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1
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Meevassana J, Vongsuly CW, Nakbua T, Kamolratanakul S, Thitiwanichpiwong P, Bin-Alee F, Keelawat S, Kitkumthorn N. Selected Alu methylation levels in the gastric carcinogenesis cascade. PeerJ 2025; 13:e19485. [PMID: 40416611 PMCID: PMC12101442 DOI: 10.7717/peerj.19485] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2024] [Accepted: 04/27/2025] [Indexed: 05/27/2025] Open
Abstract
Background Genome-wide hypomethylation, a common epigenetic change that occurs during cancer development, primarily affects repetitive elements, such as Alu repeats. Consequently, Alu repeats can be used as a surrogate marker of genomic hypomethylation. Methods In this study, we aimed to investigate the correlation between Alu methylation levels and the multistage course of gastric carcinogenesis. Results We found that the Alu methylation levels in gastric cancer tissue decreased compared with those in normal gastric tissue, with the change in methylation levels and pattern being most significant between chronic gastritis and intestinal metaplasia. Moreover, Alu methylation levels were not associated with Helicobacter pylori or Epstein-Barr virus infection. Conclusions Finally, our sensitivity and specificity analyses suggested that Alu methylation level can be used to distinguish gastric cancer tissue from normal tissue. Thus, Alu methylation level shows promise as biomarker for gastric cancer diagnosis.
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Affiliation(s)
- Jiraroch Meevassana
- Center of Excellence in Burn and Wound Care, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Chawisa Wanda Vongsuly
- Center of Excellence in Burn and Wound Care, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Tanchanok Nakbua
- Center of Excellence in Burn and Wound Care, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Supitcha Kamolratanakul
- Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
| | | | - Fardeela Bin-Alee
- Faculty of Medicine, Princess of Naradhiwas University, Narathiwat, Thailand
| | - Somboon Keelawat
- Department of Pathology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Nakarin Kitkumthorn
- Department of Oral Biology, Faculty of Dentistry, Mahidol University, Bangkok, Thailand
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2
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Lee HK, Shin CM, Chang YH, Yoon H, Park YS, Kim N, Lee DH. Gastric microbiome signature for predicting metachronous recurrence after endoscopic resection of gastric neoplasm. Gastric Cancer 2024; 27:1031-1045. [PMID: 38970748 DOI: 10.1007/s10120-024-01532-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2024] [Accepted: 06/29/2024] [Indexed: 07/08/2024]
Abstract
BACKGROUND Changes in gastric microbiome are associated with gastric carcinogenesis. Studies on the association between gastric mucosa-associated gastric microbiome (MAM) and metachronous gastric cancer are limited. This study aimed to identify gastric MAM as a predictive factor for metachronous recurrence following endoscopic resection of gastric neoplasms. METHOD Microbiome analyses were conducted for 81 patients in a prospective cohort to investigate surrogate markers to predict metachronous recurrence. Gastric MAM in non-cancerous corporal biopsy specimens was evaluated using Illumina MiSeq platform targeting 16S ribosomal DNA. RESULTS Over a median follow-up duration of 53.8 months, 16 metachronous gastric neoplasms developed. Baseline gastric MAM varied with Helicobacter pylori infection status, but was unaffected by initial pathologic diagnosis, presence of atrophic gastritis, intestinal metaplasia, or synchronous lesions. The group with metachronous recurrence did not exhibit distinct phylogenetic diversity compared with the group devoid of recurrence but showed significant difference in β-diversity. The study population could be classified into two distinct gastrotypes based on baseline gastric MAM: gastrotype 1, Helicobacter-abundant; gastrotype 2: Akkermansia-abundant. Patients in gastrotype 2 showed higher risk of metachronous recurrence than gastrotype (Cox proportional hazard analysis, adjusted hazard ratio [95% confidence interval]: 5.10 [1.09-23.79]). CONCLUSIONS Gastric cancer patients can be classified into two distinct gastrotype groups by their MAM profiles, which were associated with different risk of metachronous recurrence.
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Affiliation(s)
- Ho-Kyoung Lee
- Department of Internal Medicine, Seoul National University Bundang Hospital, 82 Gumi-Ro 173 Beon-Gil, Bundang-Gu, Seongnam-Si, Gyeonggi-Do, 13620, South Korea
| | - Cheol Min Shin
- Department of Internal Medicine, Seoul National University Bundang Hospital, 82 Gumi-Ro 173 Beon-Gil, Bundang-Gu, Seongnam-Si, Gyeonggi-Do, 13620, South Korea.
| | - Young Hoon Chang
- Department of Internal Medicine, Seoul National University Bundang Hospital, 82 Gumi-Ro 173 Beon-Gil, Bundang-Gu, Seongnam-Si, Gyeonggi-Do, 13620, South Korea
| | - Hyuk Yoon
- Department of Internal Medicine, Seoul National University Bundang Hospital, 82 Gumi-Ro 173 Beon-Gil, Bundang-Gu, Seongnam-Si, Gyeonggi-Do, 13620, South Korea
| | - Young Soo Park
- Department of Internal Medicine, Seoul National University Bundang Hospital, 82 Gumi-Ro 173 Beon-Gil, Bundang-Gu, Seongnam-Si, Gyeonggi-Do, 13620, South Korea
| | - Nayoung Kim
- Department of Internal Medicine, Seoul National University Bundang Hospital, 82 Gumi-Ro 173 Beon-Gil, Bundang-Gu, Seongnam-Si, Gyeonggi-Do, 13620, South Korea
| | - Dong Ho Lee
- Department of Internal Medicine, Seoul National University Bundang Hospital, 82 Gumi-Ro 173 Beon-Gil, Bundang-Gu, Seongnam-Si, Gyeonggi-Do, 13620, South Korea
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3
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Yang HJ, Seo SI, Lee J, Huh CW, Kim JS, Park JC, Kim H, Shin H, Shin CM, Park CH, Lee SK. Sample Collection Methods in Upper Gastrointestinal Research. J Korean Med Sci 2023; 38:e255. [PMID: 37582502 PMCID: PMC10427214 DOI: 10.3346/jkms.2023.38.e255] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Accepted: 07/16/2023] [Indexed: 08/17/2023] Open
Abstract
In recent years, significant translational research advances have been made in the upper gastrointestinal (GI) research field. Endoscopic evaluation is a reasonable option for acquiring upper GI tissue for research purposes because it has minimal risk and can be applied to unresectable gastric cancer. The optimal number of biopsy samples and sample storage is crucial and might influence results. Furthermore, the methods for sample acquisition can be applied differently according to the research purpose; however, there have been few reports on methods for sample collection from endoscopic biopsies. In this review, we suggested a protocol for collecting study samples for upper GI research, including microbiome, DNA, RNA, protein, single-cell RNA sequencing, and organoid culture, through a comprehensive literature review. For microbiome analysis, one or two pieces of biopsied material obtained using standard endoscopic forceps may be sufficient. Additionally, 5 mL of gastric fluid and 3-4 mL of saliva is recommended for microbiome analyses. At least one gastric biopsy tissue is necessary for most DNA or RNA analyses, while proteomics analysis may require at least 2-3 biopsy tissues. Single cell-RNA sequencing requires at least 3-5 tissues and additional 1-2 tissues, if possible. For successful organoid culture, multiple sampling is necessary to improve the quality of specimens.
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Affiliation(s)
- Hyo-Joon Yang
- Division of Gastroenterology, Department of Internal Medicine and Gastrointestinal Cancer Center, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Seung In Seo
- Division of Gastroenterology, Department of Internal Medicine, Kangdong Sacred Heart Hospital, Hallym University College of Medicine, Seoul, Korea
| | - Jin Lee
- Department of Internal Medicine, Inje University College of Medicine, Haeundae Paik Hospital, Busan, Korea
| | - Cheal Wung Huh
- Division of Gastroenterology, Department of Internal Medicine, Yongin Severance Hospital, Yonsei University College of Medicine, Yongin, Korea
| | - Joon Sung Kim
- Division of Gastroenterology, Department of Internal Medicine, College of Medicine, Incheon St. Mary's Hospital, The Catholic University of Korea, Incheon, Korea
| | - Jun Chul Park
- Division of Gastroenterology, Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
| | - Hyunki Kim
- Department of Pathology, Yonsei University College of Medicine, Seoul, Korea
| | - Hakdong Shin
- Department of Food Science and Biotechnology, Sejong University, Seoul, Korea
| | - Cheol Min Shin
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Chan Hyuk Park
- Department of Internal Medicine, Hanyang University Guri Hospital, Hanyang University College of Medicine, Guri, Korea.
| | - Sang Kil Lee
- Division of Gastroenterology, Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea.
