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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.

A new version of nanorate DNA sequencing, with an error rate lower than five errors per billion base pairs and compatible with whole-exome and targeted capture, enables epidemiological-scale studies of somatic mutation and selection and the generation of high-resolution selection maps across coding and non-coding sites for many genes.

A combination of whole-genome NanoSeq with deep whole-exome and targeted NanoSeq is used to accurately characterize mutation rates and genes under positive selection in sperm cells.

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 report the mutational landscape of 29 cell types from microdissected biopsies from 19 organs and explore the mechanisms underlying mutation rates in normal tissues.

Chordoma is a rare often incurable malignant bone tumour. Here, the authors investigate driver mutations of sporadic chordoma in 104 cases, revealing duplications in notochordal transcription factor brachyury (T), PI3K signalling mutations, and mutations in LYST, a potential novel cancer gene in chordoma.

Sequencing of human induced pluripotent stem cell lines highlights pervasive mutagenesis, heterogeneity between clones derived from the same individual during a single reprogramming experiment and positive selection for acquired mutations in BCOR.

Mutational signature analysis of blood cells isolated from 23 chemotherapy-exposed samples and 9 nonexposed controls characterizes the effects of various drugs on mutational burden, signature exposure and cell types.

Histologically normal tissues of individuals with a germline NF1 mutation exhibited multiple second NF1 hits, unrelated to their tumors, that conferred a selective advantage.

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.

Sequencing the genomes of individual skin cells called melanocytes has revealed a rich landscape of DNA changes. These insights shed light on the origins of melanoma, an aggressive type of cancer.

Whole-gene sequencing of microdissected gastric glands from individuals with and without gastric cancer reveals distinct patterns of somatic mutations and provides insights into influences on the somatic evolution of the gastric epithelium.

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.

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.

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.

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

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.

Persistent DNA lesions can occur throughout the human lifespan and can remain in the genome of affected cells for several years and generate a substantial proportion of the mutational burden.

The local mutation rate in Escherichia coli has evolved to reduce the risk of deleterious mutations, leading to a non-random occurrence of mutations and suggesting that DNA protection and repair mechanisms preferentially target more important genes.

Analysis of the somatic mutations landscape of 111 patients with psoriasis vulgaris shows that the disease is unlikely to be driven by clonal expansions caused by somatic mutations in keratinocytes. A mutational footprint associated with psoralen treatment was observed and characterized.

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.

Whole-genome sequencing of healthy human epithelial crypts from the small intestines of 39 individuals highlights APOBEC enzymes as a common contributor to the overall mutational burden in this tissue.

It is unclear whether somatic mutation rates are elevated in Lynch Syndrome (LS), which is the most common cause of hereditary colorectal cancer. Here, the authors use whole-genome sequencing and organoid cultures to show that normal tissues in LS patients are genomically stable, while ancestor cells of neoplastic tissues undergo multiple cycles of clonal evolution.

Whole-genome sequencing is used to analyse the landscape of somatic mutation in intestinal crypts from 16 mammalian species, revealing that rates of somatic mutation inversely scale with the lifespan of the animal across species.

Inherited mutations in MUTYH have been shown to predispose patients to colorectal cancers. Here, the authors show that MUTYH mutations lead to an increased somatic base substitution mutation rate in normal intestinal epithelial cells, which is the likely cause for the increased cancer risk.

Pathogenic variants of DDX3X are associated with neurodevelopmental disorders (NDD) and cancer. Here, the authors perform saturation genome editing of DDX3X to test the functional impact of 12,776 variants, develop a machine learning classifier to identify variants relevant for NDD, and show that DDX3X predominantly acts as a tumour suppressor in cancer.

Whole-genome sequencing analysis of somatic mutations in liver samples from patients with chronic liver disease identifies driver mutations in metabolism-related genes such as FOXO1, and shows that these variants frequently exhibit convergent evolution.

Somatic mutations obtained from laser microdissected biopsies of human tissues are used to reconstruct the developmental phylogenies of these tissues back to the zygote.

By integrating healthcare and exome-sequencing data from parent–offspring trios of patients with developmental disorders, 28 genes that had not previously been associated with developmental disorders were identified.

A study of the evolution of the SARS-CoV-2 virus in England between September 2020 and June 2021 finds that interventions capable of containing previous variants were insufficient to stop the more transmissible Alpha and Delta variants.

Whole-genome sequencing of liver microdissections from five healthy individuals and nine with cirrhosis demonstrates the effects of liver disease on the genome, including increased rates of mutation, complex structural variation and different mutational signatures.

Whole-genome sequencing of normal human endometrial glands shows that most are clonal cell populations and frequently carry cancer driver mutations that occur early in life, and that parity has a protective effect.

Analysis of blood from a healthy human show that haematopoietic stem cells increase rapidly in numbers through early life, reaching a stable plateau in adulthood, and contribute to myeloid and B lymphocyte populations throughout life.

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.