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Mohammadpour S, Torshizi Esfahani A, Sarpash S, Vakili F, Zafarjafarzadeh N, Mashaollahi A, Pardakhtchi A, Nazemalhosseini-Mojarad E. Hippo Signaling Pathway in Colorectal Cancer: Modulation by Various Signals and Therapeutic Potential. Anal Cell Pathol (Amst) 2024; 2024:5767535. [PMID: 39431199 PMCID: PMC11489006 DOI: 10.1155/2024/5767535] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2023] [Revised: 07/07/2024] [Accepted: 08/19/2024] [Indexed: 10/22/2024] Open
Abstract
Colorectal cancer (CRC) stands as a significant global health issue, marked by elevated occurrence and mortality statistics. Despite the availability of various treatments, including chemotherapy, radiotherapy, and targeted therapy, CRC cells often exhibit resistance to these interventions. As a result, it is imperative to identify the disease at an earlier stage and enhance the response to treatment by acquiring a deeper comprehension of the processes driving tumor formation, aggressiveness, metastasis, and resistance to therapy. The Hippo pathway plays a critical role in facilitating the initiation of tumorigenesis and frequently experiences disruption within CRC because of genetic mutations and modified expression in its fundamental constituents. Targeting upstream regulators or core Hippo pathway components may provide innovative therapeutic strategies for modulating Hippo signaling dysfunction in CRC. To advance novel therapeutic techniques for CRC, it is imperative to grasp the involvement of the Hippo pathway in CRC and its interaction with alternate signaling pathways, noncoding RNAs, gut microbiota, and the immune microenvironment. This review seeks to illuminate the function and control of the Hippo pathway in CRC, ultimately aiming to unearth innovative therapeutic methodologies for addressing this ailment.
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Affiliation(s)
- Somayeh Mohammadpour
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Amir Torshizi Esfahani
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - SeyedKasra Sarpash
- Department of Cellular and Molecular Biology, Faculty of Advanced Science and Technology, Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Fatemeh Vakili
- Department of Cellular and Molecular Biology, Faculty of Advanced Science and Technology, Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Nikta Zafarjafarzadeh
- Department of Cellular and Molecular Biology, Faculty of Advanced Science and Technology, Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Amirhesam Mashaollahi
- Department of Cellular and Molecular Biology, Faculty of Advanced Science and Technology, Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Ali Pardakhtchi
- Department of Cellular and Molecular Biology, Faculty of Advanced Science and Technology, Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Ehsan Nazemalhosseini-Mojarad
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Akanyibah FA, Zhu Y, Wan A, Ocansey DKW, Xia Y, Fang AN, Mao F. Effects of DNA methylation and its application in inflammatory bowel disease (Review). Int J Mol Med 2024; 53:55. [PMID: 38695222 DOI: 10.3892/ijmm.2024.5379] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Accepted: 04/15/2024] [Indexed: 05/12/2024] Open
Abstract
Inflammatory bowel disease (IBD) is marked by persistent inflammation, and its development and progression are linked to environmental, genetic, immune system and gut microbial factors. DNA methylation (DNAm), as one of the protein modifications, is a crucial epigenetic process used by cells to control gene transcription. DNAm is one of the most common areas that has drawn increasing attention recently, with studies revealing that the interleukin (IL)‑23/IL‑12, wingless‑related integration site, IL‑6‑associated signal transducer and activator of transcription 3, suppressor of cytokine signaling 3 and apoptosis signaling pathways are involved in DNAm and in the pathogenesis of IBD. It has emerged that DNAm‑associated genes are involved in perpetuating the persistent inflammation that characterizes a number of diseases, including IBD, providing a novel therapeutic strategy for exploring their treatment. The present review discusses DNAm‑associated genes in the pathogenesis of IBD and summarizes their application as possible diagnostic, prognostic and therapeutic biomarkers in IBD. This may provide a reference for the particular form of IBD and its related methylation genes, aiding in clinical decision‑making and encouraging therapeutic alternatives.
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Affiliation(s)
- Francis Atim Akanyibah
- Department of Laboratory Medicine, Lianyungang Clinical College, Jiangsu University, Lianyungang, Jiangsu 222006, P.R. China
| | - Yi Zhu
- The People's Hospital of Danyang, Affiliated Danyang Hospital of Nantong University, Zhenjiang, Jiangsu 212300, P.R. China
| | - Aijun Wan
- Zhenjiang College, Zhenjiang, Jiangsu 212028, P.R. China
| | - Dickson Kofi Wiredu Ocansey
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China
| | - Yuxuan Xia
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China
| | - An-Ning Fang
- Basic Medical School, Anhui Medical College, Hefei, Anhui 230061, P.R. China
| | - Fei Mao
- Department of Laboratory Medicine, Lianyungang Clinical College, Jiangsu University, Lianyungang, Jiangsu 222006, P.R. China
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Pan J, Li J, Gao Y. The value of 7 peripheral blood serum ratios in diagnosis and prediction of disease activity of patients within inflammatory bowel disease individuals. Front Med (Lausanne) 2023; 10:1122005. [PMID: 37089594 PMCID: PMC10113552 DOI: 10.3389/fmed.2023.1122005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Accepted: 03/21/2023] [Indexed: 04/25/2023] Open
Abstract
Objective In recent years, a number of studies have suggested that inflammation-based biomarkers can be applied in the diagnostics and prognostic testing of disease. However, the association between these ratios and inflammatory bowel disease (IBD) remains unclear. We aimed to investigate the role of these inflammation-based ratios in patients with IBD. Methods Retrospective analysis of 362 patients with IBD and 100 healthy individuals from January 2016 and December 2021. The receiver operating characteristic curve and logistic regression analysis was applied to explore the diagnostic and predictive performance of the seven ratio markers [neutrophil- to-albumin ratio (NAR), neutrophil-to-pre-albumin ratio (NPAR), albumin-to-alkaline-phosphatase ratio (AAPR), albumin-to-globulin ratio (AGR), albumin-to-fibrinogen ratio (AFR), fibrinogen-to-pre-albumin ratio (FPR), and Prognostic Nutritional Index (PNI)] regarding to disease activity in IBD individuals. Results Compared with healthy controls, patients with Crohn's disease (CD) or ulcerative colitis (UC) exhibited higher levels of NAR, NPAR, FPR (P < 0.001), lower levels of AAPR, and PNI (P < 0.001). Multivariate logistic regression showed that the level of NPAR (OR = 1.12, 95%CI: 1.02-1.23, P = 0.016) and AGR (OR = 1.01, 95%CI: 1.01-1.12, P < 0.001) was an independent risk factor of IBD. Then, we found the level of NPAR (OR = 1.10, 95%CI: 1.01-1.20, P = 0.02) and PNI (OR = 0.83, 95%CI: 0.71-0.96, P = 0.01) was independently associated with disease activity. Besides, a positive association was observed between the level of NPAR and two clinical scores [Harvey Bradshaw index (HBI) in patients with CD, Mayo score in patients with UC]. Finally, the level of NPAR (P = 0.002) and PNI (P = 0.003) showed a significant difference in the IBD-associated neoplasia group and IBD without neoplasia group. Conclusion Our data first suggests NPAR as a putative biomarker for diagnosing and predicting disease activity in patients with IBD. Investigations involving a larger number of IBD individuals are necessary to validate its use as an easily obtained peripheral blood biomarker of IBD.
