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Yamada H, Abe S, Charvat H, Ando T, Maeda M, Murakami K, Oka S, Maekita T, Sugimoto M, Furuta T, Kaise M, Yamamichi N, Takamaru H, Sasaki A, Oda I, Nanjo S, Suzuki N, Sugiyama T, Kodama M, Mizukami K, Ito M, Kotachi T, Shimazu T, Yamamoto S, Ushijima T. Precision risk stratification of primary gastric cancer after eradication of H. pylori by a DNA methylation marker: a multicentre prospective study. Gut 2025:gutjnl-2025-335039. [PMID: 40240063 DOI: 10.1136/gutjnl-2025-335039] [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] [Received: 02/07/2025] [Accepted: 03/14/2025] [Indexed: 04/18/2025]
Abstract
BACKGROUND Precision cancer risk stratification for gastric cancer is urgently needed for the growing number of healthy people after Helicobacter pylori eradication. The epimutation burden in non-malignant tissues has been associated with cancer risk in multiple cross-sectional studies. OBJECTIVE To confirm the clinical usefulness of a DNA methylation marker for epimutation burden, and to identify a cut-off methylation level for a super-high-risk population. DESIGN Healthy people after H. pylori eradication with open-type atrophy were prospectively recruited. DNA methylation levels of a marker gene, RIMS1, were measured in biopsy specimens from gastric antrum and body. The primary endpoint was the incidence rate of gastric cancer in quartiles of the methylation levels. RESULTS 1624 participants had at least one endoscopic follow-up with a median follow-up of 4.05 years, and a primary gastric cancer developed in 27 participants. The highest quartile of RIMS1 methylation levels had a higher incidence rate (972.8 per 100 000 person-years) than the lowest quartile (127.1). Cox regression analysis revealed a univariate HR of 7.7 (95% CI 1.8-33.7) and an age- and sex-adjusted HR of 5.7 (95% CI 1.3-25.5). As a secondary objective, a cut-off methylation level of 25.7% (95% CI 1.7-7.7) was obtained to identify a population with a super-high risk based on the number needed to screen of 1000. CONCLUSION A DNA methylation marker can risk-stratify healthy people after H. pylori eradication even though all of them have clinically high risk. Individuals with super-high risk will need more frequent gastric cancer screening than currently recommended. TRIAL REGISTRATION NUMBER UMIN-CTR000016894.
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Affiliation(s)
- Harumi Yamada
- Department of Epigenomics, Institute for Advanced Life Sciences, Hoshi University, Tokyo, Japan
- Department of Gastrointestinal Surgery, Kyoto University, Kyoto, Japan
- Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan
| | - Seiichiro Abe
- Endoscopy Division, National Cancer Center Hospital, Tokyo, Japan
| | - Hadrien Charvat
- Faculty of International Liberal Arts, Juntendo University, Tokyo, Japan
- Division of International Health Policy Research, Institute for Cancer Control, National Cancer Center, Tokyo, Japan
| | - Takayuki Ando
- Third Department of Internal Medicine, University of Toyama, Toyama, Japan
| | - Masahiro Maeda
- Department of Gastrointestinal Surgery, Kyoto University, Kyoto, Japan
- Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan
| | - Kazunari Murakami
- Department of Gastroenterology, Faculty of Medicine, Oita University, Oita, Japan
| | - Shiro Oka
- Department of Gastroenterology, Hiroshima University Hospital, Hiroshima, Japan
| | - Takao Maekita
- Second Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan
| | - Mitsushige Sugimoto
- Division of Digestive Endoscopy, Shiga University of Medical Science Hospital, Shiga, Japan
- Division of Genome-Wide Infectious Microbiology, Research Center for GLOBAL and LOCAL Infectious Disease, Oita University, Oita, Japan
| | - Takahisa Furuta
- Center for Clinical Research, Hamamatsu University School of Medicine, Shizuoka, Japan
| | - Mitsuru Kaise
- Department of Gastroenterology, Nippon Medical School, Graduate School of Medicine, Tokyo, Japan
| | - Nobutake Yamamichi
- Department of Gastroenterology, The University of Tokyo, Graduate School of Medicine, Tokyo, Japan
| | | | - Akiko Sasaki
- Gastroenterology Medicine Center, Shonan Kamakura General Hospital, Kanagawa, Japan
| | - Ichiro Oda
- Endoscopy Division, National Cancer Center Hospital, Tokyo, Japan
| | - Sohachi Nanjo
- Third Department of Internal Medicine, University of Toyama, Toyama, Japan
| | - Nobuhiro Suzuki
- Department of Internal Medicine, Joetsu General Hospital, Niigata, Japan
| | - Toshiro Sugiyama
- Third Department of Internal Medicine, University of Toyama, Toyama, Japan
- Health Sciences University of Hokkaido, Hokkaido, Japan (Present adrress)
| | - Masaaki Kodama
- Department of Gastroenterology, Faculty of Medicine, Oita University, Oita, Japan
- Department of Advanced Medical Sciences, Faculty of Medicine, Oita University, Oita, Japan
| | - Kazuhiro Mizukami
- Department of Gastroenterology, Faculty of Medicine, Oita University, Oita, Japan
| | - Masanori Ito
- Department of Gastroenterology, Hiroshima University Hospital, Hiroshima, Japan
| | - Takahiro Kotachi
- Department of Gastroenterology, Hiroshima University Hospital, Hiroshima, Japan
| | - Taichi Shimazu
- Epidemiology and Prevention Group, Research Center for Cancer Prevention andScreening, National Cancer Center, Tokyo, Japan
| | | | - Toshikazu Ushijima
- Department of Epigenomics, Institute for Advanced Life Sciences, Hoshi University, Tokyo, Japan
- Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan
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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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Tahara S, Tahara T, Yamazaki J, Shijimaya T, Horiguchi N, Funasaka K, Fukui T, Nakagawa Y, Shibata T, Naganuma M, Tsukamoto T, Ohmiya N. Helicobacter pylori infection associated DNA methylation in primary gastric cancer significantly correlates with specific molecular and clinicopathological features. Mol Carcinog 2024; 63:266-274. [PMID: 37846801 DOI: 10.1002/mc.23650] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2023] [Revised: 08/23/2023] [Accepted: 10/01/2023] [Indexed: 10/18/2023]
Abstract
Helicobacter pylori induces DNA methylation in gastric mucosa, which links to gastric cancer (GC) risk. In contrast, CpG island methylator phenotype (CIMP) is defined as high levels of cancer-specific methylation and provides distinct molecular and clinicopathological features of GC. The association between those two types of methylation in GC remains unclear. We examined DNA methylation of well-validated H. pylori infection associated genes in GC and its adjacent mucosa and investigated its association with CIMP, various molecular subtypes and clinical features. We studied 50 candidate loci in 24 gastric samples to identify H. pylori infection associated genes. Identified loci were further examined in 624 gastric tissue from 217 primary GC, 217 adjacent mucosa, and 190 mucosae from cancer-free subjects. We identified five genes (IGF2, SLC16A2, SOX11, P2RX7, and MYOD1) as hypermethylated in H. pylori infected gastric mucosa. In non-neoplastic mucosa, methylation of H. pylori infection associated genes was higher in patients with GC than those without. In primary GC tissues, higher methylation of H. pylori infection associated genes correlated with CIMP-positive and its related features, such as MLH1 methylated cases. On the other hand, GC with lower methylation of these genes presented aggressive clinicopathological features including undifferentiated histopathology, advanced stage at diagnosis. H. pylori infection associated DNA methylation is correlated with CIMP, specific molecular and clinicopathological features in GC, supporting its utility as promising biomarker in this tumor type.
