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Endocrine therapies are the main adjuvant therapy for estrogen receptor positive breast cancer, but 30% of patients recur. Here, the authors discover that endocrine therapy upregulates Rac1 signalling component P-Rex1, and inhibition of Rac1 reduces tumour growth in refractory breast cancer models.

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.

Genome-wide analyses identify genetic loci and plasma proteins associated with polycystic ovary syndrome (PCOS). This study highlights the hormonal and metabolic foundations of the disease and explores the impact of polygenic risk for PCOS in both sexes.

The molecular basis and evolution of GPCR selectivity for chemical messengers are poorly understood. Here, authors use an interdisciplinary approach to identify mechanisms of ligand selectivity in adrenergic and dopamine receptors.

Longitudinal metatranscriptomics in a prospective cohort of 1,164 adults hospitalized for COVID-19 reveals that azithromycin offered no apparent anti-inflammatory benefit but enriched the respiratory microbiome with potential pathogens and antimicrobial resistance genes.

DNA-sequencing data from primary tumours and paired metastases from participants in the TRACERx lung study and PEACE autopsy programme are used to analyse the metastatic diversity of advanced non-small cell lung cancer and the seeding patterns that underpin it.

Tracking oceanic microbial populations in situ over time is challenging. Here, the authors use autonomous underwater vehicles to show how microbes at the deep chlorophyll maximum respond to diel cycles and isopycnal uplift by a cyclonic eddy.

It remains unclear why some BRCA-deficient high-grade serous carcinomas (HGSC) do not respond to platinum-based therapy. Here, multi-omic analysis of BRCA1- and BRCA2-deficient HGSC attributes co-occurring mutations, DNA repair deficiency and tumor microenvironment features to short survival in these patients.

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.

Conventional type 1 dendritic cells (cDC1) can boost the precursor exhausted T cell population thought to be essential for efficacy of immune checkpoint therapy. Here the authors enhance this cellular network using Flt3L to expand cDC1s and then map the movement of T cells and DCs between tumors and lymph nodes.

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.

An analysis of 24,202 critical cases of COVID-19 identifies potentially druggable targets in inflammatory signalling (JAK1), monocyte–macrophage activation and endothelial permeability (PDE4A), immunometabolism (SLC2A5 and AK5), and host factors required for viral entry and replication (TMPRSS2 and RAB2A).

Decreased brain volumes and increased NfL levels can be observed earlier than disease diagnosis in short-tandem-repeat-associated neurological diseases.

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.

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.

Neoantigen-based adoptive T cell therapies represent a personalized approach for cancer immunotherapy. Here the authors describe NEO-STIM, an ex vivo T cell induction platform to STIMulate peripheral blood T cells to generate responses against tumor NEOantigens.

This paper uses multiomics to profile a large cohort of meningioma samples to highlight the role of the tumor microenvironment in driving the epigenetic changes underpinning tumor classification and prediction of outcome.

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.

The APOE-ε4 allele is the strongest genetic risk factor for late-onset Alzheimer’s disease, but it is not deterministic. Here, the authors show that common genetic variation changes how APOE-ε4 influences cognition.

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.

Rare coding variants that reduce the activity of a protein can have a beneficial impact on health. Here, researchers identify rare genetic variants in the CHRNB3 gene that associate with reduced cigarette smoking across diverse populations.

The combination of JWST and ALMA data here unravel the history of the gas content of a quiescent galaxy, which became quenched through an act of self-sabotage. Black-hole accretion feedback heated the galaxy’s surrounding material, preventing its accretion.

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.

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.

The chemistry of group 13 metals (M) is dominated by +1 and +3 oxidation states, so MX₂ species are typically metal–metal-bonded dimers, M(II)₂X₄ or mixed-valence species M(I)M(III)X₄. Now, monomeric M(II)(boryl)₂ radicals have been prepared for gallium, indium and thallium. The compounds — structurally characterized by X-ray crystallography — are stable up to 130 °C and exhibit dominant metal-centred radical character.

The authors analyzed the whole-exome sequences of over 16,000 individuals and found that very rare variants predicted to disrupt the SETD1A gene confer substantial risk for schizophrenia. Damaging variants in SETD1A were also associated with diverse, severe developmental disorders, providing an important genetic link between schizophrenia and other neurodevelopmental disorders.

In flowering plants, DNA–FD–14-3-3 recruits FT to the florigen activation complex both through DNA–FT interactions and by reducing liquid phase condensation of FD protein, which promotes dimerization, leading to FT recruitment.

The composition and potential roles of extracellular vesicles released by gut archaea are poorly understood. Here, Weinberger et al. show that extracellular vesicles produced by human gut-derived methanogenic archaea are enriched in adhesin-like proteins, can be taken up by macrophages, and elicit responses in immune and epithelial cells.

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.

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.

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.

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.

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.

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.

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.

The advantage of living in cities compared with rural areas with respect to height and BMI in children and adolescents has generally become smaller globally from 1990 to 2020, except in sub-Saharan Africa.

Evidence from four complementary methodological approaches, harnessing genotype and phenotype data, identifies potential causal links between inflammatory bowel disease in parents and autism in children.

Methods used to date a network of marine sediment cores reveal that rapid retreat of the Ross Ice Shelf was contemporaneous with the lowering of nearby outlet glaciers, implicating warm ocean waters as a driver of Antarctic deglaciation.