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Affiliation(s)
- Jun Pan
- Department of Gastroenterology, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei, China
| | - Jiao Li
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Yuanjun Gao
- Department of Gastroenterology, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei, China
- *Correspondence: Yuanjun Gao,
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Shah SC, Itzkowitz SH. Colorectal Cancer in Inflammatory Bowel Disease: Mechanisms and Management. Gastroenterology 2022; 162:715-730.e3. [PMID: 34757143 PMCID: PMC9003896 DOI: 10.1053/j.gastro.2021.10.035] [Citation(s) in RCA: 394] [Impact Index Per Article: 131.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Revised: 10/14/2021] [Accepted: 10/25/2021] [Indexed: 12/12/2022]
Abstract
Patients with inflammatory bowel disease (IBD) are at increased risk of developing colorectal cancer (CRC), despite decreases in CRC incidence in recent years. Chronic inflammation is the driver of neoplastic progression, resulting in dysplastic precursor lesions that may arise in multiple areas of the colon through a process of field cancerization. Colitis-associated CRC shares many molecular similarities with sporadic CRC, and preclinical investigations have demonstrated a potential role for the microbiome in concert with the host immune system in the development of colitis-associated colorectal cancer (CAC). Some unique molecular differences occur in CAC, but their role in the pathogenesis and behavior of inflammation-associated cancers remains to be elucidated. Nonconventional types of dysplasia have been increasingly recognized, but their natural history is not well defined, and they have not been incorporated into surveillance algorithms. The concept of cumulative inflammatory burden highlights the importance of considering histologic inflammation over time as an important risk factor for CAC. Dysplasia is arguably the most important risk factor for developing CAC, and advances have been made in the endoscopic detection and removal of precancerous lesions, thereby deferring or avoiding surgical resection. Some of the agents used to treat IBD are chemopreventive. It is hoped that by gaining better control of the underlying inflammation with newer medications and better endoscopic detection and management, a more sophisticated appreciation of clinicopathologic risk factors, and growing awareness of the genetic, immunologic, and environmental causes of colitis- associated neoplasia, that colitis-associated colorectal neoplasia will become even more predictable and manageable in the coming years.
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Affiliation(s)
- Shailja C Shah
- Division of Gastroenterology, University of California San Diego, San Diego, California; GI Section, VA San Diego Healthcare Center, San Diego, California
| | - Steven H Itzkowitz
- The Dr Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, New York.
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Yalchin M, Baker AM, Graham TA, Hart A. Predicting Colorectal Cancer Occurrence in IBD. Cancers (Basel) 2021; 13:2908. [PMID: 34200768 PMCID: PMC8230430 DOI: 10.3390/cancers13122908] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2021] [Revised: 05/27/2021] [Accepted: 06/01/2021] [Indexed: 12/13/2022] Open
Abstract
Patients with colonic inflammatory bowel disease (IBD) are at an increased risk of developing colorectal cancer (CRC), and are therefore enrolled into a surveillance programme aimed at detecting dysplasia or early cancer. Current surveillance programmes are guided by clinical, endoscopic or histological predictors of colitis-associated CRC (CA-CRC). We have seen great progress in our understanding of these predictors of disease progression, and advances in endoscopic technique and management, along with improved medical care, has been mirrored by the falling incidence of CA-CRC over the last 50 years. However, more could be done to improve our molecular understanding of CA-CRC progression and enable better risk stratification for patients with IBD. This review summarises the known risk factors associated with CA-CRC and explores the molecular landscape that has the potential to complement and optimise the existing IBD surveillance programme.
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Affiliation(s)
- Mehmet Yalchin
- Inflammatory Bowel Disease Department, St. Mark’s Hospital, Watford R.d., Harrow HA1 3UJ, UK
- Centre for Genomics and Computational Biology, Barts Cancer Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse S.q., London EC1M 6BQ, UK; (A.-M.B.); (T.A.G.)
| | - Ann-Marie Baker
- Centre for Genomics and Computational Biology, Barts Cancer Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse S.q., London EC1M 6BQ, UK; (A.-M.B.); (T.A.G.)
| | - Trevor A. Graham
- Centre for Genomics and Computational Biology, Barts Cancer Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse S.q., London EC1M 6BQ, UK; (A.-M.B.); (T.A.G.)
| | - Ailsa Hart
- Inflammatory Bowel Disease Department, St. Mark’s Hospital, Watford R.d., Harrow HA1 3UJ, UK
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Yi JM. DNA Methylation Change Profiling of Colorectal Disease: Screening towards Clinical Use. Life (Basel) 2021; 11:life11050412. [PMID: 33946400 PMCID: PMC8147151 DOI: 10.3390/life11050412] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Revised: 04/20/2021] [Accepted: 04/26/2021] [Indexed: 02/06/2023] Open
Abstract
Colon cancer remains one of the leading causes of cancer-related deaths worldwide. Transformation of colon epithelial cells into invasive adenocarcinomas has been well known to be due to the accumulation of multiple genetic and epigenetic changes. In the past decade, the etiology of inflammatory bowel disease (IBD) which is characterized by chronic inflammation of the intestinal mucosa, was only partially explained by genetic studies providing susceptibility loci, but recently epigenetic studies have provided critical evidences affecting IBD pathogenesis. Over the past decade, A deep understanding of epigenetics along with technological advances have led to identifying numerous genes that are regulated by promoter DNA hypermethylation in colorectal diseases. Recent advances in our understanding of the role of DNA methylation in colorectal diseases could improve a multitude of powerful DNA methylation-based biomarkers, particularly for use as diagnosis, prognosis, and prediction for therapeutic approaches. This review focuses on the emerging potential for translational research of epigenetic alterations into clinical utility as molecular biomarkers. Moreover, this review discusses recent progress regarding the identification of unknown hypermethylated genes in colon cancers and IBD, as well as their possible role in clinical practice, which will have important clinical significance, particularly in the era of the personalized medicine.
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Affiliation(s)
- Joo Mi Yi
- Department of Microbiology and Immunology, College of Medicine, Inje University, Busan 47392, Korea;
- Innovative Therapeutics Research Institute, College of Medicine, Inje University, Busan 47392, Korea
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Rosa I, Silva P, da Mata S, Magro F, Carneiro F, Peixoto A, Silva M, Sousa HT, Roseira J, Parra J, Barosa R, Vieira A, Brito MJ, Lago P, Coelho A, Moleiro J, Pereira da Silva J, Fonseca R, Albuquerque C, Dias Pereira A. Methylation patterns in dysplasia in inflammatory bowel disease patients. Scand J Gastroenterol 2020; 55:646-655. [PMID: 32456486 DOI: 10.1080/00365521.2020.1766552] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Background and aims: Inflammatory Bowel Disease (IBD) with colonic involvement increases colorectal cancer risk. However, the distinction between IBD related and sporadic dysplasia in IBD patients is difficult. Some data favors the importance of abnormal DNA methylation in IBD-related carcinogenesis. We aimed to define methylation patterns in patients with colonic cancer or dysplasia diagnosis following an IBD diagnosis.Methods: Multicentric cross-sectional study-91 samples from colonic mucosa with/without dysplasia from 9 patients with IBD-related dysplasia/cancer and 26 patients with IBD and sporadic dysplasia/cancer were included. Methylation patterns of CpG islands in the promoter regions of 67 genes were studied by Methylation-specific Multiplex Ligation-dependent Probe Amplification.Results: Mean age at IBD diagnosis: 42 ± 16 years;at dysplasia diagnosis: 56 ± 14 years. Twenty-ninepatients had ulcerative colitis. Twenty-five patients had at least 1 lesion endoscopically described as adenoma-like, 4 at least 1 non-adenoma like, 3 had cancer and 3 had dysplasia in flat mucosa. No patient had both adenoma-like and non-adenoma-like lesions. Patients with an IBD-related lesion were significantly younger at IBD diagnosis (p = .003) and at dysplasia/cancer diagnosis (p = .039). Promoter methylation of IGF2, RARB, ESR1, CHFR, CDH13, WT1, GATA5, WIF1genes was significantly associated to dysplasia/cancer; methylation of MSH6, TIMP3 was significantly associated to IBD-related dysplasia/cancer. Promoter methylation of MSH6, MSH3, RUNX3, CRABP1, TP73, RARB, CDH13, PAX5, WT1, THBS1, TP53, SFRP1, WIF1, APAF1, BCL2 genes was significantly associated to active IBD.Conclusions: Methylation analysis, namely of MSH6, may contribute to the classification of dysplastic lesions in IBD- to be further tested in prospective studies.
