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DNA Repair Oct 2020The APOBEC family of cytidine deaminases has been proposed to represent a major enzymatic source of mutations in cancer. Here, we summarize available evidence that links... (Review)
Review
The APOBEC family of cytidine deaminases has been proposed to represent a major enzymatic source of mutations in cancer. Here, we summarize available evidence that links APOBEC deaminases to cancer mutagenesis. We also highlight newly identified human cell models of APOBEC mutagenesis, including cancer cell lines with suspected endogenous APOBEC activity and a cell system of telomere crisis-associated mutations. Finally, we draw on recent data to propose potential causes of APOBEC misregulation in cancer, including the instigating factors, the relevant mutator(s), and the mechanisms underlying generation of the genome-dispersed and clustered APOBEC-induced mutations.
Topics: APOBEC Deaminases; Animals; Humans; Mutagenesis; Mutation; Neoplasms
PubMed: 32818816
DOI: 10.1016/j.dnarep.2020.102905 -
PLoS Computational Biology Jul 2023Stochastic models of sequential mutation acquisition are widely used to quantify cancer and bacterial evolution. Across manifold scenarios, recurrent research questions...
Stochastic models of sequential mutation acquisition are widely used to quantify cancer and bacterial evolution. Across manifold scenarios, recurrent research questions are: how many cells are there with n alterations, and how long will it take for these cells to appear. For exponentially growing populations, these questions have been tackled only in special cases so far. Here, within a multitype branching process framework, we consider a general mutational path where mutations may be advantageous, neutral or deleterious. In the biologically relevant limiting regimes of large times and small mutation rates, we derive probability distributions for the number, and arrival time, of cells with n mutations. Surprisingly, the two quantities respectively follow Mittag-Leffler and logistic distributions regardless of n or the mutations' selective effects. Our results provide a rapid method to assess how altering the fundamental division, death, and mutation rates impacts the arrival time, and number, of mutant cells. We highlight consequences for mutation rate inference in fluctuation assays.
Topics: Humans; Mutation; Mutation Rate; Neoplasms; Probability; Bacteria; Models, Genetic
PubMed: 37428805
DOI: 10.1371/journal.pcbi.1011289 -
Nature Genetics May 2023Detecting mutations from single DNA molecules is crucial in many fields but challenging. Next-generation sequencing (NGS) affords tremendous throughput but cannot...
Detecting mutations from single DNA molecules is crucial in many fields but challenging. Next-generation sequencing (NGS) affords tremendous throughput but cannot directly sequence double-stranded DNA molecules ('single duplexes') to discern the true mutations on both strands. Here we present Concatenating Original Duplex for Error Correction (CODEC), which confers single duplex resolution to NGS. CODEC affords 1,000-fold higher accuracy than NGS, using up to 100-fold fewer reads than duplex sequencing. CODEC revealed mutation frequencies of 2.72 × 10 in sperm of a 39-year-old individual, and somatic mutations acquired with age in blood cells. CODEC detected genome-wide, clonal hematopoiesis mutations from single DNA molecules, single mutated duplexes from tumor genomes and liquid biopsies, microsatellite instability with 10-fold greater sensitivity and mutational signatures, and specific tumor mutations with up to 100-fold fewer reads. CODEC enables more precise genetic testing and reveals biologically significant mutations, which are commonly obscured by NGS errors.
Topics: Male; Humans; Adult; Semen; Mutation; Neoplasms; Sequence Analysis, DNA; DNA; High-Throughput Nucleotide Sequencing
PubMed: 37106072
DOI: 10.1038/s41588-023-01376-0 -
Journal of Autoimmunity Jul 2022Systemic sclerosis (SSc) is associated with secondary malignancies. Previous studies have suggested that mutated cancer proteins, such as RNA polymerase III, are...
OBJECTIVES
Systemic sclerosis (SSc) is associated with secondary malignancies. Previous studies have suggested that mutated cancer proteins, such as RNA polymerase III, are autoantigens promoting an inflammatory response in SSc. However, it has never been previously investigated whether non-neoplastic tissue in SSc harbors mutations which may play a role in SSc pathogenesis.
METHODS
Skin biopsies were obtained from 8 sequential patients with a progressive form of early stage SSc (with severe skin and/or lung involvement). Areas of dermal fibrosis were microdissected and analyzed with deep, whole exome sequencing. Gene mutation patterns were compared to autologous buccal mucosal cells as a control.
RESULTS
SSc skin biopsies were hypermutated with an average of 58 mutations/10 base pairs. The mutational pattern in all samples exhibited a clock-like signature, which is ubiquitous in cancers and in senescent cells. Of the 1997 genes we identified which were mutated in at least two SSc patients, 39 genes represented cancer drivers (i.e. tumor suppressor genes or oncogenes) which are commonly found in gynecological, squamous and gastrointestinal cancer signatures. Of all the mutations, the most common mutated genes were important in regulating pathways related to epigenetic histone modifications, DNA repair and genome integrity.
