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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 -
Methods in Molecular Biology (Clifton,... 2020The ethylating agent ethyl methanesulfonate (EMS) is widely used for inducing random point mutations. In Arabidopsis, treatment with EMS causes GC-to-AT transitions with...
The ethylating agent ethyl methanesulfonate (EMS) is widely used for inducing random point mutations. In Arabidopsis, treatment with EMS causes GC-to-AT transitions with great efficiency: it has been estimated that a population of 50,000 well-mutagenized plants harbors one or more transitions in almost every GC pair of the genome. These properties, combined with ease of use, make EMS a mutagen of choice for genetic screens. Here, we describe a protocol for mutagenizing Arabidopsis seed with EMS. In addition, we briefly consider the germ line sectors typically induced by this treatment, and approaches for estimating the rate of induced mutations.
Topics: Arabidopsis; Ethyl Methanesulfonate; Mutagenesis; Mutagens; Mutation; Mutation Rate; Seeds
PubMed: 31975292
DOI: 10.1007/978-1-0716-0342-0_2 -
Nature Sep 2021Over the course of an individual's lifetime, normal human cells accumulate mutations. Here we compare the mutational landscape in 29 cell types from the soma and...
Over the course of an individual's lifetime, normal human cells accumulate mutations. Here we compare the mutational landscape in 29 cell types from the soma and germline using multiple samples from the same individuals. Two ubiquitous mutational signatures, SBS1 and SBS5/40, accounted for the majority of acquired mutations in most cell types, but their absolute and relative contributions varied substantially. SBS18, which potentially reflects oxidative damage, and several additional signatures attributed to exogenous and endogenous exposures contributed mutations to subsets of cell types. The rate of mutation was lowest in spermatogonia, the stem cells from which sperm are generated and from which most genetic variation in the human population is thought to originate. This was due to low rates of ubiquitous mutational processes and may be partially attributable to a low rate of cell division in basal spermatogonia. These results highlight similarities and differences in the maintenance of the germline and soma.
Topics: Aged; Clone Cells; Female; Germ Cells; Germ-Line Mutation; Health; Humans; Male; Microdissection; Middle Aged; Mutation Rate; Organ Specificity; Oxidative Stress; Spermatogonia
PubMed: 34433962
DOI: 10.1038/s41586-021-03822-7 -
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 -
Science (New York, N.Y.) Mar 2020Somatic mutations acquired in healthy tissues as we age are major determinants of cancer risk. Whether variants confer a fitness advantage or rise to detectable...
Somatic mutations acquired in healthy tissues as we age are major determinants of cancer risk. Whether variants confer a fitness advantage or rise to detectable frequencies by chance remains largely unknown. Blood sequencing data from ~50,000 individuals reveal how mutation, genetic drift, and fitness shape the genetic diversity of healthy blood (clonal hematopoiesis). We show that positive selection, not drift, is the major force shaping clonal hematopoiesis, provide bounds on the number of hematopoietic stem cells, and quantify the fitness advantages of key pathogenic variants, at single-nucleotide resolution, as well as the distribution of fitness effects (fitness landscape) within commonly mutated driver genes. These data are consistent with clonal hematopoiesis being driven by a continuing risk of mutations and clonal expansions that become increasingly detectable with age.
Topics: Aging; Biological Evolution; Gene Frequency; Genetic Drift; Genetic Fitness; Genetics, Population; Hematopoiesis; Hematopoietic Stem Cells; Humans; Models, Genetic; Mutation; Mutation Rate; Selection, Genetic
PubMed: 32217721
DOI: 10.1126/science.aay9333 -
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