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Affiliation(s)
- Isadora Rosa
- Gastroenterology Department, Instituto Português de Oncologia de Lisboa, Francisco Gentil, EPE, Lisboa, Portugal
| | - Patrícia Silva
- Molecular Pathobiology Investigation Unit, Instituto Português de Oncologia de Lisboa, Francisco Gentil, EPE, Lisboa, Portugal
| | - Sara da Mata
- Pathology Department, Instituto Português de Oncologia de Lisboa, Francisco Gentil, EPE, Lisboa, Portugal
| | - Fernando Magro
- Gastroenterology Department, Centro Hospitalar de São João, EPE, Porto, Portugal
| | - Fátima Carneiro
- Pathology Department, Centro Hospitalar de São João, EPE, Porto, Portugal
| | - Armando Peixoto
- Gastroenterology Department, Centro Hospitalar de São João, EPE, Porto, Portugal
| | - Marco Silva
- Gastroenterology Department, Centro Hospitalar de São João, EPE, Porto, Portugal
| | - Helena T Sousa
- Gastroenterology Department, Centro Hospitalar Universitário do Algarve, EPE, Unidade de Portimão, Portimão, Portugal.,Algarve Biomedical Center, Campus Gambelas - Universidade do Algarve, Faro, Portugal
| | - Joana Roseira
- Gastroenterology Department, Centro Hospitalar Universitário do Algarve, EPE, Unidade de Portimão, Portimão, Portugal.,Algarve Biomedical Center, Campus Gambelas - Universidade do Algarve, Faro, Portugal
| | - José Parra
- Pathology Department, Centro Hospitalar Universitário do Algarve, EPE, Unidade de Portimão, Portimão, Portugal
| | - Rita Barosa
- Gastroenterology Department, Hospital Garcia de Orta, EPE, Almada, Portugal
| | - Ana Vieira
- Gastroenterology Department, Hospital Garcia de Orta, EPE, Almada, Portugal
| | - Maria José Brito
- Pathology Department, Hospital Garcia de Orta, EPE, Almada, Portugal
| | - Paula Lago
- Gastroenterology Department, Centro Hospitalar do Porto, EPE - Hospital de Santo António, Porto, Portugal
| | - André Coelho
- Portuguese Inflammatory Bowel Diseases Study Group, Porto, Portugal
| | - Joana Moleiro
- Gastroenterology Department, Instituto Português de Oncologia de Lisboa, Francisco Gentil, EPE, Lisboa, Portugal
| | - João Pereira da Silva
- Gastroenterology Department, Instituto Português de Oncologia de Lisboa, Francisco Gentil, EPE, Lisboa, Portugal
| | - Ricardo Fonseca
- Pathology Department, Instituto Português de Oncologia de Lisboa, Francisco Gentil, EPE, Lisboa, Portugal
| | - Cristina Albuquerque
- Molecular Pathobiology Investigation Unit, Instituto Português de Oncologia de Lisboa, Francisco Gentil, EPE, Lisboa, Portugal
| | - A Dias Pereira
- Gastroenterology Department, Instituto Português de Oncologia de Lisboa, Francisco Gentil, EPE, Lisboa, Portugal
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- Portuguese Inflammatory Bowel Diseases Study Group, Porto, Portugal
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Fan JM, Zheng ZR, Zeng YM, Chen XY. MiR-323-3p Targeting Transmembrane Protein with EGF-Like and 2 Follistatin Domain (TMEFF2) Inhibits Human Lung Cancer A549 Cell Apoptosis by Regulation of AKT and ERK Signaling Pathways. Med Sci Monit 2020; 26:e919454. [PMID: 32009129 PMCID: PMC7011573 DOI: 10.12659/msm.919454] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Background Non-small-cell lung cancer (NSCLC) is predominant and has low 5-year relative survival rate. Therefore, the mechanisms of NSCLC tumorigenesis must be comprehensively elucidated. MicroRNA-323-3p (miR-323-3p) has been widely explored and found to exert functions in tumorigenesis of several cancer types. However, the expression pattern and biological function of miR-323-3p and the molecular mechanism underlying NSCLC development and progression remain unclear. Material/Methods Quantitative reverse-transcription polymerase chain reaction was used to detect the expression of miR-323-3p and TMEFF2 in NSCLC cell lines (A549, NCI-H3255, and H1299) and normal cell line (BEAS-2B). Methylthiazolyl tetrazolium, colony formation, and flow cytometry assays were performed to evaluate the effects of miR-323-3p and TMEFF2 on cell proliferation. Transwell assay was conducted to determine the effects of TMEFF2 on cell migration and invasion. Dual-luciferase reporter assay was used to verify whether TMEFF2 is a target of miR-323-3p. Western blot analysis was performed to analyze protein expression. Results The expression of miR-323-3p increased in the 3 NSCLC cell lines (A549, NCI-H3255, and H1299). miR-323-3p regulated cellular progression by directly suppressing TMEFF2 expression and indirectly prohibited the activation of AKT and ERK pathways in NSCLC. Conclusions Overall, miR-323-3p was considered a lung cancer oncogene and could be a valuable target for NSCLC therapy.
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Affiliation(s)
- Ji-Min Fan
- Department of Pulmonary and Critical Care Medicine, Second Affiliated Hospital of Fujian Medical University, Respiratory Medicine Center of Fujian Province, Quanzhou, Fujian, China (mainland)
| | - Zheng-Rong Zheng
- Department of Surgical Oncology, Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, China (mainland)
| | - Yi-Ming Zeng
- Department of Pulmonary and Critical Care Medicine, Second Affiliated Hospital of Fujian Medical University, Respiratory Medicine Center of Fujian Province, Quanzhou, Fujian, China (mainland)
| | - Xiao-Yang Chen
- Department of Pulmonary and Critical Care Medicine, Second Affiliated Hospital of Fujian Medical University, Respiratory Medicine Center of Fujian Province, Quanzhou, Fujian, China (mainland)
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Zeng Z, Mukherjee A, Zhang H. From Genetics to Epigenetics, Roles of Epigenetics in Inflammatory Bowel Disease. Front Genet 2019; 10:1017. [PMID: 31737035 PMCID: PMC6834788 DOI: 10.3389/fgene.2019.01017] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2019] [Accepted: 09/24/2019] [Indexed: 02/05/2023] Open
Abstract
Inflammatory bowel disease (IBD) is a destructive, recurrent, and heterogeneous disease. Its detailed pathogenesis is still unclear, although available evidence supports that IBD is caused by a complex interplay between genetic predispositions, environmental factors, and aberrant immune responses. Recent breakthroughs with regard to its genetics have offered valuable insights into the sophisticated genetic basis, but the identified genetic factors only explain a small part of overall disease variance. It is becoming increasingly apparent that epigenetic factors can mediate the interaction between genetics and environment, and play a fundamental role in the pathogenesis of IBD. This review outlines recent genetic and epigenetic discoveries in IBD, with a focus on the roles of epigenetics in disease susceptibility, activity, behavior and colorectal cancer (CRC), and their potential translational applications.
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Affiliation(s)
- Zhen Zeng
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
- Center for Inflammatory Bowel Disease, West China Hospital, Sichuan University, Chengdu, China
| | | | - Hu Zhang
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
- Center for Inflammatory Bowel Disease, West China Hospital, Sichuan University, Chengdu, China
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10
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Shah SC, Itzkowitz SH. Management of Inflammatory Bowel Disease-Associated Dysplasia in the Modern Era. Gastrointest Endosc Clin N Am 2019; 29:531-548. [PMID: 31078251 PMCID: PMC7354094 DOI: 10.1016/j.giec.2019.02.008] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
This article begins with a brief overview of risk factors for colorectal neoplasia in inflammatory bowel disease to concretize the approach to risk stratification. It then provides an up-to-date review of diagnosis and management of dysplasia in inflammatory bowel disease, which integrates new and emerging data in the field. This is particularly relevant in an era of increased attention to cost- and resource-containment from the health systems vantage point, coupled with a heightened prioritization of patient quality of life and shared decision-making. Also provided is a brief discussion of the status of newer therapeutic techniques, such as endoscopic submucosal dissection.
