-
Genes Sep 2021Oncogene amplification is closely linked to the pathogenesis of a broad spectrum of human malignant tumors. The amplified genes localize either to the extrachromosomal... (Review)
Review
Oncogene amplification is closely linked to the pathogenesis of a broad spectrum of human malignant tumors. The amplified genes localize either to the extrachromosomal circular DNA, which has been referred to as cytogenetically visible double minutes (DMs), or submicroscopic episome, or to the chromosomal homogeneously staining region (HSR). The extrachromosomal circle from a chromosome arm can initiate gene amplification, resulting in the formation of DMs or HSR, if it had a sequence element required for replication initiation (the replication initiation region/matrix attachment region; the IR/MAR), under a genetic background that permits gene amplification. In this article, the nature, intracellular behavior, generation, and contribution to cancer genome plasticity of such extrachromosomal circles are summarized and discussed by reviewing recent articles on these topics. Such studies are critical in the understanding and treating human cancer, and also for the production of recombinant proteins such as biopharmaceuticals by increasing the recombinant genes in the cells.
Topics: Animals; Chromothripsis; DNA, Circular; Gene Amplification; Humans; Neoplasms
PubMed: 34680928
DOI: 10.3390/genes12101533 -
Cold Spring Harbor Perspectives in... Feb 2015Changes in gene copy number are among the most frequent mutational events in all genomes and were among the mutations for which a physical basis was first known. Yet... (Review)
Review
Changes in gene copy number are among the most frequent mutational events in all genomes and were among the mutations for which a physical basis was first known. Yet mechanisms of gene duplication remain uncertain because formation rates are difficult to measure and mechanisms may vary with position in a genome. Duplications are compared here to deletions, which seem formally similar but can arise at very different rates by distinct mechanisms. Methods of assessing duplication rates and dependencies are described with several proposed formation mechanisms. Emphasis is placed on duplications formed in extensively studied experimental situations. Duplications studied in microbes are compared with those observed in metazoan cells, specifically those in genomes of cancer cells. Duplications, and especially their derived amplifications, are suggested to form by multistep processes often under positive selection for increased copy number.
Topics: DNA; DNA Transposable Elements; Gene Amplification; Gene Deletion; Gene Dosage; Gene Duplication; Genes, Bacterial; Inverted Repeat Sequences; Models, Genetic; Mutation Rate; Plasmids
PubMed: 25646380
DOI: 10.1101/cshperspect.a016592 -
The Journal of Biological Chemistry 2021Sirtuin 1 (SIRT1) is a protein deacetylase that maintains genome stability by preventing the activation of latent replication origins. Amplified genes in cancer cells...
Sirtuin 1 (SIRT1) is a protein deacetylase that maintains genome stability by preventing the activation of latent replication origins. Amplified genes in cancer cells localize on either extrachromosomal double minutes (DMs) or the chromosomal homogeneously staining region. Previously, we found that a plasmid with a mammalian replication initiation region and a matrix attachment region spontaneously mimics gene amplification in cultured animal cells and efficiently generates DMs and/or an homogeneously staining region. Here, we addressed the possibility that SIRT1 might be involved in initiation region/matrix attachment region-mediated gene amplification using SIRT1-knockout human COLO 320DM cells. Consequently, we found that extrachromosomal amplification was infrequent in SIRT1-deficient cells, suggesting that DNA breakage caused by latent origin activation prevented the formation of stable extrachromosomal amplicons. Moreover, we serendipitously found that reporter gene expression from the amplified repeats, which is commonly silenced by repeat-induced gene silencing (RIGS) in SIRT1-proficient cells, was strikingly higher in SIRT1-deficient cells, especially in the culture treated with the histone deacetylase inhibitor butyrate. Compared with the SIRT1-proficient cells, the gene expression per copy was up to thousand-fold higher in the sorter-isolated highest 10% cells among the SIRT1-deficient cells. These observations suggest that SIRT1 depletion alleviates RIGS. Thus, SIRT1 may stabilize extrachromosomal amplicons and facilitate RIGS. This result could have implications in cancer malignancy and protein expression.
