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Stunnenberg et al. use a model of lipopolysaccharide injection in humans to characterize the transcriptomic landscape of bone marrow and blood immune cells during the hyperinflammatory and immunosuppressed phases of systemic inflammation.

Here, Libertini and colleagues devise a computation tool that can analyze whole-genome bisulfite sequencing (WGBS) data to recover of ∼30% of the lost differential methylation position information. They use COMETgazer and COMETvintage to analyze 13 diffferent methylome data to demonstrate their performance.

Translational control of gene expression can lead to significant divergence between mRNA and protein abundance. Here, the authors describe transcriptional rewiring and translational buffering during transition from naïve to primed pluripotency through quantitation of mRNA-abundance, translation rate and protein expression.

WNT-activating mutations in CTNNB1 are common in hepatoblastoma, but downstream molecular phenotypes are heterogenous. Using multiomic approaches, the authors identify distinct subgroups of hepatoblastoma cells based on WNT-signaling patterns and create a biobank of patient-derived hepatoblastoma organoids representing these subtypes.

Hypoxic conditioning—controlled, brief and repeated exposure to moderate levels of low-oxygen air—is safe in people with Parkinson’s disease, with participants reporting mild, short-term improvement in Parkinson’s symptoms.

Celiac disease is linked to responsiveness to dietary gluten, which manifests itself as immune cell activation and the immunopathology including destruction of the epithelium of the small intestine. Here the authors apply single cell transcriptomics to characterise the immune cell compartment of the human small intestine during active Celiac disease.

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

A package of papers investigates the functional regulatory elements in genomes that have been obtained from human tissue samples and cell lines. The implications of the project are presented here from three viewpoints. See Articles p.317, p.331, p.337 & p.344 and Letters p.350, p.355, p.360 & p.365

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 cancer, global DNA methylation loss and CpG island hypermethylation are commonly observed. Here, in breast cancer the authors find that hyper-variability of partially methylated domains is the prime source of DNA methylation variation and that these domains fuel CpG island hypermethylation.

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.

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.

Atlasi et al. demonstrate that transcriptome and epigenome resetting during serum-to-2i pluripotency conversion involves minimal enhancer–promoter rewiring and is instead linked to 2i-enhancer activation via Esrrb-mediated H3K27 acetylation.

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.

Functional characterisation of non-coding risk variants for colorectal cancer is missing. Here the authors conduct a large-scale proteome-wide analysis of disease associated SNPs to characterize allele-specific transcription factor binding landscape in colorectal cancer and identify one functionally significant SNP.

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.

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.

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 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.

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.

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.

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.

The dynamics and molecular mechanisms of T cell therapies are probed in cancer organoids.

Here, the authors show that combining γ9δ2 TCR-mediated metabolic and co-stimulatory stress targeting by chimeric NKG2D or anti-CD277 co-receptors shapes transcriptomic heterogeneity of engineered T cells and is associated with improved control of solid tumors.

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.

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.

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.

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.

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.

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.

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.

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.

The ETV6-RUNX1 chimeric- and native RUNX1-responsive regulomes in paediatric B-acute lymphoblastic leukemia (B-ALL) remain to be characterized. Here, the authors reveal functional antagonism between the two transcription factors predominantly for the regulation of cell cycle-associated pathways and dependency on native RUNX1 for tumorigenesis which can be targeted pharmacologically.

Numerous genetic variants, including those located in the non-coding regions of the genome, are known to be associated with blood cells traits. Here, Frontini and colleagues investigate their potential regulatory functions using epigenomic data and promoter long-range interactions.

The molecular mechanisms mediating the impact of environmental factors in atherosclerosis are unclear. Here, the authors examine CD14+ blood monocyte’s transcriptome and epigenome signatures to find differential methylation and expression of ARID5B to be associated with human atherosclerosis.

Bernhard Radlwimmer and colleagues report whole-genome bisulfite sequencing of 13 Burkitt lymphomas and nine follicular lymphomas. They find that both types of germinal center B cell lymphomas show global hypomethylation compared to normal germinal center B cell precursors and identify regions of differential methylation that correlate with somatic mutations and differential gene expression.

Polycomb Repressive Complex 2, an important regulator of embryonic development, exists in two configurations, PRC2.1 and PRC2.2. Here the authors dissect the functional contributions of these two PRC2 subunits and observed complex-specific alterations in the cell state of pluripotent and early differentiating cells.

Recent studies using in depth DNA sequencing techniques led to the identification of cancer driver genes but mainly focused on the effect on their expression. Here, the authors analyse 266 cases of breast cancer and report gene expression signatures associated with the number and character of signature mutations.

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.

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

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.

Germline pseudogenes have an important role in human evolution. Here, the authors analyse sequencing data from 660 cancer samples and find evidence for the formation of somatically acquired pseudogenes, a new class of mutation, which may contribute to cancer development.

Brd4, a reader of histone acetylation, is a transcriptional co-activator implicated in the maintenance of embryonic stem cells (ESCs). A study now shows that Brd4 is dispensable in mouse ESCs maintained in ground state pluripotency, and that cooperative activity of Tet1/2 and ESC-specific transcription factors compensates for its loss.