenotype.

Dnmt3a mutations in mouse haematopoietic stem and progenitor cells equivalent to R882 mutations in human cause increased mitochondrial respiration, suggesting that this is a mechanism of clonal haematopoiesis and a potential therapeutic target.

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

CREBBP and KMT2D mutations frequently co-occur in B cell lymphomas with unclear significance. Here the authors show that they cooperate to skew B cell fate decisions and induce a CD8-depleted immune-evasive microenvironment to facilitate lymphomagenesis.

Irx3 and Irx5 are effectors of the FTO locus, which is associated with obesity. Son et al. show regulation of hypothalamic neurogenesis by Irx3 and Irx5, uncovering a role for these genes in leptin response and energy homeostasis.

Genetic variants at multiple loci of chr5p15.33 have been associated with susceptibility to numerous cancers. Here the authors show that the association of one of these loci may be explained by a variant, rs36115365, influencing telomerase reverse transcriptase (TERT) expression via ZNF148.

A high-throughput small-molecule drug screening platform enabled the detection of compounds targeting the functional interactions of receptor tyrosine kinases and identifies four new EGFR triple-mutant inhibitors.

Electrical excitability in neuroendocrine SCLC cells promotes tumour progression through action potential firing, increasing ATP demand and oxidative phosphorylation dependency, whereas non-neuroendocrine cells provide metabolic support, driving a tumour-autonomous cycle that enhances tumorigenesis and metastasis.

Using viral barcode tracing to detect interactions between glioblastoma cells and non-malignant astrocytes in patient samples, investigators discovered a pathway that reduces tumour-specific immunity and identified potential therapeutic targets.

Here the authors show that the nucleus undergoes a transient ‘metamorphosis’ within a nuclear–cytoplasmic DNA damage response linked to health and disease. Through this process, the nuclear envelope projects tubules that capture damaged DNA, mediating its repair.