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Affiliation(s)
- Sayumi Tahara
- Department of Diagnostic Pathology I, Fujita Health University School of Medicine, Toyoake, Japan
| | - Tomomitsu Tahara
- Department of Gastroenterology, Fujita Health University School of Medicine, Toyoake, Japan
- Third Department of Internal Medicine, Kansai Medical University, Hirakata, Japan
| | - Jumpei Yamazaki
- Translational Research Unit, Veterinary Teaching Hospital, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, Japan
- One Health Research Center, Hokkaido University, Sapporo, Japan
| | - Takuya Shijimaya
- Third Department of Internal Medicine, Kansai Medical University, Hirakata, Japan
| | - Noriyuki Horiguchi
- Department of Gastroenterology, Fujita Health University School of Medicine, Toyoake, Japan
| | - Kohei Funasaka
- Department of Gastroenterology, Fujita Health University School of Medicine, Toyoake, Japan
| | - Toshiro Fukui
- Third Department of Internal Medicine, Kansai Medical University, Hirakata, Japan
| | - Yoshihito Nakagawa
- Department of Gastroenterology, Fujita Health University School of Medicine, Toyoake, Japan
| | - Tomoyuki Shibata
- Department of Gastroenterology, Fujita Health University School of Medicine, Toyoake, Japan
| | - Makoto Naganuma
- Third Department of Internal Medicine, Kansai Medical University, Hirakata, Japan
| | - Tetsuya Tsukamoto
- Department of Diagnostic Pathology I, Fujita Health University School of Medicine, Toyoake, Japan
| | - Naoki Ohmiya
- Department of Advanced Endoscopy, Fujita Health University, Toyoake, Aichi, Japan
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Irie T, Yamada H, Takeuchi C, Liu YY, Charvat H, Shimazu T, Ando T, Maekita T, Abe S, Takamaru H, Kodama M, Murakami K, Sugimoto K, Sakamoto K, Ushijima T. The methylation level of a single cancer risk marker gene reflects methylation burden in gastric mucosa. Gastric Cancer 2023; 26:667-676. [PMID: 37219707 DOI: 10.1007/s10120-023-01399-w] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Accepted: 05/12/2023] [Indexed: 05/24/2023]
Abstract
BACKGROUND Gastric cancer risk can be accurately predicted by measuring the methylation level of a single marker gene in gastric mucosa. However, the mechanism is still uncertain. We hypothesized that the methylation level measured reflects methylation alterations in the entire genome (methylation burden), induced by Helicobacter pylori (H. pylori) infection, and thus cancer risk. METHODS Gastric mucosa of 15 healthy volunteers without H. pylori infection (G1), 98 people with atrophic gastritis (G2), and 133 patients with gastric cancer (G3) after H. pylori eradication were collected. Methylation burden of an individual was obtained by microarray analysis as an inverse of the correlation coefficient between the methylation levels of 265,552 genomic regions in the person's gastric mucosa and those in an entirely healthy mucosa. RESULTS The methylation burden significantly increased in the order of G1 (n = 4), G2 (n = 18), and G3 (n = 19) and was well correlated with the methylation level of a single marker gene (r = 0.91 for miR124a-3). The average methylation levels of nine driver genes tended to increase according to the risk levels (P = 0.08 between G2 vs G3) and was also correlated with the methylation level of a single marker gene (r = 0.94). Analysis of more samples (14 G1, 97 G2, and 131 G3 samples) yielded significant increases of the average methylation levels between risk groups. CONCLUSIONS The methylation level of a single marker gene reflects the methylation burden, which includes driver gene methylation, and thus accurately predicts cancer risk.
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Affiliation(s)
- Takahiro Irie
- Department of Epigenomics, Institute for Advanced Life Sciences, Hoshi University, Tokyo, Japan
- Department of Coloproctological Surgery, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Harumi Yamada
- Department of Epigenomics, Institute for Advanced Life Sciences, Hoshi University, Tokyo, Japan
- Department of Surgery, Kyoto University, Kyoto, Japan
| | - Chihiro Takeuchi
- Department of Epigenomics, Institute for Advanced Life Sciences, Hoshi University, Tokyo, Japan
| | - Yu-Yu Liu
- Department of Epigenomics, Institute for Advanced Life Sciences, Hoshi University, Tokyo, Japan
| | - Hadrien Charvat
- Faculty of International Liberal Arts, Juntendo University, Tokyo, Japan
| | - Taichi Shimazu
- Division of Behavioral Sciences, National Cancer Center Institute for Cancer Control, National Cancer Center, Tokyo, 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
| | - Seiichiro Abe
- Endoscopy Division, National Cancer Center Hospital, Tokyo, Japan
| | | | - Masaaki Kodama
- Department of Gastroenterology Faculty of Medicine, Oita University, Oita, Japan
| | - Kazunari Murakami
- Department of Gastroenterology Faculty of Medicine, Oita University, Oita, Japan
| | - Kiichi Sugimoto
- Department of Coloproctological Surgery, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Kazuhiro Sakamoto
- Department of Coloproctological Surgery, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Toshikazu Ushijima
- Department of Epigenomics, Institute for Advanced Life Sciences, Hoshi University, Tokyo, Japan.
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la Torre A, Lo Vecchio F, Greco A. Epigenetic Mechanisms of Aging and Aging-Associated Diseases. Cells 2023; 12:cells12081163. [PMID: 37190071 DOI: 10.3390/cells12081163] [Citation(s) in RCA: 30] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2022] [Revised: 04/04/2023] [Accepted: 04/07/2023] [Indexed: 05/17/2023] Open
Abstract
Aging is an inevitable outcome of life, characterized by a progressive decline in tissue and organ function. At a molecular level, it is marked by the gradual alterations of biomolecules. Indeed, important changes are observed on the DNA, as well as at a protein level, that are influenced by both genetic and environmental parameters. These molecular changes directly contribute to the development or progression of several human pathologies, including cancer, diabetes, osteoporosis, neurodegenerative disorders and others aging-related diseases. Additionally, they increase the risk of mortality. Therefore, deciphering the hallmarks of aging represents a possibility for identifying potential druggable targets to attenuate the aging process, and then the age-related comorbidities. Given the link between aging, genetic, and epigenetic alterations, and given the reversible nature of epigenetic mechanisms, the precisely understanding of these factors may provide a potential therapeutic approach for age-related decline and disease. In this review, we center on epigenetic regulatory mechanisms and their aging-associated changes, highlighting their inferences in age-associated diseases.
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Affiliation(s)
- Annamaria la Torre
- Laboratory of Gerontology and Geriatrics, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, 71013 Foggia, Italy
| | - Filomena Lo Vecchio
- Laboratory of Gerontology and Geriatrics, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, 71013 Foggia, Italy
| | - Antonio Greco
- Complex Unit of Geriatrics, Department of Medical Sciences, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, 71013 Foggia, Italy
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Zeng Y, Rong H, Xu J, Cao R, Li S, Gao Y, Cheng B, Zhou T. DNA Methylation: An Important Biomarker and Therapeutic Target for Gastric Cancer. Front Genet 2022; 13:823905. [PMID: 35309131 PMCID: PMC8931997 DOI: 10.3389/fgene.2022.823905] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2021] [Accepted: 02/07/2022] [Indexed: 12/12/2022] Open
Abstract
Gastric cancer (GC) is a very common malignancy with a poor prognosis, and its occurrence and development are closely related to epigenetic modifications. Methylation of DNA before or during gastric cancer is an interesting research topic. This article reviews the studies on DNA methylation related to the cause, diagnosis, treatment, and prognosis of gastric cancer and aims to find cancer biomarkers to solve major human health problems.
