Gastric cancer and gene copy number variation: emerging cancer drivers for targeted therapy

Liang, Luming; Jy, Fang; Xu, Jin-Quan

doi:10.1038/onc.2015.209

Cited by 124 publications

(133 citation statements)

References 149 publications

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“…Gene amplifications are found in many circumstances when an increase in gene dosage improves growth rate. Gene amplifications contribute to loss of growth control and to resistance to therapeutic agents in tumors (12)(13)(14)(15), to the emergence of antibiotic resistance in pathogens (16,17), and to improved growth of S. enterica in which a single inefficient enzyme serves functions in both histidine and tryptophan biosynthesis (18). Duplications that include genes encoding permeases increase the growth rate of Salmonella enterica serovar Typhimurium under carbon-limiting conditions (19), and amplification of a region containing the clc cluster of genes that enable degradation of chlorocatechol allows a strain of Pseudomonas putida to grow on chlorobenzene as the sole carbon source (20).…”

Section: Discussionmentioning

confidence: 99%

A Synonymous Mutation Upstream of the Gene Encoding a Weak-Link Enzyme Causes an Ultrasensitive Response in Growth Rate

et al. 2016

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When microbes are faced with an environmental challenge or opportunity, preexisting enzymes with promiscuous secondary activities can be recruited to provide newly important functions. Mutations that increase the efficiency of a new activity often compromise the original activity, resulting in an inefficient bifunctional enzyme. We have investigated the mechanisms by which growth of Escherichia coli can be improved when fitness is limited by such an enzyme, E383A ProA (ProA*). ProA* can serve the functions of both ProA (required for synthesis of proline) and ArgC (required for synthesis of arginine), albeit poorly. We identified four genetic changes that improve the growth rate by up to 6.2-fold. Two point mutations in the promoter of the proBA* operon increase expression of the entire operon. Massive amplification of a genomic segment around the proBA* operon also increases expression of the entire operon. Finally, a synonymous point mutation in the coding region of proB creates a new promoter for proA*. This synonymous mutation increases the level of ProA* by 2-fold but increases the growth rate by 5-fold, an ultrasensitive response likely arising from competition between two substrates for the active site of the inefficient bifunctional ProA*. IMPORTANCEThe high-impact synonymous mutation we discovered in proB is remarkable for two reasons. First, most polar effects documented in the literature are detrimental. This finding demonstrates that polar effect mutations can have strongly beneficial effects, especially when an organism is facing a difficult environmental challenge for which it is poorly adapted. Furthermore, the consequence of the synonymous mutation in proB is a 2-fold increase in the level of ProA* but a disproportionately large 5.1-fold increase in growth rate. While ultrasensitive responses are often found in signaling networks and genetic circuits, an ultrasensitive response to an adaptive mutation has not been previously reported. Metabolic enzymes, although prodigious catalysts, are not perfectly specific for their physiological substrates. They typically possess secondary activities as a consequence of the assemblage of highly reactive functional groups, metal ions, and cofactors in their active sites. Secondary activities that are physiologically irrelevant, either because they are too inefficient to contribute to fitness or because the enzyme never encounters the substrate, are termed promiscuous activities (1).Promiscuous activities are important from an evolutionary standpoint because they provide a reservoir of catalytic potential within a proteome that can be drawn upon when the environment changes. A promiscuous activity may become important for fitness when a new source of carbon, nitrogen, or phosphorous appears in the environment or when a previously available compound, such as an amino acid or cofactor, becomes unavailable. A promiscuous activity may also become critical when the organism is exposed to a novel toxin, such as an antibiotic or pesticide.A newly recruited pro...

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Section: Discussionmentioning

confidence: 99%

A Synonymous Mutation Upstream of the Gene Encoding a Weak-Link Enzyme Causes an Ultrasensitive Response in Growth Rate

et al. 2016

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“…Previous studies have shown that there are two classical pathways associated with the development of colorectal cancers (CRCs) and GCs: microsatellite instability (MSI) and chromosomal instability (CIN) [6][7][8][9][10]. A recent study showed that molecular alterations in GC can be classified into four subgroups; that is, MSI-type tumors, CIN-type tumors, Epstein-Barr virus (EBV)-associated tumors, and genomically stable (GS) tumors [8].…”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, the MSI phenotype shows characteristic histological features and favorable prognosis compared with microsatellite stable (MSS) cancer [7,8]. On the other hand, CIN is closely associated with accumulation of multiple losses of heterozygosity, p53 mutations, and DNA aneuploidy (e.g., chromosomal damage in tumor cells) [6][7][8]. EBV-associated GC is a distinct subtype that accounts for nearly 10 % of GCs.…”

