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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.

Many transcriptomic profiles have been deposited in public archives but are underused for the interpretation of experiments. Here the authors report GenomicSuperSignature for interpreting new transcriptomic datasets through comparison to public archives, without high-performance computing requirements.

During malaria transmission, the liver acts as a portal into the vertebrate host and is a major vaccine target. Here, Hildebrandt et al combine spatial and single cell transcriptomics to delineate host-parasite interactions within distinct spatial regions of the tissue.

This mega-analysis of brain resting-state functional connectivity in young individuals with major depressive disorder scanned at six sites across four countries identified hub regions of the attentional and default mode networks as predictors of depression severity.

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.

This study shows how different myeloid cell types contribute to damage and repair following cerebrovascular injury, a pathology common to many central nervous system disorders, and offers new therapeutic opportunities to improve clinical outcomes.

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.

Cortical maps of diffusion MRI microstructure follow cytoarchitectural and laminar differentiation, align with sensory-fugal and sensorimotor-association axes, and reflect oscillatory dynamics, neurotransmitter distributions, and cognition/behavior.

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.

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.

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.

A combined geochemical and multi-omics analysis across a 4,600-km transect in the central Pacific Ocean reveals that dinoflagellates play a previously unrecognized role in ecosystem and biogeochemical processes.

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.

Ordovas-Montanes and colleagues describe the composition of the nasal cellular ecosystem and signatures of disease severity in vaccinated and unvaccinated adults during infection with the ancestral, Delta and Omicron variants of SARS-CoV-2.

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.

Microglia mediate the early and selective degeneration of corticostriatal synapses and the development of cognitive deficits in presymptomatic Huntington’s disease via the complement cascade.

Liquid biopsies allow the non-invasive detection of somatic mutations from tumours. Here, the authors develop and test MSK-ACCESS, an NGS-based clinical assay for identifying low frequency mutations in 129 genes and describe how it benefits patients in the clinic.

A machine-learning classifier predicts the origin of cancer of unknown primary based on electronic health records and next-generation sequencing data, showing that patients treated accordingly to model predictions had significantly better outcomes.

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.

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.

In a randomized phase 2 trial, sotigalimab, a CD40 agonist, did not significantly improve overall survival in patients with previously untreated metastatic pancreatic cancer when combined with chemotherapy or with nivolumab and chemotherapy. Multi-omic exploratory analyses provide insights into immunologic features associated with clinical benefit.

The optical detection of two virulence factors of Mycobacterium tuberculosis on extracellular vesicles in blood allowed for the diagnosis of tuberculosis in paediatric cases that were missed by clinical microbiological assays.

Charles Roberts, Peter Park, Bradley Bernstein and colleagues examine the consequences of SMARCB1 loss on enhancer landscapes in human rhabdoid tumors. They show that SMARCB1 is essential for the integrity and abundance of SWI/SNF complexes and facilitates their targeting to appropriate enhancers.

An integrated analysis of de novo and inherited coding variants in 42,607 individuals with autism spectrum disorder identifies 60 risk genes of which five have not previously been associated with neurodevelopmental disorders.

Enteropathogenic Escherichia coli EspL is a cysteine protease that cleaves RHIM-containing proteins and blocks inflammasome signalling during infection.

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.

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.

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 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.

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.

MLKL is regarded as an executor of the necroptotic inflammatory cell death pathway. Here authors show, by introducing a mutation into mouse MLKL representing a frequently occurring human single nucleotide polymorphism, that MLKL mutations could critically alter the inflammatory response and the clearance of Salmonella from organs upon infection.

Hyperactivation of inflammasome-induced IL-1β can cause immunopathology and is a feature of autoinflammatory diseases. Here, the authors show how ubiquitination of IL-1β limits its activity by targeting it for proteasomal degradation and preventing its cleavage by caspase-1.

Salmonella enterica serovar 4,[5],12:i:- (Salmonella 4,[5],12:i:-) is a major pathogen of humans and animals with a reported incidence in Australia three times higher than the UK and USA. Here, the authors report the circulation, antimicrobial resistance signatures, and effects on host cells, of three Salmonella4,[5],12:i:- lineages within Australia.

A single-cell RNA-seq analysis of placental villous tissue provides a deconvolution reference atlas of fetal and maternal placental cell types, and indicates that placental cellular heterogeneity in preeclampsia might contribute to differences in bulk gene expression.

Non-receptor tyrosine kinases such as Src play fundamental roles in host–pathogen interactions and phagocytosis. Here, Young et al. show that an enteropathogenic Escherichia coli(EPEC) protein, EspJ, inhibits Src activity by simultaneous amidation and ADP ribosylation of a conserved residue on the kinase.

Wamsteeker Cusulin and colleagues report that stress-induced glucocorticoid release can trigger metaplasticity at GABAergic synapses on neuroendocrine neurons of the hypothalamus in rodents. Following stress, these GABAergic synapses gain the ability to undergo long-term depression in vitro, which involves amplification of mGluR signaling and retrograde suppression of synaptic transmission via persistent activation of presynaptic μ-opioid receptors. This form of plasticity may serve as a mechanism for behavioral stress adaptation.

MSK-IMPACT is a clinical sequencing platform able to detect genomic mutations, copy number alterations and structural variants in a panel of cancer-related genes. This assay is implemented prospectively to inform patient enrollment in genomically matched clinical trials at Memorial Sloan Kettering Cancer Center (MSKCC). Sequencing results of tumor and matched normal tissue from a cohort of >10,000 patients with detailed clinical annotation provide an overview of the genomic landscape of advanced solid cancers and bring new insights into molecularly guided cancer therapy.

Inoue and colleagues find that stress triggers a noradrenaline-dependent metaplastic change at GABAergic synapses onto paraventricular neurons of the hypothalamus in rodents. This metaplasticity depends on mGluR1, enables these synapses to undergo long-term potentiation during afferent bursts stimulation in vitro and possibly contributes to the neuroendocrine sensitization to stress.

Multi-ancestry genome-wide analyses identify new risk loci for age-related macular degeneration. Ancestry-specific analyses identify distinct effects at major risk loci, including smaller effect sizes for CFH risk alleles in haplotypes of African ancestry.

Whole genomes of 185 atypical enteropathogenic Escherichia coli (aEPEC) isolates reveal 30 LEE (locus of enterocyte effacement) subtypes in 3 major lineages, varying in insertion site preference and their complement of non-LEE encoded effector genes.