EBV-infection in cardiac and non-cardiac gastric adenocarcinomas is associated with promoter methylation of p16, p14 and APC, but not hMLH1

Geddert, Helene; Hausen, Axel zur; Gabbert, Helmut E.; Sarbia, Mario

doi:10.1007/s13402-011-0028-6

Cited by 47 publications

(30 citation statements)

References 35 publications

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“…As previously reported [33], all EBV-positive tumors exhibited extreme CIMP, distinct from that in the MSI subtype [10] (CDKN2A promoter hypermethylation versus MLH1 hypermethylation) [34]. Furthermore, in concordance with prior data [35,36], the study revealed a strong predilection for PIK3CA mutation in EBV positive tumors, with nonsilent PIK3CA mutations found in 80% of this subgroup (P < 0.001), that could be targeted using PI(3)-kinase inhibition.…”

Section: Molecular Classiication Of Gastric Cancers By "The Cancer Gesupporting

confidence: 88%

“…CIN tumors were mostly located in the gastroesophageal junction/ cardia, whereas most of the EBV-positive tumors were located in the gastric fundus or body. Genomically, stable tumors were diagnosed at an earlier age compared to MSI tumors; most EBV-positive cases were male (81%), in concordance with previous results [32].As previously reported [33], all EBV-positive tumors exhibited extreme CIMP, distinct from that in the MSI subtype [10] (CDKN2A promoter hypermethylation versus MLH1 hypermethylation) [34]. Furthermore, in concordance with prior data [35,36], the study revealed a strong predilection for PIK3CA mutation in EBV positive tumors, with nonsilent PIK3CA mutations found in 80% of this subgroup (P < 0.001), that could be targeted using PI(3)-kinase inhibition.…”

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confidence: 89%

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Molecular Prognostic Factors in Gastric Cancer

Lazăr¹,

Tăban²,

Cornianu³

et al. 2017

Gastric Cancer

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Gastric cancer represents a major health problem worldwide. Literature data have demonstrated that gastric tumors present a high molecular heterogeneity, responsible for the process of carcinogenesis and dissemination. By revealing the molecular subtype of the tumor, it is possible to assess its behavior, the outcome of the patient, and the treatment approach, according to its genetic and epigenetic proile. This chapter aims to highlight some of the many diferent genetic mutations, epigenetic alterations, as well as aberrant signaling pathways involved in the pathogenesis of stomach cancers, each of these molecular abnormalities acting in a speciic stage of the disease. Moreover, the manuscript describes the novel therapeutic agents that target some of these aberrant molecular signaling pathways. Unfortunately, only a few agents are currently part of the standard treatment of gastric cancer, while most of the others remain to prove their therapeutic eicacy in the seting of clinical trials. By discovering the diferent molecular subtypes of gastric cancer, as well as numerous classes of targeted molecular agents, in the future, we would be able to perform an individualized treatment, associated with maximum eiciency and less costs.Keywords: gastric cancer, molecular classiication, gene expressions-based prognostic scoring system, molecular biomarkers, molecular targeted treatment IntroductionDespite a decline in the incidence in past decades, gastric cancer remains a major health problem globally [1,2], being the ifth most common type of cancer worldwide, with almost one million new cases estimated to have occurred in 2012, according to Globocan [3]. Furthermore, stomach cancer represents the third leading cause of cancer death in both sexes worldwide (723,000 deaths) [3].© 2017 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.According to the World Health Organization classiication, the vast majority of gastric cancers are adenocarcinomas, divided into papillary, tubular, mucinous (colloid), and poorly cohesive carcinomas (including signet-ring cell carcinoma and other variants) [4]. Although it was proposed a long time ago (1965), the Lauren classiication is still widely used in clinical practice and subdivides gastric carcinomas into intestinal and difuse types, associated with diferent pathogenesis, ways of spreading, and outcome [5]. Unfortunately, these two classiication systems have litle clinical impact, making the development of classiiers that can deine prognosis and guide patient's treatment as an urgent need.Literature data have demonstrated that the development of gastric cancer is associated in the majority of cases with infectious agents such as the Gram-negative spiral bacterium Helicobacter pylori (most often) [6] and Epstein-Barr virus (EBV) (about 9% o...

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Section: Molecular Classiication Of Gastric Cancers By "The Cancer Gesupporting

confidence: 88%

supporting

confidence: 89%

Molecular Prognostic Factors in Gastric Cancer

Lazăr¹,

Tăban²,

Cornianu³

et al. 2017

Gastric Cancer

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“…7 Increasing evidences showed significantly higher frequencies of promoter cytosine-guanine dinucleotide (CpG) methylation of tumor suppressor genes (eg, p14, p15, p16, p73, APC, E-cadherin, CDH1, and PTEN) in EBV-associated gastric cancer than EBV-negative gastric cancer. [8][9][10] EBVdriven aberrant promoter methylation will lead to the transcriptional silence of tumor suppressors in EBV-associated gastric cancer, thus resulting in uncontrolled cell expansive growth. 11 Aberrant promoter methylation contributes to human gastric carcinogenesis.…”