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4
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Moon HS. Risk factors for early gastric cancer: focus on Helicobacter pylori gastritis. JOURNAL OF THE KOREAN MEDICAL ASSOCIATION 2022. [DOI: 10.5124/jkma.2022.65.5.259] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Background: Gastric cancer is a global health problem, and the incidence and geographical distribution of different types of gastric cancer varies. Particularly, noncardiac gastric cancer is more prevalent in East Asia, Central and Eastern Europe, Latin America, and Africa. Infection with Helicobacter pylori, which was discovered in 1982, is a common cause of chronic gastritis, and the association between H. pylori infection and gastric adenocarcinoma is well established.Current Concepts: Gastric cancer is histologically divided into 2 types: intestinal and diffuse. H. pylori infection is considered as the main risk factor for the development of both types of gastric tumors. The most documented course of development of stomach cancer is following cellular metaplasia due to chronic inflammation, damage, and repair. Various molecular alterations caused by H. pylori are identified not only in gastric cancer but also in precancerous lesions. Recently, many studies have attempted to diagnose H. pylori gastritis and precancerous lesions using endoscopy.Discussion and Conclusion: Recent studies have shown that eradication therapy stabilizes or reduces the risk of developing gastric cancer. Therefore, the diagnosis and understanding of gastritis and precancerous lesions caused by H. pylori are the first step in the prevention of gastric cancer.
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5
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Kim HJ, Kim N, Kim HW, Park JH, Shin CM, Lee DH. Promising aberrant DNA methylation marker to predict gastric cancer development in individuals with family history and long-term effects of H. pylori eradication on DNA methylation. Gastric Cancer 2021; 24:302-313. [PMID: 32915372 DOI: 10.1007/s10120-020-01117-w] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2020] [Accepted: 08/23/2020] [Indexed: 02/07/2023]
Abstract
OBJECTIVE It remains unknown whether individuals with a family history (FH) of gastric cancer (GC) are associated with aberrant DNA methylation. The aim of this study was to investigate the association between aberrant DNA methylation and FH of GC. DESIGN Using quantitative MethyLight assay, MOS, miR124a-3, NKX6-1, EMX1, CDH1, and TWIST1 methylation levels in the noncancerous gastric mucosa was compared between subjects with and without FH based on GC and Helicobacter pylori (Hp) infection. Changes in the methylation levels were evaluated over time after Hp eradication. RESULTS In Hp-positive GC patients, MOS (P < 0.001), CDH1 (P < 0.001), and TWIST1 (P = 0.004) methylation were decreased in subjects with FH (n = 64) than in those without FH (n = 58). In Hp-positive controls, MOS methylation was lower in subjects with FH (n = 73) than in those without FH (n = 50) (P = 0.042), while miR124a-3 (P = 0.006), NKX6-1 (P < 0.001), and CDH1 (P < 0.001) methylation were higher in subjects with FH. CDH1 methylation constantly decreased from 2 years in GC patients and 3-4 years in controls after Hp eradication (all P < 0.001). A persistent decrease in methylation over time was not observed in other genes after eradication. CONCLUSION The methylation of MOS and CDH1 provided an association between aberrant DNA methylation and gastric carcinogenesis in FH of GC, a useful marker for GC risk in individuals with FH. Furthermore, CDH1 methylation decreased after Hp eradication.
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Affiliation(s)
- Hee Jin Kim
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, South Korea.,Department of Internal Medicine, Gyeongsang National University College of Medicine and Gyeongsang National University Changwon Hospital, Changwon, South Korea
| | - Nayoung Kim
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, South Korea. .,Department of Internal Medicine and Liver Research Institute, Seoul National University, Seoul, South Korea. .,Tumor Microenvironment Global Core Research Center, Seoul National University, Seoul, South Korea.
| | - Hyoung Woo Kim
- Department of Internal Medicine, Chungbuk National University College of Medicine and Medical Research Institute, Cheongju, South Korea
| | - Ji Hyun Park
- Department of Internal Medicine and Liver Research Institute, Seoul National University, Seoul, South Korea
| | - Cheol Min Shin
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, South Korea
| | - Dong Ho Lee
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, South Korea.,Department of Internal Medicine and Liver Research Institute, Seoul National University, Seoul, South Korea.,Tumor Microenvironment Global Core Research Center, Seoul National University, Seoul, South Korea
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6
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Zhang A, Yan S, Cao M, Wu D, Zhou J, Yu Z, Wu M, Liu Y, Lu S, Hu G, Zhao J. Abnormal methylation of PIK3AP1 was involved in regulating the immune inflammatory response of GES-1 cells induced by Helicobacter pylori. Biochem Biophys Res Commun 2020; 524:36-42. [DOI: 10.1016/j.bbrc.2020.01.007] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2019] [Accepted: 01/03/2020] [Indexed: 02/06/2023]
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7
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Yamashita S, Nanjo S, Rehnberg E, Iida N, Takeshima H, Ando T, Maekita T, Sugiyama T, Ushijima T. Distinct DNA methylation targets by aging and chronic inflammation: a pilot study using gastric mucosa infected with Helicobacter pylori. Clin Epigenetics 2019; 11:191. [PMID: 31829249 PMCID: PMC6907118 DOI: 10.1186/s13148-019-0789-8] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2019] [Accepted: 11/25/2019] [Indexed: 02/06/2023] Open
Abstract
Background Aberrant DNA methylation is induced by aging and chronic inflammation in normal tissues. The induction by inflammation is widely recognized as acceleration of age-related methylation. However, few studies addressed target genomic regions and the responsible factors in a genome-wide manner. Here, we analyzed methylation targets by aging and inflammation, taking advantage of the potent methylation induction in human gastric mucosa by Helicobacter pylori infection-triggered inflammation. Results DNA methylation microarray analysis of 482,421 CpG probes, grouped into 270,249 genomic blocks, revealed that high levels of methylation were induced in 44,461 (16.5%) genomic blocks by inflammation, even after correction of the influence of leukocyte infiltration. A total of 61.8% of the hypermethylation was acceleration of age-related methylation while 21.6% was specific to inflammation. Regions with H3K27me3 were frequently hypermethylated both by aging and inflammation. Basal methylation levels were essential for age-related hypermethylation while even regions with little basal methylation were hypermethylated by inflammation. When limited to promoter CpG islands, being a microRNA gene and high basal methylation levels strongly enhanced hypermethylation while H3K27me3 strongly enhanced inflammation-induced hypermethylation. Inflammation was capable of overriding active transcription. In young gastric mucosae, genes with high expression and frequent mutations in gastric cancers were more frequently methylated than in old ones. Conclusions Methylation by inflammation was not simple acceleration of age-related methylation. Targets of aberrant DNA methylation were different between young and old gastric mucosae, and driver genes were preferentially methylated in young gastric mucosa.
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Affiliation(s)
- Satoshi Yamashita
- Division of Epigenomics, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Sohachi Nanjo
- Division of Epigenomics, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.,Third Department of Internal Medicine, University of Toyama, Toyama, Japan
| | - Emil Rehnberg
- Division of Epigenomics, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Naoko Iida
- Division of Epigenomics, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Hideyuki Takeshima
- Division of Epigenomics, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Takayuki Ando
- Third Department of Internal Medicine, University of Toyama, Toyama, Japan
| | - Takao Maekita
- Second Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan
| | - Toshiro Sugiyama
- Third Department of Internal Medicine, University of Toyama, Toyama, Japan
| | - Toshikazu Ushijima
- Division of Epigenomics, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.
