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Cancer Research Jul 2020Ras is frequently mutated in cancer, however, there is a lack of consensus in the literature regarding the cancer mutation frequency of Ras, with quoted values varying... (Review)
Review
Ras is frequently mutated in cancer, however, there is a lack of consensus in the literature regarding the cancer mutation frequency of Ras, with quoted values varying from 10%-30%. This variability is at least in part due to the selective aggregation of data from different databases and the dominant influence of particular cancer types and particular Ras isoforms within these datasets. To provide a more definitive figure for Ras mutation frequency in cancer, we cross-referenced the data in all major publicly accessible cancer mutation databases to determine reliable mutation frequency values for each Ras isoform in all major cancer types. These percentages were then applied to current U.S. cancer incidence statistics to estimate the number of new patients each year that have Ras-mutant cancers. We find that approximately 19% of patients with cancer harbor Ras mutations, equivalent to approximately 3.4 million new cases per year worldwide. We discuss the Ras isoform and mutation-specific trends evident within the datasets that are relevant to current Ras-targeted therapies.
Topics: Humans; Incidence; Mutation; Mutation Rate; Neoplasms; Signal Transduction; ras Proteins
PubMed: 32209560
DOI: 10.1158/0008-5472.CAN-19-3682 -
Cells Dec 2020Germline alterations in many genes coding for proteins regulating DNA repair and DNA damage response (DDR) to DNA double-strand breaks (DDSB) have been recognized as... (Review)
Review
Germline alterations in many genes coding for proteins regulating DNA repair and DNA damage response (DDR) to DNA double-strand breaks (DDSB) have been recognized as pathogenic factors in hereditary cancer predisposition. The ATM-CHEK2-p53 axis has been documented as a backbone for DDR and hypothesized as a barrier against cancer initiation. However, although CHK2 kinase coded by the gene expedites the DDR signal, its function in activation of p53-dependent cell cycle arrest is dispensable. mutations rank among the most frequent germline alterations revealed by germline genetic testing for various hereditary cancer predispositions, but their interpretation is not trivial. From the perspective of interpretation of germline variants, we review the current knowledge related to the structure of the gene, the function of CHK2 kinase, and the clinical significance of germline mutations in patients with hereditary breast, prostate, kidney, thyroid, and colon cancers.
Topics: Animals; Checkpoint Kinase 2; Genetic Predisposition to Disease; Germ-Line Mutation; Humans; Mutation Rate; Neoplasms; Substrate Specificity
PubMed: 33322746
DOI: 10.3390/cells9122675 -
Nature Apr 2022The rates and patterns of somatic mutation in normal tissues are largely unknown outside of humans. Comparative analyses can shed light on the diversity of mutagenesis...
The rates and patterns of somatic mutation in normal tissues are largely unknown outside of humans. Comparative analyses can shed light on the diversity of mutagenesis across species, and on long-standing hypotheses about the evolution of somatic mutation rates and their role in cancer and ageing. Here we performed whole-genome sequencing of 208 intestinal crypts from 56 individuals to study the landscape of somatic mutation across 16 mammalian species. We found that somatic mutagenesis was dominated by seemingly endogenous mutational processes in all species, including 5-methylcytosine deamination and oxidative damage. With some differences, mutational signatures in other species resembled those described in humans, although the relative contribution of each signature varied across species. Notably, the somatic mutation rate per year varied greatly across species and exhibited a strong inverse relationship with species lifespan, with no other life-history trait studied showing a comparable association. Despite widely different life histories among the species we examined-including variation of around 30-fold in lifespan and around 40,000-fold in body mass-the somatic mutation burden at the end of lifespan varied only by a factor of around 3. These data unveil common mutational processes across mammals, and suggest that somatic mutation rates are evolutionarily constrained and may be a contributing factor in ageing.
Topics: Animals; Humans; Longevity; Mammals; Mutagenesis; Mutation; Mutation Rate
PubMed: 35418684
DOI: 10.1038/s41586-022-04618-z -
Single-molecule genome-wide mutation profiles of cell-free DNA for non-invasive detection of cancer.Nature Genetics Aug 2023Somatic mutations are a hallmark of tumorigenesis and may be useful for non-invasive diagnosis of cancer. We analyzed whole-genome sequencing data from 2,511 individuals...
