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There is currently no approved influenza vaccine for newborns, so development of such a vaccine is warranted. Here the authors show, using a African green monkey newborn model, that an adjuvanted nanoparticle vaccine containing the stem region of influenza hemagglutinin can induce robust IgG responses, with the functionality of the antibodies linked to viral clearance.

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).

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.

Factors limiting CNS remyelination with age are poorly understood. Here the authors show that aged Treg lose capacity to support CNS remyelination in mice, which can be restored in a young environment.

High-depth sequencing of non-cancerous tissue from patients with metastatic cancer reveals single-base mutational signatures of alcohol, smoking and cancer treatments, and reveals how exogenous factors, including cancer therapies, affect somatic cell evolution.

Xenotransplantation of a genetically edited pig kidney with a thymic autograft into a brain-dead human for 61 days with immunosuppression resulted in stable kidney function without proteinuria, and xenograft rejection was treated and reversed by the end of the study.

Esophageal adenocarcinoma is characterised by frequent amplifications in oncogenes. Here, the authors use short- and long-read sequencing approaches to analyze primary tumor samples and tumour-derived organoids and to investigate the mechanisms underlying complex amplifications.

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.

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.

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.

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.

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.

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.

Rebecca Fitzgerald and colleagues used genome sequence analyses to study the progression from premalignant Barrett's esophagus to esophageal adenocarcinoma (EAC) and found that the majority of recurrently mutated genes in EAC were also mutated in precursor lesions and that only mutations in TP53 and SMAD4 were stage specific.

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.

Rebecca Fitzgerald and colleagues report the whole-genome sequences of 129 esophageal adenocarcinomas, showing frequent copy number alterations and prevalent mutations in receptor tyrosine kinases concomitant with mitogenic activation. They further characterize mutation signatures and find three distinct molecular subtypes with potential for application to clinical diagnosis and treatment.

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.

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.

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.

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.

Rebecca Fitzgerald and colleagues report whole-genome sequence analyses of 23 paired samples of Barrett's esophagus and esophageal adenocarcinoma. Their analyses of the clonal architecture of these lesions shows that copy number increases and heterogeneity persists during development of esophageal adenocarcinoma.

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.

Rebecca Fitzgerald completed her medical degree at the University of Cambridge, followed by doctoral research at Stanford University, and then postdoctoral research alongside specialist training in gastroenterology at Barts and the London Hospitals. She started her own independent group the MRC Cancer Unit in 2001 with an honorary gastroenterology consultant position at Addenbrooke’s Hospital. In 2014, she was elected to chair in cancer prevention, and in 2022 inaugural director of the department of oncology at the Early Cancer Institute, University of Cambridge.

Ganguli et al. show that CDKN2A loss in Barrett’s esophagus prevents esophageal adenocarcinoma initiation by counterselecting subsequent TP53 loss and report context-dependent effects of 9p21 gene co-deletions on disease progression.

Sequencing tumour genomes can reveal information about the processes that drive the formation of cancer. Here, the authors describe a method that can detect these mutational signatures from small amounts of DNA and degraded samples.

TANK-binding kinase-1 (TBK1) and its homologue IκB kinase-ε (IKKε) are critical in the induction of the interferon response and the response to infection by pathogens. Here the authors show that pharmacological targeting of TBK1 AND IKKε reduces the immunopathology seen in a murine model of SARS-COV-2 infection.

The NLRP3 inflammasome is important for inducing IL-1β and IL-18 inflammatory responses. Here the authors show, by generating and characterizing Peli2 deficient mice and immune cells, that an E3 ubiquitin ligase Pellino2 promotes inflammasome priming by inducing NLRP3 ubiquitination and by targeting IRAK1.

The incidence of esophageal squamous cell carcinoma varies significantly across different geographical regions. Mutational signature analysis of tumors sampled from high- and low-incidence areas suggests that these variations may not be explained by mutagenic exposures.

A high-throughput chemical–genetic screening approach for the discovery of targets and chemicals to treat Mycobacterium tuberculosis yields tenfold more hit compounds than conventional whole-cell screening methods.

It is critical to understand what drives the progression of oesophageal adenocarcinoma (OAC) from a pre-cancerous state. Here, the authors use whole-genome sequencing to characterise the mutational processes and drivers of OAC progression from Barrett’s Oesophagus, as well as their prognostic associations.

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.

BAG3 is a Hsp70 co-chaperone that is highly expressed in muscles. Here the authors show that several myofibrillar myopathy causing BAG3 mutations are not impaired in Hsp70 binding, but rather impair the ADP-ATP exchange step of the Hsp70 cycle, causing the aggregation of BAG3, Hsp70 and Hsp70 clients and leading to a collapse of protein homeostasis.

Early cancer biology and detection research is limited owing to a lack of clinical samples from pre-malignant and early-stage tumours. This Review discusses engineered in vitro systems that mimic early disease stages to investigate tumour progression and identify biomarkers for early cancer detection.

This Review describes how the latest advances in so-called –omics technologies have helped to provide novel insights into the development and biology of oesophageal adenocarcinoma and its precursor lesion Barrett oesophagus. The authors discuss how these molecular profiles could improve patient management in the future, including early diagnosis and monitoring of response to therapy.