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Affiliation(s)
- Shailja C. Shah
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Steven H. Itzkowitz
- Division of Gastroenterology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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11
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Pekow J, Hernandez K, Meckel K, Deng Z, Haider HI, Khalil A, Zhang C, Talisila N, Siva S, Jasmine F, Li YC, Rubin DT, Hyman N, Bissonnette M, Weber C, Kibriya MG. IBD-associated Colon Cancers Differ in DNA Methylation and Gene Expression Profiles Compared With Sporadic Colon Cancers. J Crohns Colitis 2019; 13:884-893. [PMID: 30753380 PMCID: PMC7327274 DOI: 10.1093/ecco-jcc/jjz014] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIMS As ulcerative colitis [UC]-associated colorectal cancer [CRC] and sporadic CRC differ in presentation and molecular features, we sought to evaluate differences in the impact of DNA methylation on gene expression. METHODS DNA methylation was assessed in 11 UC-CRCs and adjacent tissue and 11 sporadic CRCs and adjacent tissue, using Illumina arrays. RNA sequencing was performed on 10 UC-CRCs and adjacent tissue and eight sporadic CRCs and adjacent tissues. Differences in DNA methylation and transcript expression, as well as their correlation in the same tissues, were assessed. Immunohistochemistry was performed for three proteins, ANPEP, FAM92A1, and STK31, all of which exhibited an inverse correlation between DNA methylation and transcript expression in UC. RESULTS Thirty three loci demonstrated differences in DNA methylation between UC-CRC and adjacent tissue. In contrast, there were 4204 differentially methylated loci between sporadic colon cancer and adjacent tissue. Eight hundred eighty six genes as well as 10 long non-coding RNAs [lncRNA] were differentially expressed between UC-CRC and adjacent tissues. Although there were no differentially methylated loci between UC and sporadic CRC, 997 genes and 38 lncRNAs were differentially expressed between UC-CRC and sporadic CRC. In UC, 18 genes demonstrated a negative correlation between DNA methylation and transcript expression. Evaluation of protein expression related to three genes, ANPEP, FAM92A1, and STK31, confirmed down-regulation of ANPEP and up-regulation of STK31 in UC-CRC. CONCLUSIONS Regulation of transcript expression by DNA methylation involves genes key to colon carcinogenesis and may account for differences in presentation and outcomes between inflammatory bowel disease and sporadic colon cancer.
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Affiliation(s)
- Joel Pekow
- University of Chicago, Section of Gastroenterology, Hepatology, and Nutrition,Corresponding author: Joel Pekow, MD, 900 East 57th St, MB #9, University of Chicago Medicine, Section of Gastroenterology, Hepatology, and Nutrition, Chicago, IL 60637, USA. Tel: 773-702-2774; Fax: 773-702-2281;
| | - Kyle Hernandez
- University of Chicago, Center for Research Informatics,University of Chicago, Department of Pediatrics
| | - Katherine Meckel
- University of Chicago, Section of Gastroenterology, Hepatology, and Nutrition
| | - Zifeng Deng
- University of Chicago, Section of Gastroenterology, Hepatology, and Nutrition
| | - Haider I Haider
- University of Chicago, Section of Gastroenterology, Hepatology, and Nutrition
| | - Abdurahman Khalil
- University of Chicago, Section of Gastroenterology, Hepatology, and Nutrition
| | | | - Nitya Talisila
- University of Chicago, Section of Gastroenterology, Hepatology, and Nutrition
| | - Shivi Siva
- University of Chicago, Section of Gastroenterology, Hepatology, and Nutrition
| | | | - Yan Chun Li
- University of Chicago, Section of Gastroenterology, Hepatology, and Nutrition
| | - David T Rubin
- University of Chicago, Section of Gastroenterology, Hepatology, and Nutrition
| | - Neil Hyman
- University of Chicago, Department of Surgery
| | - Marc Bissonnette
- University of Chicago, Section of Gastroenterology, Hepatology, and Nutrition
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12
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Zandvakili I, Lazaridis KN. Cell-free DNA testing: future applications in gastroenterology and hepatology. Therap Adv Gastroenterol 2019; 12:1756284819841896. [PMID: 31019553 PMCID: PMC6466469 DOI: 10.1177/1756284819841896] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2018] [Accepted: 03/04/2019] [Indexed: 02/04/2023] Open
Abstract
The application of next-generation sequencing in clinical practice is increasing as accuracy and interpretation have improved and the cost continues to decline rapidly. Cell-free DNA is a unique source for next-generation sequencing that could change routine clinical practice in gastroenterology and hepatology. Testing of cell-free DNA in blood and fecal samples is an easy, rapid, and noninvasive method to assess for premalignant, malignant, metabolic, infectious, inflammatory, and autoimmune gastrointestinal and liver diseases. In this review, we describe cell-free DNA technologies, current applications of cell-free DNA testing, and proposed cell-free DNA targets for gastrointestinal and hepatic diseases, with a specific focus on malignancy. In addition, we provide commentary on how cell-free DNA can be integrated into clinical practice and help guide diagnosis, prognosis, disease management, and therapeutic response.
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Affiliation(s)
- Inuk Zandvakili
- Division of Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA
| | - Konstantinos N. Lazaridis
- Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA
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13
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Kisiel JB, Klepp P, Allawi HT, Taylor WR, Giakoumopoulos M, Sander T, Yab TC, Moum BA, Lidgard GP, Brackmann S, Mahoney DW, Roseth A, Ahlquist DA. Analysis of DNA Methylation at Specific Loci in Stool Samples Detects Colorectal Cancer and High-Grade Dysplasia in Patients With Inflammatory Bowel Disease. Clin Gastroenterol Hepatol 2019; 17:914-921.e5. [PMID: 29775793 PMCID: PMC6368476 DOI: 10.1016/j.cgh.2018.05.004] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2017] [Revised: 03/08/2018] [Accepted: 05/07/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Patients with inflammatory bowel diseases (IBDs), including ulcerative colitis and Crohn's disease, are at increased risk for colorectal cancer (CRC). Analyses of DNA methylation patterns in stool samples have been reported to detect CRC in patients with IBD. We sought to validate these findings in larger cohorts and assess the accuracy of analysis of DNA methylation patterns in stool for detection of CRC and high-grade dysplasia (HGD) normalized to methylation level at ZDHHC1. METHODS We obtained buffered, frozen stool samples from a US case-control study and from 2 European surveillance cohorts (referral or population based) of patients with chronic ulcerative colitis (n = 248), Crohn's disease (n = 82), indeterminate colitis (n = 2), or IBD with primary sclerosing cholangitis (n = 38). Stool samples were collected before bowel preparation for colonoscopy or at least 1 week after colonoscopy. Among the study samples, stools from individuals with IBD but without neoplasia were used as controls (n = 291). DNA was isolated from stool, exposed to bisulfite, and then assayed by multiplex quantitative allele-specific real-time target and signal amplification. We analyzed methylation levels of BMP3, NDRG4, VAV3, and SFMBT2 relative to the methylation level of ZDHHC1, and compared these between patients with CRC or HGD and controls. RESULTS Levels of methylation at BMP3 and VAV3, relative to ZDHHC1 methylation, identified patients with CRC and HGD with an area under the curve value of 0.91 (95% CI, 0.77-1.00). Methylation levels at specific promotor regions of these genes identified 11 of the 12 patients with CRC and HGD, with 92% sensitivity (95% CI, 60%-100%) and 90% specificity (95% CI, 86%-93%). The proportion of false-positive results did not differ significantly among the case-control, referral cohort, and population cohort studies (P = .60) when the 90% specificity cut-off from the whole sample set was applied. CONCLUSIONS In an analysis of stool samples from 3 independent studies of 332 patients with IBD, we associated levels of methylation at 2 genes (BMP3 and VAV3), relative to level of methylation at ZDHHC1, with detection of CRC and HGD. These methylation patterns identified patients with CRC and HGD with more than 90% specificity, and might be used in CRC surveillance.
