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Genome-wide association studies (GWAS) have identified over 200 genetic risk loci for breast cancer, but the target genes in these loci remain largely unknown. Here, the authors conduct multi-ancestry transcriptome-wide association studies to discover potential breast cancer susceptibility genes, which are further explored with single-cell sequencing and in vitro experiments.

Anderson localization has been previously reported in 1D and 3D but it has remained elusive in 2D environments. Here the authors report probable observation of 2D Anderson localization using ultracold atoms in a weak interaction regime.

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

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.

Augustine et al. present a multimodal graph neural network that identifies cancer immunotherapy targets. It distinguishes approved and prospective targets, and promising candidates are validated using a clinically relevant patient-derived platform.

In this phase 2 trial, Perez et al. reported the safety of the vitamin D receptor agonist paricalcitol with gemcitabine and nab-paclitaxel in patients with metastatic pancreatic ductal adenocarcinoma and the pharmacodynamic effects of paricalcitol in fibroblasts and immune cells.

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.

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.

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.

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.

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.

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.

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.

Humanized glucagon-like peptide 1 receptor (GLP1R) mouse models are used to investigate the neural circuitry through which small-molecule GLP1R agonists modulate feeding, with implications for how these orally delivered weight-loss drugs engage brain reward circuits.

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.

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.

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.

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.

Waterfield and colleagues report the transcription factor RUNX1 expressed in mTECs profoundly influences the diversity of thymic mimetic cells that express tissue-specific antigens.

Lin et al. developed and validated a polygenic risk score (PRS-KLK3int) that incorporates SNP-SNP interactions involving KLK3 to predict prostate cancer aggressiveness. PRS-KLK3int consistently outperforms existing risk scores and can improve the identification of high-risk groups before the biological onset of aggressive disease.

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.

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

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.

RNA velocity is a widely used method to predict the fate of single cells. Here the authors show that the concept can be adapted to predict the fate of individual human subjects, using RNA velocity of whole blood at a single point in time to predict future clinical outcomes and treatment responses.

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).

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.

Longitudinal multi-omic analysis of pre-vaccination, hospitalized COVID-19 patients identifies early immune markers predicting durable or suboptimal memory T and B cell responses, revealing potential pathways that shape long-term SARS-CoV-2 immunity.

A mitochondrial complex I inhibitor exhibited dose-limiting toxicities, including neurotoxicity, in patients with acute myeloid leukemia and solid tumors, warranting further studies to evaluate the mechanism linking oxidative phosphorylation inhibition and neurotoxicity.

Aptamers, single-stranded oligonucleotides capable of binding to specific targets, are composed of only four similar nucleobases, limiting their therapeutic potential. Now, alenomers—DNA-barcoded, chemically diverse aptamer-like molecules that integrate amino acids, lipids and sugars at precise sites—have been developed. This modular platform enables the rapid discovery of high-affinity, stable aptamers.

Kozlova et al. report a functional role for NDRG1 in regulating R-loops and DNA repair, thereby linking cancer-associated fibroblast-derived extracellular matrix to chemotherapy responses in pancreatic cancer.

Whole-genome sequencing, transcriptome-wide association and fine-mapping analyses in over 7,000 individuals with critical COVID-19 are used to identify 16 independent variants that are associated with severe illness in COVID-19.

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

STING–type-I interferon pathway regulates the immunogenicity of several cancer types, including head and neck squamous cell carcinoma. Here the authors describe that glutamine metabolism in the tumour microenvironment dampens the STING–type-I interferon pathway by epigenetically silencing the expression of BATF2, which functions as a tumour suppressor.

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.

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