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8
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Kim N. Chemoprevention of gastric cancer by Helicobacter pylori eradication and its underlying mechanism. J Gastroenterol Hepatol 2019; 34:1287-1295. [PMID: 30828872 DOI: 10.1111/jgh.14646] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2019] [Revised: 02/23/2019] [Accepted: 03/01/2019] [Indexed: 12/11/2022]
Abstract
The cascade of gastric cancer, a leading cause of cancer incidence and mortality, is multifactorial. Helicobacter pylori (HP) infection plays a major role in gastric cancer (GC), and there has been an accumulation of data regarding the chemopreventive effect of HP eradication. However, it remains unclear how HP infection causes GC and how HP eradication prevents GC. To clarify this issue, the following approaches were performed in this review article. First, how HP-induced atrophic gastritis (AG) and intestinal metaplasia (IM) provoke the development of GC is shown, followed by how long HP eradication takes to induce a reversible change in AG and IM. Second, epigenetic studies of PTPN6, MOS, DCC, CRK, and VAV1 were performed in noncancerous gastric specimens in terms of HP status. Among these genes, MOS was found to be a possible surrogate marker for GC development. HP eradication decreased aberrant DNA methylation in a gene-specific manner, and MOS played a role in metachronous gastric neoplasms. Third, transforming growth factor-β1 (TGF-β1) and TGF-β1-induced epithelial-mesenchymal transition (EMT) markers were investigated in gastric mucosa. HP infection triggered the TGF-β1-induced EMT pathway and caused the emergence of GC stem cells, such as CD44v8-10. When HP was eradicated, these two pathways were inhibited. Finally, a 2222 cohort study showed that HP eradication significantly decreased the risk of noncardiac GC. Taken together, HP eradication is effective as a primary GC prevention method, and its underlying mechanism includes reversibility of AG and IM, methylation, EMT, and stem cells.
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Affiliation(s)
- Nayoung Kim
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, South Korea.,Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, South Korea.,Tumor Microenvironment Global Core Research Center, Seoul National University, Seoul, South Korea
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9
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Connor M, Arbibe L, Hamon M. Customizing Host Chromatin: a Bacterial Tale. Microbiol Spectr 2019; 7:10.1128/microbiolspec.bai-0015-2019. [PMID: 30953433 PMCID: PMC11590419 DOI: 10.1128/microbiolspec.bai-0015-2019] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2018] [Indexed: 12/14/2022] Open
Abstract
Successful bacterial colonizers and pathogens have evolved with their hosts and have acquired mechanisms to customize essential processes that benefit their lifestyle. In large part, bacterial survival hinges on shaping the transcriptional signature of the host, a process regulated at the chromatin level. Modifications of chromatin, either on histone proteins or on DNA itself, are common targets during bacterium-host cross talk and are the focus of this article.
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Affiliation(s)
- Michael Connor
- Institut Pasteur, G5 Chromatine et Infection, Paris, France
| | - Laurence Arbibe
- INSERM U1151, CNRS UMR 8253, Institut Necker Enfants Malades, INEM Institute Department of Immunology, Infectiology and Hematology, Paris, France
| | - Mélanie Hamon
- Institut Pasteur, G5 Chromatine et Infection, Paris, France
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10
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Woo HD, Fernandez-Jimenez N, Ghantous A, Degli Esposti D, Cuenin C, Cahais V, Choi IJ, Kim YI, Kim J, Herceg Z. Genome-wide profiling of normal gastric mucosa identifies Helicobacter pylori- and cancer-associated DNA methylome changes. Int J Cancer 2018; 143:597-609. [PMID: 29574700 DOI: 10.1002/ijc.31381] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2017] [Revised: 02/12/2018] [Accepted: 03/02/2018] [Indexed: 12/11/2022]
Abstract
The large geographic variations in the incidence of gastric cancer (GC) are likely due to differential environmental exposures, in particular to Helicobacter pylori (H. pylori) infection. We aimed to investigate the impact of H. pylori on the epigenome in normal gastric mucosa and methylation changes associated with cancer risk independent of H. pylori. A discovery set of normal gastric mucosa from GC cases (n = 42) and controls (n = 42), nested in a large case-control study and stratified by H. pylori status, were subjected to genome-wide methylation profiling. Single-nucleotide polymorphism arrays from peripheral blood leukocytes were used to conduct methylation quantitative trait loci (mQTL) analysis. A validation set of gastric mucosa samples (n = 180) was used in the replication phase. We found 1,924 differentially methylated positions (DMPs) and 438 differentially methylated regions (DMRs) associated with H. pylori infection, most of which were hypermethylated. Significant methylation alterations identified in the initial set were successfully replicated. Furthermore, the H. pylori-associated DMP/Rs showed marked stability ('epigenetic memory') after H. pylori clearance. Interestingly, we found 152 DMRs associated with cancer risk independent of the H. pylori status in normal gastric mucosa. The methylation score derived from three biomarkers was a strong predictor of GC. Finally, the mQTL analysis indicated that the H. pylori- and cancer-specific methylation signatures were minimally affected by genetic variation. The comprehensively characterized methylome changes associated with H. pylori infection and GC risk in our study might serve as potential biomarkers for early cancer progression in tumour-free gastric mucosa.
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Affiliation(s)
- Hae Dong Woo
- Epigenetics Group, International Agency for Research on Cancer (IARC), 150 Cours Albert Thomas, Lyon, 69372, France
- Department of Cancer Biomedical Science, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang, 10408, Republic of Korea
| | - Nora Fernandez-Jimenez
- Epigenetics Group, International Agency for Research on Cancer (IARC), 150 Cours Albert Thomas, Lyon, 69372, France
| | - Akram Ghantous
- Epigenetics Group, International Agency for Research on Cancer (IARC), 150 Cours Albert Thomas, Lyon, 69372, France
| | - Davide Degli Esposti
- Epigenetics Group, International Agency for Research on Cancer (IARC), 150 Cours Albert Thomas, Lyon, 69372, France
| | - Cyrille Cuenin
- Epigenetics Group, International Agency for Research on Cancer (IARC), 150 Cours Albert Thomas, Lyon, 69372, France
| | - Vincent Cahais
- Epigenetics Group, International Agency for Research on Cancer (IARC), 150 Cours Albert Thomas, Lyon, 69372, France
| | - Il Ju Choi
- Center for Gastric Cancer, National Cancer Center Hospital, National Cancer Center, Goyang, 10408, Republic of Korea
| | - Young-Il Kim
- Center for Gastric Cancer, National Cancer Center Hospital, National Cancer Center, Goyang, 10408, Republic of Korea
| | - Jeongseon Kim
- Department of Cancer Biomedical Science, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang, 10408, Republic of Korea
| | - Zdenko Herceg
- Epigenetics Group, International Agency for Research on Cancer (IARC), 150 Cours Albert Thomas, Lyon, 69372, France
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11
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Pirini F, Noazin S, Jahuira-Arias MH, Rodriguez-Torres S, Friess L, Michailidi C, Cok J, Combe J, Vargas G, Prado W, Soudry E, Pérez J, Yudin T, Mancinelli A, Unger H, Ili-Gangas C, Brebi-Mieville P, Berg DE, Hayashi M, Sidransky D, Gilman RH, Guerrero-Preston R. Early detection of gastric cancer using global, genome-wide and IRF4, ELMO1, CLIP4 and MSC DNA methylation in endoscopic biopsies. Oncotarget 2018; 8:38501-38516. [PMID: 28418867 PMCID: PMC5503549 DOI: 10.18632/oncotarget.16258] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2017] [Accepted: 02/24/2017] [Indexed: 12/15/2022] Open
Abstract
Clinically useful molecular tools to triage gastric cancer patients are not currently available. We aimed to develop a molecular tool to predict gastric cancer risk in endoscopy-driven biopsies obtained from high-risk gastric cancer clinics in low resource settings. We discovered and validated a DNA methylation biomarker panel in endoscopic samples obtained from 362 patients seen between 2004 and 2009 in three high-risk gastric cancer clinics in Lima, Perú, and validated it in 306 samples from the Cancer Genome Atlas project (“TCGA”). Global, epigenome wide and gene-specific DNA methylation analyses were used in a Phase I Biomarker Development Trial to identify a continuous biomarker panel that combines a Global DNA Methylation Index (GDMI) and promoter DNA methylation levels of IRF4, ELMO1, CLIP4 and MSC. We observed an inverse association between the GDMI and histological progression to gastric cancer, when comparing gastritis patients without metaplasia (mean = 5.74, 95% CI, 4.97−6.50), gastritis patients with metaplasia (mean = 4.81, 95% CI, 3.77−5.84), and gastric cancer cases (mean = 3.38, 95% CI, 2.82−3.94), respectively (p < 0.0001). Promoter methylation of IRF4 (p < 0.0001), ELMO1 (p < 0.0001), CLIP4 (p < 0.0001), and MSC (p < 0.0001), is also associated with increasing severity from gastritis with no metaplasia to gastritis with metaplasia and gastric cancer. Our findings suggest that IRF4, ELMO1, CLIP4 and MSC promoter methylation coupled with a GDMI>4 are useful molecular tools for gastric cancer risk stratification in endoscopic biopsies.