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Affiliation(s)
- John B Kisiel
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.
| | - Pasquale Klepp
- Department of Internal Medicine, Lovisenberg Hospital, Oslo, Norway; Clinical Medicine, University Hospital, University of Oslo, Oslo, Norway
| | - Hatim T Allawi
- Department of Gastroenterology, Akershus University Hospital, University of Oslo, Oslo, Norway
| | - William R Taylor
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | | | | | - Tracy C Yab
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Bjorn A Moum
- Department of Gastroenterology, Oslo University Hospital, Oslo, Norway
| | | | - Stephan Brackmann
- Department of Gastroenterology, Akershus University Hospital, University of Oslo, Oslo, Norway; Clinical Medicine, University Hospital, University of Oslo, Oslo, Norway
| | - Douglas W Mahoney
- Department of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota
| | - Arne Roseth
- Department of Internal Medicine, Lovisenberg Hospital, Oslo, Norway
| | - David A Ahlquist
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
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14
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Azuara D, Aussó S, Rodriguez-Moranta F, Guardiola J, Sanjuan X, Lobaton T, Boadas J, Piqueras M, Monfort D, Guinó E, Moreno V, Capellá G, de Oca J. New Methylation Biomarker Panel for Early Diagnosis of Dysplasia or Cancer in High-Risk Inflammatory Bowel Disease Patients. Inflamm Bowel Dis 2018; 24:2555-2564. [PMID: 30099509 DOI: 10.1093/ibd/izy255] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2017] [Indexed: 02/07/2023]
Abstract
BACKGROUND The risk of developing colorectal cancer (CRC) is increased in patients with inflammatory bowel disease (IBD) of the colon. The aim of the study was to evaluate the effectiveness of selected methylation gene panel for the early detection of CRC in high-risk IBD patients. METHODS In a discovery phase, 73 biopsies of 48 IBD patients (associated or not to CRC) were analyzed from genome-wide DNA methylation analysis using the Illumina Human Methylation 450K BeadChip. The panel of 5 genes selected (EYA4, SLIT2, FLI1, USP44, and SND1) was validated prospectively using methylation-specific melting curve analysis in biopsies of diseased and adjacent healthy tissue of 203 patients: 38 with IBD and associated neoplasia, 81 patients with IBD (25 of them with high risk), 48 with sporadic CRC, and 36 healthy controls. RESULTS The prevalence of methylation was higher in patients with IBD and associated neoplasia (both in diseased and adjacent healthy tissue, 71% and 52%, respectively) than in healthy controls (2/36, 6%; P = 6.72E-05). Methylation in IBD patients at high risk of dysplasia or cancer was more frequently detected than in patients at low risk (92% vs 57%; odds ratio, 8.63; P = 0.001). EYA4 and SLIT2 were the markers most frequently methylated. Differences in methylation levels were more evident in healthy mucosa (82% vs 15% high vs low risk, respectively; P = 1.25E-05). CONCLUSIONS Analysis of this panel of methylation markers may help in the early identification of colorectal dysplasia or cancer in high-risk IBD patients.
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Affiliation(s)
- Daniel Azuara
- Translational Research Laboratory, Catalan Insitute of Oncology (ICO), Bellvitge Biomedical Research Institute (IDIBELL)-CIBERONC, L'Hospitalet de Llobregat, Barcelona, Spain
| | - Susanna Aussó
- Unit of Biomarkers and Susceptibility, Cancer Prevention and Control Program, ICO-IDIBELL and CIBERESP, L'Hospitalet de Llobregat, Barcelona, Spain
| | - Francisco Rodriguez-Moranta
- Department of Gastroenterology, University Hospital Bellvitge (HUB-IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain
| | - Jordi Guardiola
- Department of Gastroenterology, University Hospital Bellvitge (HUB-IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain
| | - Xavier Sanjuan
- Department of Pathology, University Hospital Bellvitge (HUB-IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain
| | - Triana Lobaton
- Department of Gastroenterology, Germans Trias i Pujol University Hospital, Badalona, Barcelona, Spain
| | - Jaume Boadas
- Department of Gastroenterology, Hospital of Terrassa, Terrassa Health Consortium (CST), Terrassa, Barcelona, Spain
| | - Marta Piqueras
- Department of Gastroenterology, Hospital of Terrassa, Terrassa Health Consortium (CST), Terrassa, Barcelona, Spain
| | - David Monfort
- Department of Gastroenterology, Hospital of Terrassa, Terrassa Health Consortium (CST), Terrassa, Barcelona, Spain
| | - Elisabet Guinó
- Unit of Biomarkers and Susceptibility, Cancer Prevention and Control Program, ICO-IDIBELL and CIBERESP, L'Hospitalet de Llobregat, Barcelona, Spain
| | - Victor Moreno
- Unit of Biomarkers and Susceptibility, Cancer Prevention and Control Program, ICO-IDIBELL and CIBERESP, L'Hospitalet de Llobregat, Barcelona, Spain
| | - Gabriel Capellá
- Translational Research Laboratory, Catalan Insitute of Oncology (ICO), Bellvitge Biomedical Research Institute (IDIBELL)-CIBERONC, L'Hospitalet de Llobregat, Barcelona, Spain
| | - Javier de Oca
- Department of General and Digestive Surgery, Colorectal Unit, University Hospital Bellvitge (HUB-IDIBELL)-CIBERONC, L'Hospitalet de Llobregat, Barcelona, Spain
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15
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Xue M, Shi L, Wang W, Chen S, Wang L. An Overview of Molecular Profiles in Ulcerative Colitis-Related Cancer. Inflamm Bowel Dis 2018; 24:1883-1894. [PMID: 29945208 DOI: 10.1093/ibd/izy221] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2017] [Indexed: 12/16/2022]
Abstract
Ulcerative colitis (UC) is an independent risk factor of colorectal cancer (CRC). Both genetic and epigentic events induce a unique molecular profile during the development from UC to UC-related CRC (UCRC). These molecular changes play varied roles in DNA repair, immune response, cell metabolism, and interaction with the microbiota during the carcinogenesis process. This review will systmatically discuss the molecular characteristics of UCRC and point out the future perspectives in this research field.
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Affiliation(s)
- Meng Xue
- Department of Gastroenterology, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.,Institute of Gastroenterology, Zhejiang University, Hangzhou, Zhejiang, China
| | - Liuhong Shi
- Department of Ultrasound, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Weijia Wang
- Department of Cardiology, School of Medicine, the Johns Hopkins Hospital, Baltimore, Maryland
| | - Shujie Chen
- Department of Gastroenterology, Sir Runrun Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Liangjing Wang
- Department of Gastroenterology, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.,Institute of Gastroenterology, Zhejiang University, Hangzhou, Zhejiang, China
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16
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Zhen Y, Luo C, Zhang H. Early detection of ulcerative colitis-associated colorectal cancer. Gastroenterol Rep (Oxf) 2018; 6:83-92. [PMID: 29780595 PMCID: PMC5952942 DOI: 10.1093/gastro/goy010] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2018] [Revised: 02/17/2018] [Accepted: 03/26/2018] [Indexed: 02/05/2023] Open
Abstract
Colitis-associated colorectal cancer (CACC) is one of the most serious complications of inflammatory bowel disease (IBD), particularly in ulcerative colitis (UC); it accounts for approximately 15% of all-causes mortality among IBD patients. Because CACC shows a worse prognosis and higher mortality than sporadic colorectal cancer, early detection is critical. Colonoscopy is primarily recommended for surveillance and several advanced endoscopic imaging techniques are emerging. In addition, recent studies have reported on attempts to develop clinically relevant biomarkers for surveillance using various biosamples, which may become high-performance screening tools in the future, so the best approach and technique for cancer surveillance in long-standing UC patients remain under debate. This review gives a comprehensive description and summary about what progress has been made in terms of early CACC detection.
