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Frontiers in Endocrinology 2022The cAMP-signaling cancers, which are defined by functionally-significant somatic mutations in one or more elements of the cAMP signaling pathway, have an unexpectedly... (Review)
Review
The cAMP-signaling cancers, which are defined by functionally-significant somatic mutations in one or more elements of the cAMP signaling pathway, have an unexpectedly wide range of cell origins, clinical manifestations, and potential therapeutic options. Mutations in at least 9 cAMP signaling pathway genes (, and ) have been identified as driver mutations in human cancer. Although all cAMP-signaling pathway cancers are driven by mutation(s) that impinge on a single signaling pathway, the ultimate tumor phenotype reflects interactions between five critical variables: (1) the precise gene(s) that undergo mutation in each specific tumor type; (2) the effects of specific allele(s) in any given gene; (3) mutations in modifier genes (mutational "context"); (4) the tissue-specific expression of various cAMP signaling pathway elements in the tumor stem cell; and (5) and the precise biochemical regulation of the pathway components in tumor cells. These varying oncogenic mechanisms reveal novel and important targets for drug discovery. There is considerable diversity in the "druggability" of cAMP-signaling components, with some elements (GPCRs, cAMP-specific phosphodiesterases and kinases) appearing to be prime drug candidates, while other elements (transcription factors, protein-protein interactions) are currently refractory to robust drug-development efforts. Further refinement of the precise driver mutations in individual tumors will be essential for directing priorities in drug discovery efforts that target these mutations.
Topics: Humans; Signal Transduction; Mutation; Neoplasms; Phenotype
PubMed: 36313756
DOI: 10.3389/fendo.2022.1024423 -
Methods in Cell Biology 2020The maternally inherited mitochondrial DNA (mtDNA) is a circular 16,569bp double stranded DNA that encodes 37 genes, 24 of which (2 rRNAs and 22 tRNAs) are necessary for...
The maternally inherited mitochondrial DNA (mtDNA) is a circular 16,569bp double stranded DNA that encodes 37 genes, 24 of which (2 rRNAs and 22 tRNAs) are necessary for transcription and translation of 13 polypeptides that are all subunits of respiratory chain. Pathogenic mutations in mtDNA cause respiratory chain dysfunction, and are the underlying defect in an ever-increasing number of mtDNA-related encephalomyopathies with distinct phenotypes. In this chapter, we present an overview of mtDNA mutations and describe the molecular techniques currently employed in our laboratory to detect two types of mtDNA mutations: single-large-scale rearrangements and point mutations.
Topics: DNA Mutational Analysis; DNA, Mitochondrial; Gene Rearrangement; Genome, Mitochondrial; High-Throughput Nucleotide Sequencing; Humans; Mutation; Point Mutation; Polymerase Chain Reaction; Polymorphism, Restriction Fragment Length
PubMed: 32183969
DOI: 10.1016/bs.mcb.2019.11.009 -
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 -
Current Biology : CB Jun 2014The large number of cell divisions required to make a human body inevitably leads to the accumulation of somatic mutations. Such mutations cause individuals to be... (Review)
Review
The large number of cell divisions required to make a human body inevitably leads to the accumulation of somatic mutations. Such mutations cause individuals to be somatic mosaics. Recent advances in genomic technology now allow measurement of somatic diversity. Initial studies confirmed the expected high levels of somatic mutations within individuals. Going forward, the big questions concern the degree to which those somatic mutations influence disease. Theory predicts that the frequency of mutant cells should vary greatly between individuals. Such somatic mutational variability between individuals could explain much of the diversity in the risk of disease. But how variable is mosaicism between individuals in reality? What is the relation between the fraction of cells carrying a predisposing mutation and the risk of disease? What kinds of heritable somatic change lead to disease besides classical DNA mutations? What molecular processes connect a predisposing somatic change to disease? We know that predisposing somatic mutations strongly influence the onset of cancer. Likewise, neurodegenerative diseases may often begin from somatically mutated cells. If so, both neurodegeneration and cancer may be diseases of later life for which much of the risk may be set by early life somatic mutations.