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Affiliation(s)
- Francesca Pirini
- Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
| | - Sassan Noazin
- The Johns Hopkins University, Bloomberg School of Public Health, Department of International Health, Baltimore, MD, USA
| | - Martha H Jahuira-Arias
- The Johns Hopkins University, School of Medicine, Otolaryngology Department, Head and Neck Cancer Research Division, Baltimore, MD, USA.,Universidad Peruana Cayetano Heredia, Lima, Perú
| | - Sebastian Rodriguez-Torres
- The Johns Hopkins University, School of Medicine, Otolaryngology Department, Head and Neck Cancer Research Division, Baltimore, MD, USA
| | - Leah Friess
- The Johns Hopkins University, School of Medicine, Otolaryngology Department, Head and Neck Cancer Research Division, Baltimore, MD, USA
| | - Christina Michailidi
- The Johns Hopkins University, School of Medicine, Otolaryngology Department, Head and Neck Cancer Research Division, Baltimore, MD, USA
| | - Jaime Cok
- Hospital Nacional Cayetano Heredia, Pathology Department, Lima, Perú
| | - Juan Combe
- Instituto Nacional de Enfermedades Neoplásicas, Gastroenterology Department, Lima, Perú
| | - Gloria Vargas
- Hospital Nacional Arzobispo Loayza, Gastroenterology Department, Lima, Perú
| | - William Prado
- Hospital Nacional Dos de Mayo, Gastroenterology Department, Lima, Perú
| | - Ethan Soudry
- The Johns Hopkins University, School of Medicine, Otolaryngology Department, Head and Neck Cancer Research Division, Baltimore, MD, USA
| | - Jimena Pérez
- The Johns Hopkins University, School of Medicine, Otolaryngology Department, Head and Neck Cancer Research Division, Baltimore, MD, USA
| | - Tikki Yudin
- The Johns Hopkins University, School of Medicine, Otolaryngology Department, Head and Neck Cancer Research Division, Baltimore, MD, USA
| | - Andrea Mancinelli
- The Johns Hopkins University, School of Medicine, Otolaryngology Department, Head and Neck Cancer Research Division, Baltimore, MD, USA
| | - Helen Unger
- The Johns Hopkins University, School of Medicine, Otolaryngology Department, Head and Neck Cancer Research Division, Baltimore, MD, USA
| | - Carmen Ili-Gangas
- Laboratory of Molecular Pathology, Department of Pathological Anatomy, School of Medicine, Universidad de La Frontera, Temuco, Chile.,Center of Excellence in Translational Medicine - Scientific and Technological Bioresource Nucleus (CEMT-BIOREN), Universidad de La Frontera, Temuco, Chile
| | - Priscilla Brebi-Mieville
- Laboratory of Molecular Pathology, Department of Pathological Anatomy, School of Medicine, Universidad de La Frontera, Temuco, Chile.,Center of Excellence in Translational Medicine - Scientific and Technological Bioresource Nucleus (CEMT-BIOREN), Universidad de La Frontera, Temuco, Chile
| | - Douglas E Berg
- Washington University Medical School, Department of Molecular Microbiology, St Louis, MO, USA.,University of California San Diego, Department of Medicine, La Jolla, CA, USA
| | - Masamichi Hayashi
- The Johns Hopkins University, School of Medicine, Otolaryngology Department, Head and Neck Cancer Research Division, Baltimore, MD, USA.,Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - David Sidransky
- The Johns Hopkins University, School of Medicine, Otolaryngology Department, Head and Neck Cancer Research Division, Baltimore, MD, USA
| | - Robert H Gilman
- The Johns Hopkins University, Bloomberg School of Public Health, Department of International Health, Baltimore, MD, USA.,Universidad Peruana Cayetano Heredia, Lima, Perú
| | - Rafael Guerrero-Preston
- The Johns Hopkins University, School of Medicine, Otolaryngology Department, Head and Neck Cancer Research Division, Baltimore, MD, USA.,University of Puerto Rico School of Medicine, Department of Obstetrics and Gynecology, San Juan, Puerto Rico
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12
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Rhyu MG, Oh JH, Hong SJ. Species-specific role of gene-adjacent retroelements in human and mouse gastric carcinogenesis. Int J Cancer 2017; 142:1520-1527. [PMID: 29055047 DOI: 10.1002/ijc.31120] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2017] [Revised: 09/22/2017] [Accepted: 10/09/2017] [Indexed: 12/15/2022]
Abstract
Helicobacter pylori (HP) infection promotes the recruitment of bone marrow stem cells into chronic gastritis lesions. Some of these marrow stem cells can differentiate into gastric epithelial cells and neoplastic cells. We propose that HP-associated methylation could stabilize trans-differentiation of marrow-derived stem cells and that an unstable methylation status is associated with a risk of gastric cancer. Pathobiologic behavior of experimental mouse gastric cancer is mild compared to invasive and metastatic human gastric cancer. Differences in epigenetic stabilization of adult cell phenotypes between humans and mice could provide a foundation to explore the development of invasive and metastatic gastric cancer. Retroelements are highly repetitive sequences that play an essential role in the generation of species diversity. In this review, we analyzed retroelements adjacent to human and mouse housekeeping genes and proposed a possible epigenetic mechanism for HP-associated carcinogenesis.
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Affiliation(s)
- Mun-Gan Rhyu
- Department of Microbiology, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Jung-Hwan Oh
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Seung-Jin Hong
- Department of Microbiology, College of Medicine, The Catholic University of Korea, Seoul, Korea
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13
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Yoon H, Kim N, Shin CM, Lee HS, Kim BK, Kang GH, Kim JM, Kim JS, Lee DH, Jung HC. Risk Factors for Metachronous Gastric Neoplasms in Patients Who Underwent Endoscopic Resection of a Gastric Neoplasm. Gut Liver 2016; 10:228-36. [PMID: 26087797 PMCID: PMC4780452 DOI: 10.5009/gnl14472] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Background/Aims To identify the risk factors for metachronous gastric neoplasms in patients who underwent an endoscopic resection of a gastric neoplasm. Methods We prospectively collected clinicopathologic data and measured the methylation levels of HAND1, THBD, APC, and MOS in the gastric mucosa by methylation-specific real-time polymerase chain reaction in patients who underwent endoscopic resection of gastric neoplasms. Results A total of 257 patients with gastric neoplasms (113 low-grade dysplasias, 25 high-grade dysplasias, and 119 early gastric cancers) were enrolled. Metachronous gastric neoplasm developed in 7.4% of patients during a mean follow-up of 52 months. The 5-year cumulative incidence of metachronous gastric neoplasm was 4.8%. Multivariate analysis showed that moderate/severe corpus intestinal metaplasia and family history of gastric cancer were independent risk factors for metachronous gastric neoplasm development; the hazard ratios were 4.12 (95% confidence interval [CI], 1.23 to 13.87; p=0.022) and 3.52 (95% CI, 1.09 to 11.40; p=0.036), respectively. The methylation level of MOS was significantly elevated in patients with metachronous gastric neoplasms compared age- and sex-matched patients without metachronous gastric neoplasms (p=0.020). Conclusions In patients who underwent endoscopic resection of gastric neoplasms, moderate/severe corpus intestinal metaplasia and a family history of gastric cancer were independent risk factors for metachronous gastric neoplasm, and MOS was significantly hypermethylated in patients with metachronous gastric neoplasms.
