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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.

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.

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.

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.

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.

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.

Spatiotemporal regulation of wound healing in mice and humans occurs via retinoic acid and hypoxia signalling, which regulate the differentiation of CD201⁺ fibroblast progenitors into proinflammatory and myofibroblast states.

Wartewig et al. show that PDCD1 in T cell lymphoma restricts glycolytic energy and acetyl-CoA production. Inhibition of PD-1 signaling enforces ACLY activity and generates extramitochondrial acetyl-CoA for histone acetylation to enable AP-1 hyperactivation.

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.

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

Smoke is a solid. Whether from cigarettes, cooking fires or other sources, it is comprised of tiny particles that injure the lung and can lead to lung cancer and chronic obstructive pulmonary disorder, characterized by laborious breathing. Steven D. Shapiro and his colleagues take a look at imaging data in people suggesting that these two conditions have more in common mechanistically than was previously thought. Both diseases seem to stem in part from the ability of inhaled particles to trigger inflammation, a process examined by Robert M. Senior and his colleagues.

Using an integrated metabologenomics approach, the biosynthetic pathway for the pestalamides is revealed and over 200 high-confidence targets are identified for future studies.

Comparative studies of the immune response to simian immunodeficiency virus in two nonhuman primate species provide insight into a central aspect of HIV infection—the ability of the virus to cause chronic activation of the immune system (pages 1077–1087).

MicroRNAs contribute to HIV-1 latency in resting T cells. This finding could potentially be used in the development of therapies targeted to purge the latent reservoir in an effort to clear the body of virus (pages 1241–1247).

Little is known about how pathogenic T cells gain access to the uninflamed brain in multiple sclerosis and experimental autoimmune encephalomyelitis. A new study reports that interleukin 17–producing T helper cells enter the uninflamed central nervous system through the choroid plexus by a CCR6-CCL20–dependent mechanism.

Here, Schoeler et al. investigate how interaction between dietary lipids and the gut microbiota affect hepatic steatosis and host metabolism, showing that dietary lipids impact the gut microbiota composition independent on fiber intake in humans and mice.

By studying individuals along a spectrum of cardiometabolic disease and adjusting for effects of lifestyle and medication, this investigation identifies alterations of the metabolome and microbiome from dysmetabolic conditions, such as obesity and type 2 diabetes, to ischemic heart disease.

There is no cure for osteoarthritis—the most common disease of the joints. By piecing together the molecular events that drive the progression of this debilitating disease, recent studies published in Nature Medicine put hypoxia-inducible factor-2α (HIF-2α) in the driver's seat, opening up new avenues for early detection and treatment (pages 678–686 and 687–693).

Better analytical methods are needed to extract biological meaning from genome-wide association studies (GWAS) of psychiatric disorders. Here the authors take GWAS data from over 60,000 subjects, including patients with schizophrenia, bipolar disorder and major depression, and identify common etiological pathways shared amongst them.

An analysis of 2,173 individuals from the MetaCardis cohort quantifies the individual and combinatorial effects of a range of drugs on host health, metabolome and gut microbiome in cardiometabolic disease.

The anaerobic gut bacterium Faecalibacterium prausnitzii was isolated and adapted for oxygen tolerance to develop a next-generation probiotic for the treatment of conditions such as inflammatory bowel disease and type 2 diabetes.

Peptides only 28 amino acids long retain the specificity of a parental antibody.

A recent study has put together the three-dimensional structures of proteins involved in the central metabolism of one organism, providing insight into the evolution of metabolic networks.

As a differentiated cell proceeds toward the pluripotent state, markers turn on and off in an orderly fashion.

A cohort of immunodeficient children lead near-normal lives after bone marrow transplantation, despite a profound deficiency of innate lymphoid cells (ILCs).

Gut microbes are known to influence whole-body metabolism. Here Everard et al.show the adaptor protein MyD88 in intestinal epithelial cells is sensitive to changes in the diet and affects composition of the gut microbiota, which influences the development of obesity and associated diseases.