Topics: Humans; Mosaicism; Neoplasms; Neurodegenerative Diseases
PubMed: 24937287
DOI: 10.1016/j.cub.2014.05.021 -
World Journal of Gastroenterology Jun 2012There is an increasing understanding of the roles that microsatellite instability (MSI) plays in Lynch syndrome (by mutations) and sporadic (by mainly epigenetic... (Review)
Review
There is an increasing understanding of the roles that microsatellite instability (MSI) plays in Lynch syndrome (by mutations) and sporadic (by mainly epigenetic changes) gastrointestinal (GI) and other cancers. Deficient DNA mismatch repair (MMR) results in the strong mutator phenotype known as MSI, which is the hallmark of cancers arising within Lynch syndrome. MSI is characterized by length alterations within simple repeated sequences called microsatellites. Lynch syndrome occurs primarily because of germline mutations in one of the MMR genes, mainly MLH1 or MSH2, less frequently MSH6, and rarely PMS2. MSI is also observed in about 15% of sporadic colorectal, gastric, and endometrial cancers and in lower frequencies in a minority of other cancers where it is often associated with the hypermethylation of the MLH1 gene. miRNAs are small noncoding RNAs that regulate gene expression at the posttranscriptional level and are critical in many biological processes and cellular pathways. There is accumulating evidence to support the notion that the interrelationship between MSI and miRNA plays a key role in the pathogenesis of GI cancer. As a possible new mechanism underlying MSI, overexpression of miR-155 has been shown to downregulate expression of MLH1, MSH2, and MSH6. Thus, a subset of MSI-positive (MSI+) cancers without known MMR defects may result from miR-155 overexpression. Target genes of frameshift mutation for MSI are involved in various cellular functions, such as DNA repair, cell signaling, and apoptosis. A novel class of target genes that included not only epigenetic modifier genes, such as HDAC2, but also miRNA processing machinery genes, including TARBP2 and XPO5, were found to be mutated in MSI+ GI cancers. Thus, a subset of MSI+ colorectal cancers (CRCs) has been proposed to exhibit a mutated miRNA machinery phenotype. Genetic, epigenetic, and transcriptomic differences exist between MSI+ and MSI- cancers. Molecular signatures of miRNA expression apparently have the potential to distinguish between MSI+ and MSI- CRCs. In this review, we summarize recent advances in the MSI pathogenesis of GI cancer, with the focus on its relationship with miRNA as well as on the potential to use MSI and related alterations as biomarkers and novel therapeutic targets.
Topics: Animals; Colorectal Neoplasms, Hereditary Nonpolyposis; DNA Mismatch Repair; Epigenesis, Genetic; Gene Expression Regulation, Neoplastic; Genetic Predisposition to Disease; Humans; MicroRNAs; Microsatellite Instability; Mutation; Phenotype; Transcription, Genetic
PubMed: 22719182
DOI: 10.3748/wjg.v18.i22.2745 -
PLoS Computational Biology Nov 2015Landscapes exhibiting multiple secondary structures arise in natural RNA molecules that modulate gene expression, protein synthesis, and viral infection [corrected]. We...
Landscapes exhibiting multiple secondary structures arise in natural RNA molecules that modulate gene expression, protein synthesis, and viral infection [corrected]. We report herein that high-throughput chemical experiments can isolate an RNA's multiple alternative secondary structures as they are stabilized by systematic mutagenesis (mutate-and-map, M2) and that a computational algorithm, REEFFIT, enables unbiased reconstruction of these states' structures and populations. In an in silico benchmark on non-coding RNAs with complex landscapes, M2-REEFFIT recovers 95% of RNA helices present with at least 25% population while maintaining a low false discovery rate (10%) and conservative error estimates. In experimental benchmarks, M2-REEFFIT recovers the structure landscapes of a 35-nt MedLoop hairpin, a 110-nt 16S rRNA four-way junction with an excited state, a 25-nt bistable hairpin, and a 112-nt three-state adenine riboswitch with its expression platform, molecules whose characterization previously required expert mutational analysis and specialized NMR or chemical mapping experiments. With this validation, M2-REEFFIT enabled tests of whether artificial RNA sequences might exhibit complex landscapes in the absence of explicit design. An artificial flavin mononucleotide riboswitch and a randomly generated RNA sequence are found to interconvert between three or more states, including structures for which there was no design, but that could be stabilized through mutations. These results highlight the likely pervasiveness of rich landscapes with multiple secondary structures in both natural and artificial RNAs and demonstrate an automated chemical/computational route for their empirical characterization.
Topics: Algorithms; Computational Biology; Models, Molecular; Mutation; Nucleic Acid Conformation; RNA; Riboswitch; Sequence Analysis, RNA
PubMed: 26566145
DOI: 10.1371/journal.pcbi.1004473 -
Current Opinion in Genetics &... Oct 2022Mutation is the origin of all genetic variation, good and bad. The mutation process can evolve in response to mutations, positive or negative selection, and genetic... (Review)
Review
Mutation is the origin of all genetic variation, good and bad. The mutation process can evolve in response to mutations, positive or negative selection, and genetic drift, but how these forces contribute to mutation-rate variation is an unsolved problem at the heart of genetics research. Mutations can be challenging to measure, but genome sequencing and other tools have allowed for the collection of larger and more detailed datasets, particularly in the yeast-model system. We review key hypotheses for the evolution of mutation rates and describe recent advances in understanding variation in mutational properties within and among yeast species. The multidimensional spectrum of mutations is increasingly recognized as holding valuable clues about how this important process evolves.
