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A global network of researchers was formed to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity; this paper reports 13 genome-wide significant loci and potentially actionable mechanisms in response to infection.

Genome-wide association analysis in over one million individuals of European ancestry identifies 2,103 independent genetic signals (including 113 new loci) associated with blood pressure traits.

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 large genome-wide association study of more than 5 million individuals reveals that 12,111 single-nucleotide polymorphisms account for nearly all the heritability of height attributable to common genetic variants.

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.

A genome-wide association meta-analysis study of blood lipid levels in roughly 1.6 million individuals demonstrates the gain of power attained when diverse ancestries are included to improve fine-mapping and polygenic score generation, with gains in locus discovery related to sample size.

The Cancer Genome Atlas Research Network report integrated genomic and molecular analyses of 164 squamous cell carcinomas and adenocarcinomas of the oesophagus; they find genomic and molecular features that differentiate squamous and adenocarcinomas of the oesophagus, and strong similarities between oesophageal adenocarcinomas and the chromosomally unstable variant of gastric adenocarcinoma, suggesting that gastroesophageal adenocarcinoma is a single disease entity.

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.

Association analyses in over 1 million individuals identify 535 new loci influencing blood pressure traits. The results provide new insights into blood pressure regulation and highlight shared genetic architecture between blood pressure and lifestyle exposures.

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.

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.

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

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.

A trans-ancestry meta-analysis of GWAS of glycemic traits in up to 281,416 individuals identifies 99 novel loci, of which one quarter was found due to the multi-ancestry approach, which also improves fine-mapping of credible variant sets.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Meta-analyses in up to 1.3 million individuals identify 87 rare-variant associations with blood pressure traits. On average, rare variants exhibit effects ~8 times larger than the mean effects of common variants and implicate candidate causal genes at associated regions.

The human Fallopian tube (FT) is implicated as a site of origin for pelvic serous cancers. Here the authors conduct multi-omics analysis on over 100 FTs. The results challenge the assumption that BRCA1/2 mutation carriers exhibit significant molecular alterations in normal FTs before loss of heterozygosity (LOH) occurs, and suggest that tumorigenesis in BRCA1/2 carriers requires LOH or secondary genetic events rather than haploinsufficiency alone.

Monitoring hemodynamics in the brain is important in understanding medical imaging data and mechanisms of disease. Here the authors use high-throughput two-photon microscopy with an axially-extended Bessel focus to measure vessel size and blood flow down to capillary scale in the awake mouse brain.

Tuberous sclerosis complex (TSC) is a rare genetic disease causing multisystem tumour growth. Here the authors analyse 111 TSC-associated tissues for TSC1/TSC2 status, DNA mutations, copy number aberrations, differential gene expression and DNA methylation patterns providing a comprehensive genomic landscape.

An investigation using various methods reports an association between adeno-associated virus 2 and paediatric hepatitis of unknown aetiology.

Chronic infection with SARS-CoV-2 leads to the emergence of viral variants that show reduced susceptibility to neutralizing antibodies in an immunosuppressed individual treated with convalescent plasma.

Sera from vaccinated individuals and some monoclonal antibodies show a modest reduction in neutralizing activity against the B.1.1.7 variant of SARS-CoV-2; but the E484K substitution leads to a considerable loss of neutralizing activity.

Mark Caulfield, Paul Elliott and colleagues use data from the UK Biobank to perform genome-wide association analysis for blood pressure traits. They identify and validate 107 novel loci and highlight new biological pathways for potential therapeutic intervention for hypertension.

EY6A, a neutralizing antibody isolated from a patient convalescing from COVID-19, binds the receptor binding domain of the SARS-CoV-2 spike glycoprotein with high affinity, at a location away from the binding site for the ACE2 receptor, similar to the one recognized by CR3022.

In a phase 2 trial of patients with untreated, recurrent and progressive brain metastases treated with an anti-programmed cell death protein 1 inhibitor, the overall intracranial benefit rate was 42.1%, which met the prespecified primary endpoint.

High-grade meningiomas have a poor prognosis with virtually no effective systemic therapies. Here, the authors report results of a phase 2 clinical trial demonstrating safety and activity of pembrolizumab, a PD-1 inhibitor, in patients with recurrent and residual high-grade meningiomas.

Leptomeningeal metastases from solid tumors are a rare complication with a very poor prognosis. Here the authors report the efficacy and safety of combined ipilimumab and nivolumab in patients with leptomeningeal carcinomatosis.

The SARS-CoV-2 spike glycoprotein is flexible, and its receptor-binding domain (RBD) fluctuates between open and closed conformations. Disulfide bonds are engineered into the spike ectodomain to lock the RBD in the closed state, leading to a construct with high thermostability.

Medulloblastoma is the most common malignant brain tumour in children; having assembled over 1,000 samples the authors report that somatic copy number aberrations are common in medulloblastoma, in particular a tandem duplication of SNCAIP, a gene associated with Parkinson’s disease, which is restricted to subgroup 4α, and translocations of PVT1, which are restricted to Group 3.

A genome-wide association study of critically ill patients with COVID-19 identifies genetic signals that relate to important host antiviral defence mechanisms and mediators of inflammatory organ damage that may be targeted by repurposing drug treatments.

A multi-ancestry meta-regression study analyses diverse genome-wide association studies and genome loci associated with tobacco and alcohol use.

In a large, partially prospective cohort of patients with molecularly profiled and clinically annotated meningioma, the extent of surgical resection and radiotherapy (RT) response correlate with molecular classification, which can be used in a molecular model to predict clinical outcomes in response to RT.

Adaptive optics (AO) corrects sample aberrations and allows high spatial resolution at depth in vivo. Here the authors report an AO method for Bessel focus; they apply AO Bessel focus scanning fluorescence microscopy to volumetric imaging and measure synaptic calcium and glutamate activity in vivo.