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Affiliation(s)
- Hyuk Yoon
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Nayoung Kim
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea.,Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Cheol Min Shin
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Hye Seung Lee
- Department of Pathology, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Bo Kyoung Kim
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Gyeong Hoon Kang
- Department of Pathology, Laboratory of Epigenetics, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Jung Mogg Kim
- Department of Microbiology, Hanyang University College of Medicine, Seoul, Korea
| | - Joo Sung Kim
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Dong Ho Lee
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea.,Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Hyun Chae Jung
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
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14
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Tie J, Zhang X, Fan D. Epigenetic roles in the malignant transformation of gastric mucosal cells. Cell Mol Life Sci 2016; 73:4599-4610. [PMID: 27464701 PMCID: PMC5097112 DOI: 10.1007/s00018-016-2308-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2016] [Revised: 06/10/2016] [Accepted: 07/08/2016] [Indexed: 12/14/2022]
Abstract
Gastric carcinogenesis occurs when gastric epithelial cells transition through the initial, immortal, premalignant, and malignant stages of transformation. Epigenetic regulations contribute to this multistep process. Due to the critical role of epigenetic modifications , these changes are highly likely to be of clinical use in the future as new biomarkers and therapeutic targets for the early detection and treatment of cancers. Here, we summarize the recent findings on how epigenetic modifications, including DNA methylation, histone modifications, and non-coding RNAs, regulate gastric carcinogenesis, and we discuss potential new strategies for the diagnosis and treatments of gastric cancer. The strategies may be helpful in the further understanding of epigenetic regulation in human diseases.
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Affiliation(s)
- Jun Tie
- State Key Laboratory of Cancer Biology and Xijing Hospital of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, No. 127, West Chang-Le Road, Xi'an, Shaanxi, 710032, People's Republic of China
| | - Xiangyuan Zhang
- State Key Laboratory of Cancer Biology and Xijing Hospital of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, No. 127, West Chang-Le Road, Xi'an, Shaanxi, 710032, People's Republic of China
| | - Daiming Fan
- State Key Laboratory of Cancer Biology and Xijing Hospital of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, No. 127, West Chang-Le Road, Xi'an, Shaanxi, 710032, People's Republic of China.
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15
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Eftang LL, Klajic J, Kristensen VN, Tost J, Esbensen QY, Blom GP, Bukholm IRK, Bukholm G. GFRA3 promoter methylation may be associated with decreased postoperative survival in gastric cancer. BMC Cancer 2016; 16:225. [PMID: 26984265 PMCID: PMC4794813 DOI: 10.1186/s12885-016-2247-8] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2015] [Accepted: 03/02/2016] [Indexed: 12/31/2022] Open
Abstract
Background A large number of epigenetic alterations has been found to be implicated in the etiology of gastric cancer. We have studied the DNA methylation status of 27 500 gene promoter regions in 24 gastric adenocarcinomas from a Norwegian cohort, and aimed at identifying the hypermethylated regions. We have compared our findings to the gene expression in the same tissue, and linked our results to prognosis and survival. Methods Biopsies from gastric adenocarcinomas and adjacent normal gastric mucosa were obtained from 24 patients following surgical resection of the tumor. Genome-wide DNA methylation profiling of the tumor and matched non-cancerous mucosa was performed. The results were compared to whole transcriptome cDNA microarray analysis of the same material. Results Most of the gene promoter regions in both types of tissue showed a low degree of methylation, however there was a small, but significant hypermethylation of the tumors. Hierarchical clustering showed separate grouping of the tumor and normal tissue. Hypermethylation of the promoter region of the GFRA3 gene showed a strong correlation to post-operative survival and several of the clinicopathological parameters, however no difference was found between the two main histological types of gastric cancer. There was only a modest correlation between the DNA methylation status and gene expression. Conclusions The different DNA methylation clusters of the tumors and normal tissue indicate that aberrant DNA methylation is a distinct feature of gastric cancer, although there is little difference in the overall, and low, methylation levels between the two tissue types. The GFRA3 promoter region showed marked hypermethylation in almost all tumors, and its correlation with survival and other clinicopathological parameters may have important prognostic significance. Electronic supplementary material The online version of this article (doi:10.1186/s12885-016-2247-8) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Lars Lohne Eftang
- Department of Clinical Molecular Biology and Laboratory Science (EpiGen), Akershus University Hospital, Division of Medicine, Lørenskog, Norway. .,Department of Gastrointestinal Surgery, Akershus University Hospital, N-1478, Nordbyhagen, Lørenskog, Norway.
| | - Jovana Klajic
- Department of Clinical Molecular Biology and Laboratory Science (EpiGen), Akershus University Hospital, Division of Medicine, Lørenskog, Norway.,K.G. Jebsen Center for Breast Cancer Research, Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.,Department of Genetics, Institute for Cancer Research, OUS Radiumhospitalet Montebello, Oslo, Norway
| | - Vessela N Kristensen
- Department of Clinical Molecular Biology and Laboratory Science (EpiGen), Akershus University Hospital, Division of Medicine, Lørenskog, Norway.,Department of Genetics, Institute for Cancer Research, OUS Radiumhospitalet Montebello, Oslo, Norway
| | - Jörg Tost
- Laboratory for Epigenetics and Environment, Centre National de Génotypage, CEA - Institut de Génomique, Evry, France
| | - Qin Ying Esbensen
- Department of Clinical Molecular Biology and Laboratory Science (EpiGen), Akershus University Hospital, Division of Medicine, Lørenskog, Norway
| | - Gustav Peter Blom
- Department of Pathology, Akershus University Hospital, Lørenskog, Norway
| | - Ida Rashida Khan Bukholm
- Institute of Clinical Medicine, Akershus University Hospital and University of Oslo, Lørenskog, Norway
| | - Geir Bukholm
- Infection Control and Environmental Health, Norwegian Institute of Public Health, Oslo, Norway.,Department of Chemistry, Biotechnology and Food Science, Norwegian University of Life Sciences, Ås, Norway
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16
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Verma M. The Role of Epigenomics in the Study of Cancer Biomarkers and in the Development of Diagnostic Tools. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2016; 867:59-80. [PMID: 26530360 DOI: 10.1007/978-94-017-7215-0_5] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Epigenetics plays a key role in cancer development. Genetics alone cannot explain sporadic cancer and cancer development in individuals with no family history or a weak family history of cancer. Epigenetics provides a mechanism to explain the development of cancer in such situations. Alterations in epigenetic profiling may provide important insights into the etiology and natural history of cancer. Because several epigenetic changes occur before histopathological changes, they can serve as biomarkers for cancer diagnosis and risk assessment. Many cancers may remain asymptomatic until relatively late stages; in managing the disease, efforts should be focused on early detection, accurate prediction of disease progression, and frequent monitoring. This chapter describes epigenetic biomarkers as they are expressed during cancer development and their potential use in cancer diagnosis and prognosis. Based on epigenomic information, biomarkers have been identified that may serve as diagnostic tools; some such biomarkers also may be useful in identifying individuals who will respond to therapy and survive longer. The importance of analytical and clinical validation of biomarkers is discussed, along with challenges and opportunities in this field.
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Affiliation(s)
- Mukesh Verma
- Epidemiology and Genomics Research Program, Division of Cancer Control and Population Sciences, National Cancer Institute (NCI), National Institutes of Health (NIH), Suite# 4E102. 9609 Medical Center Drive, MSC 9763, Bethesda, MD, 20892-9726, USA.
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17
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Hudler P. Challenges of deciphering gastric cancer heterogeneity. World J Gastroenterol 2015; 21:10510-10527. [PMID: 26457012 PMCID: PMC4588074 DOI: 10.3748/wjg.v21.i37.10510] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2015] [Revised: 06/19/2015] [Accepted: 08/31/2015] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer is in decline in most developed countries; however, it still accounts for a notable fraction of global mortality and morbidity related to cancer. High-throughput methods are rapidly changing our view and understanding of the molecular basis of gastric carcinogenesis. Today, it is widely accepted that the molecular complexity and heterogeneity, both inter- and intra-tumour, of gastric adenocarcinomas present significant obstacles in elucidating specific biomarkers for early detection of the disease. Although genome-wide sequencing and gene expression studies have revealed the intricate nature of the molecular changes that occur in tumour landscapes, the collected data and results are complex and sometimes contradictory. Several aberrant molecules have already been tested in clinical trials, although their diagnostic and prognostic utilities have not been confirmed thus far. The gold standard for the detection of sporadic gastric cancer is still the gastric endoscopy, which is considered invasive. In addition, genome-wide association studies have confirmed that genetic variations are important contributors to increased cancer risk and could participate in the initiation of malignant transformation. This hypothesis could in part explain the late onset of sporadic gastric cancers. The elaborate interplay of polymorphic low penetrance genes and lifestyle and environmental risk factors requires additional research to decipher their relative impacts on tumorigenesis. The purpose of this article is to present details of the molecular heterogeneity of sporadic gastric cancers at the DNA, RNA, and proteome levels and to discuss issues relevant to the translation of basic research data to clinically valuable tools. The focus of this work is the identification of relevant molecular changes that could be detected non-invasively.
