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Despite often being poorly immunogenic, some subsets of patients with hormone receptor-positive, HER2-negative (HR + /HER2-) breast cancer benefit from immunotherapy. Here, the authors present a randomised pilot clinical trial comparing a neoadjuvant run-in of either nab-paclitaxel or pembrolizumab (anti-PD-1) monotherapy, followed by the combination, in patients with stage II-III HR + /HER2- breast cancer.

A combination of high-resolution spatial imaging, spatial proteomics and transcriptional data reveals sparse and heterogeneous bacterial signals in gliomas and brain metastases.

Through analysis of the electronic medical records of 284,592 vaccinated patients, using a sequence–symmetry analysis, Kwan et al. show that the risk of postural orthostatic tachycardia syndrome (POTS) is increased after COVID-19 vaccination compared to a 90-day control period before exposure—although 5.35 times lower than the risk of POTS occurrence after SARS-CoV-2 infection.

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.

mRNA vaccines targeting SARS-CoV-2 also sensitize tumours to immune checkpoint inhibitors.

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.

A study reports whole-genome sequences for 490,640 participants from the UK Biobank and combines these data with phenotypic data to provide new insights into the relationship between human variation and sequence variation.

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.

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.

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.

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.

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.

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 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.

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.

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.

Individuals with long COVID show marked biological changes in cortisol and immune factors relative to convalescent populations.

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.

A suite of methods enables programmable species- and locus-specific editing of bacteria in communities.

Current antiretroviral therapy usually results in HIV or SIV rebound if treatment is stopped. Here the authors demonstrate virus remission in macaques persisting for two years after early treatment with a regimen optimized to penetrate virus reservoirs and sustain antiviral activity after treatment cessation.

Genetic and testing data from England show that the SARS-CoV-2 variant of concern B.1.1.7 has a transmission advantage over other lineages.

A systematic census at 1,636 sites around Australia from 2008 to 2021 finds that more than 30% of shallow invertebrate species in cool latitudes exhibit a high extinction risk due to declining populations and oceanic barriers, but tropical coral species remain relatively stable.

Whalen et al. report that increased DNA end resection in BRCA-deficient, PARP inhibitor-resistant cancers leads to increased sensitivity to DNA nicks, limiting tumor formation in mice, and propose the therapeutic exploration of nickases.

In this study, Aggarwal and colleagues perform prospective sequencing of SARS-CoV-2 isolates derived from asymptomatic student screening and symptomatic testing of students and staff at the University of Cambridge. They identify important factors that contributed to within university transmission and onward spread into the wider community.

A CRISPR-Cas13 enzyme is shown to have potent anti-phage activity that is harnessed to produce a phage genome engineering method with broad utility.

In some systems, a single protein comprising reverse transcriptase (RT), integrase and maturase enables concerted sequence integration and crRNA production. Here, analyses including the structure of a Cas6-RT-Cas1—Cas2 complex suggest coordination between all three active sites and capacity to acquire CRISPR sequences from RNA and DNA substrates.

Borgs are remarkably large, divergent archaeal extrachromosomal elements with metabolic genes linked to the methane cycle.

Here, Lou et al. apply metagenomics and microbiome cultivation to infant fecal samples and uncover co-existing members encoding extracellular fucosidases that initiate 2’-fucosyllactose (2’FL) breakdown and can promote extensive growth of Bifidobacterium breve.

Ceramides are a type of sphingolipid (SL) that have been shown to play a role in several metabolic disorders. Here, the authors investigate the effect of SL-production by gut Bacteroides on host SL homeostasis and show that microbiome-derived SLs enter host circulation and alter ceramide production.

Genomic analyses of major clades of huge phages sampled from across Earth’s ecosystems show that they have diverse genetic inventories, including a variety of CRISPR–Cas systems and translation-relevant genes.

Post-international travel quarantine has been widely implemented to mitigate SARS-CoV-2 transmission, but the impacts of such policies are unclear. Here, the authors used linked genomic and contact tracing data to assess the impacts of a 14-day quarantine on return to England in summer 2020.

The pathways responsible for inositol lipid production in human gut Bacteroides are characterized and these lipids are important for capsule expression and antimicrobial peptide resistance in vitro and colonization in vivo.

Weiss et al. engineered the tobacco rattle virus to express the RNA-guided TnpB enzyme ISYmu1 and guide RNA for transgene-free germline editing in Arabidopsis thaliana.

Cryo-EM structures of CRISPR–CasΦ, a small RNA-guided enzyme unique to bacteriophages, reveal how CasΦ binds to and cleaves DNA, paving the way for engineering of improved CasΦ variants for diagnostics and genome-editing applications.

Evan Eichler and colleagues identify a recurrent microdeletion on 16p12.1 associated with developmental, cognitive and neuropsychiatric phenotypes. They also show that more severe phenotypes are frequently correlated with the presence of a second large genomic rearrangement, supporting a complex model of pathogenesis that may underlie the variable expressivity typical of many microdeletion syndromes.

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.