Topics: Cell Line, Tumor; Gene Amplification; Gene Knockout Techniques; Gene Silencing; Genomic Instability; Humans; Sirtuin 1
PubMed: 33539925
DOI: 10.1016/j.jbc.2021.100356 -
Biomolecular Concepts Dec 2013Gene amplification was recognized as a physiological process during the development of Drosophila melanogaster. Intriguingly, mammalian cells use this mechanism to... (Review)
Review
Gene amplification was recognized as a physiological process during the development of Drosophila melanogaster. Intriguingly, mammalian cells use this mechanism to overexpress particular genes for survival under stress, such as during exposure to cytotoxic drugs. One well-known example is the amplification of the dihydrofolate reductase gene observed in methotrexate-resistant cells. Four models have been proposed for the generation of amplifications: extrareplication and recombination, the breakage-fusion-bridge cycle, double rolling-circle replication, and replication fork stalling and template switching. Gene amplification is a typical genetic alteration in cancer, and historically many oncogenes have been identified in the amplified regions. In this regard, novel cancer-associated genes may remain to be identified in the amplified regions. Recent comprehensive approaches have further revealed that co-amplified genes also contribute to tumorigenesis in concert with known oncogenes in the same amplicons. Considering that cancer develops through the alteration of multiple genes, gene amplification is an effective acceleration machinery to promote tumorigenesis. Identification of cancer-associated genes could provide novel and effective therapeutic targets.
Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; DNA Replication; Disease Models, Animal; Drug Resistance, Neoplasm; Gene Amplification; Humans; Neoplasms; Oncogenes; Recombination, Genetic
PubMed: 25436757
DOI: 10.1515/bmc-2013-0026 -
Cells Dec 2022Gene amplifications have been known for several decades as physiological processes in amphibian and flies, e.g., during eggshell development in and as part of... (Review)
Review
Gene amplifications have been known for several decades as physiological processes in amphibian and flies, e.g., during eggshell development in and as part of pathological processes in humans, specifically in tumors and drug-resistant cells. The long-held belief that a physiological gene amplification does not occur in humans was, however, fundamental questioned by findings that showed gene amplification in human stem cells. We hypothesis that the physiological and the pathological, i.e., tumor associated processes of gene amplification share at their beginning the same underlying mechanism. Re-replication was reported both in the context of tumor related genome instability and during restricted time windows in development causing the known developmental gene amplification in . There is also growing evidence that gene amplification and re-replication were present in human stem cells. It appears likely that stem cells utilize a re-replication mechanism that has been developed early in evolution as a powerful tool to increase gene copy numbers very efficiently. Here, we show that, several decades ago, there was already evidence of gene amplification in non-tumor mammalian cells, but that was not recognized at the time and interpreted accordingly. We give an overview on gene amplifications during normal mammalian development, the possible mechanism that enable gene amplification and hypothesize how tumors adopted this capability for gene amplification.
Topics: Animals; Humans; Gene Amplification; Gene Dosage; Neural Stem Cells; Neoplasms; Drosophila; Mammals
PubMed: 36611942
DOI: 10.3390/cells12010148 -
Molecular Pharmacology Apr 2022Amplification of pro-oncogenic kinases is a common genetic alteration driving tumorigenic phenotypes. Cancer cells rely on the amplified kinases to sustain cell... (Review)
Review
Amplification of pro-oncogenic kinases is a common genetic alteration driving tumorigenic phenotypes. Cancer cells rely on the amplified kinases to sustain cell proliferation, survival, and growth, presenting an opportunity to develop therapies targeting the amplified kinases. Utilizing small molecule catalytic inhibitors as therapies to target amplified kinases is plagued by de novo resistance driven by increased expression of the target, and amplified kinases can drive tumorigenic phenotypes independent of catalytic activity. Here, we discuss the emergence of proteolysis-targeting chimeras that provide an opportunity to target these oncogenic drivers effectively. SIGNIFICANCE STATEMENT: Protein kinases contribute to tumorigenesis through catalytic and noncatalytic mechanisms, and kinase gene amplifications are well described mechanisms of resistance to small molecule catalytic inhibitors. Repurposing catalytic inhibitors for the development of protein degraders will offer improved clinical benefits by targeting noncatalytic functions of kinases that promote tumorigenesis and overcoming resistance due to amplification.
Topics: Carcinogenesis; Cell Proliferation; Gene Amplification; Humans; Neoplasms; Protein Kinases
PubMed: 35115411
DOI: 10.1124/molpharm.121.000306 -
Oncotarget Feb 2016Gene amplifications are mostly an attribute of tumor cells and drug resistant cells. Recently, we provided evidence for gene amplifications during differentiation of...