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18
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Sugano K, Tack J, Kuipers EJ, Graham DY, El-Omar EM, Miura S, Haruma K, Asaka M, Uemura N, Malfertheiner P. Kyoto global consensus report on Helicobacter pylori gastritis. Gut 2015; 64:1353-1367. [PMID: 26187502 PMCID: PMC4552923 DOI: 10.1136/gutjnl-2015-309252] [Citation(s) in RCA: 1161] [Impact Index Per Article: 116.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2015] [Revised: 06/25/2015] [Accepted: 06/26/2015] [Indexed: 12/12/2022]
Abstract
OBJECTIVE To present results of the Kyoto Global Consensus Meeting, which was convened to develop global consensus on (1) classification of chronic gastritis and duodenitis, (2) clinical distinction of dyspepsia caused by Helicobacter pylori from functional dyspepsia, (3) appropriate diagnostic assessment of gastritis and (4) when, whom and how to treat H. pylori gastritis. DESIGN Twenty-three clinical questions addressing the above-mentioned four domains were drafted for which expert panels were asked to formulate relevant statements. A Delphi method using an anonymous electronic system was adopted to develop the consensus, the level of which was predefined as ≥80%. Final modifications of clinical questions and consensus were achieved at the face-to-face meeting in Kyoto. RESULTS All 24 statements for 22 clinical questions after extensive modifications and omission of one clinical question were achieved with a consensus level of >80%. To better organise classification of gastritis and duodenitis based on aetiology, a new classification of gastritis and duodenitis is recommended for the 11th international classification. A new category of H. pylori-associated dyspepsia together with a diagnostic algorithm was proposed. The adoption of grading systems for gastric cancer risk stratification, and modern image-enhancing endoscopy for the diagnosis of gastritis, were recommended. Treatment to eradicate H. pylori infection before preneoplastic changes develop, if feasible, was recommended to minimise the risk of more serious complications of the infection. CONCLUSIONS A global consensus for gastritis was developed for the first time, which will be the basis for an international classification system and for further research on the subject.
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Affiliation(s)
- Kentaro Sugano
- Department of Medicine, Jichi Medical University, Tochigi, Japan
| | - Jan Tack
- Translational Research Center for Gastrointestinal Disorders, University of Leuven, Leuven, Belgium
| | - Ernst J Kuipers
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, Netherland
| | - David Y Graham
- Department of Medicine, Michael E DeBakery VA Medical Center, Baylor College of Medicine, Houston, USA
| | - Emad M El-Omar
- Division of Applied Medicine, Institute of Medical Sciences, Aberdeen University, Aberdeen, UK
| | | | - Ken Haruma
- Department of Gastroenterology, Kawasaki Medical School, Kurashiki, Japan
| | - Masahiro Asaka
- Department of Cancer Preventive Medicine, Hokkaido University, Sapporo, Japan
| | - Naomi Uemura
- Kohnodai Hospital, National Center for Global Health and Medicine, Ichikawa, Japan
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19
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Peczek L, Zuk K, Stec-Michalska K, Medrek M, Nawrot B. The influence of Helicobacter pylori eradication on the expression and methylation status of the FHIT gene in non-cancerous gastric mucosa of dyspeptic patients. J Dig Dis 2015; 16:385-94. [PMID: 25943773 DOI: 10.1111/1751-2980.12252] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVE To investigate the effect of Helicobacter pylori (H. pylori) eradication on the expression level of the FHIT gene and its methylation status in the gastric mucosa of dyspeptic patients with or without a family history of gastric cancer (FHGC). METHODS In all, 31 patients with H. pylori infection including 13 with FHGC were enrolled in the study. The effectiveness of H. pylori eradication were confirmed by UBT, RUT and multiplex PCR (the presence of selected H. pylori strains) for biopsy samples from the antrum and corpus. Histopathological assessment was also performed. The expression of FHIT mRNA was determined by quantitative reverse transcription-polymerase chain reaction and the methylation status of the FHIT promoter was assessed by methylation-specific polymerase chain reaction. RESULTS After H. pylori eradication, the improvement of inflammation from superficial gastritis to normal mucosa (G → N) was observed in 39% of the patients without FHGC and in 54% of those with FHGC. FHIT mRNA expression was increased in patients without FHGC after H. pylori eradication (P < 0.05), while there was no statistically significant change in gene methylation status after H. pylori eradication (P > 0.05). For the samples from those with FHGC, the FHIT mRNA expression was not significantly changed and the methylation status fluctuated evenly. CONCLUSIONS H. pylori eradication results in the improvement of gastric mucosal inflammation and histopathological non-atrophic changes. The FHIT gene expression is increased in patients without FHGC, which may contribute to the prevention of GC development.
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Affiliation(s)
- Lukasz Peczek
- Department of Bioorganic Chemistry, Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences, Lodz, Poland
| | - Karolina Zuk
- Department of Bioorganic Chemistry, Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences, Lodz, Poland
| | | | - Marta Medrek
- Department of Gastroenterology, Medical University of Lodz, Lodz, Poland
| | - Barbara Nawrot
- Department of Bioorganic Chemistry, Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences, Lodz, Poland
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20
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Abstract
Epigenetic changes frequently occur in human gastric cancer. Gene promoter region hypermethylation, genomic global hypomethylation, histone modifications, and alterations of noncoding RNAs are major epigenetic changes in gastric cancer. As a key risk factor of gastric cancer, H. pylori infection is an independent predictive indicator of gene methylation. A growing number of epigenetic studies in gastric cancer have provided lots of potential diagnostic and prognostic markers and therapeutic targets.
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Affiliation(s)
- Mingzhou Guo
- Department of Gastroenterology and Hepatology, Chinese PLA General Hospital, #28 Fuxing Road, Beijing, 100853, China,
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21
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Wang Y, Huang LH, Xu CX, Xiao J, Zhou L, Cao D, Liu XM, Qi Y. Connexin 32 and 43 promoter methylation in Helicobacter pylori-associated gastric tumorigenesis. World J Gastroenterol 2014; 20:11770-9. [PMID: 25206281 PMCID: PMC4155367 DOI: 10.3748/wjg.v20.i33.11770] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2013] [Revised: 03/11/2014] [Accepted: 03/19/2014] [Indexed: 02/06/2023] Open
Abstract
AIM To explore the mechanism of abnormal Connexin (Cx) 32 and Cx43 expression in the gastric mucosa after Helicobacter pylori (H. pylori) infection. METHODS Biopsy specimens of gastric mucosa in different gastric carcinogenesis stages with H. pylori infection, that is, non-atrophic gastritis (NAG; n = 24), chronic atrophic gastritis (CAG; n = 25), intestinal metaplasia (IM; n = 28), dysplasia (DYS; n = 24), and gastric cancer (GC; n = 30), as well as specimens of normal gastric mucosa without H. pylori infection (NGM; n = 25), were confirmed by endoscopy and pathological examination. Cx32 and Cx43 mRNA expression was detected by real-time polymerase chain reaction (PCR). Cx32 and Cx43 promoter CpG island methylation status was determined by methylation-specific PCR (MSP), bisulfite PCR sequencing (BSP) and MassArray methods. RESULTS The relative mRNA expression levels in the gastric mucosa of patients with NGM, NAG, CAG, IM, DYS and GC were 0.146 ± 0.011, 0.133 ± 0.026, 0.107 ± 0.035, 0.039 ± 0.032, 0.037 ± 0.01 and 0.03 ± 0.011 for Cx32; and 0.667 ± 0.057, 0.644 ± 0.051, 0.624 ± 0.049, 0.555 ± 0.067, 0.536 ± 0.058 and 0.245 ± 0.121 for Cx43, respectively, which were gradually decreasing and significantly different (GC vs NGM: P < 0.001 for Cx32, P < 0.001 for Cx43). The promoter methylation levels in the gastric mucosa from NGM to GC stages by MSP were 38.8% ± 9.0%, 43.1% ± 9.4%, 56.5% ± 3.1%, 64.4% ± 9.7%, 72.5% ± 4.2% and 79.6% ± 6.8% for Cx32; and 49.0% ± 3.9%, 58.1% ± 5.0%, 66.5% ± 7.9%, 74.0% ± 8.8%, 78.3% ± 3.6% and 88.7% ± 6.2% for Cx43, respectively, which were gradually increasing and significantly different (P = 0.039, P = 0.019). The promoter methylation levels by BSP and MassArray exhibited similar trends. Cx32 and Cx43 mRNA expression was negatively correlated with promoter methylation status and gastric carcinogenesis stages (P < 0.001, P = 0.016). CONCLUSION Cx32 and Cx43 mRNA expression decreased gradually during H. pylori infection-associated gastric carcinogenesis, and it is associated with hypermethylation of these genes' promoter.