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Affiliation(s)
- Yunqing Zeng
- Department of Gastroenterology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Huimin Rong
- Department of Reconstructive Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Jianwei Xu
- Department of Pancreatic Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Ruyue Cao
- Department of Gastroenterology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Shuhua Li
- Department of Gastroenterology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Yanjing Gao
- Department of Gastroenterology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Baoquan Cheng
- Department of Gastroenterology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Tao Zhou
- Department of Geriatric Medicine, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- *Correspondence: Tao Zhou,
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Hozhabri H, Ghasemi Dehkohneh RS, Razavi SM, Razavi SM, Salarian F, Rasouli A, Azami J, Ghasemi Shiran M, Kardan Z, Farrokhzad N, Mikaeili Namini A, Salari A. Comparative analysis of protein-protein interaction networks in metastatic breast cancer. PLoS One 2022; 17:e0260584. [PMID: 35045088 PMCID: PMC8769308 DOI: 10.1371/journal.pone.0260584] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2020] [Accepted: 11/12/2021] [Indexed: 12/27/2022] Open
Abstract
Metastatic lesions leading causes of the majority of deaths in patients with the breast cancer. The present study aimed to provide a comprehensive analysis of the differentially expressed genes (DEGs) in the brain (MDA-MB-231 BrM2) and lung (MDA-MB-231 LM2) metastatic cell lines obtained from breast cancer patients compared with those who have primary breast cancer. We identified 981 and 662 DEGs for brain and lung metastasis, respectively. Protein-protein interaction (PPI) analysis revealed seven shared (PLCB1, FPR1, FPR2, CX3CL1, GABBR2, GPR37, and CXCR4) hub genes between brain and lung metastasis in breast cancer. Moreover, GNG2 and CXCL8, C3, and PTPN6 in the brain and SAA1 and CCR5 in lung metastasis were found as unique hub genes. Besides, five co-regulation of clusters via seven important co-expression genes (COL1A2, LUM, SPARC, THBS2, IL1B, CXCL8, THY1) were identified in the brain PPI network. Clusters screening followed by biological process (BP) function and pathway enrichment analysis for both metastatic cell lines showed that complement receptor signalling, acetylcholine receptor signalling, and gastric acid secretion pathways were common between these metastases, whereas other pathways were site-specific. According to our findings, there are a set of genes and functional pathways that mark and mediate breast cancer metastasis to the brain and lungs, which may enable us understand the molecular basis of breast cancer development in a deeper levele to the brain and lungs, which may help us gain a more complete understanding of the molecular underpinnings of breast cancer development.
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Affiliation(s)
- Hossein Hozhabri
- Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran
- Salari Institute of Cognitive and Behavioral Disorders (SICBD), Karaj, Alborz, Iran
- Systems Biology Research Lab, Bioinformatics Group, Systems Biology of the Next Generation Company (SBNGC), Qom, Iran
| | - Roxana Sadat Ghasemi Dehkohneh
- Salari Institute of Cognitive and Behavioral Disorders (SICBD), Karaj, Alborz, Iran
- Systems Biology Research Lab, Bioinformatics Group, Systems Biology of the Next Generation Company (SBNGC), Qom, Iran
- Department of Cell and Molecular Biology and Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, Iran
| | - Seyed Morteza Razavi
- Salari Institute of Cognitive and Behavioral Disorders (SICBD), Karaj, Alborz, Iran
- Systems Biology Research Lab, Bioinformatics Group, Systems Biology of the Next Generation Company (SBNGC), Qom, Iran
- Department of Cell and Molecular Biology, Faculty of Biological Sciences, Kharazmi University, Tehran, Iran
| | - S. Mostafa Razavi
- Department of Chemical, Biomolecular and Corrosion Engineering, The University of Akron, Akron, Ohio, United States of America
| | - Fatemeh Salarian
- Systems Biology Research Lab, Bioinformatics Group, Systems Biology of the Next Generation Company (SBNGC), Qom, Iran
- Department of Cellular Biotechnology, Cell Science Research Center, Royan Institute for Biotechnology, ACECR, Isfahan, Iran
| | - Azade Rasouli
- Systems Biology Research Lab, Bioinformatics Group, Systems Biology of the Next Generation Company (SBNGC), Qom, Iran
- Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Jalil Azami
- Systems Biology Research Lab, Bioinformatics Group, Systems Biology of the Next Generation Company (SBNGC), Qom, Iran
- Faculty of Veterinary Medicine, Urmia University, Urmia, Iran
| | - Melika Ghasemi Shiran
- Salari Institute of Cognitive and Behavioral Disorders (SICBD), Karaj, Alborz, Iran
- Systems Biology Research Lab, Bioinformatics Group, Systems Biology of the Next Generation Company (SBNGC), Qom, Iran
- Department of Biology, Faculty of Sciences, Central Tehran Branch, Islamic Azad University, Tehran, Iran
| | - Zahra Kardan
- Systems Biology Research Lab, Bioinformatics Group, Systems Biology of the Next Generation Company (SBNGC), Qom, Iran
- Department of Cellular Molecular Biology, Faculty of Life Science and Biotechnology, Shahid Beheshti University, Tehran, Iran
| | - Negar Farrokhzad
- Systems Biology Research Lab, Bioinformatics Group, Systems Biology of the Next Generation Company (SBNGC), Qom, Iran
- Department of Biology, Faculty of Sciences, University of Guilan, Rasht, Iran
| | - Arsham Mikaeili Namini
- Systems Biology Research Lab, Bioinformatics Group, Systems Biology of the Next Generation Company (SBNGC), Qom, Iran
- Department of Animal Biology, Faculty of Biological Sciences, Kharazmi University, Tehran, Iran
| | - Ali Salari
- Salari Institute of Cognitive and Behavioral Disorders (SICBD), Karaj, Alborz, Iran
- Systems Biology Research Lab, Bioinformatics Group, Systems Biology of the Next Generation Company (SBNGC), Qom, Iran
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
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8
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Choi Y, Kim N, Yoon H, Shin CM, Park YS, Lee DH, Park YS, Ahn SH, Suh YS, Park DJ, Kim HH. The Incidence and Risk Factors for Metachronous Gastric Cancer in the Remnant Stomach after Gastric Cancer Surgery. Gut Liver 2021; 16:366-374. [PMID: 34462394 PMCID: PMC9099384 DOI: 10.5009/gnl210202] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Revised: 06/10/2021] [Accepted: 06/23/2021] [Indexed: 01/04/2023] Open
Abstract
Background/Aims Less invasive surgical treatment is performed in East Asia to preserve postoperative digestive function and reduce complications such as postgastrectomy syndromes, but there is an issue of metachronous gastric cancer (GC) in the remaining stomach. This study aimed to analyze the incidence of metachronous GC and its risk factors in patients who had undergone partial gastrectomy. Methods A total of 3,045 GC patients who had undergone curative gastric partial resection at Seoul National University Bundang Hospital were enrolled and analyzed retrospectively for risk factors, including age, sex, smoking, alcohol, Helicobacterpylori status, family history of GC, histological type, and surgical method. Results Metachronous GC in the remaining stomach occurred in 35 of the 3,045 patients (1.1%) 23 in the distal gastrectomy group (18 with Billroth-I anastomosis, five with Billroth-II anastomosis), seven in the proximal gastrectomy (PG) group, and five in the pylorus-preserving gastrectomy (PPG) group. Univariate and multivariate Cox regression analyses showed that age ≥60 years (p=0.005) and surgical method used (PG or PPG, p<0.001) were related risk factors for metachronous GC, while male sex and intestinal type histology were potential risk factors. Conclusions Metachronous GC was shown to be related to older age and the surgical method used (PG or PPG). Regular and careful follow-up with endoscopy should be performed in the case of gastric partial resection, especially in patients with male sex and intestinal type histology as well as those aged ≥60 years undergoing the PG or PPG surgical method.