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Affiliation(s)
- Yu Zhen
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Chengxin Luo
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Hu Zhang
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
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Nagy P, Szatmári Z, Sándor GO, Lippai M, Hegedűs K, Juhász G. Drosophila Atg16 promotes enteroendocrine cell differentiation via regulation of intestinal Slit/Robo signaling. Development 2017; 144:3990-4001. [PMID: 28982685 DOI: 10.1242/dev.147033] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2016] [Accepted: 09/25/2017] [Indexed: 12/22/2022]
Abstract
Genetic variations of Atg16l1, Slit2 and Rab19 predispose to the development of inflammatory bowel disease (IBD), but the relationship between these mutations is unclear. Here we show that in Drosophila guts lacking the WD40 domain of Atg16, pre-enteroendocrine (pre-EE) cells accumulate that fail to differentiate into properly functioning secretory EE cells. Mechanistically, loss of Atg16 or its binding partner Rab19 impairs Slit production, which normally inhibits EE cell generation by activating Robo signaling in stem cells. Importantly, loss of Atg16 or decreased Slit/Robo signaling triggers an intestinal inflammatory response. Surprisingly, analysis of Rab19 and domain-specific Atg16 mutants indicates that their stem cell niche regulatory function is independent of autophagy. Our study reveals how mutations in these different genes may contribute to IBD.
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Affiliation(s)
- Péter Nagy
- Department of Anatomy, Cell and Developmental Biology, Eötvös Loránd University, Pázmány s. 1/C, Budapest, H-1117 Hungary
| | - Zsuzsanna Szatmári
- Department of Anatomy, Cell and Developmental Biology, Eötvös Loránd University, Pázmány s. 1/C, Budapest, H-1117 Hungary
| | - Gyöngyvér O Sándor
- Department of Anatomy, Cell and Developmental Biology, Eötvös Loránd University, Pázmány s. 1/C, Budapest, H-1117 Hungary
| | - Mónika Lippai
- Department of Anatomy, Cell and Developmental Biology, Eötvös Loránd University, Pázmány s. 1/C, Budapest, H-1117 Hungary
| | - Krisztina Hegedűs
- Department of Anatomy, Cell and Developmental Biology, Eötvös Loránd University, Pázmány s. 1/C, Budapest, H-1117 Hungary
| | - Gábor Juhász
- Department of Anatomy, Cell and Developmental Biology, Eötvös Loránd University, Pázmány s. 1/C, Budapest, H-1117 Hungary
- Institute of Genetics, Biological Research Centre, Hungarian Academy of Sciences, Temesvári krt. 62, Szeged, H-6726 Hungary
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Abstract
INTRODUCTION Aberrant DNA methylation frequently occurs in the inflammatory mucosa in ulcerative colitis (UC) and is involved in UC-related tumorigenesis. We performed comprehensive DNA methylation profiling of the promoter regions of the inflamed rectal mucosae of patients with UC. DESIGN The methylation status of the promoter CpG islands (CGIs) of 45 cancer/inflammation or age-related candidate genes and the LINE1 repetitive element were examined in the colonic mucosae of 84 cancer-free patients with UC by bisulfite pyrosequencing. Methylation status of selected genes (DPYS, N33, MIR1247, GSTP1, and SOX11) was also determined in 14 neoplastic lesions (5 with high-grade dysplasia and 9 with carcinoma) and 8 adjacent tissues derived from 12 patients. An Infinium HumanMethylation450 BeadChip array was used to characterize the methylation status of >450,000 CpG sites for 10 patients with UC. RESULTS Clustering analysis based on the methylation status of the candidate genes clearly distinguished the inflammatory samples from the noninflammatory samples. The hypermethylation of the promoter CGIs strongly correlated with increased disease duration, which is a known risk factor for the development of colon cancer. Genome-wide methylation analyses revealed a high rate of hypermethylation in the severe phenotype of UC, particularly at the CGIs. Exclusively hypermethylated promoter CGIs in the severe phenotypes were significantly related to genes involved in biosynthetic processes, the regulation of metabolic processes, and nitrogen compound metabolic processes. CONCLUSION Our findings suggest the potential utility of DNA methylation as a molecular marker and therapeutic target for UC-related tumorigenesis.
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19
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Candidate predisposing germline copy number variants in early onset colorectal cancer patients. Clin Transl Oncol 2016; 19:625-632. [PMID: 27888432 DOI: 10.1007/s12094-016-1576-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2016] [Accepted: 11/10/2016] [Indexed: 01/04/2023]
Abstract
PURPOSE A great proportion of the heritability of colorectal cancer (CRC) still remains unexplained, and rare variants, as well as copy number changes, have been proposed as potential candidates to explain the so-called 'missing heritability'. We aimed to identify rare high-to-moderately penetrant copy number variants (CNVs) in patients suspected of having hereditary CRC due to an early onset. METHODS/PATIENTS We have selected for genome-wide copy number analysis, 27 MMR-proficient early onset CRC patients (<50 years) without identifiable germline mutations in Mendelian genes related to this phenotype. Rare CNVs were selected by removing all CNVs detected at MAF >1% in the in-house control CNV database (n = 629 healthy controls). Copy number assignment was checked by duplex real-time quantitative PCR or multiplex ligation probe amplification. Somatic mutation analysis in candidate genes included: loss of heterozygosity studies, point mutation screening, and methylation status of the promoter. RESULTS We have identified two rare germline deletions involving the AK3 and SLIT2 genes in two patients. The search for a second somatic mutational event in the corresponding CRC tumors showed loss of heterozygosity in AK3, and promoter hypermethylation in SLIT2. Both genes have been previously related to colorectal carcinogenesis. CONCLUSIONS These findings suggest that AK3 and SLIT2 may be potential candidates involved in genetic susceptibility to CRC.
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20
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Dulai PS, Sandborn WJ, Gupta S. Colorectal Cancer and Dysplasia in Inflammatory Bowel Disease: A Review of Disease Epidemiology, Pathophysiology, and Management. Cancer Prev Res (Phila) 2016; 9:887-894. [PMID: 27679553 DOI: 10.1158/1940-6207.capr-16-0124] [Citation(s) in RCA: 126] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2016] [Revised: 08/25/2016] [Accepted: 08/30/2016] [Indexed: 02/07/2023]
Abstract
Crohn disease and ulcerative colitis are chronic inflammatory bowel diseases (IBD) characterized by recurrent episodes of mucosal inflammation. This chronic mucosal inflammation has several potential consequences, one of which is the occurrence of colitis-associated colorectal cancer. Over the past decade, our understanding of the epidemiology, pathophysiology, and overall approach to diagnosing and managing colitis-associated colorectal cancer has grown considerably. In the current review article, we outline these advancements and highlight areas in need of further research. Cancer Prev Res; 9(12); 887-94. ©2016 AACR.