CONCLUSIONS
Somatic hypermutation occurs in fibrotic skin in patients with early progressive SSc. Cancer driver gene mutations may potentially play a fundamental role in the pathogenesis of SSc.
Topics: Fibrosis; Genomic Instability; Humans; Neoplasms; Scleroderma, Systemic; Skin
PubMed: 35803104
DOI: 10.1016/j.jaut.2022.102847 -
JCI Insight Oct 2018Our understanding of the molecular pathogenesis of childhood cancers has advanced substantially, but their fundamental causes remain poorly understood. Recently,... (Review)
Review
Our understanding of the molecular pathogenesis of childhood cancers has advanced substantially, but their fundamental causes remain poorly understood. Recently, multiple mechanisms of DNA damage and repair have been associated with mutations observed in human cancers. Here, we review the physiologic functions and oncogenic activities of transposable genetic elements. In particular, we focus on the recent studies implicating DNA transposases RAG1/2 and PGBD5 as oncogenic mutators that promote genomic rearrangements in childhood leukemias and solid tumors. We outline future studies that will be needed to define the contributions of transposons to mutational processes that become dysregulated in cancer cells. In addition, we discuss translational approaches, including synthetic lethal strategies, for identifying and developing improved clinical therapies to target oncogenic transposons and transposases.
Topics: Carcinogenesis; Child; DNA Damage; DNA Repair; DNA Transposable Elements; Gene Rearrangement; Humans; Mutation; Neoplasms; Transposases
PubMed: 30333322
DOI: 10.1172/jci.insight.123172 -
Journal of Clinical Oncology : Official... Mar 2017Myelodysplastic syndrome (MDS) is clonal disorder characterized by ineffective hematopoiesis and a tendency to evolve into acute myeloid leukemia (AML). Genetic studies... (Review)
Review
Myelodysplastic syndrome (MDS) is clonal disorder characterized by ineffective hematopoiesis and a tendency to evolve into acute myeloid leukemia (AML). Genetic studies have enabled the identification of a set of recurrently mutated genes central to the pathogenesis of MDS, which can be organized into a limited number of cellular processes, including RNA splicing, epigenetic and traditional transcriptional regulation, and signal transduction. The sequential accumulation of mutations drives disease evolution from asymptomatic clonal hematopoiesis to frank MDS, and, ultimately, to secondary AML. This detailed understanding of the molecular landscape of MDS, coupled with the emergence of cost- and time-effective methodologies for DNA sequencing has led to the introduction of genetic studies into the clinical realm. Here, we review recent advances in our genetic understanding of MDS, with a particular focus on the emerging role for mutational data in clinical management as a potential tool to assist in diagnosis, risk stratification, and therapeutic decision-making.
Topics: Humans; Mutation; Myelodysplastic Syndromes
PubMed: 28297619
DOI: 10.1200/JCO.2016.71.0806 -
Molecular Oncology Feb 2022Small cell carcinoma (SCC) of the uterine cervix is a rare and aggressive form of neuroendocrine carcinoma, which resembles small cell lung cancer (SCLC) in its...
Small cell carcinoma (SCC) of the uterine cervix is a rare and aggressive form of neuroendocrine carcinoma, which resembles small cell lung cancer (SCLC) in its histology and poor survival rate. Here, we sought to define the genetic underpinning of SCCs of the uterine cervix and compare their mutational profiles with those of human papillomavirus (HPV)-positive head and neck squamous cell carcinomas, HPV-positive cervical carcinomas, and SCLCs using publicly available data. Using a combination of whole-exome and targeted massively parallel sequencing, we found that the nine uterine cervix SCCs, which were HPV18-positive (n = 8) or HPV16-positive (n = 1), harbored a low mutation burden, few copy number alterations, and other than TP53 in two cases no recurrently mutated genes. The majority of mutations were likely passenger missense mutations, and only few affected previously described cancer-related genes. Using RNA-sequencing, we identified putative viral integration sites on 18q12.3 and on 8p22 in two SCCs of the uterine cervix. The overall nonsilent mutation rate of uterine cervix SCCs was significantly lower than that of SCLCs, HPV-driven cervical adeno- and squamous cell carcinomas, or HPV-positive head and neck squamous cell carcinomas. Unlike SCLCs, which are reported to harbor almost universal TP53 and RB1 mutations and a dominant tobacco smoke-related signature 4, uterine cervix SCCs rarely harbored mutations affecting these genes (2/9, 22% TP53; 0% RB1) and displayed a dominant aging (67%) or APOBEC mutational signature (17%), akin to HPV-driven cancers, including cervical adeno- and squamous cell carcinomas and head and neck squamous cell carcinomas. Taken together, in contrast to SCLCs, which are characterized by highly recurrent TP53 and RB1 alterations, uterine cervix SCCs were positive for HPV leading to inactivation of the suppressors p53 and RB, suggesting that these SCCs are convergent phenotypes.
