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IR@PKUHSC  > 北京大学临床肿瘤学院  > 分子肿瘤学研究室  > 期刊论文
学科主题: 临床医学
题名:
Integrative Identification of Epstein-Barr Virus-Associated Mutations and Epigenetic Alterations in Gastric Cancer
作者: Liang, Qiaoyi1,2,5; Yao, Xiaotian6; Tang, Senwei6; Zhang, Jingwan1,2,5; Yau, Tung On1,2,5; Li, Xiaoxing1,2,5; Tang, Ceen-Ming7; Kang, Wei3; Lung, Raymond W. M.3; Li, Jing Woei4; Chan, Ting Fung4; Xing, Rui8; Lu, Youyong8; Lo, Kwok Wai3; Wong, Nathalie3; To, Ka Fai3; Yu, Chang6; Chan, Francis K. L.1,2,5; Sung, Joseph J. Y.1,2,5; Yu, Jun1,2,5
关键词: Genome Sequencing ; Transcriptome ; Methylation ; AKT2
刊名: GASTROENTEROLOGY
发表日期: 2014-12-01
DOI: 10.1053/j.gastro.2014.08.036
卷: 147, 期:6, 页:1350-+
收录类别: SCI
文章类型: Article
WOS标题词: Science & Technology
类目[WOS]: Gastroenterology & Hepatology
研究领域[WOS]: Gastroenterology & Hepatology
关键词[WOS]: MEMBRANE-PROTEIN 2A ; PROMOTER HYPERMETHYLATION ; GENE-EXPRESSION ; CELL-LINES ; HELICOBACTER-PYLORI ; EPITHELIAL-CELLS ; SEQUENCING DATA ; UP-REGULATION ; CYCLIN A1 ; RNA-SEQ
英文摘要:

BACKGROUND & AIMS: The mechanisms by which Epstein-Barr virus (EBV) contributes to the development of gastric cancer are unclear. We investigated EBV-associated genomic and epigenomic variations in gastric cancer cells and tumors. METHODS: We performed whole-genome, transcriptome, and epigenome sequence analyses of a gastric adenocarcinoma cell line (AGS cells), before and after EBV infection. We then looked for alterations in gastric tumor samples, with (n = 34) or without (n = 100) EBV infection, collected from patients at the Prince of Wales Hospital, Chinese University of Hong Kong (from 1998 through 2004), or the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China (from 1999 through 2006). RESULTS: Transcriptome analysis showed that infected cells expressed 9 EBV genes previously detected in EBV-associated gastric tumors and 71 EBV genes not previously reported in gastric tumors. Ten viral genes that had not been reported previously in gastric cancer but were expressed most highly in EBV-infected cells also were expressed in primary EBV-positive gastric tumors. Whole-genome sequence analysis identified 45 EBV-associated nonsynonymous mutations. These mutations, in genes such as AKT2, CCNA1, MAP3K4, and TGFBR1, were associated significantly with EBV-positive gastric tumors, compared with EBV-negative tumors. An activating mutation in AKT2 was associated with reduced survival times of patients with EBV-positive gastric cancer (P = .006); this mutation was found to dysregulate mitogen-activated protein kinase signaling. Integrated epigenome and transcriptome analyses identified 216 genes transcriptionally down-regulated by EBV-associated hypermethylation; methylation of ACSS1, FAM3B, IHH, and TRABD increased significantly in EBV-positive tumors. Overexpression of Indian hedgehog (IHH) and TraB domain containing (TRABD) increased proliferation and colony formation of gastric cancer cells, whereas knockdown of these genes reduced these activities. We found 5 signaling pathways (axon guidance, focal adhesion formation, interactions among cytokines and receptors, mitogen-activated protein kinase signaling, and actin cytoskeleton regulation) to be affected commonly by EBV-associated genomic and epigenomic alterations. CONCLUSIONS: By using genomic, transcriptome, and epigenomic comparisons of EBV infected vs noninfected gastric cancer cells and tumor samples, we identified alterations in genes, gene expression, and methylation that affect different signaling networks. These might be involved in EBV-associated gastric carcinogenesis.

语种: 英语
所属项目编号: 2012AA02A203 ; 81272304 ; 2010CB529305 ; T12-403-11 ; JCYJ 20120619152326450
项目资助者: China 863 Program ; National Natural Science Foundation of China ; China 973 Program ; Theme-based Research Scheme of the Hong Kong Research Grants Council ; Shenzhen Municipal Science and Technology RD fund ; Shenzhen Virtual University Park Support Scheme
WOS记录号: WOS:000345524800032
Citation statistics:
内容类型: 期刊论文
URI标识: http://ir.bjmu.edu.cn/handle/400002259/58024
Appears in Collections:北京大学临床肿瘤学院_分子肿瘤学研究室_期刊论文

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作者单位: 1.BGI Shenzhen, Shenzhen, Peoples R China
2.Univ Oxford, Dept Pharmacol, Oxford OX1 3QT, England
3.Chinese Univ Hong Kong, Hong Kong Bioinformat Ctr, Inst Digest Dis, Hong Kong, Hong Kong, Peoples R China
4.Chinese Univ Hong Kong, Hong Kong Bioinformat Ctr, Dept Med & Therapeut, State Key Lab Digest Dis,Li Ka Shing Inst Hlth Sc, Hong Kong, Hong Kong, Peoples R China
5.Chinese Univ Hong Kong, Hong Kong Bioinformat Ctr, Dept Anat & Cellular Pathol, Hong Kong, Hong Kong, Peoples R China
6.Chinese Univ Hong Kong, Hong Kong Bioinformat Ctr, Sch Life Sci, Hong Kong, Hong Kong, Peoples R China
7.Chinese Univ Hong Kong, Shenzhen Res Inst, Shenzhen, Peoples R China
8.Peking Univ, Key Lab Carcinogenesis & Translat Res, Lab Mol Oncol, Minist Educ,Canc Hosp Inst, Beijing 100871, Peoples R China

Recommended Citation:
Liang, Qiaoyi,Yao, Xiaotian,Tang, Senwei,et al. Integrative Identification of Epstein-Barr Virus-Associated Mutations and Epigenetic Alterations in Gastric Cancer[J]. GASTROENTEROLOGY,2014,147(6):1350-+.
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