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Epigenetic clocks are promising biomarkers of biological aging but require longitudinal evaluation. In this longitudinal study, the authors evaluated whether temporal acceleration of multiple epigenetic clocks was associated with mortality, and report that faster increases in several clocks were linked to higher risk of death, independent of baseline epigenetic age and other confounders.

Many genetic loci have been identified to be associated with kidney disease, but the molecular mechanisms are not well understood. Here, the authors perform epigenome-wide association studies on kidney function measures to identify epigenetic marks and pathways involved in kidney function.

Serum urate concentration can be studied in large datasets to find genetic and epigenetic loci that may be related to cardiometabolic traits. Here the authors identify and replicate 100 urate-associated CpGs, which provide insights into urate GWAS loci and shared CpGs of urate and cardiometabolic traits.

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

Davies, Black et al., investigate the frequency, cause, molecular associations, and prognostic implications of homologous recombination deficiency (HRD) in primary estrogen receptor-positive and HER2-negative breast cancer. HRD was less frequent (8.4%), induced mainly by alterations acting on BRCA1/BRCA2/RAD51C/PALB2, but not associated with patient outcome after adjuvant systemic therapy.

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.

While transcriptomics have enhanced our understanding for cancer, spatial transcriptomics enable the characterisation of cellular interactions. Here, the authors integrate single cell data with spatial information for HER2 + tumours and develop tools for the prediction of interactions between tumour-infiltrating cells.

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 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.

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.

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.

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.

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.

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.

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.

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.

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 DNA methylation landscape of triple-negative breast cancer remains to be characterised. Here, the authors analyse tumour methylome profiles and the genomic context of CpG methylation and identify two epigenetic subtypes with distinct transcriptional patterns.

Stig Bojesen, Georgia Chenevix-Trench, Alison Dunning and colleagues report common variants at the TERT-CLPTM1L locus associated with mean telomere length measured in whole blood. They also identify associations at this locus to breast or ovarian cancer susceptibility and report functional studies in breast and ovarian cancer tissue and cell lines.

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.

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.

Epigenetic clocks based on DNA methylation levels are estimators of chronological age. Here, the authors perform a GWAS of epigenetic aging rates in blood and find SNP variants in the TERT locus associated with increased intrinsic epigenetic age are also associated with longer telomeres.

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.

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.

Fine-mapping of causal variants and integration of epigenetic and chromatin conformation data identify likely target genes for 150 breast cancer risk regions.

BRCA-deficient breast cancer is characterised by homologous recombination deficiency. Here, the authors show that hypermethylated BRCA1 phenotypically copies mutated BRCA1 in triple negative breast cancers.

Although Huntington’s disease (HD) is a well-studied genetic disorder, less is known about the epigenetic changes underlying it. Here, the authors characterize DNA methylation levels in tissues from patients, a mouse huntingtin (Htt) gene knock-in model, and a transgenic HTT sheep model, and provide evidence that HD is accompanied by DNA methylation changes in these three species.

The mystery of mammalian lifespan is examined through DNA methylation dynamics, revealing an inverse relationship between lifespan and average methylation rate changes in bivalent promoter regions. Results vary depending on chromatin context.

This genome-wide association study identifies five significant SNPs in two loci which are associated with the epigenetic age of post-mortem cerebellar tissue according to a DNA methylation based biomarker of human aging.

Paul Pharoah and colleagues report the results of a large genome-wide association study of ovarian cancer. They identify new susceptibility loci for different epithelial ovarian cancer histotypes and use integrated analyses of genes and regulatory features at each locus to predict candidate susceptibility genes, including OBFC1.

Presence of islet autoantibodies precedes the onset of type 1 diabetes but it does not predict whether and how fast symptomatic disease appears. Here authors present a model to predict and visualize progression to diabetes by using a large longitudinal data set on autoantibodies and clinical parameters as input.

Studies on the ‘epigenetic clock’, a recently identified ageing biomarker, suggest that pathology might be linked to tissue-specific accelerated ageing. Here, the authors investigate ageing in the human brain and identify genetic loci associated with accelerated ageing in different brain regions.

The authors identify causality-enriched CpGs linked to aging using Mendelian randomization. They develop new epigenetic clocks, DamAge and AdaptAge, that more reliably track age-related changes, offering insights into aging mechanisms and interventions.

Heterochronic parabiosis ameliorates age-related diseases in mice, but how it affects epigenetic aging and long-term health was not known. Here, the authors show that in mice exposure to young circulation leads to reduced epigenetic aging, an effect that persists for several months after removing the youthful circulation.

DNA methylation profiles from 26 bat species accurately predicts chronological age, while longevity-related methylation patterns across the genome suggest that bat longevity results from augmented immune response and cancer suppression.

Deep learning can predict spatial variations in gene expression from haematoxylin-and-eosin-stained histopathology images of patients with cancer.

Authors have previously reported on the efficacy and safety of the recombinant spike protein nanoparticle vaccine, NVX-CoV2373, in healthy adults. In this work, they assess anti-spike binding IgG, anti-RBD binding IgG and neutralising antibody titer as correlates of risk and protection against COVID-19.

In ER + /HER2- breast cancer, patients with PAM50 HER2-enriched tumors have an elevated relapse risk. The subtype is less estrogen dependent, while being highly proliferative, immune infiltrated and FGFR4-expressing, indicating novel therapy targets.

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.

The exceptionally long-lived naked mole-rat is characterized by the lack of increased mortality with aging. Here the authors perform epigenetic studies to show that naked mole-rats epigenetically age despite their non-increasing mortality rate.

Methods to probe DNA methylation in the majority of non-human mammals are lacking. Here the authors developed a Mammalian Methylation Array that includes 36k well-conserved CpGs in mammals which will facilitate cross-species comparisons. They annotate the conserved CpGs in > 200 species. The array allows one to measure methylation in all mammalian species including unsequenced ones.

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.