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Affiliation(s)
- Yonghoon Choi
- 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, Seoul National University College of Medicine, Seoul, Korea
| | - Hyuk Yoon
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Cheol Min Shin
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Young Soo Park
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Dong Ho Lee
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea.,Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Young Suk Park
- Department of Surgery, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Sang-Hoon Ahn
- Department of Surgery, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Yun-Suhk Suh
- Department of Surgery, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Do Joong Park
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
| | - Hyung Ho Kim
- Department of Surgery, Seoul National University Bundang Hospital, Seongnam, Korea.,Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
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9
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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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10
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Canale M, Casadei-Gardini A, Ulivi P, Arechederra M, Berasain C, Lollini PL, Fernández-Barrena MG, Avila MA. Epigenetic Mechanisms in Gastric Cancer: Potential New Therapeutic Opportunities. Int J Mol Sci 2020; 21:E5500. [PMID: 32752096 PMCID: PMC7432799 DOI: 10.3390/ijms21155500] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Revised: 07/27/2020] [Accepted: 07/29/2020] [Indexed: 02/07/2023] Open
Abstract
Gastric cancer (GC) is one of the deadliest malignancies worldwide. Complex disease heterogeneity, late diagnosis, and suboptimal therapies result in the poor prognosis of patients. Besides genetic alterations and environmental factors, it has been demonstrated that alterations of the epigenetic machinery guide cancer onset and progression, representing a hallmark of gastric malignancies. Moreover, epigenetic mechanisms undergo an intricate crosstalk, and distinct epigenomic profiles can be shaped under different microenvironmental contexts. In this scenario, targeting epigenetic mechanisms could be an interesting therapeutic strategy to overcome gastric cancer heterogeneity, and the efforts conducted to date are delivering promising results. In this review, we summarize the key epigenetic events involved in gastric cancer development. We conclude with a discussion of new promising epigenetic strategies for gastric cancer treatment.
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Affiliation(s)
- Matteo Canale
- Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, 47014 Meldola, Italy; (M.C.); (P.U.)
| | - Andrea Casadei-Gardini
- Department of Oncology and Hematology, Division of Oncology, University of Modena and Reggio Emilia, 41125 Modena, Italy
| | - Paola Ulivi
- Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, 47014 Meldola, Italy; (M.C.); (P.U.)
| | - Maria Arechederra
- Program of Hepatology, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain; (M.A.); (C.B.); (M.G.F.-B.)
- IdiSNA, Navarra Institute for Health Research, 31008 Pamplona, Spain
| | - Carmen Berasain
- Program of Hepatology, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain; (M.A.); (C.B.); (M.G.F.-B.)
- IdiSNA, Navarra Institute for Health Research, 31008 Pamplona, Spain
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Carlos III Health Institute), 28029 Madrid, Spain
| | - Pier-Luigi Lollini
- Laboratory of Immunology and Biology of Metastasis, Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, 40126 Bologna, Italy;
| | - Maite G. Fernández-Barrena
- Program of Hepatology, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain; (M.A.); (C.B.); (M.G.F.-B.)
- IdiSNA, Navarra Institute for Health Research, 31008 Pamplona, Spain
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Carlos III Health Institute), 28029 Madrid, Spain
| | - Matías A. Avila
- Program of Hepatology, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain; (M.A.); (C.B.); (M.G.F.-B.)
- IdiSNA, Navarra Institute for Health Research, 31008 Pamplona, Spain
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Carlos III Health Institute), 28029 Madrid, Spain
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11
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Anderson BW, Suh YS, Choi B, Lee HJ, Yab TC, Taylor WR, Dukek BA, Berger CK, Cao X, Foote PH, Devens ME, Boardman LA, Kisiel JB, Mahoney DW, Slettedahl SW, Allawi HT, Lidgard GP, Smyrk TC, Yang HK, Ahlquist DA. Detection of Gastric Cancer with Novel Methylated DNA Markers: Discovery, Tissue Validation, and Pilot Testing in Plasma. Clin Cancer Res 2018; 24:5724-5734. [PMID: 29844130 DOI: 10.1158/1078-0432.ccr-17-3364] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2017] [Revised: 03/09/2018] [Accepted: 05/23/2018] [Indexed: 12/16/2022]
Abstract
Purpose: Gastric adenocarcinoma is the third most common cause of cancer mortality worldwide. Accurate and affordable noninvasive detection methods have potential value for screening and surveillance. Herein, we identify novel methylated DNA markers (MDM) for gastric adenocarcinoma, validate their discrimination for gastric adenocarcinoma in tissues from geographically separate cohorts, explore marker acquisition through the oncogenic cascade, and describe distributions of candidate MDMs in plasma from gastric adenocarcinoma cases and normal controls.Experimental Design: Following discovery by unbiased whole-methylome sequencing, candidate MDMs were validated by blinded methylation-specific PCR in archival case-control tissues from U.S. and South Korean patients. Top MDMs were then assayed by an analytically sensitive method (quantitative real-time allele-specific target and signal amplification) in a blinded pilot study on archival plasma from gastric adenocarcinoma cases and normal controls.Results: Whole-methylome discovery yielded novel and highly discriminant candidate MDMs. In tissue, a panel of candidate MDMs detected gastric adenocarcinoma in 92% to 100% of U.S. and South Korean cohorts at 100% specificity. Levels of most MDMs increased progressively from normal mucosa through metaplasia, adenoma, and gastric adenocarcinoma with variation in points of greatest marker acquisition. In plasma, a 3-marker panel (ELMO1, ZNF569, C13orf18) detected 86% (95% CI, 71-95) of gastric adenocarcinomas at 95% specificity.Conclusions: Novel MDMs appear to accurately discriminate gastric adenocarcinoma from normal controls in both tissue and plasma. The point of aberrant methylation during oncogenesis varies by MDM, which may have relevance to marker selection in clinical applications. Further exploration of these MDMs for gastric adenocarcinoma screening and surveillance is warranted. Clin Cancer Res; 24(22); 5724-34. ©2018 AACR.
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Affiliation(s)
- Bradley W Anderson
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Yun-Suhk Suh
- Department of Surgery, Seoul National University College of Medicine, Seoul, South Korea
| | - Boram Choi
- Department of Surgery and Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea
| | - Hyuk-Joon Lee
- Department of Surgery and Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea
| | - Tracy C Yab
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - William R Taylor
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Brian A Dukek
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Calise K Berger
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Xiaoming Cao
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Patrick H Foote
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Mary E Devens
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Lisa A Boardman
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - John B Kisiel
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Douglas W Mahoney
- Department of Biomedical Statistics and Information, Mayo Clinic, Rochester, Minnesota
| | - Seth W Slettedahl
- Department of Biomedical Statistics and Information, Mayo Clinic, Rochester, Minnesota
| | | | | | - Thomas C Smyrk
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | - Han-Kwang Yang
- Department of Surgery and Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea
| | - David A Ahlquist
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.