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22
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Nanoscale chromatin profiling of gastric adenocarcinoma reveals cancer-associated cryptic promoters and somatically acquired regulatory elements. Nat Commun 2014; 5:4361. [DOI: 10.1038/ncomms5361] [Citation(s) in RCA: 61] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2013] [Accepted: 06/10/2014] [Indexed: 02/07/2023] Open
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23
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Kang C, Song JJ, Lee J, Kim MY. Epigenetics: An emerging player in gastric cancer. World J Gastroenterol 2014; 20:6433-6447. [PMID: 24914365 PMCID: PMC4047329 DOI: 10.3748/wjg.v20.i21.6433] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2013] [Revised: 01/21/2014] [Accepted: 02/20/2014] [Indexed: 02/06/2023] Open
Abstract
Cancers, like other diseases, arise from gene mutations and/or altered gene expression, which eventually cause dysregulation of numerous proteins and noncoding RNAs. Changes in gene expression, i.e., upregulation of oncogenes and/or downregulation of tumor suppressor genes, can be generated not only by genetic and environmental factors but also by epigenetic factors, which are inheritable but nongenetic modifications of cellular chromosome components. Identification of the factors that contribute to individual cancers is a prerequisite to a full understanding of cancer mechanisms and the development of customized cancer therapies. The search for genetic and environmental factors has a long history in cancer research, but epigenetic factors only recently began to be associated with cancer formation, progression, and metastasis. Epigenetic alterations of chromatin include DNA methylation and histone modifications, which can affect gene-expression profiles. Recent studies have revealed diverse mechanisms by which chromatin modifiers, including writers, erasers and readers of the aforementioned modifications, contribute to the formation and progression of cancer. Furthermore, functional RNAs, such as microRNAs and long noncoding RNAs, have also been identified as key players in these processes. This review highlights recent findings concerning the epigenetic alterations associated with cancers, especially gastric cancer.
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24
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Loh M, Liem N, Vaithilingam A, Lim PL, Sapari NS, Elahi E, Mok ZY, Cheng CL, Yan B, Pang B, Salto-Tellez M, Yong WP, Iacopetta B, Soong R. DNA methylation subgroups and the CpG island methylator phenotype in gastric cancer: a comprehensive profiling approach. BMC Gastroenterol 2014; 14:55. [PMID: 24674026 PMCID: PMC3986689 DOI: 10.1186/1471-230x-14-55] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2013] [Accepted: 03/25/2014] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Methylation-induced silencing of promoter CpG islands in tumor suppressor genes plays an important role in human carcinogenesis. In colorectal cancer, the CpG island methylator phenotype (CIMP) is defined as widespread and elevated levels of DNA methylation and CIMP+ tumors have distinctive clinicopathological and molecular features. In contrast, the existence of a comparable CIMP subtype in gastric cancer (GC) has not been clearly established. To further investigate this issue, in the present study we performed comprehensive DNA methylation profiling of a well-characterised series of primary GC. METHODS The methylation status of 1,421 autosomal CpG sites located within 768 cancer-related genes was investigated using the Illumina GoldenGate Methylation Panel I assay on DNA extracted from 60 gastric tumors and matched tumor-adjacent gastric tissue pairs. Methylation data was analysed using a recursively partitioned mixture model and investigated for associations with clinicopathological and molecular features including age, Helicobacter pylori status, tumor site, patient survival, microsatellite instability and BRAF and KRAS mutations. RESULTS A total of 147 genes were differentially methylated between tumor and matched tumor-adjacent gastric tissue, with HOXA5 and hedgehog signalling being the top-ranked gene and signalling pathway, respectively. Unsupervised clustering of methylation data revealed the existence of 6 subgroups under two main clusters, referred to as L (low methylation; 28% of cases) and H (high methylation; 72%). Female patients were over-represented in the H tumor group compared to L group (36% vs 6%; P = 0.024), however no other significant differences in clinicopathological or molecular features were apparent. CpG sites that were hypermethylated in group H were more frequently located in CpG islands and marked for polycomb occupancy. CONCLUSIONS High-throughput methylation analysis implicates genes involved in embryonic development and hedgehog signaling in gastric tumorigenesis. GC is comprised of two major methylation subtypes, with the highly methylated group showing some features consistent with a CpG island methylator phenotype.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | | | | | - Richie Soong
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
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Shiotani A, Cen P, Graham DY. Eradication of gastric cancer is now both possible and practical. Semin Cancer Biol 2013; 23:492-501. [PMID: 23876852 DOI: 10.1016/j.semcancer.2013.07.004] [Citation(s) in RCA: 65] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2013] [Accepted: 07/12/2013] [Indexed: 01/06/2023]
Abstract
In 1994, Helicobacter pylori was declared a human carcinogen. Evidence has now accumulated to show that at least 95% of gastric cancers are etiologically related to H. pylori. An extensive literature regarding atrophic gastritis and its effects on acid secretion, gastric microflora, and its tight association with gastric cancer has been rediscovered, confirmed, and expanded. Methods to stratify cancer risk based on endoscopic and histologic findings or serologic testing of pepsinogen levels and H. pylori testing have been developed producing practical primary and secondary gastric cancer prevention strategies. H. pylori eradication halts progressive mucosal damage. Cure of the infection in those with non-atrophic gastritis will essentially prevent subsequent development of gastric cancer. For all, the age-related progression in cancer risk is halted and likely reduced as eradication reduces or eliminates mucosal inflammation and reverses or reduces H. pylori-associated molecular events such aberrant activation-induced cytidine deaminase expression, double strand DNA breaks, impaired DNA mismatch repair and aberrant DNA methylation. Those who have developed atrophic gastritis/gastric atrophy however retain some residual risk for gastric cancer which is proportional to the extent and severity of atrophic gastritis. Primary and secondary cancer prevention starts with H. pylori eradication and cancer risk stratification to identify those at higher risk who should also be considered for secondary cancer prevention programs. Japan has embarked on population-wide H. pylori eradication coupled with surveillance targeted to those with significant remaining risk. We anticipate that countries with high gastric cancer burdens will follow their lead. We provide specific recommendations on instituting practical primary and secondary gastric cancer prevention programs as well identifying research needed to make elimination of gastric cancer both efficient and cost effective.
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Affiliation(s)
- Akiko Shiotani
- Department of Internal Medicine, Kawasaki Medical School, Okayama, Japan
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Shin CM, Kim N, Lee HS, Park JH, Ahn S, Kang GH, Kim JM, Kim JS, Lee DH, Jung HC. Changes in aberrant DNA methylation after Helicobacter pylori eradication: a long-term follow-up study. Int J Cancer 2013; 133:2034-42. [PMID: 23595635 DOI: 10.1002/ijc.28219] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2012] [Accepted: 04/03/2013] [Indexed: 12/12/2022]
Abstract
Changes of DNA methylation in gastric mucosae after eradication of Helicobacter pylori have not been clarified yet. From this background, we investigated time course of DNA methylation following H. pylori eradication in 221 successfully H. pylori eradicated subjects with endoscopic follow-up at least for 6 months, including 114 controls, 53 subjects with gastric dysplasia and 54 patients with early gastric cancer. All dysplasia and gastric cancer patients underwent endoscopic resection at the time of enrollment. The methylation levels in LOX, APC and MOS genes from noncancerous gastric mucosae using quantitative methylation-specific PCR, as well as the histologic findings of gastric mucosae, were compared before and after eradication. Average follow-up duration was 26.0 months (range: 6 to 76 months). H. pylori eradication decreased methylation levels in LOX (p-value for slope < 0.001) but not in APC. In MOS, decrease of its methylation level following H. pylori eradication was significant among controls without intestinal metaplasia (IM) (p-value for slope < 0.05); however, it was not observed among patients with IM or those with dysplasia or gastric cancer. After H. pylori eradication, methylation level in MOS persistently increased in patients with dysplasia or gastric cancer (p < 0.01). In conclusion, H. pylori eradication decreases aberrant DNA methylation with gene-specific manner. Methylation level in MOS is associated with IM and may be used as a surrogate marker for gastric cancer risk, regardless of H. pylori eradication history.