Gene amplifications are mostly an attribute of tumor cells and drug resistant cells. Recently, we provided evidence for gene amplifications during differentiation of human and mouse neural progenitor cells. Here, we report gene amplifications in differentiating mouse myoblasts (C2C12 cells) covering a period of 7 days including pre-fusion, fusion and post-fusion stages. After differentiation induction we found an increase in copy numbers of CDK4 gene at day 3, of NUP133 at days 4 and 7, and of MYO18B at day 4. The amplification process was accompanied by gamma-H2AX foci that are indicative of double stand breaks. Amplifications during the differentiating process were also found in primary human myoblasts with the gene CDK4 and NUP133 amplified both in human and mouse myoblasts. Amplifications of NUP133 and CDK4 were also identified in vivo on mouse transversal cryosections at stage E11.5. In the course of myoblast differentiation, we found amplifications in cytoplasm indicative of removal of amplified sequences from the nucleus. The data provide further evidence that amplification is a fundamental mechanism contributing to the differentiation process in mammalians.
Topics: Animals; Cell Differentiation; Cell Line; Gene Amplification; Humans; Mice; Muscle Development; Myoblasts
PubMed: 26760505
DOI: 10.18632/oncotarget.6845 -
Cancer Research and Treatment Apr 2020Mesenchymal epithelial transition (MET) is a proto-oncogene that encodes a heterodimeric transmembrane receptor tyrosine kinase for the hepatocyte growth factor....
PURPOSE
Mesenchymal epithelial transition (MET) is a proto-oncogene that encodes a heterodimeric transmembrane receptor tyrosine kinase for the hepatocyte growth factor. Aberrant MET signaling has been described in several solid tumors-especially non-small cell lung cancer- and is associated with tumor progression and adverse prognosis. As MET is a potential therapeutic target, information regarding its prevalence and clinicopathological relevance is crucial.
MATERIALS AND METHODS
We investigated MET expression and gene amplification in 113 gallbladder cancers using tissue microarray. Immunohistochemistry was used to evaluate MET overexpression, and silver/fluorescence in situ hybridization (ISH) was used to assess gene copy number.
RESULTS
MET overexpression was found in 37 cases of gallbladder carcinoma (39.8%), and gene amplification was present in 17 cases (18.3%). MET protein expression did not correlate with MET amplification. MET amplification was significantly associated with aggressive clinicopathological features, including high histological grade, advanced pT category, lymph node metastasis, and advanced American Joint Committee on Cancer stage. There was no significant correlation between any clinicopathological factors and MET overexpression. No difference in survival was found with respect to MET overexpression and amplification status.
CONCLUSION
Our data suggested that MET might be a potential therapeutic target for targeted therapy in gallbladder cancer, because MET amplification was found in a subset of tumors associated with adverse prognostic factors. Detection of MET amplification by ISH might be a useful predictive biomarker test for anti-MET therapy.
Topics: Adult; Aged; Aged, 80 and over; Female; Gallbladder Neoplasms; Gene Amplification; Humans; Male; Middle Aged; Prevalence; Proto-Oncogene Mas; Proto-Oncogene Proteins c-met
PubMed: 31645095
DOI: 10.4143/crt.2019.370 -
Blood Jul 2022
Topics: Gene Amplification; Humans; Leukemia, Myeloid, Acute; Myeloid-Lymphoid Leukemia Protein
PubMed: 35834280
DOI: 10.1182/blood.2022016499 -
Cancer Discovery May 2022Extrachromosomal DNA circles (ecDNA) are a common mechanism for oncogene amplification and are associated with worse clinical outcomes compared with other types of...
Extrachromosomal DNA circles (ecDNA) are a common mechanism for oncogene amplification and are associated with worse clinical outcomes compared with other types of oncogene amplification. Several recent discoveries of ecDNA hubs-local congregations of ecDNAs in the nucleus-highlight unique features of ecDNA biology that may contribute to higher oncogene expression and rapid tumor evolution.
Topics: Cell Nucleus; DNA; Gene Amplification; Humans; Neoplasms; Oncogenes
PubMed: 35398879
DOI: 10.1158/2159-8290.CD-22-0076