Section: Introductionmentioning

confidence: 99%

Genetic differences stratified by PCR-based microsatellite analysis in gastric intramucosal neoplasia

et al. 2016

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Background Although genetic alterations in patients with advanced gastric cancer have been extensively studied, those in patients with intramucosal neoplasia (IMN) are still poorly understood. Methods We evaluated genetic differences in 158 IMNs, including 51 low-grade dysplasias, 58 high-grade dysplasias (HGDs), 30 intramucosal cancers (IMCs), and 19 mixed tumors (composed of IMC and HGD within the same tumor), using PCR-based microsatellite analysis [allelic imbalance (AI) and microsatellite instability (MSI)]. We classified the DNA methylation status as a hypermethylated epigenome, a moderately methylated epigenome, or a hypomethylated epigenome. In addition, p53 overexpression, b-catenin nuclear localization, and mucin expression were also examined. Results From cluster analysis, the IMNs examined were categorized into four subgroups as follows. Tumors in subgroup 1 were characterized by MSI-high status, a hypermethylated epigenome, and loss or reduction of expression of MLH-1. Tumors in subgroup 2 showed a mixed pattern consisting of AI and MSI. In contrast, tumors in subgroup 3, which showed accumulation of multiple AIs, were closely associated with HGD, IMC, or mixed tumor and exhibited nuclear expression of b-catenin. Tumors in subgroup 4, which were generally low-grade dysplasias, exhibited a low frequency of AIs and no MSI. Although the mucin phenotype was not correlated with any subgroup, expression of mucin was associated with some subgroups. Overexpression of p53 was common in all subgroups. Conclusion The approach described herein was useful for studying genetic differences in IMNs. In addition, we suggest that stratification of genetic differences may help to identify genetic molecular profiles in IMNs.

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“…Hundreds to thousands of copies of mtDNA exist per cell. The accumulation of somatic mutations in mtDNA results in metabolic dysfunction and causes late-onset and age-related diseases, such as multiple sclerosis, primary biliary cirrhosis, psoriasis, type-2 diabetes, schizophrenia, gastric cancer, and colorectal cancer (9)(10)(11)(12). In an inflammatory environment, mtDNA is subject to damage induced by reactive oxygen species (ROS) (13), and it accumulates more mutations than nuclear DNA because it lacks histones and related protective systems (14).…”

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confidence: 99%

Increased Copy Number Variation of mtDNA in an Array-based Digital PCR Assay Predicts Ulcerative Colitis-associated Colorectal Cancer

Tanaka

Kobunai

Yamamoto

et al. 2017

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Abstract. Aim: Mitochondrial dysfunction plays a central role in carcinogenesis in numerous cancer-related diseases.We examined the copy number variation of mitochondrial DNA (mtDNA) Ulcerative colitis (UC) is a type of inflammatory bowel disease (IBD), and disease-related long-standing inflammation results in increased risk of colitic cancer. The cumulative risks of invasive adenocarcinoma have been shown to be 0.5%, 4.1%, and 6.1% at 10, 20, and 30 years, respectively (1), and colitic cancer, especially the advanced type, determines patient outcomes. Currently, in order to detect dysplastic lesions early, colonoscopy together with random and target biopsies are considered to be the most effective detection option, especially for longstanding UC; however, the characteristics of colitic cancer, such as flat mucosal lesions and widespread distribution, make early detection difficult (2). Another problem with surveillance colonoscopy is its invasiveness and cost effectiveness; therefore, we thought that another modality for the detection of colitic cancer and identification of predictors of patients at high risk was needed.As clinical indicators, the extent and severity of inflammation and the duration of disease have been observed to increase the cumulative risk of dysplasia or invasive colorectal cancer in IBD (3-6). From a molecular perspective, we studied genetic variance in non-neoplastic mucosa. We observed lower DNA copy numbers and lower expression of RUNX3 in non-neoplastic rectal mucosa in cancer-free UC patients (UC-nonCa) than in patients with colitic cancer (UC-Ca) (7). In another study, we identified 20 genes that showed differences in expressions between UC-Ca and UC-nonCa mucosae, and we introduced a prediction model that achieved a markedly high accuracy rate of 83% and negative predictive value of 100% (8). These studies contributed to a better understanding of the genetics of colitic cancer and methods of prediction.Recently, the genetic alteration of mitochondrial DNA (mtDNA) has attracted attention as a target for various diseases. The mitochondrion is a small organelle in cells that plays an important role in the production of energy 713 *These Authors contributed equally to this study.

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Gastric cancer and gene copy number variation: emerging cancer drivers for targeted therapy

Cited by 124 publications

References 149 publications

A Synonymous Mutation Upstream of the Gene Encoding a Weak-Link Enzyme Causes an Ultrasensitive Response in Growth Rate

A Synonymous Mutation Upstream of the Gene Encoding a Weak-Link Enzyme Causes an Ultrasensitive Response in Growth Rate

Genetic differences stratified by PCR-based microsatellite analysis in gastric intramucosal neoplasia

Increased Copy Number Variation of mtDNA in an Array-based Digital PCR Assay Predicts Ulcerative Colitis-associated Colorectal Cancer

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