Topics: Biological Evolution; Evolution, Molecular; Genetic Drift; Mutation; Mutation Rate; Selection, Genetic
PubMed: 35834945
DOI: 10.1016/j.gde.2022.101953 -
The Journal of Clinical Endocrinology... Jun 2022Head and neck paragangliomas (HNPGLs) are rare neoplasms with a high degree of heritability. Paragangliomas present as polygenic diseases caused by combined alterations...
CONTEXT
Head and neck paragangliomas (HNPGLs) are rare neoplasms with a high degree of heritability. Paragangliomas present as polygenic diseases caused by combined alterations in multiple genes; however, many driver changes remain unknown.
OBJECTIVE
The objective of the study was to analyze somatic mutation profiles in HNPGLs.
METHODS
Whole-exome sequencing of 42 tumors and matched normal tissues obtained from Russian patients with HNPGLs was carried out. Somatic mutation profiling included variant calling and utilizing MutSig and SigProfiler packages.
RESULTS
57% of patients harbored germline and somatic variants in paraganglioma (PGL) susceptibility genes or potentially related genes. Somatic variants in novel genes were found in 17% of patients without mutations in any known PGL-related genes. The studied cohort was characterized by 6 significantly mutated genes: SDHD, BCAS4, SLC25A14, RBM3, TP53, and ASCC1, as well as 4 COSMIC single base substitutions (SBS)-96 mutational signatures (SBS5, SBS29, SBS1, and SBS7b). Tumors with germline variants specifically displayed SBS11 and SBS19, when an SBS33-specific mutational signature was identified for cases without those. Beta allele frequency analysis of copy number variations revealed loss of heterozygosity of the wild-type allele in 1 patient with germline mutation c.287-2A>G in the SDHB gene. In patients with germline mutation c.A305G in the SDHD gene, frequent potential loss of chromosome 11 was observed.
CONCLUSION
These results give an understanding of somatic changes and the mutational landscape associated with HNPGLs and are important for the identification of molecular mechanisms involved in tumor development.
Topics: Carrier Proteins; DNA Copy Number Variations; Germ-Line Mutation; Head and Neck Neoplasms; Humans; Mutation; Paraganglioma; RNA-Binding Proteins; Succinate Dehydrogenase
PubMed: 35460558
DOI: 10.1210/clinem/dgac250 -
Proceedings of the National Academy of... Feb 2003Most human tumors are highly heterogenous. We have hypothesized that this heterogeneity results from a mutator phenotype. Our premise is that normal mutation rates are... (Review)
Review
Most human tumors are highly heterogenous. We have hypothesized that this heterogeneity results from a mutator phenotype. Our premise is that normal mutation rates are insufficient to account for the multiple mutations found in human cancers, and, instead, that cancers must exhibit a mutator phenotype early during their evolution. Here, we examine the current status and implications of the mutator phenotype hypothesis for the prognosis, treatment, and prevention of human cancers.
Topics: Base Sequence; Genome, Human; Humans; Molecular Sequence Data; Mutation; Neoplasms; Phenotype
PubMed: 12552134
DOI: 10.1073/pnas.0334858100 -
Nature Genetics Feb 2022The infinite sites model of molecular evolution posits that every position in the genome is mutated at most once. By restricting the number of possible mutation...
The infinite sites model of molecular evolution posits that every position in the genome is mutated at most once. By restricting the number of possible mutation histories, haplotypes and alleles, it forms a cornerstone of tumor phylogenetic analysis and is often implied when calling, phasing and interpreting variants or studying the mutational landscape as a whole. Here we identify 18,295 biallelic mutations, where the same base is mutated independently on both parental copies, in 559 (21%) bulk sequencing samples from the Pan-Cancer Analysis of Whole Genomes study. Biallelic mutations reveal ultraviolet light damage hotspots at E26 transformation-specific (ETS) and nuclear factor of activated T cells (NFAT) binding sites, and hypermutable motifs in POLE-mutant and other cancers. We formulate recommendations for variant calling and provide frameworks to model and detect biallelic mutations. These results highlight the need for accurate models of mutation rates and tumor evolution, as well as their inference from sequencing data.
Topics: Alleles; Evolution, Molecular; Genome, Human; Humans; Models, Genetic; Mutation; Mutation Rate; Neoplasms; Whole Genome Sequencing
PubMed: 35145300
DOI: 10.1038/s41588-021-01005-8