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Scourzic et al. show that germinal centre B cells display an enhanced ability to reprogram to induced pluripotent stem cells compared to mature B cells. This ability indicates their higher plasticity level and is T follicular helper cell-dependent.

Taxanes, such as docetaxel or cabazitaxel, are one of the few chemotherapy options for metastatic castration-resistant prostate cancer (mCRPC). Here, the authors discover that FOXJ1 modulation of microtubule dynamics regulates resistance to docetaxel in mCRPC.

An ultrasmall particle adjuvant therapy reprogrammes the tumour microenvironment of a resistant melanoma to a pro-inflammatory state, enhances antitumour immunity and synergizes with immune checkpoint inhibitors to prolong survival in murine models.

Risk associated with genetically defined forms of autism spectrum disorder (ASD) can propagate by means of transcriptional regulation to affect convergently dysregulated pathways, providing insight into the convergent impact of ASD genetic risk on human neurodevelopment.

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.

A multi-institute, multi-platform initiative generates standard metrics and best practices for spatial transcriptomics analysis.

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.

Nease and colleagues demonstrate that the methyltransferase FTSJ1 mediates selenocysteine-specific tRNA methylation of selenoproteins, which protects melanoma cells against oxidative stress and promotes metastasis.

Kazachstania pintolopesii is a highly prevalent fungal symbiont that can trigger type 2 immunity and influence the composition of the gut mycobiome, as well as immune and disease phenotypes.

Anandasabapathy and colleagues show that the inhibitory receptor PD-1 impacts the specification of tissue-resident memory T cells in the skin.

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.

EchoNext, a deep learning model for electrocardiograms trained and validated in diverse health systems, successfully detects many forms of structural heart disease, supporting the potential of artificial intelligence to expand access to heart disease screening at scale.

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.

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.

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.

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.

Remote tumours cause liver dysfunction by releasing extracellular vesicles and particles containing palmitic acid, which induces TNF signalling in Kupffer cells, resulting in inflammation, fatty deposits and metabolic dysregulation, thus both reducing the efficacy and increasing the toxicity of chemotherapies.

Upper tract urothelial carcinoma (UTUC) is an aggressive cancer and largely uncharacterised cancer. Here, Faltas and colleagues report its distinctive molecular and immune landscape compared to urothelial carcinoma of the bladder and explore the role of FGFR3 signaling in UTUC biology.

Large-effect variants in autism remain elusive. Here, the authors use long-read sequencing to assemble phased genomes for 189 individuals, identifying pathogenic variants in TBL1XR1, MECP2, and SYNGAP1, plus nine candidate structural variants missed by short-read methods.

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

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.

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.

TCF1⁺ progenitor-exhausted CD8⁺ T cell populations mediate durable antitumor immunity. Upon antigenic stimulation, effector T cells upregulate aerobic glycolysis to support their cytotoxic phenotype. Here, Mittal and colleagues find that loss of metabolic regulator PKM2 enriches for TCF1⁺ progenitor-exhausted-like cells and improves responsiveness to PD-1 blockade.

A high-fructose diet in mice improves the survival of intestinal epithelial cells, which leads to an increase in gut surface area, enhanced absorption of lipids and the promotion of tumour growth and obesity.

Aarrestad et al. show that, in contrast to psychedelics, the nonhallucinogenic psychoplastogen tabernanthalog promotes neuroplasticity through 5-HT_2AR activation without immediately increasing extracellular glutamate levels or immediate early gene expression.

The JAK2^V617F mutation leads to epigenetic rewiring in a cell-intrinsic and cell-type-specific manner, influencing inflammation states and differentiation trajectories in patients with myeloproliferative neoplasms.

In human and mouse models of ovarian cancer, endoplasmic reticulum stress and the activation of the IRE1α–XBP1 pathway decreases the metabolic fitness of T cells and limits their anti-tumour functions.

There is still a need for effective HIV vaccines. In this phase I clinical trial, the authors show that an HIV-1 vaccine candidate, ConM SOSIP.v7, is well-tolerated in HIV-negative adults and that it elicits a strain-specific neutralising antibody response that differed between female and male participants.

Adoro and colleagues report the involvement of the IRE1α–XBP1 signaling axis in protecting hematopoietic stem and progenitor cells from proteomic stress and as a safeguard against leukemic transformation.

The impact of variants of uncertain significance (VUS) on protein function and cancer risk remain unclear. Here, the authors focus on the functional impact of VUS of the PALB2 gene and identify defects in DNA damage repair by homologous recombination associated with increased risk of breast cancer.

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.

IL-33 induces tertiary lymphoid structures.

Genomic analyses applied to 14 childhood- and adult-onset psychiatric disorders identifies five underlying genomic factors that explain the majority of the genetic variance of the individual disorders.

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.

Vertebral osteoblasts in mouse and human are formed from a precursor skeletal stem cell population that is distinct from long bone skeletal stem cells in function, location and transcriptional programme.

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.

Wei et al. perform spatial transcriptomic profiling on synovial tissue biopsy samples from individuals with recent-onset rheumatoid arthritis, finding TGFβ signaling and fibrogenic fibroblast activation drive a treatment-refractory tissue phenotype.

The IRE1α-XBP1 arm of the unfolded protein response (UPR) has been associated with immunosuppression and cancer progression. Here the authors show that IRE1α-XBP1 activation is associated with poor overall survival in patients with non-small cell lung cancer and that IRE1α loss in cancer cells promotes anti-tumor immune responses in lung cancer preclinical models.

Cancer-associated cachexia is characterized by loss of body weight, skeletal muscle and adipose tissue which relates to higher mortality in cancer patients. Here, the authors show in a lung cancer murine model that both ActRIIB signalling inhibition and restoring appetite are necessary to revert cachexia and improve survival in female mice.

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.

This study uses single-nucleus RNA sequencing to analyze lung tissue from 141 individuals with chronic obstructive pulmonary disease. Distinct patterns of spatially resolved changes in cell composition and cell states that correlate with clinical features are highlighted.

Joint profiling of chromatin and splicing in the brain uncovers shared and distinct patterns.

In a prespecified secondary analysis of the SURMOUNT-OSA trial, tirzepatide improved cardiometabolic outcomes in patients with moderate-to-severe obstructive sleep apnea and obesity.

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.

Blood metabolites are influenced by a combination of genetic and environmental factors. Here, Yousri and colleagues perform a whole-exome sequencing study in combination with a metabolomics analysis to identify metabolic quantitative trait loci in a Middle Eastern population.

A multi-modal analysis of pre-metastatic liver biopsies from patients with localized pancreatic cancer with a minimum of 3 years of follow-up shows that immunological, proliferative and metabolomic features distinguish patients who develop metastases from disease-free survivors and can be used to predict outcomes.

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.

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.

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.