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12
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李 勇, 檀 碧. Vav基因家族的分子调控机制及其与消化系恶性肿瘤的关系. Shijie Huaren Xiaohua Zazhi 2017; 25:2102-2108. [DOI: 10.11569/wcjd.v25.i23.2102] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Vav基因家族包括Vav1、Vav2、Vav3基因, 在生理及病理过程中都发挥着重要的调控作用. 近年来发现Vav基因家族成员与消化系恶性肿瘤有较为密切的关系, 已取得了一些研究成果. 但迄今为止有关Vav基因家族成员与消化系恶性肿瘤关系的研究还不全面, 且有一些结果不一致. 因此, 总结Vav基因家族成员的调控机制并分析其在消化系恶性肿瘤中发挥的作用有可能对阐明发病机制、提出新的治疗靶点有益. 故本文对Vav基因家族的分子功能、调控机制及在消化系恶性肿瘤中的作用进行了综述及总结, 并对该基因家族的潜在价值进行了预测.
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13
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Clarke MA, Luhn P, Gage JC, Bodelon C, Dunn ST, Walker J, Zuna R, Hewitt S, Killian JK, Yan L, Miller A, Schiffman M, Wentzensen N. Discovery and validation of candidate host DNA methylation markers for detection of cervical precancer and cancer. Int J Cancer 2017; 141:701-710. [PMID: 28500655 DOI: 10.1002/ijc.30781] [Citation(s) in RCA: 53] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2016] [Accepted: 04/13/2017] [Indexed: 01/03/2023]
Abstract
Human papillomavirus (HPV) testing has been recently introduced as an alternative to cytology for cervical cancer screening. However, since most HPV infections clear without causing clinically relevant lesions, additional triage tests are required to identify women who are at high risk of developing cancer. We performed DNA methylation profiling on formalin-fixed, paraffin-embedded tissue specimens from women with benign HPV16 infection and histologically confirmed cervical intraepithelial neoplasia grade 3, and cancer using a bead-based microarray covering 1,500 CpG sites in over 800 genes. Methylation levels in individual CpG sites were compared using a t-test, and results were summarized by computing p-values. A total of 12 candidate genes (ADCYAP1, ASCL1, ATP10, CADM1, DCC, DBC1, HS3ST2, MOS, MYOD1, SOX1, SOX17 and TMEFF2) identified by DNA methylation profiling, plus an additional three genes identified from the literature (EPB41L3, MAL and miR-124) were chosen for validation in an independent set of 167 liquid-based cytology specimens using pyrosequencing and targeted, next-generation bisulfite sequencing. Of the 15 candidate gene markers, 10 had an area under the curve (AUC) of ≥ 0.75 for discrimination of high grade squamous intraepithelial lesions or worse (HSIL+) from <HSIL cytology using at least one assay. Overall, SOX1, DCC, and EPB41L3 showed the best discrimination with AUC values of ≥0.80, irrespective of methylation detection assay. In addition to verifying candidate markers from the literature (e.g., SOX1 and EPB41L3), we identified novel markers that may be considered for detection of cervical precancer and cancer and warrant further validation in prospective studies.
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Affiliation(s)
- Megan A Clarke
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD
| | | | - Julia C Gage
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD
| | - Clara Bodelon
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD
| | - S Terence Dunn
- Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK
| | - Joan Walker
- Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK
| | - Rosemary Zuna
- Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK
| | - Stephen Hewitt
- Center for Cancer Research, National Cancer Institute, Bethesda, MD
| | - J Keith Killian
- Center for Cancer Research, National Cancer Institute, Bethesda, MD
| | | | | | - Mark Schiffman
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD
| | - Nicolas Wentzensen
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD
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14
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Yoshida S, Yamashita S, Niwa T, Mori A, Ito S, Ichinose M, Ushijima T. Epigenetic inactivation of FAT4 contributes to gastric field cancerization. Gastric Cancer 2017; 20:136-145. [PMID: 26792292 DOI: 10.1007/s10120-016-0593-5] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2015] [Accepted: 01/05/2016] [Indexed: 02/07/2023]
Abstract
BACKGROUND Gastric cancer (GC) is highly influenced by aberrant methylation, and accumulation of aberrant methylation in gastric mucosae produces an epigenetic field for cancerization. Nevertheless, the individual driver genes involved in such field cancerization are still unclear. Here, we aimed to demonstrate that FAT4, a novel tumor suppressor identified by exome sequencing of GC, is methylation-silenced and that such methylation is involved in epigenetic field cancerization for GC. METHODS A transcription start site was determined by the 5' rapid amplification of complementary DNA ends method. DNA methylation was analyzed by bisulfite sequencing with use of a next-generation sequencer or quantitative methylation-specific PCR. Gene expression was analyzed by quantitative reverse transcription PCR. RESULTS A single transcription start site was identified for FAT4 in gastric epithelial cells, and a CpG island was located in the FAT4 promoter region. FAT4 was highly methylated in two of 13 GC cell lines and was not expressed in them. Removal of FAT4 methylation by a DNA demethylating agent (5-aza-2'-deoxycytidine) restored its expression in the two cell lines. In primary GC samples, FAT4 was methylated in 12 of 82 GCs (14.6 %). FAT4 methylation was associated with the presence of the CpG island methylator phenotype but not with prognosis, tumor invasion, lymph node metastasis, or histological types. In noncancerous gastric mucosae, high FAT4 methylation levels were associated with the presence of GC and Helicobacter pylori infection. CONCLUSIONS FAT4 was methylation-silenced in GCs. Its methylation in gastric mucosae was associated with H. pylori infection and likely contributed to epigenetic field cancerization.
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Affiliation(s)
- Satoshi Yoshida
- Division of Epigenomics, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
- Second Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan
| | - Satoshi Yamashita
- Division of Epigenomics, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Tohru Niwa
- Division of Epigenomics, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Akiko Mori
- Division of Epigenomics, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Seiji Ito
- Department of Gastroenterological Surgery, Aichi Cancer Center Central Hospital, Nagoya, Japan
| | - Masao Ichinose
- Second Department of Internal Medicine, Wakayama Medical University, Wakayama, 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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15
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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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16
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Abstract
Stomach cancer remains, stubbornly, highly prevalent in East Asia. Still, stomach cancer has few biomarkers by which it can be predicted. Helicobacter pylori infection, a known carcinogen of stomach cancer, usually goes undetected prior to cancer diagnosis, due to the poor mucosal environments that its related gastric atrophy causes. We propose, herein, an endoscopic-biopsy-based cancer-predicting DNA methylation marker. We semi-quantitatively examined the methylation-variable sites near the CpG-island margins by radioisotope-labeling methylation-specific polymerase chain reaction in association with H. pylori, which increases age-related over-methylation in CpG islands of gastric mucosa. These age-related methylation patterns of the transitional-CpG sites are proposed as useful surrogate markers for stomach cancer. It would be helpful for setting the optimal screening interval for high-risk subjects as well as for estimating the prognosis and the predictability for recurrence of early gastric cancer in patients having undergone endoscopic submucosal dissection. New screening-interval guidelines for gastric cancer should be suggested considering individual risk based on age, severity of atrophy, H. pylori status, and DNA methylation pattern.
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Affiliation(s)
- Jung-Hwan Oh
- Departments of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Sung-Hoon Jung
- Departments of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Seung-Jin Hong
- Microbiology, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Mun-Gan Rhyu
- Microbiology, College of Medicine, The Catholic University of Korea, Seoul, Korea
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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: 51] [Impact Index Per Article: 5.1] [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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Abstract
DNA methylation plays a significant role in gastric carcinogenesis. The CpG island methylator phenotype (CIMP) characterizes distinct subtypes of gastric cancer (GC) and the relationship between specific methylation patterns and clinicopathological features has been evaluated. Altered DNA methylation is also observed in Helicobacter pylori-infected gastric mucosa, and its potential utility for GC risk estimation has been suggested. The ability to detect small amounts of methylated DNA among tissues allows us to use DNA methylation as a molecular biomarker in GC in a variety of samples, including serum, plasma and gastric washes. The DNA methylation status of nontargeted tissue, particularly blood, has been associated with predisposition to GC. We focus on the recent development of DNA methylation-based biomarkers in GC.