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Affiliation(s)
- Cheol Min Shin
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seoungnam, Gyeonggi-do, Korea
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27
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Calcagno DQ, Gigek CO, Chen ES, Burbano RR, Smith MDAC. DNA and histone methylation in gastric carcinogenesis. World J Gastroenterol 2013; 19:1182-92. [PMID: 23482412 PMCID: PMC3587474 DOI: 10.3748/wjg.v19.i8.1182] [Citation(s) in RCA: 89] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/29/2012] [Revised: 06/13/2012] [Accepted: 06/28/2012] [Indexed: 02/06/2023] Open
Abstract
Epigenetic alterations contribute significantly to the development and progression of gastric cancer, one of the leading causes of cancer death worldwide. Epigenetics refers to the number of modifications of the chromatin structure that affect gene expression without altering the primary sequence of DNA, and these changes lead to transcriptional activation or silencing of the gene. Over the years, the study of epigenetic processes has increased, and novel therapeutic approaches that target DNA methylation and histone modifications have emerged. A greater understanding of epigenetics and the therapeutic potential of manipulating these processes is necessary for gastric cancer treatment. Here, we review recent research on the effects of aberrant DNA and histone methylation on the onset and progression of gastric tumors and the development of compounds that target enzymes that regulate the epigenome.
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Cheng ASL, Li MS, Kang W, Cheng VY, Chou JL, Lau SS, Go MY, Lee CC, Ling TK, Ng EK, Yu J, Huang TH, To KF, Chan MW, Sung JJY, Chan FKL. Helicobacter pylori causes epigenetic dysregulation of FOXD3 to promote gastric carcinogenesis. Gastroenterology 2013; 144:122-133.e9. [PMID: 23058321 DOI: 10.1053/j.gastro.2012.10.002] [Citation(s) in RCA: 112] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2012] [Revised: 08/25/2012] [Accepted: 10/03/2012] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Deregulation of forkhead box (Fox) proteins, an evolutionarily conserved family of transcriptional regulators, leads to tumorigenesis. Little is known about their regulation or functions in the pathogenesis of gastric cancer. Promoter hypermethylation occurs during Helicobacter pylori-induced gastritis. We investigated whether the deregulated genes contribute to gastric tumorigenesis. METHODS We used integrative genome-wide scans to identify concomitant hypermethylated genes in mice infected with H pylori and human gastric cancer samples. We also analyzed epigenetic gene silencing in gastric tissues from patients with H pylori infection and gastritis, intestinal metaplasia, gastric tumors, or without disease (controls). Target genes were identified by chromatin immunoprecipitation microarrays and expression and luciferase reporter analyses. RESULTS Methylation profile analyses identified the promoter of FOXD3 as the only genomic region with increased methylation in mice and humans during progression of H pylori-associated gastric tumors. FOXD3 methylation also correlated with shorter survival times of patients with gastric cancer. Genome demethylation reactivated FOXD3 expression in gastric cancer cell lines. Transgenic overexpression of FOXD3 significantly inhibited gastric cancer cell proliferation and invasion, and reduced growth of xenograft tumors in mice, at least partially, by promoting tumor cell apoptosis. FOXD3 bound directly to the promoters of, and activated transcription of, genes encoding the cell death regulators CYFIP2 and RARB. Levels of FOXD3, CYFIP2, and RARB messenger RNAs were reduced in human gastric tumor samples, compared with control tissues. CONCLUSIONS FOXD3-mediated transcriptional control of tumor suppressors is deregulated by H pylori infection-induced hypermethylation; this could perturb the balance between cell death and survival. These findings identify a pathway by which epigenetic changes affect gastric tumor suppression.
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Affiliation(s)
- Alfred S L Cheng
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, China.
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Tahara T, Arisawa T. Potential usefulness of DNA methylation as a risk marker for digestive cancer associated with inflammation. Expert Rev Mol Diagn 2012; 12:489-97. [PMID: 22702365 DOI: 10.1586/erm.12.38] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
DNA methylation has been deeply involved in the development and progression of digestive cancer, while aberrant DNA methylation has also often been observed in aged and inflammatory digestive tissues. Helicobacter pylori-related chronic gastritis, ulcerative colitis, and hepatitis B virus- and hepatitis C virus-related chronic hepatitis, are significant risk factors for developing cancer. A number of studies have revealed the specific methylation patterns for specific tissue types. DNA methylation status is stably transmitted to daughter cells. Also, unlike genetic mutations, it is possible to detect very tiny amounts of methylated DNA among tissues. Therefore, the use of aberrant methylation as a marker could be applicable to risk estimation of cancer development. We discuss the potential usefulness of DNA methylation as a risk marker for inflammation-associated digestive cancer, especially with attempts on gastric cancer, ulcerative colitis-associated cancer, and hepatitis B virus- and hepatitis C virus-related hepatocellular carcinoma.
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Affiliation(s)
- Tomomitsu Tahara
- Department of Gastroenterology, Fujita Health University School of Medicine, Toyoake, 1-98 Dengakugakubo Kutsukake-cho, Toyoake, Aichi, 470-1192, Japan.
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Shin CM, Kim N, Park JH, Kang GH, Kim JS, Jung HC, Song IS. Prediction of the risk for gastric cancer using candidate methylation markers in the non-neoplastic gastric mucosae. J Pathol 2012; 226:654-65. [PMID: 22252584 DOI: 10.1002/path.2990] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2011] [Revised: 08/11/2011] [Accepted: 08/19/2011] [Indexed: 12/13/2022]
Abstract
Aberrant DNA methylation is frequently found during gastric carcinogenesis. Recently, we identified potential methylation markers important for Helicobacter pylori-induced gastric carcinogenesis using an Illumina methylation chip assay. In this study, we evaluated the candidate genes as markers for gastric cancer (GC) in a large Korean population. DNA methylation of PTPN6, MOS, DCC, CRK, and VAV1 was evaluated in non-neoplastic gastric specimens using quantitative methylation-specific PCR in patients with GC (n = 207) and their age- and gender-matched controls (n = 207). Methylation levels in 125 GC samples were also compared. H. pylori infection status was categorized as negative, active, or past infection according to the results of endoscopy-based tests (CLOtest, histology, and culture), H. pylori serology, and serum pepsinogen test. In the controls, active H. pylori infection increased methylation levels in DCC, CRK, MOS, and VAV1 but decreased methylation levels in PTPN6 (all p < 0.05); the methylation levels in MOS remained increased in patients with past H. pylori infection compared to H. pylori-negative subjects (p < 0.001). Methylation levels in MOS in non-neoplastic gastric mucosae increased in the presence of GC, regardless of H. pylori infection status (p < 0.01). Methylation levels in all genes but DCC decreased significantly in GC specimens compared to neoplastic gastric mucosae (p < 0.01); however, methylation levels in GC tissues were not correlated with those in their background gastric mucosae. Hypomethylation of MOS in GC tissues was associated with tumour invasion, nodal metastasis, and undifferentiated histology (p < 0.05). To summarize, among the candidate genes, DNA methylation of MOS may reflect the duration of H. pylori exposure and may be a marker for the development of GC.
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Affiliation(s)
- Cheol Min Shin
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seoungnam, Gyeonggi-do, Korea
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Niller HH, Banati F, Ay E, Minarovits J. Microbe-Induced Epigenetic Alterations. PATHO-EPIGENETICS OF DISEASE 2012:419-455. [DOI: 10.1007/978-1-4614-3345-3_14] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Abstract
Methylation of cytosine bases in DNA provides a layer of epigenetic control in many eukaryotes that has important implications for normal biology and disease. DNA methylation is a crucial epigenetic modification of the genome that is involved in regulating many cellular processes. A growing number of human diseases including cancer have been found to be associated with aberrant DNA methylation. Recent advancements in the rapidly evolving field of cancer epigenetics have described extensive reprogramming of every component of the epigenetic machinery in cancer, such as DNA demethylation. In this review, we discuss the current understanding of alterations in DNA methylation composing the epigenetic landscape that occurs in gastric cancer compared with normal cells, the roles of these changes in gastric cancer initiation and progression, and the potential use of this knowledge in designing more effective treatment strategies.
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