Genetic, epigenetic, and clinicopathologic features of gastric carcinomas with the CpG island methylator phenotype and an association with Epstein–Barr virus

Kusano, Masanobu; Toyota, Minoru; Suzuki, Hiromu; Akino, Kimishige; Aoki, Fugaku; Fujita, Masahiro; Hosokawa, Masao; Shinomura, Yasuhisa; Imai, Kohzoh; Tokino, Takashi

doi:10.1002/cncr.21789

Cited by 158 publications

(162 citation statements)

References 39 publications

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“…23,24,26,27 They also show a lack of TP53 mutations. 6,23,24,28,29 This trend was also recorded in the Asian Cancer Research Group data set. 7 It has been suggested that the profound global DNA effects are responsible for the distinctive clinicopathologic features of EBV gastric cancers 20 including male predominance 9,30 and proximal location.…”

Section: Discussionsupporting

confidence: 62%

A protein and mRNA expression-based classification of gastric cancer

et al. 2016

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The overall survival of gastric carcinoma patients remains poor despite improved control over known risk factors and surveillance. This highlights the need for new classifications, driven towards identification of potential therapeutic targets. Using sophisticated molecular technologies and analysis, three groups recently provided genetic and epigenetic molecular classifications of gastric cancer (The Cancer Genome Atlas, 'Singapore-Duke' study, and Asian Cancer Research Group). Suggested by these classifications, here, we examined the expression of 14 biomarkers in a cohort of 146 gastric adenocarcinomas and performed unsupervised hierarchical clustering analysis using less expensive and widely available immunohistochemistry and in situ hybridization. Ultimately, we identified five groups of gastric cancers based on Epstein-Barr virus (EBV) positivity, microsatellite instability, aberrant E-cadherin, and p53 expression; the remaining cases constituted a group characterized by normal p53 expression. In addition, the five categories correspond to the reported molecular subgroups by virtue of clinicopathologic features. Furthermore, evaluation between these clusters and survival using the Cox proportional hazards model showed a trend for superior survival in the EBV and microsatellite-instable related adenocarcinomas. In conclusion, we offer as a proposal a simplified algorithm that is able to reproduce the recently proposed molecular subgroups of gastric adenocarcinoma, using immunohistochemical and in situ hybridization techniques. Gastric carcinoma is the fifth most common malignancy and the third leading cause of cancer-related death worldwide. Despite better control over known risk factors and development of new chemotherapeutic and targeted agents, in the United States, the 5-year overall survival for gastric cancer patients is only 29%. 1 With regard to patient stratification, although several morphologic classifications have been developed, one broadly used system is the Lauren classification, which divides gastric adenocarcinoma into intestinal and diffuse types. 2 The simple two-tiered classification gives a general understanding of the histogenesis and biology of gastric cancer, and has been particularly helpful in evaluating the epidemiologic data. Another widely used system is the WHO classification, which is based on more precise histologic patterns. It is an all-inclusive system, which recognizes all the rare subtypes that were not identified in the Lauren classification. 3 Nevertheless, its clinical utility is doubtful as there is little difference in outcomes between the distinct histological subgroups.Following the successful Trastuzumab for Gastric Cancer (ToGA) trial, the only validated predictive biomarker for personalized therapy of gastric cancer is limited to human epidermal growth factor receptor (Her2) protein expression. 4 Recently, anti-vascular endothelial growth factor receptor 2 (VEGFR2) antibody (ramucirumab) has been FDA approved, and anti-epidermal growth factor receptor (EGFR) an...

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Section: Discussionsupporting

confidence: 62%

A protein and mRNA expression-based classification of gastric cancer

et al. 2016

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“…[35][36][37] The difference in CpG island hypermethylation between intestinal and diffuse types has not been well characterized. Using different DNA methylation markers and different methodology, CpG island methylator phenotype was found to be associated with 'diffuse' histology in some reports 33,38 but not in others. 39,40 These controversial findings are most likely due to the use of differing DNA methylation marker panels as well as methods of analysis.…”

Section: Methylation In Gc Was Revealed For the First Time In Thismentioning

confidence: 99%

“…[21][22][23]30,32,33 However, these previous studies used a small number of CpG island loci by MSP. In our study analyzing 27 CpG island loci by MethyLight, which overcomes some variability problems of MSP, the average MI of EBV-positive GCs and MSI-positive GCs was 0.98 and 0.48, respectively, whereas that of GCs negative for both was 0.37.…”

Section: Methylation In Gc Was Revealed For the First Time In Thismentioning

confidence: 99%

DNA methylation profiles of gastric carcinoma characterized by quantitative DNA methylation analysis

Kang

Lee

Cho

et al. 2008

Laboratory Investigation

153

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Transcriptional silencing by CpG island hypermethylation is a potential mechanism for the inactivation of tumor-related genes. Virtually, all types of human cancers show CpG island hypermethylation, and gastric carcinoma (GC) is one of the tumors with a high frequency of aberrant CpG island hypermethylation. In this study, we prescreened DNA methylation of 170 CpG island loci in a training set of 8 paired GC and GC-associated non-neoplastic mucosae (GCN) using MethyLight technology and selected 27 DNA methylation markers showing higher methylation frequency or level in GC than in GCN. These markers were then analyzed in a tester set of 25 paired GC and GCN and 27 chronic gastritis (CG) from non-cancer patients to generate their DNA methylation profiles. We identified 17 novel methylation markers in GC, including SFRP4, SEZ6L, TWIST1, BCL2, KL, TERT, SCGB3A1, IGF2, GRIN2B, SFRP5, DLEC1, HOXA1, CYP1B1, SMAD9, MT1G, NR3C1, and HOXA10. Of the 27 selected CpG island loci, 23 were methylated in GC, GCN, and CG and the remainder four loci (DLEC1, CHFR, CYP1B1, and NR3C1) were only methylated in GC. We found that the number of methylated loci was significantly higher in GC than in GCN or CG and that Helicobacter pylori infection was strongly associated with aberrant CpG island hypermethylation in CG. Hypermethylation was more prevalent in Epstein-Barr virus (EBV)-positive GC than in EBV-negative GC and in diffuse-type GC than in intestinal-type GC. Through our large-scale screening of 170 CpG island loci, we found 17 new DNA methylation markers of GC, which may serve as useful markers that may identify a distinct subset of GC.

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“…The studies of Park et al2 and Shigeyasu et al3 were classified as the multiple gene panel group because over 15 CIMP marker genes were used in each of them. An et al , 4 Ben Ayed‐Guerfali et al , 5 He et al , 6 Ksiaa et al7, and Kusano et al8 were classified as the p16 or MINT ‐based gene panel group, whereas the remaining 3 studies (Chang et al , 9 Chen et al10 and Liu et al11) were classified as the mixed gene panel group because there were no similarities among them. By subgroup analysis, we found that CIMP‐H was significantly associated with poor prognosis in the p16 or MINT ‐based gene panel group, but not in the other 2 subgroups (Figure 1A).…”

Section: Figurementioning

confidence: 99%