Somatic mutations are a hallmark of tumorigenesis and may be useful for non-invasive diagnosis of cancer. We analyzed whole-genome sequencing data from 2,511 individuals in the Pan-Cancer Analysis of Whole Genomes (PCAWG) study as well as 489 individuals from four prospective cohorts and found distinct regional mutation type-specific frequencies in tissue and cell-free DNA from patients with cancer that were associated with replication timing and other chromatin features. A machine-learning model using genome-wide mutational profiles combined with other features and followed by CT imaging detected >90% of patients with lung cancer, including those with stage I and II disease. The fixed model was validated in an independent cohort, detected patients with cancer earlier than standard approaches and could be used to monitor response to therapy. This approach lays the groundwork for non-invasive cancer detection using genome-wide mutation features that may facilitate cancer screening and monitoring.
Topics: Humans; Cell-Free Nucleic Acids; Prospective Studies; Mutation; Neoplasms; Mutation Rate; Lung Neoplasms
PubMed: 37500728
DOI: 10.1038/s41588-023-01446-3 -
PLoS Genetics Oct 2019Viral quasispecies refers to a population structure that consists of extremely large numbers of variant genomes, termed mutant spectra, mutant swarms or mutant clouds....
Viral quasispecies refers to a population structure that consists of extremely large numbers of variant genomes, termed mutant spectra, mutant swarms or mutant clouds. Fueled by high mutation rates, mutants arise continually, and they change in relative frequency as viral replication proceeds. The term quasispecies was adopted from a theory of the origin of life in which primitive replicons) consisted of mutant distributions, as found experimentally with present day RNA viruses. The theory provided a new definition of wild type, and a conceptual framework for the interpretation of the adaptive potential of RNA viruses that contrasted with classical studies based on consensus sequences. Standard clonal analyses and deep sequencing methodologies have confirmed the presence of myriads of mutant genomes in viral populations, and their participation in adaptive processes. The quasispecies concept applies to any biological entity, but its impact is more evident when the genome size is limited and the mutation rate is high. This is the case of the RNA viruses, ubiquitous in our biosphere, and that comprise many important pathogens. In virology, quasispecies are defined as complex distributions of closely related variant genomes subjected to genetic variation, competition and selection, and that may act as a unit of selection. Despite being an integral part of their replication, high mutation rates have an upper limit compatible with inheritable information. Crossing such a limit leads to RNA virus extinction, a transition that is the basis of an antiviral design termed lethal mutagenesis.
Topics: Evolution, Molecular; High-Throughput Nucleotide Sequencing; Mutation Rate; Origin of Life; Quasispecies; RNA Viruses; Viral Vaccines; Virus Replication
PubMed: 31622336
DOI: 10.1371/journal.pgen.1008271 -
Nature Aug 2023Recent studies have documented frequent evolution of clones carrying common cancer mutations in apparently normal tissues, which are implicated in cancer development....
Recent studies have documented frequent evolution of clones carrying common cancer mutations in apparently normal tissues, which are implicated in cancer development. However, our knowledge is still missing with regard to what additional driver events take place in what order, before one or more of these clones in normal tissues ultimately evolve to cancer. Here, using phylogenetic analyses of multiple microdissected samples from both cancer and non-cancer lesions, we show unique evolutionary histories of breast cancers harbouring der(1;16), a common driver alteration found in roughly 20% of breast cancers. The approximate timing of early evolutionary events was estimated from the mutation rate measured in normal epithelial cells. In der(1;16)(+) cancers, the derivative chromosome was acquired from early puberty to late adolescence, followed by the emergence of a common ancestor by the patient's early 30s, from which both cancer and non-cancer clones evolved. Replacing the pre-existing mammary epithelium in the following years, these clones occupied a large area within the premenopausal breast tissues by the time of cancer diagnosis. Evolution of multiple independent cancer founders from the non-cancer ancestors was common, contributing to intratumour heterogeneity. The number of driver events did not correlate with histology, suggesting the role of local microenvironments and/or epigenetic driver events. A similar evolutionary pattern was also observed in another case evolving from an AKT1-mutated founder. Taken together, our findings provide new insight into how breast cancer evolves.
Topics: Adolescent; Adult; Female; Humans; Young Adult; Breast Neoplasms; Cell Lineage; Clone Cells; Epigenesis, Genetic; Epithelial Cells; Epithelium; Evolution, Molecular; Microdissection; Mutagenesis; Mutation; Mutation Rate; Premenopause; Tumor Microenvironment
PubMed: 37495687
DOI: 10.1038/s41586-023-06333-9 -
Nature Biotechnology Oct 2021Identification and quantification of low-frequency mutations remain challenging despite improvements in the baseline error rate of next-generation sequencing...
