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

Zhao, Jin; Liang, Qiaoyi; Cheung, Ka Shing; Kang, Wei; Lung, Raymond Wai Ming; Tong, Joanna H.; To, Ka Fai; Sung, Joseph J.Y.; Yu, Jun

doi:10.1002/cncr.27724

Cited by 134 publications

(119 citation statements)

References 23 publications

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“…Apparently, variant 3 is differently affected by the methylation of DNA as not all the isoforms derived from this variant increased their expression under the same conditions, and it may indicate that variant 3 and the 498-bp isoform are benefited by the lack of DNA methylation in comparison with other derived isoforms. In general, these results are in agreement with previous reports, 15,28,29 suggesting that DNA methylation could underlie an isoform switch in IL-15RA. Whether the effect of DNA methylation on IL-15Ra gene is due to cis or trans methylation is not known as AZA acts as a general inhibitor of de novo methylation; however, Diniz et al found evidence of regulation on a CpG island located on the regulatory 5' upstream region and on the exon 1 of the IL-15Ra gene.…”

Section: Discussionsupporting

confidence: 94%

New IL-15 receptor-α splicing variants identified in intestinal epithelial Caco-2 cells

et al. 2016

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IL-15 is a pleiotropic cytokine related to IL-2 which acts at a broader level than its counterpart. It is presented through its specific high-affinity receptor, IL-15Ra. Both cytokine and receptor are tightly regulated at multiple levels and are widely distributed. Thus, deregulation of their expression leads to an inflammatory immune response. Variants of splicing of IL-15Ra have been described in immune and barrier cells; however, their presence has not been focused on intestinal epithelial cells. In this study, we describe five new alternative variants of splicing of IL-15Ra in Caco-2 cells. Four of them were expressed into proteins inside Caco-2 cells, but these were unable to bind IL-15 or to follow the secretory pathway. However, the expression of mRNA itself might be relevant to diseases such as celiac disease, inflammatory bowel disease or colorectal cancer.

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Section: Discussionsupporting

confidence: 94%

New IL-15 receptor-α splicing variants identified in intestinal epithelial Caco-2 cells

et al. 2016

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“…The process involves a series of tumor suppressor genes (eg, p14, p15, p16, APC, CDH, MGMT and PTEN), which result in uncontrolled cell growth. 20,21 Of note, although microsatellite-instable gastric adenocarcinomas are also associated with hypermethylation and silencing of genes (and their promoters) in a distinctive pattern. EBV gastric cancers having a more extensive pattern of methylation of promoter and non-promoter CpG islands.…”

Section: Discussionmentioning

confidence: 99%

“…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. 31 Notably, the purported younger age has not been confirmed by recent analysis.…”

Section: Discussionmentioning

confidence: 99%

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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“…This subset of gastric carcinoma, 8 to 10% of cases, is more prevalent in Caucasian and Hispanic patients than Asians, and it shows no association with Helicobacter pylori infection (22). In these cases, EBV appears to play a direct oncogenic role through genome-wide alteration of promoter methylation (24), microRNA (miRNA) expression, and expression of genes involved in cell motility and transformation pathways (25). The integration status of EBV in gastric carcinoma remains poorly understood.…”

mentioning

confidence: 99%

Landscape of DNA Virus Associations across Human Malignant Cancers: Analysis of 3,775 Cases Using RNA-Seq

Khoury¹,

Tannir

Williams³

et al. 2013

J Virol

198

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Elucidation of tumor-DNA virus associations in many cancer types has enhanced our knowledge of fundamental oncogenesis mechanisms and provided a basis for cancer prevention initiatives. RNA-Seq is a novel tool to comprehensively assess such associations. We interrogated RNA-Seq data from 3,775 malignant neoplasms in The Cancer Genome Atlas database for the presence of viral sequences. Viral integration sites were also detected in expressed transcripts using a novel approach. The detection capacity of RNA-Seq was compared to available clinical laboratory data. Human papillomavirus (HPV) transcripts were detected using RNA-Seq analysis in head-and-neck squamous cell carcinoma, uterine endometrioid carcinoma, and squamous cell carcinoma of the lung. Detection of HPV by RNA-Seq correlated with detection by in situ hybridization and immunohistochemistry in squamous cell carcinoma tumors of the head and neck. Hepatitis B virus and Epstein-Barr virus (EBV) were detected using RNA-Seq in hepatocellular carcinoma and gastric carcinoma tumors, respectively. Integration sites of viral genes and oncogenes were detected in cancers harboring HPV or hepatitis B virus but not in EBV-positive gastric carcinoma. Integration sites of expressed viral transcripts frequently involved known coding areas of the host genome. No DNA virus transcripts were detected in acute myeloid leukemia, cutaneous melanoma, low-and high-grade gliomas of the brain, and adenocarcinomas of the breast, colon and rectum, lung, prostate, ovary, kidney, and thyroid. In conclusion, this study provides a large-scale overview of the landscape of DNA viruses in human malignant cancers. While further validation is necessary for specific cancer types, our findings highlight the utility of RNA-Seq in detecting tumor-associated DNA viruses and identifying viral integration sites that may unravel novel mechanisms of cancer pathogenesis.

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

Cited by 134 publications

References 23 publications

New IL-15 receptor-α splicing variants identified in intestinal epithelial Caco-2 cells

New IL-15 receptor-α splicing variants identified in intestinal epithelial Caco-2 cells

A protein and mRNA expression-based classification of gastric cancer

Landscape of DNA Virus Associations across Human Malignant Cancers: Analysis of 3,775 Cases Using RNA-Seq

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