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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.

Neville, Ferguson et al. show that non-canonical Polycomb repressive complex 1.1-mediated gene silencing is antagonized by DOT1L and is required for the therapeutic efficacy of Menin and DOT1L inhibitors in mixed-lineage leukaemia.

A subset of pediatric gliomas harbour alterations in fibroblast growth factor receptor (FGFR)-family proteins. Here, the authors characterise the genomic landscape of 11,635 gliomas across ages and use isogenic model systems to explore the underlying biology of FGFR1-altered gliomas and potential therapeutic vulnerabilities.

The functional impact of most missense variants remains unknown. Here the authors perform deep mutational scanning of the tumor suppressor SMARCB1 and find missense mutations that retain detectable protein expression but disrupt function similar to protein-null mutations

Mutation profiling of pediatric cancers can help determine treatment options, however, large-scale datasets are rare. Here, the authors describe an institutional application of targeted sequencing to pediatric solid tumours, and identify potential therapeutic implications for identified mutations.

Glioblastoma (GBM) invasion into brain parenchyma presents significant challenges for treatment. Here, the authors employ multi-omics analysis of orthotopic GBM xenograft mouse models to show that GBM cellular states are correlated both to the propensity to invade by distinct anatomical routes and to the programs that GBM cells activate during invasion.

Post-translational redox modification of protein cysteine residues has emerged as a mode of immune cell regulation. Now, a deep redox proteomics study identifies redox-regulated and druggable cysteines in immunological proteins.

Dual cyclin A/B RxL inhibitors selectively kill small cell lung cancer cells and other cancer cells with high E2F activity.

SWI/SNF complexes are mutated in 20% of cancers, yet the underlying mechanisms are poorly understood. Here, the authors identify a compensatory mechanism of chromatin regulation that becomes essential in cancers carrying mutations that broadly inactivate SWI/SNF.

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.

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.

Analysis of a placebo-controlled trial of a BCMA-targeting CAR-T cell therapy in patients with myasthenia gravis shows that CAR-T cell infusion selectively remodels the systemic immune environment, with elimination of BCMA-high plasma cells and activated plasmacytoid dendritic cells and changes in the autoreactive B cell repertoire.

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.

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.

Co-occurring mutations in the tumor suppressor LKB1 are frequent in KRAS-mutant lung cancers. Here, the authors show that LKB1 regulates JNK-dependent stress signaling apoptotic dependencies of KRAS-mutant tumors, making LKB1-deficient cells vulnerable to MCL-1 inhibition.

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

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.

A population of TRAIL-positive astrocytes in glioblastoma contributes to an immunosuppressive tumour microenvironment and this mechanism can be targeted with an engineered oncolytic virus to improve outcomes.

Independent but complementary studies from Vakoc and Stegmaier identify and characterize a role for ETV6 in counteracting the transcriptional activity of EWS–FLI during Ewing sarcoma development, which may be targeted for therapeutic benefits.

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.

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.

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.

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.

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 Mouse Cancer Cell line Atlas (MCCA) provides major advances towards a mechanistic understanding of cancer genomes.

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.

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.

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.

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 prognostic impact of genetic subtypes in diffuse large B-cell lymphoma not otherwise specified (DLBCL-NOS) remains unclear. Here, the authors use data from multiple clinical trials to identify DLBCL-NOS genetic subtypes that are associated with patient outcomes, showing their potential value for prognostic stratification, trial design, and PET response monitoring.

Duplaquet, Li et al. identify and characterize KDM6A as an epigenetic regulator that impacts chromatin accessibility to modulate ASCL1-to-NEUROD1 subtype switching in small cell lung cancer.

Regulatory DNA screens often lack nucleotide-level resolution. Here, authors present an end-to-end CRISPR base-editing and sequencing framework that maps regulatory variants at single-nucleotide resolution, revealing enhancer mutations that alter CD19 expression and enable CAR-T therapy resistance.

Majzner and colleagues show that engineering T cells with a membrane-tethered version of the signaling adaptor molecule SLP-76 alongside a chimeric antigen receptor (CAR) enhances CAR T cell activity against low-antigen-density tumors.

Temozolomide therapy seems to lead to mismatch repair deficiency and hypermutation in gliomas, but not to an increase in response to immunotherapy.

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.

PPM1D is a known mediator of p53 signalling, and has been linked to treatment resistance in glioma. In this work, the authors utilise genomics, proteomics, and mouse models to determine the role of PPM1D in the development of diffuse midline glioma.

A follow-up analysis of a clinical trial that evaluated anti-PD-1 therapy in patients with cancer who are living with HIV provides mechanistic insights into transcriptomic, cellular and cytokine changes related to immune checkpoint inhibitor treatment and identifies a signature associated with clinical response.

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.

Advanced pancreatic cancer is associated with tissue wasting; however, the timing of tissue loss prior to diagnosis and the potential utility of such loss for earlier pancreatic cancer detection are not well understood. Here the authors show that skeletal muscle loss can be detected on CT imaging 1–2 years before a clinical diagnosis of pancreatic cancer.

HIV-1 integrase forms an RNA-binding module on the luminal side of the mature capsid lattice.

Global Burden of Disease estimates show that between 1990 and 2023, the prevalence and burden of drug use disorders, inclusive of amphetamine, cannabis, cocaine and opioid use, have been increasing in high-income countries, particularly in the USA.

T- and NK-cell lymphomas (TCL) are a group of lymphoid malignancies characterized by poor prognosis, but the absence of appropriate pre-clinical models has hampered the development of effective therapies. Here the authors establish several pre-clinical models and identify vulnerabilities that could be further exploited to treat patients afflicted by these diseases.

Most patients with metastatic melanoma still develop primary or acquired resistance to immune checkpoint inhibition (ICI). Here the authors report the results of a phase II trial of cryoablation and ICI in patients with unresectable melanoma progressing on ICI.

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.