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Affiliation(s)
- Tomomitsu Tahara
- Department of Gastroenterology, Fujita Health University School of Medicine, 1-98 Dengakugakubo Kutsukake-cho, Toyoake, Aichi, 470-1192, Japan
| | - Tomiyasu Arisawa
- Department of Gastroenterology, Kanazawa Medical University, Ishikawa, Japan
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19
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Paska AV, Hudler P. Aberrant methylation patterns in cancer: a clinical view. Biochem Med (Zagreb) 2015; 25:161-176. [PMID: 26110029 PMCID: PMC4470106 DOI: 10.11613/bm.2015.017] [Citation(s) in RCA: 70] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2015] [Accepted: 04/30/2015] [Indexed: 12/14/2022] Open
Abstract
Epigenetic mechanisms, such as DNA methylation, DNA hydroxymethylation, post-translational modifications (PTMs) of histone proteins affecting nucleosome remodelling, and regulation by small and large non-coding RNAs (ncRNAs) work in concert with cis and trans acting elements to drive appropriate gene expression. Advances in detection methods and development of dedicated platforms and methylation arrays resulted in an explosion of information on aberrantly methylated sequences linking deviations in epigenetic landscape with the initiation and progression of complex diseases. Here, we consider how DNA methylation changes in malignancies, such as breast, pancreatic, colorectal, and gastric cancer could be exploited for the purpose of developing specific diagnostic tools. DNA methylation changes can be applicable as biomarkers for detection of malignant disease in easily accessible tissues. Methylation signatures are already proving to be an important marker for determination of drug sensitivity. Even more, promoter methylation patterns of some genes, such as MGMT, SHOX2, and SEPT9, have already been translated into commercial clinical assays aiding in patient assessment as adjunct diagnostic tools. In conclusion, the changes in DNA methylation patterns in tumour cells are slowly gaining entrance into routine diagnostic tests as promising biomarkers and as potential therapeutic targets.
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Affiliation(s)
- Alja Videtic Paska
- Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Petra Hudler
- Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
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Somatic DNA Hypomethylation in H. pylori-Associated High-Risk Gastritis and Gastric Cancer: Enhanced Somatic Hypomethylation Associates with Advanced Stage Cancer. Clin Transl Gastroenterol 2015; 6:e85. [PMID: 25928808 PMCID: PMC4459532 DOI: 10.1038/ctg.2015.14] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2014] [Revised: 03/10/2015] [Accepted: 03/19/2015] [Indexed: 01/06/2023] Open
Abstract
Objectives: Helicobacter pylori-related high-risk gastritis (HRG) is a severe risk factor for gastric cancer (GC). The link between HRG and long-term risk for GC may involve genetic and epigenetic alterations underlying a field defect, i.e. a region of the mucosa prone to cancer development. Global DNA hypomethylation is a pervasive alteration in GC that associates with chromosomal instability and poor prognosis. The aim of this study was to determine the chronology of this alteration along the progression of HRG to GC, to test the hypothesis that it occurs early in the chronology of this pathway and plays a mechanistic role in the long-term cancer risk. Methods: We comparatively measured the genomic methylation level in gastric biopsies from 94 GC patients and 16 of their cancer-free relatives, 38 HRG patients, and 17 GERD patients, using a quantitative enzymatic method. Results: GC biopsies were hypomethylated compared to their matching non-tumor mucosa (P=9.4 × 10−12), irrespective of the tumor location or patients' country of origin. Genome-wide hypomethylation was also found in gastric mucosa of GC (P=1.5 × 10−5) and HRG (P=0.004) patients compared with healthy donors and GC relatives, regardless of the biopsy location within the stomach or previous H. pylori eradication therapy. An enhanced hypomethylation, distinguished by a bi-slope distribution of the differences in methylation between tumor and normal tissues, associated with a more invasive (P=0.005) and advanced stage (P=0.017) type of GC. Conclusions: Universal DNA demethylation in normal gastric mucosa in GC patients appears sporadic rather than familial. Genomic hypomethylation in HRG possibly contributes to a field defect for cancerization that is not reversed by bacterial eradication. Enhanced somatic hypomethylation may stratify GC for prognostic purposes.
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21
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Liu G, Li DZ, Jiang CS, Wang W. Transduction motif analysis of gastric cancer based on a human signaling network. ACTA ACUST UNITED AC 2015; 47:369-75. [PMID: 24838641 PMCID: PMC4075304 DOI: 10.1590/1414-431x20143527] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2013] [Accepted: 01/13/2014] [Indexed: 11/22/2022]
Abstract
To investigate signal regulation models of gastric cancer, databases and literature were used to construct the signaling network in humans. Topological characteristics of the network were analyzed by CytoScape. After marking gastric cancer-related genes extracted from the CancerResource, GeneRIF, and COSMIC databases, the FANMOD software was used for the mining of gastric cancer-related motifs in a network with three vertices. The significant motif difference method was adopted to identify significantly different motifs in the normal and cancer states. Finally, we conducted a series of analyses of the significantly different motifs, including gene ontology, function annotation of genes, and model classification. A human signaling network was constructed, with 1643 nodes and 5089 regulating interactions. The network was configured to have the characteristics of other biological networks. There were 57,942 motifs marked with gastric cancer-related genes out of a total of 69,492 motifs, and 264 motifs were selected as significantly different motifs by calculating the significant motif difference (SMD) scores. Genes in significantly different motifs were mainly enriched in functions associated with cancer genesis, such as regulation of cell death, amino acid phosphorylation of proteins, and intracellular signaling cascades. The top five significantly different motifs were mainly cascade and positive feedback types. Almost all genes in the five motifs were cancer related, including EPOR, MAPK14, BCL2L1, KRT18, PTPN6, CASP3, TGFBR2, AR, and CASP7. The development of cancer might be curbed by inhibiting signal transductions upstream and downstream of the selected motifs.
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Affiliation(s)
- G Liu
- Department of Gastroenterology, Fuzhou General Hospital of Nanjing Command, Fuzhou, China
| | - D Z Li
- Department of Gastroenterology, Fuzhou General Hospital of Nanjing Command, Fuzhou, China
| | - C S Jiang
- Department of Gastroenterology, Fuzhou General Hospital of Nanjing Command, Fuzhou, China
| | - W Wang
- Department of Gastroenterology, Fuzhou General Hospital of Nanjing Command, Fuzhou, China
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22
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Asada K, Nakajima T, Shimazu T, Yamamichi N, Maekita T, Yokoi C, Oda I, Ando T, Yoshida T, Nanjo S, Fujishiro M, Gotoda T, Ichinose M, Ushijima T. Demonstration of the usefulness of epigenetic cancer risk prediction by a multicentre prospective cohort study. Gut 2015; 64:388-96. [PMID: 25379950 PMCID: PMC4345890 DOI: 10.1136/gutjnl-2014-307094] [Citation(s) in RCA: 111] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2014] [Revised: 04/27/2014] [Accepted: 05/08/2014] [Indexed: 12/18/2022]
Abstract
BACKGROUND Epigenetic alterations accumulate in normal-appearing tissues of patients with cancer, producing an epigenetic field defect. Cross-sectional studies show that the degree of the defect may be associated with risk in some types of cancer, especially cancers associated with chronic inflammation. OBJECTIVE To demonstrate, by a multicentre prospective cohort study, that the risk of metachronous gastric cancer after endoscopic resection (ER) can be predicted by assessment of the epigenetic field defect using methylation levels. DESIGN Patients with early gastric cancer, aged 40-80 years, who planned to have, or had undergone, ER, were enrolled at least 6 months after Helicobacter pylori infection discontinued. Methylation levels of three preselected genes (miR-124a-3, EMX1 and NKX6-1) were measured by quantitative methylation-specific PCR. Patients were followed up annually by endoscopy, and the primary endpoint was defined as detection of a metachronous gastric cancer. Authentic metachronous gastric cancers were defined as cancers excluding those detected within 1 year after the enrolment. RESULTS Among 826 patients enrolled, 782 patients had at least one follow-up, with a median follow-up of 2.97 years. Authentic metachronous gastric cancers developed in 66 patients: 29, 16 and 21 patients at 1-2, 2-3 and ≥3 years after the enrolment, respectively. The highest quartile of the miR-124a-3 methylation level had a significant univariate HR (95% CI) (2.17 (1.07 to 4.41); p=0.032) and a multivariate-adjusted HR (2.30 (1.03 to 5.10); p=0.042) of developing authentic metachronous gastric cancers. Similar trends were seen for EMX1 and NKX6-1. CONCLUSIONS Assessment of the degree of an epigenetic field defect is a promising cancer risk marker that takes account of life history.