Identification and quantification of low-frequency mutations remain challenging despite improvements in the baseline error rate of next-generation sequencing technologies. Here, we describe a method, termed SaferSeqS, that addresses these challenges by (1) efficiently introducing identical molecular barcodes in the Watson and Crick strands of template molecules and (2) enriching target sequences with strand-specific PCR. The method achieves high sensitivity and specificity and detects variants at frequencies below 1 in 100,000 DNA template molecules with a background mutation rate of <5 × 10 mutants per base pair (bp). We demonstrate that it can evaluate mutations in a single amplicon or simultaneously in multiple amplicons, assess limited quantities of cell-free DNA with high recovery of both strands and reduce the error rate of existing PCR-based molecular barcoding approaches by >100-fold.
Topics: Biomarkers, Tumor; DNA Mutational Analysis; DNA, Neoplasm; High-Throughput Nucleotide Sequencing; Humans; Mutation; Mutation Rate; Polymerase Chain Reaction
PubMed: 33941929
DOI: 10.1038/s41587-021-00900-z -
Science (New York, N.Y.) Jun 2023The rich diversity of morphology and behavior displayed across primate species provides an informative context in which to study the impact of genomic diversity on...
The rich diversity of morphology and behavior displayed across primate species provides an informative context in which to study the impact of genomic diversity on fundamental biological processes. Analysis of that diversity provides insight into long-standing questions in evolutionary and conservation biology and is urgent given severe threats these species are facing. Here, we present high-coverage whole-genome data from 233 primate species representing 86% of genera and all 16 families. This dataset was used, together with fossil calibration, to create a nuclear DNA phylogeny and to reassess evolutionary divergence times among primate clades. We found within-species genetic diversity across families and geographic regions to be associated with climate and sociality, but not with extinction risk. Furthermore, mutation rates differ across species, potentially influenced by effective population sizes. Lastly, we identified extensive recurrence of missense mutations previously thought to be human specific. This study will open a wide range of research avenues for future primate genomic research.
Topics: Animals; Humans; Biological Evolution; Genome; Mutation Rate; Phylogeny; Primates; Genetic Variation; Population Density
PubMed: 37262161
DOI: 10.1126/science.abn7829 -
Nature Jan 2020Chronic inflammation is accompanied by recurring cycles of tissue destruction and repair and is associated with an increased risk of cancer. However, how such cycles...
Chronic inflammation is accompanied by recurring cycles of tissue destruction and repair and is associated with an increased risk of cancer. However, how such cycles affect the clonal composition of tissues, particularly in terms of cancer development, remains unknown. Here we show that in patients with ulcerative colitis, the inflamed intestine undergoes widespread remodelling by pervasive clones, many of which are positively selected by acquiring mutations that commonly involve the NFKBIZ, TRAF3IP2, ZC3H12A, PIGR and HNRNPF genes and are implicated in the downregulation of IL-17 and other pro-inflammatory signals. Mutational profiles vary substantially between colitis-associated cancer and non-dysplastic tissues in ulcerative colitis, which indicates that there are distinct mechanisms of positive selection in both tissues. In particular, mutations in NFKBIZ are highly prevalent in the epithelium of patients with ulcerative colitis but rarely found in both sporadic and colitis-associated cancer, indicating that NFKBIZ-mutant cells are selected against during colorectal carcinogenesis. In further support of this negative selection, we found that tumour formation was significantly attenuated in Nfkbiz-mutant mice and cell competition was compromised by disruption of NFKBIZ in human colorectal cancer cells. Our results highlight common and discrete mechanisms of clonal selection in inflammatory tissues, which reveal unexpected cancer vulnerabilities that could potentially be exploited for therapeutics in colorectal cancer.
Topics: Adaptor Proteins, Signal Transducing; Animals; Cell Line, Tumor; Colitis, Ulcerative; Colorectal Neoplasms; Humans; Mice; Mutation Rate; Signal Transduction
PubMed: 31853061
DOI: 10.1038/s41586-019-1856-1 -
Current Opinion in Genetics &... Jun 2020Germline mutations are the source of all heritable variation. In the past few years, whole genome sequencing has allowed direct and comprehensive surveys of mutation... (Review)
Review
Germline mutations are the source of all heritable variation. In the past few years, whole genome sequencing has allowed direct and comprehensive surveys of mutation patterns in humans and other species. These studies have documented substantial variation in both mutation rates and spectra across primates, the causes of which remain unclear. Here, we review what is currently known about mutation rates in primates, highlight the factors proposed to explain the variation across species, and discuss some implications of these findings on our understanding of the chronology of primate evolution and the process of mutagenesis.
Topics: Animals; Biological Evolution; Genome; Genomics; Mutation; Mutation Rate; Primates
PubMed: 32634682
DOI: 10.1016/j.gde.2020.05.028