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Affiliation(s)
- Parambir S Dulai
- Division of Gastroenterology, University of California San Diego, La Jolla, California
| | - William J Sandborn
- Division of Gastroenterology, University of California San Diego, La Jolla, California
| | - Samir Gupta
- Division of Gastroenterology, University of California San Diego, La Jolla, California. .,Veterans Affairs San Diego Healthcare System, San Diego, California.,Moores Cancer Center, University of California San Diego, La Jolla, California
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21
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Ginesta MM, Diaz-Riascos ZV, Busquets J, Pelaez N, Serrano T, Peinado MÀ, Jorba R, García-Borobia FJ, Capella G, Fabregat J. APC promoter is frequently methylated in pancreatic juice of patients with pancreatic carcinomas or periampullary tumors. Oncol Lett 2016; 12:2210-2216. [PMID: 27602165 DOI: 10.3892/ol.2016.4868] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2015] [Accepted: 05/23/2016] [Indexed: 12/18/2022] Open
Abstract
Early detection of pancreatic and periampullary neoplasms is critical to improve their clinical outcome. The present authors previously demonstrated that DNA hypermethylation of adenomatous polyposis coli (APC), histamine receptor H2 (HRH2), cadherin 13 (CDH13), secreted protein acidic and cysteine rich (SPARC) and engrailed-1 (EN-1) promoters is frequently detected in pancreatic tumor cells. The aim of the present study was to assess their prevalence in pancreatic juice of carcinomas of the pancreas and periampullary area. A total of 135 pancreatic juices obtained from 85 pancreatic cancer (PC), 26 ampullary carcinoma (AC), 10 intraductal papillary mucinous neoplasm (IPMN) and 14 chronic pancreatitis (CP) patients were analyzed. The methylation status of the APC, HRH2, CDH13, SPARC and EN-1 promoters was analyzed using methylation specific-melting curve analysis (MS-MCA). Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations were also tested with allele-specific quantitative polymerase chain reaction amplification. Out of the 5 promoters analyzed, APC (71%) and HRH2 (65%) were the most frequently methylated in PC juice. APC methylation was also detected at a high frequency in AC (76%) and IPMN (80%), but only occasionally observed in CP (7%). APC methylation had a high sensitivity (71-80%) for all types of cancer analyzed. The panel (where a sample scored as positive when ≥2 markers were methylated) did not outperform APC as a single marker. Finally, KRAS detection in pancreatic juice offered a lower sensitivity (50%) and specificity (71%) for detection of any cancer. APC hypermethylation in pancreatic juice, as assessed by MS-MCA, is a frequent event of potential clinical usefulness in the diagnosis of pancreatic and periampullary neoplasms.
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Affiliation(s)
- Mireia M Ginesta
- Translational Research Laboratory, Catalan Institute of Oncology, Bellvitge Biomedical Research Institute, Duran i Reynals Hospital, 08907 Barcelona, Spain
| | - Zamira Vanessa Diaz-Riascos
- Translational Research Laboratory, Catalan Institute of Oncology, Bellvitge Biomedical Research Institute, Duran i Reynals Hospital, 08907 Barcelona, Spain
| | - Juli Busquets
- Department of General and Digestive Surgery, Bellvitge University Hospital, 08907 Barcelona, Spain
| | - Núria Pelaez
- Department of General and Digestive Surgery, Bellvitge University Hospital, 08907 Barcelona, Spain
| | - Teresa Serrano
- Department of Pathology, Bellvitge University Hospital, 08907 Barcelona, Spain
| | - Miquel Àngel Peinado
- Department of Mechanism of Tumor Progression, Institute of Predictive and Personalized Cancer Medicine, 08916 Barcelona, Spain
| | - Rosa Jorba
- Department of Surgery, Joan XXIII Hospital, 43005 Tarragona, Spain
| | | | - Gabriel Capella
- Translational Research Laboratory, Catalan Institute of Oncology, Bellvitge Biomedical Research Institute, Duran i Reynals Hospital, 08907 Barcelona, Spain
| | - Joan Fabregat
- Department of General and Digestive Surgery, Bellvitge University Hospital, 08907 Barcelona, Spain
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A Biomarker Panel to Detect Synchronous Neoplasm in Non-neoplastic Surveillance Biopsies from Patients with Ulcerative Colitis. Inflamm Bowel Dis 2016; 22:1568-74. [PMID: 27135485 DOI: 10.1097/mib.0000000000000789] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
BACKGROUND Patients with ulcerative colitis (UC) are at risk for colorectal neoplasia. Challenges associated with surveillance colonoscopy with random biopsies for detection of dysplasia/cancer are well-documented. This study extended our findings in UC-associated colorectal cancer to include low-grade dysplasia (LGD) patients, testing whether our biomarker panel detects any UC-associated neoplasm. METHODS DNA from the LGD area and the corresponding nonadjacent, non-dysplastic section from 171 UC-LGD patients was extracted. TaqMan SNP Genotyping Assays for TNF-α, IL-1β, and IL23R were used to evaluate polymorphisms for each gene. Bisulfite-treated DNA was used for methylation testing of RUNX3, COX2, and MINT1. LGD data were combined with UC-cancer patient data for statistical testing. Logistic regression analyses determined associations between genetic/epigenetic/clinical variables and UC-associated neoplasia. Receiver operating characteristic analyses were performed to determine the final synchronous neoplasm detection panel. RESULTS Comparison of nonadjacent, non-dysplastic DNA from UC-neoplasm patients versus UC-controls indicated that TNF-α, IL-1β, and methylation of RUNX3, MINT1, and COX2 were significantly different (P < 0.0001). In multivariable analysis, all remained significant with an area under the curve of 0.85, exceeding the clinical variable panel area under the curve. Combining clinical and experimental variables yielded a neoplasm biomarker panel with an area under the curve of 0.95 (sensitivity and specificity of 82% and 91%, respectively). Analysis of DNA from LGD with known progression compared with LGD without progression indicated a significant difference in RUNX3 methylation. CONCLUSIONS A combined clinical, genetic, and epigenetic model for detecting synchronous neoplasm by testing of non-neoplastic colonic tissue had favorable operating characteristics and could complement current patient care.
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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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Herszényi L, Barabás L, Miheller P, Tulassay Z. Colorectal cancer in patients with inflammatory bowel disease: the true impact of the risk. Dig Dis 2014; 33:52-57. [PMID: 25531497 DOI: 10.1159/000368447] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
Patients with long-standing inflammatory bowel disease (IBD) have an increased risk of colorectal cancer (CRC). The association between IBD and CRC is well supported, but reported risk estimates vary widely. Although recent evidence from population-based studies reports a decline in risk, CRC accounts for 10-15% of all deaths in IBD. The potential causes of recent epidemiological trends and the real magnitude of risk of CRC in IBD are subjects of debate. The molecular pathway leading to CRC differs from the classic adenoma-to-CRC sequence. Chronic inflammation contributes to the development of low- and high-grade dysplasia which may further convert into CRC. Patients with a young age at onset, long-standing and extensive colitis with severe inflammatory burden, a family history of sporadic CRC, and concomitant primary sclerosing cholangitis are at greatest risk. The CRC risk in patients with colonic Crohn's disease is similar to that of ulcerative colitis. IBD-associated CRC can frequently be detected at late stages and at a younger age. The long-term prognosis of CRC may be poorer in patients with IBD than in those with sporadic CRC. Regular surveillance colonoscopies may permit earlier detection of CRC, with a corresponding improved prognosis. The interval between surveillance colonoscopies is dependent on each patient's personal risk profile.
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Affiliation(s)
- László Herszényi
- Second Departments of Internal Medicine, Semmelweis University, Budapest, Hungary
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Abstract
Most of what is known about the pathogenesis of inflammatory bowel disease (IBD) pertains to complex interplay between host genetics, immunity, and environmental factors. Epigenetic modifications play pivotal roles in intestinal immunity and mucosal homeostasis as well as mediating gene-environment interactions. In this article, we provide a historical account of epigenetic research either directly related or pertinent to the pathogenesis and management of IBD. We further collate emerging evidence supporting roles for epigenetic mechanisms in relevant aspects of IBD biology, including deregulated immunity, host-pathogen recognition and mucosal integrity. Finally, we highlight key epigenetic mechanisms that link chronic inflammation to specific IBD comorbidities, including colitis-associated cancer and discuss their potential utility as novel biomarkers or pharmacologic targets in IBD therapy.