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Affiliation(s)
- Kiyoshi Asada
- Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan
| | - Takeshi Nakajima
- Endoscopy Division, National Cancer Center Hospital, Tokyo, Japan
| | - Taichi Shimazu
- Epidemiology and Prevention Division, Research Center for Cancer Prevention and Screening, National Cancer Center, Tokyo, Japan
| | | | - Takao Maekita
- Second Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan
| | - Chizu Yokoi
- Endoscopy Division, National Cancer Center Hospital, Tokyo, Japan
- Department of Gastroenterology and Hepatology, National Center for Global Health and Medicine, Tokyo, Japan
| | - Ichiro Oda
- Endoscopy Division, National Cancer Center Hospital, Tokyo, Japan
| | - Takayuki Ando
- Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan
| | - Takeichi Yoshida
- Second Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan
| | - Sohachi Nanjo
- Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan
| | | | - Takuji Gotoda
- Endoscopy Division, National Cancer Center Hospital, Tokyo, Japan
- Department of Gastroenterology and Hepatology, Tokyo Medical University, Tokyo, Japan
| | - Masao Ichinose
- Second Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan
| | - Toshikazu Ushijima
- Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan
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23
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Calcagno DQ, de Arruda Cardoso Smith M, Burbano RR. Cancer type-specific epigenetic changes: gastric cancer. Methods Mol Biol 2015; 1238:79-101. [PMID: 25421656 DOI: 10.1007/978-1-4939-1804-1_5] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Gastric cancer (GC) remains a major cause of mortality despite declining rate in the world. Epigenetic alterations contribute significantly to the development and progression of gastric tumors. Epigenetic 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 have emerged. This chapter summarizes the main epigenomic mechanisms described recently involved in gastric carcinogenesis, focusing on the roles that aberrant DNA methylation, histone modifications (histone acetylation and methylation), and miRNAs (oncogenic and tumor suppressor function of miRNA) play in the onset and progression of gastric tumors. Clinical implications of these epigenetic alterations in GC are also discussed.
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Affiliation(s)
- Danielle Queiroz Calcagno
- Núcleo de Pesquisas em Oncologia, Universidade Federal do Pará, Rua dos Mundurucus, 4487, Guamá, CEP 66073-000 Belém, PA, Brazil,
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24
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Lobatón T, Azuara D, Rodríguez-Moranta F, Loayza C, Sanjuan X, de Oca J, Fernández-Robles A, Guardiola J, Capellá G. Relationship between methylation and colonic inflammation in inflammatory bowel disease. World J Gastroenterol 2014; 20:10591-10598. [PMID: 25132780 PMCID: PMC4130871 DOI: 10.3748/wjg.v20.i30.10591] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2014] [Accepted: 04/23/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the relationship between the methylation status in the SLIT2 and TGFB2 promoters and colonic inflammation in inflammatory bowel disease patients.
METHODS: We evaluated the methylation status of 2 genes (SLIT2 and TGFB2) in 226 biopsies taken from 62 colonoscopies of 38 patients (29 ulcerative colitis and 9 Crohn’s colitis) using methylation-specific melting curve analysis. The relationships between methylation status and clinical, biological, endoscopic and histological activities were evaluated. Twenty-three of the 38 patients had a second colonoscopy and were included in a longitudinal analysis. Numerical results were given as the means ± SD of the sample and range, except when specified. Student t analysis, U Mann Whitney and ANOVA factor were used to compare the means. Qualitative results were based on the χ2 test.
RESULTS: SLIT2 methylation was more frequent in samples with endoscopic activity than with endoscopic remission (55% vs 18%, P < 0.001). SLIT2 methylation was also higher in samples with acute inflammation (56.5%) than in samples with chronic (24%) or absent inflammation (15%) (P < 0.001). For TGFB2 methylation, the correlation was only significant with endoscopic activity. Methylation was higher in the distal colon for both genes (P < 0.001 for SLIT2 and P = 0.022 for TGFB2). In the multivariate analysis, only inflammation status (and not disease duration or extension) was independently associated with SLIT2 methylation [OR = 6.6 (95%CI: 1.65-27.36), P = 0.009]. In the longitudinal analysis, the maintenance of endoscopic remission was protective for methylation.
CONCLUSION: Endoscopic and histological inflammation are predictive for SLIT2 methylation.
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25
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Toiyama Y, Okugawa Y, Goel A. DNA methylation and microRNA biomarkers for noninvasive detection of gastric and colorectal cancer. Biochem Biophys Res Commun 2014; 455:43-57. [PMID: 25128828 DOI: 10.1016/j.bbrc.2014.08.001] [Citation(s) in RCA: 125] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2014] [Revised: 07/22/2014] [Accepted: 08/01/2014] [Indexed: 02/06/2023]
Abstract
Cancer initiation and progression is controlled by both genetic and epigenetic events. Epigenetics refers to the study of mechanisms that alter gene expression without permanently altering the DNA sequence. Epigenetic alterations are reversible and heritable, and include changes in histone modifications, DNA methylation, and non-coding RNA-mediated gene silencing. Disruption of epigenetic processes can lead to altered gene function and malignant cellular transformation. Aberrant epigenetic modifications occur at the earliest stages of neoplastic transformation and are now believed to be essential players in cancer initiation and progression. Recent advances in epigenetics have not only offered a deeper understanding of the underlying mechanism(s) of carcinogenesis, but have also allowed identification of clinically relevant putative biomarkers for the early detection, disease monitoring, prognosis and risk assessment of cancer patients. At this moment, DNA methylation and non-coding RNA including with microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) represent the largest body of available literature on epigenetic biomarkers with the highest potential for cancer diagnosis. Following identification of cell-free nucleic acids in systematic circulation, increasing evidence has demonstrated the potential of cell-free epigenetic biomarkers in the blood or other body fluids for cancer detection. In this article, we summarize the current state of knowledge on epigenetic biomarkers - primarily DNA methylation and non-coding RNAs - as potential substrates for cancer detection in gastric and colorectal cancer, the two most frequent cancers within the gastrointestinal tract. We also discuss the obstacles that have limited the routine use of epigenetic biomarkers in the clinical settings and provide our perspective on approaches that might help overcome these hurdles, so that these biomarkers can be readily developed for clinical management of cancer patients.