Topics: Carcinoma, Small Cell; Carcinoma, Squamous Cell; Female; Genomics; Head and Neck Neoplasms; Humans; Mutation; Papillomavirus Infections; Uterine Cervical Neoplasms
PubMed: 33830625
DOI: 10.1002/1878-0261.12962 -
Cells May 2021The DNA repair endonuclease EndoMS/NucS is highly conserved in Archaea and Actinobacteria. This enzyme is able to recognize and cleave dsDNA carrying a mismatched base... (Review)
Review
The DNA repair endonuclease EndoMS/NucS is highly conserved in Archaea and Actinobacteria. This enzyme is able to recognize and cleave dsDNA carrying a mismatched base pair, and its activity is enhanced by the interaction with the sliding clamp of the replisome. Today, EndoMS/NucS has been established as the key protein of a non-canonical mismatch repair (MMR) pathway, acting specifically in the repair of transitions and being essential for maintaining genome stability. Despite having some particularities, such as its lower activity on transversions and the inability to correct indels, EndoMS/NucS meets the main hallmarks of a MMR. Its absence leads to a hypermutator phenotype, a transition-biased mutational spectrum and an increase in homeologous recombination. Interestingly, polymorphic EndoMS/NucS variants with a possible effect in mutation rate have been detected in clinical isolates of the relevant actinobacterial pathogen . Considering that MMR defects are often associated with the emergence of resistant bacteria, the existence of EndoMS/NucS-defective mutators could have an important role in the acquisition of antibiotic resistance in . Therefore, a further understanding of the EndoMS/NucS-mediated non-canonical MMR pathway may reveal new strategies to predict and fight drug resistance. This review is focused on the recent progress in NucS, with special emphasis on its effect on genome stability and evolvability in Actinobacteria.
Topics: Actinobacteria; Bacterial Proteins; Base Pair Mismatch; DNA Mismatch Repair; Genomic Instability; Mutation Rate
PubMed: 34070467
DOI: 10.3390/cells10061314 -
Bioinformatics (Oxford, England) Jun 2023The primary regulatory step for protein synthesis is translation initiation, which makes it one of the fundamental steps in the central dogma of molecular biology. In...
MOTIVATION
The primary regulatory step for protein synthesis is translation initiation, which makes it one of the fundamental steps in the central dogma of molecular biology. In recent years, a number of approaches relying on deep neural networks (DNNs) have demonstrated superb results for predicting translation initiation sites. These state-of-the art results indicate that DNNs are indeed capable of learning complex features that are relevant to the process of translation. Unfortunately, most of those research efforts that employ DNNs only provide shallow insights into the decision-making processes of the trained models and lack highly sought-after novel biologically relevant observations.
RESULTS
By improving upon the state-of-the-art DNNs and large-scale human genomic datasets in the area of translation initiation, we propose an innovative computational methodology to get neural networks to explain what was learned from data. Our methodology, which relies on in silico point mutations, reveals that DNNs trained for translation initiation site detection correctly identify well-established biological signals relevant to translation, including (i) the importance of the Kozak sequence, (ii) the damaging consequences of ATG mutations in the 5'-untranslated region, (iii) the detrimental effect of premature stop codons in the coding region, and (iv) the relative insignificance of cytosine mutations for translation. Furthermore, we delve deeper into the Beta-globin gene and investigate various mutations that lead to the Beta thalassemia disorder. Finally, we conclude our work by laying out a number of novel observations regarding mutations and translation initiation.
AVAILABILITY AND IMPLEMENTATION
For data, models, and code, visit github.com/utkuozbulak/mutate-and-observe.
Topics: Humans; Neural Networks, Computer; Mutation
PubMed: 37225409
DOI: 10.1093/bioinformatics/btad338 -
Trends in Parasitology Nov 2016While some amoebae reproduce sexually, many amoebae (e.g., Acanthamoeba, Naegleria) reproduce asexually and therefore, according to popular doctrine, are likely to have... (Review)
Review
While some amoebae reproduce sexually, many amoebae (e.g., Acanthamoeba, Naegleria) reproduce asexually and therefore, according to popular doctrine, are likely to have been genetically disadvantaged as a consequence. In the absence of sex, mutations are proposed to accumulate by a mechanism known as Muller's ratchet. I hypothesise that amoebae can escape the ravages of accumulated mutation by virtue of their being polyploid. The polyploid state reduces spontaneous mutation accumulation by gene conversion, the freshly mutated copy being corrected by the presence of the many other wild-type copies. In this manner these amoebae reap the benefits of an asexual reproductive existence: principally, that it is rapid and convenient. Evidence for this mechanism comes from polyploid plants, bacteria, and archaea.
Topics: Amoeba; Gene Conversion; Mutation; Polyploidy; Reproduction, Asexual
PubMed: 27599632
DOI: 10.1016/j.pt.2016.08.006