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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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Variation risks of SFRP2 hypermethylation between precancerous disease and colorectal cancer. Tumour Biol 2014; 35:10457-65. [PMID: 25053594 DOI: 10.1007/s13277-014-2313-2] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2014] [Accepted: 07/04/2014] [Indexed: 12/15/2022] Open
Abstract
DNA hypermethylation of secreted frizzled-related protein 2 (SFRP2) gene associated with the Wnt signaling pathway has been studied previously. However, the risk size and changing rules between colorectal cancer (CRC) and SFRP2 hypermethylation from precancerous disease to CRC remain unclear. The aim of work was therefore to investigate the risk size and changing rule based on detections on large numbers of tissue and feces samples. Association study and meta-analysis were performed to analyze the risk size of SFRP2 hypermethylation in tissue and fecal detections from 2,912 samples, including 1,436 patients with CRC, 866 patients with colon adenomas or polyps, and 610 samples with both normal controls. Based on normal controls as standard reference, the analysis showed that SFRP2 hypermethylation in CRC and adenoma tissues had a significantly higher risk with 92.81 (28.76-299.45) and 22.46 (4.13-122.04) odds ratio (OR) (95 % confidence interval (CI)) respectively, and that the risk sizes of SFRP2 hypermethylation in CRC and adenoma patients were 41.86 (18.91-92.67) and 11.76 (6.98-19.84) of OR (95 % CI) in fecal samples, and that the OR risk in both tissue and fecal samples increased significantly to 70.35 and 30.10 from precancerous disease (adenoma or polyp) to CRC. There were significant differences between tissue and fecal hypermethylation frequency. On the basis of the hypermethylation frequency of colorectal tissue, the coincidence rates of fecal hypermethylation in CRC and colorectal adenoma were 0.89 and 0.9, respectively. The risk size of SFRP2 hypermethylation from normal control to adenoma or polyp as well as from adenoma or polyp to CRC increased gradually in both tissue and feces. Therefore, SFRP2 hypermethylation is an important biomarker both in noninvasive diagnosis in feces detection and in colon tissue.
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28
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Wang X, Kuang YY, Hu XT. Advances in epigenetic biomarker research in colorectal cancer. World J Gastroenterol 2014; 20:4276-4287. [PMID: 24764665 PMCID: PMC3989963 DOI: 10.3748/wjg.v20.i15.4276] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2013] [Revised: 11/05/2013] [Accepted: 01/15/2014] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) causes approximately 600000 deaths annually and is the third leading cause of cancer mortality worldwide. Despite significant advancements in treatment options, CRC patient survival is still poor owing to a lack of effective tools for early diagnosis and a limited capacity for optimal therapeutic decision making. Since there exists a need to find new biomarkers to improve diagnosis of CRC, the research on epigenetic biomarkers for molecular diagnostics encourages the translation of this field from the bench to clinical practice. Epigenetic alterations are thought to hold great promise as tumor biomarkers. In this review, we will primarily focus on recent advances in the study of epigenetic biomarkers for colorectal cancer and discuss epigenetic biomarkers, including DNA methylation, microRNA expression and histone modification, in cancer tissue, stool, plasma, serum, cell lines and xenografts. These studies have improved the chances that epigenetic biomarkers will find a place in the clinical practices of screening, early diagnosis, prognosis, therapy choice and recurrence surveillance for CRC patients. However, these studies have typically been small in size, and evaluation at a larger scale of well-controlled randomized clinical trials is the next step that is necessary to increase the quality of epigenetic biomarkers and ensure their widespread clinical use.
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Methylated eyes absent 4 (EYA4) gene promotor in non-neoplastic mucosa of ulcerative colitis patients with colorectal cancer: evidence for a field effect. Inflamm Bowel Dis 2013; 19:2079-83. [PMID: 23867875 PMCID: PMC4119944 DOI: 10.1097/mib.0b013e31829b3f4d] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND Aberrant methylation of the EYA4 gene (mEYA4) highly discriminates ulcerative colitis (UC) cases with colorectal neoplasia from UC controls in both tissue and stool. It is not known if mEYA4 is also present in nonadjacent non-neoplastic mucosa (NNM) of UC patients with colorectal neoplasia. METHODS Formalin-fixed tissues from 25 UC cases with colorectal cancer (CRC) and 25 UC controls with neither CRC nor dysplasia were matched on gender, age, disease duration, disease extent, and coexistence of primary sclerosing cholangitis. DNA was extracted from sections of CRC and NNM from cases and UC control mucosae. Bisulfite-treated DNA was amplified using real-time methylation-specific PCR. The Wilcoxon rank-sum test assessed differences in mEYA4 levels from CRC, NNM, and control samples. Logistic regression was used to estimate sensitivity and specificity. RESULTS Sufficient DNA was available for 20 cases and 20 controls. The median mEYA4 level (with interquartile range) was 2 (0-5.7) in control mucosae but 93 (38.5-306) in CRC (P < 0.0001) and 27.4 (3-140) in NNM (P = 0.0009). At 95% specificity, mEYA4 was present in 80% of CRC and 50% of NNM tissue samples. The odds ratio of mEYA4 in NNM as an indicator of synchronous CRC was 19 (95% confidence interval, 2-170). CONCLUSIONS The authors demonstrate significantly higher mEYA4 levels in NNM and synchronous CRC from UC cases than in colorectal mucosae of UC controls without neoplasia. The finding of this CRC-associated field change has important implications to the use of mEYA4 as a potential UC surveillance marker in tissue or stool.
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Ventham NT, Kennedy NA, Nimmo ER, Satsangi J. Beyond gene discovery in inflammatory bowel disease: the emerging role of epigenetics. Gastroenterology 2013; 145:293-308. [PMID: 23751777 PMCID: PMC3919211 DOI: 10.1053/j.gastro.2013.05.050] [Citation(s) in RCA: 213] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2013] [Revised: 05/16/2013] [Accepted: 05/26/2013] [Indexed: 02/07/2023]
Abstract
In the past decade, there have been fundamental advances in our understanding of genetic factors that contribute to the inflammatory bowel diseases (IBDs) Crohn's disease and ulcerative colitis. The latest international collaborative studies have brought the number of IBD susceptibility gene loci to 163. However, genetic factors account for only a portion of overall disease variance, indicating a need to better explore gene-environment interactions in the development of IBD. Epigenetic factors can mediate interactions between the environment and the genome; their study could provide new insight into the pathogenesis of IBD. We review recent progress in identification of genetic factors associated with IBD and discuss epigenetic mechanisms that could affect development and progression of IBD.
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Affiliation(s)
- Nicholas T. Ventham
- Reprint requests Address requests for reprints to: Nicholas T. Ventham, Gastrointestinal Unit, Centre for Molecular Medicine, Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh EH4 2XU, Scotland. fax: +44 131 651 1085.
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31
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Carmona FJ, Azuara D, Berenguer-Llergo A, Fernández AF, Biondo S, de Oca J, Rodriguez-Moranta F, Salazar R, Villanueva A, Fraga MF, Guardiola J, Capellá G, Esteller M, Moreno V. DNA methylation biomarkers for noninvasive diagnosis of colorectal cancer. Cancer Prev Res (Phila) 2013; 6:656-65. [PMID: 23694962 DOI: 10.1158/1940-6207.capr-12-0501] [Citation(s) in RCA: 97] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
DNA methylation biomarkers for noninvasive diagnosis of colorectal cancer (CRC) and precursor lesions have been extensively studied. Different panels have been reported attempting to improve current protocols in clinical practice, although no definite biomarkers have been established. In the present study, we have examined patient biopsies starting from a comprehensive analysis of DNA methylation differences between paired normal and tumor samples in known cancer-related genes aiming to select the best performing candidates informative for CRC diagnosis in stool samples. Five selected markers were considered for subsequent analyses in independent biologic cohorts and in silico data sets. Among the five selected genes, three of them (AGTR1, WNT2 and SLIT2) were validated in stool DNA of affected patients with a detection sensitivity of 78% [95% confidence interval (CI), 56%-89%]. As a reference, DNA methylation of VIM and SEPT9 was evaluated in a subset of stool samples yielding sensitivities of 55% and 20%, respectively. Moreover, our panel may complement histologic and endoscopic diagnosis of inflammatory bowel disease (IBD)-associated neoplasia, as it was also efficient detecting aberrant DNA methylation in non-neoplastic tissue samples from affected patients. This novel panel of specific methylation markers can be useful for early diagnosis of CRC using stool DNA and may help in the follow-up of high-risk patients with IBD.
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Affiliation(s)
- F Javier Carmona
- Cancer Epigenetics and Biology Program (PEBC), Catalan Institute of Oncology (ICO-IDIBELL), Barcelona 08908, Spain
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