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Affiliation(s)
- Yuji Toiyama
- Gastrointestinal Cancer Research Laboratory, Department of Internal Medicine, Charles A. Sammons Cancer Center and Baylor Research Institute, Baylor University Medical Center, 3500 Gaston Avenue, Dallas, TX 75246, USA; Department of Gastrointestinal and Pediatric Surgery, Division of Reparative Medicine, Institute of Life Sciences, Graduate School of Medicine, Mie University, Mie 514-8507, Japan
| | - Yoshinaga Okugawa
- Gastrointestinal Cancer Research Laboratory, Department of Internal Medicine, Charles A. Sammons Cancer Center and Baylor Research Institute, Baylor University Medical Center, 3500 Gaston Avenue, Dallas, TX 75246, USA; Department of Gastrointestinal and Pediatric Surgery, Division of Reparative Medicine, Institute of Life Sciences, Graduate School of Medicine, Mie University, Mie 514-8507, Japan
| | - Ajay Goel
- Gastrointestinal Cancer Research Laboratory, Department of Internal Medicine, Charles A. Sammons Cancer Center and Baylor Research Institute, Baylor University Medical Center, 3500 Gaston Avenue, Dallas, TX 75246, USA.
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26
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Overexpression of Testes-Specific Protease 50 (TSP50) Predicts Poor Prognosis in Patients with Gastric Cancer. Gastroenterol Res Pract 2014; 2014:498246. [PMID: 24799889 PMCID: PMC3985325 DOI: 10.1155/2014/498246] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2014] [Accepted: 02/20/2014] [Indexed: 12/12/2022] Open
Abstract
Purpose. To investigate the expression of TSP50 protein in human gastric cancers and its correlation with clinical/prognostic significance. Methods. Immunohistochemistry (IHC) analysis of TSP50 was performed on a tissue microarray (TMA) containing 334 primary gastric cancers. Western blot was carried out to confirm the expression of TSP50 in gastric cancers. Results. IHC analysis revealed high expression of TSP50 in 57.2% human gastric cancer samples (191 out of 334). However, it was poorly expressed in all of the 20 adjacent nontumor tissues. This was confirmed by western blot, which showed significantly higher levels of TSP50 expression in gastric cancer tissues than adjacent nontumor tissues. A significant association was found between high levels of TSP50 and clinicopathological characteristics including junior age at surgery (P = 0.001), later TNM stage (P = 0.000), and present lymph node metastases (P = 0.003). The survival of gastric cancer patients with high expression of TSP50 was significantly shorter than that of the patients with low levels of TSP50 (P = 0.021). Multivariate Cox regression analysis indicated that TSP50 overexpression was an independent prognostic factor for gastric cancer patients (P = 0.017). Conclusions. Our data demonstrate that elevated TSP50 protein expression could be a potential predictor of poor prognosis in gastric cancer patients.
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27
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Stebbing J, Lit LC, Zhang H, Darrington RS, Melaiu O, Rudraraju B, Giamas G. The regulatory roles of phosphatases in cancer. Oncogene 2014; 33:939-53. [PMID: 23503460 DOI: 10.1038/onc.2013.80] [Citation(s) in RCA: 85] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2013] [Accepted: 02/01/2013] [Indexed: 02/06/2023]
Abstract
The relevance of potentially reversible post-translational modifications required for controlling cellular processes in cancer is one of the most thriving arenas of cellular and molecular biology. Any alteration in the balanced equilibrium between kinases and phosphatases may result in development and progression of various diseases, including different types of cancer, though phosphatases are relatively under-studied. Loss of phosphatases such as PTEN (phosphatase and tensin homologue deleted on chromosome 10), a known tumour suppressor, across tumour types lends credence to the development of phosphatidylinositol 3-kinase inhibitors alongside the use of phosphatase expression as a biomarker, though phase 3 trial data are lacking. In this review, we give an updated report on phosphatase dysregulation linked to organ-specific malignancies.
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Affiliation(s)
- J Stebbing
- Division of Cancer, Department of Surgery and Cancer, Imperial College London, London, UK
| | - L C Lit
- Division of Cancer, Department of Surgery and Cancer, Imperial College London, London, UK
| | - H Zhang
- Division of Cancer, Department of Surgery and Cancer, Imperial College London, London, UK
| | - R S Darrington
- Division of Cancer, Department of Surgery and Cancer, Imperial College London, London, UK
| | - O Melaiu
- Division of Cancer, Department of Surgery and Cancer, Imperial College London, London, UK
| | - B Rudraraju
- Division of Cancer, Department of Surgery and Cancer, Imperial College London, London, UK
| | - G Giamas
- Division of Cancer, Department of Surgery and Cancer, Imperial College London, London, UK
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28
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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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29
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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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30
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Gigek CO, Chen ES, Calcagno DQ, Wisnieski F, Burbano RR, Smith MAC. Epigenetic mechanisms in gastric cancer. Epigenomics 2012; 4:279-94. [PMID: 22690664 DOI: 10.2217/epi.12.22] [Citation(s) in RCA: 86] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Cancer is considered one of the major health issues worldwide, and gastric cancer accounted for 8% of total cases and 10% of total deaths in 2008. Gastric cancer is considered an age-related disease, and the total number of newly diagnosed cases has been increasing as a result of the higher life expectancy. Therefore, the basic mechanisms underlying gastric tumorigenesis is worth investigation. This review provides an overview of the epigenetic mechanisms, such as DNA methylation, histone modifications, chromatin remodeling complex and miRNA, involved in gastric cancer. As the studies in gastric cancer continue, the mapping of an epigenome code is not far for this disease. In conclusion, an epigenetic therapy might appear in the not too distant future.
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Affiliation(s)
- Carolina Oliveira Gigek
- Disciplina de Genética, Departamento de Morfologia e Genética, Escola Paulista de Medicina/Universidade Federal de São Paulo, Rua Botucatu 740, São Paulo, SP, Brazil.
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31
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Chiba T, Marusawa H, Ushijima T. Inflammation-associated cancer development in digestive organs: mechanisms and roles for genetic and epigenetic modulation. Gastroenterology 2012; 143:550-563. [PMID: 22796521 DOI: 10.1053/j.gastro.2012.07.009] [Citation(s) in RCA: 294] [Impact Index Per Article: 22.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2012] [Revised: 06/05/2012] [Accepted: 07/03/2012] [Indexed: 12/12/2022]
Abstract
Chronic inflammation, regardless of infectious agents, plays important roles in the development of various cancers, particularly in digestive organs, including Helicobacter pylori-associated gastric cancer, hepatitis C virus-positive hepatocellular carcinoma, and colitis-associated colon cancers. Cancer development is characterized by stepwise accumulation of genetic and epigenetic alterations of various proto-oncogenes and tumor-suppressor genes. During chronic inflammation, infectious agents such as H pylori and hepatitis C virus as well as intrinsic mediators of inflammatory responses, including proinflammatory cytokines and reactive oxygen and nitrogen species, can induce genetic and epigenetic changes, including point mutations, deletions, duplications, recombinations, and methylation of various tumor-related genes through various mechanisms. Furthermore, inflammation also modulates the expressions of microRNAs that influence the production of several tumor-related messenger RNAs or proteins. These molecular events induced by chronic inflammation work in concert to alter important pathways involved in normal cellular function, and hence accelerate inflammation-associated cancer development. Among these, recent studies highlighted an important role of activation-induced cytidine deaminase, a nucleotide-editing enzyme essential for somatic hypermutation and class-switch recombination of the immunoglobulin gene, as a genomic modulator in inflammation-associated cancer development.
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Affiliation(s)
- Tsutomu Chiba
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
| | - Hiroyuki Marusawa
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Toshikazu Ushijima
- Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan
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