Section: Introductionmentioning

confidence: 99%

Genome‐wide identification of Epstein‐Barr virus–driven promoter methylation profiles of human genes in gastric cancer cells

Zhao

Liang

Cheung

et al. 2012

Cancer

134

112

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BACKGROUND: Aberrant methylation of tumor-related genes has been reported in Epstein-Barr virus (EBV)-associated gastric cancers. This study sought to profile EBV-driven hypermethylation in EBV-infected cells. METHODS: The EBV-positive AGS gastric cancer cell line (AGS-EBV) and EBV-negative AGS cells were used in this study. DNA methyltransferase-3b (DNMT3b) activity was assessed by EpiQuick activity assay, and genome-wide DNA methylation profiles were assessed by methyl-DNA immunoprecipitation microarray assay. RESULTS: EBV infection was confirmed in AGS-EBV cells by EBV-encoded RNA in situ hybridization. Expression and activity of DNA methyltransferase-3b (DNMT3b) was significantly increased in AGS-EBV compared to AGS. Ectopic expression of LMP2A (latent membrane protein 2A) in AGS increased activity of DNMT3b. A total of 1065 genes were differentially methylated by EBV infection (foldchanges ! 2, P < .05) in AGS-EBV compared to AGS cells. The majority of the differentially methylated genes (83.2%, 886 of 1065 genes) had cytosine-guanine dinucleotide (CpG) hypermethylation in AGS-EBV (fold-changes 2.43$65.2) versus that found in AGS cells. Gene ontology analysis revealed that hypermethylated genes were enriched in the important cancer pathways (! 10 genes each, P .05) including mitogen-activated protein kinase signaling, cell adhesion molecules, wnt signaling pathway, and so forth. Six novel hypermethylated candidates (IL15RA, REC8, SSTR1, EPHB6, MDGA2, and SCARF2) were further validated. Higher levels of DNA methylation were confirmed for all these genes in AGS-EBV cells by bisulfite genomic sequencing. Furthermore, these candidates were silenced or down-regulated in AGS-EBV cells, but can be restored by demethylation treatment. CONCLUSIONS: EBV infection in AGS cells induced aberrant CpG hypermethylation of 886 genes involving in important cancer-related pathways. Induction of promoter methylation by EBV is regulated by up-regulation of DNMT3b through LMP2A. Cancer 2013;119:304-12.

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“…This led to the hypothesis, that Lynch syndrome may have caused gastric cancer associated with renal cancer in our cohort. In addition, we searched for EBV in cancer tissues, particularly since EBV is associated with hypermethylation of tumorsuppressor genes known to be involved gastric cancer (34).…”

Section: Discussionmentioning

confidence: 99%

Gastric cancer and concomitant renal cancer: A systematic immunohistochemical and molecular analysis

Betge

Pollheimer²,

Schlemmer³

et al. 2011

Oncol Rep

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Abstract. The frequency of gastric cancer in patients with renal cell carcinoma (RCC) is exceptionally high in our region suggesting a common molecular basis. Our study aimed to characterize tumors and to analyze possible underlying molecular features in 12 patients with gastric cancer and concomitant RCC. We performed an immunohistochemical analysis including p53 protein expression, proliferative activity (MIB-1), mismatch repair status (hMLH1, hMSH2, hMSH6, PMS2) and E-cadherin expression in gastric cancers, which were additionally analyzed for Epstein-Barr-Encoded-RNA (EBER) by in situ hybridization. Microsatellite instability was analyzed with a PCR multiplex system and capillary electrophoresis. KRAS mutations in codons 12 and 13 were tested by pyrosequencing. All patients had clear cell RCCs, 10 of which were well differentiated and diagnosed in an early stage, while the gastric cancers of these patients were generally poorly or undifferentiated and diagnosed in an advanced stage. Gastric cancers showed reduced E-cadherin staining in 10 out of 12 cases. Two gastric cancers demonstrated loss of hMLH1 and PMS2, which was confirmed by molecular analysis showing a high degree of microsatellite instability. All RCCs were microsatellite stable. KRAS mutation was detected in one of the two instable gastric cancers, while none of the RCCs had KRAS mutations. Another gastric cancer was positive for EBV. In conclusion, a coherent cause for gastric cancer and concomitant RCC, such as Lynch syndrome, a prominent role of KRAS mutation or EBV infection, was not found in our series. Other factors leading to a higher susceptibility for cancer must be explored to explain why individuals with RCC have a higher risk of developing gastric cancer in our region.

show abstract

EBV-infection in cardiac and non-cardiac gastric adenocarcinomas is associated with promoter methylation of p16, p14 and APC, but not hMLH1

Cited by 47 publications

References 35 publications

Molecular Prognostic Factors in Gastric Cancer

Molecular Prognostic Factors in Gastric Cancer

Genome‐wide identification of Epstein‐Barr virus–driven promoter methylation profiles of human genes in gastric cancer cells

Gastric cancer and concomitant renal cancer: A systematic immunohistochemical and molecular analysis

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