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Yan L, Gu C, Gao S, Wei B. Epigenetic regulation and therapeutic strategies in ulcerative colitis. Front Genet 2023; 14:1302886. [PMID: 38169708 PMCID: PMC10758477 DOI: 10.3389/fgene.2023.1302886] [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: 09/27/2023] [Accepted: 12/07/2023] [Indexed: 01/05/2024] Open
Abstract
Ulcerative colitis (UC) is an inflammatory bowel disease, and is characterized by the diffuse inflammation and ulceration in the colon and rectum mucosa, even extending to the caecum. Epigenetic modifications, including DNA methylations, histone modifications and non-coding RNAs, are implicated in the differentiation, maturation, and functional modulation of multiple immune and non-immune cell types, and are influenced and altered in various chronic inflammatory diseases, including UC. Here we review the relevant studies revealing the differential epigenetic features in UC, and summarize the current knowledge about the immunopathogenesis of UC through epigenetic regulation and inflammatory signaling networks, regarding DNA methylation, histone modification, miRNAs and lncRNAs. We also discuss the epigenetic-associated therapeutic strategies for the alleviation and treatment of UC, which will provide insights to intervene in the immunopathological process of UC in view of epigenetic regulation.
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Affiliation(s)
- Liwei Yan
- The First Clinical College, Shandong University of Traditional Chinese Medicine, Jinan, China
- Departments of Anorectal Surgery, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Chao Gu
- Departments of Anorectal Surgery, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Shanyu Gao
- Departments of Anorectal Surgery, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Benzheng Wei
- Center for Medical Artificial Intelligence, Shandong University of Traditional Chinese Medicine, Jinan, China
- Qingdao Academy of Chinese Medical Sciences, Shandong University of Traditional Chinese Medicine, Jinan, China
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2
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Kibriya MG, Jasmine F, Pekow J, Munoz A, Weber C, Raza M, Kamal M, Ahsan H, Bissonnette M. Pathways Related to Colon Inflammation Are Associated with Colorectal Carcinoma: A Transcriptome- and Methylome-Wide Study. Cancers (Basel) 2023; 15:2921. [PMID: 37296884 PMCID: PMC10251872 DOI: 10.3390/cancers15112921] [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: 04/20/2023] [Revised: 05/19/2023] [Accepted: 05/24/2023] [Indexed: 06/12/2023] Open
Abstract
The association of chronic inflammation with colorectal carcinoma (CRC) development is well known in ulcerative colitis (UC). However, the role of inflammatory changes in sporadic CRC pathogenesis is less widely appreciated. In this study, in the first step using RNA-seq, we identified gene-pathway-level changes in UC-associated CRC (UC CRC, n = 10) and used the changes as a proxy for inflammation in human colon to ask if there were associations of inflammatory pathway dysregulations in sporadic CRC pathogenesis (n = 8). We found down-regulations of several inflammation-related metabolic pathways (nitrogen metabolism, sulfur metabolism) and other pathways (bile secretion, fatty acid degradation) in sporadic CRC. Non-inflammation-related changes included up-regulation of the proteasome pathway. In the next step, from a larger number of paired samples from sporadic CRC patients (n = 71) from a geographically and ethnically different population and using a different platform (microarray), we asked if the inflammation-CRC association could be replicated. The associations were significant even after stratification by sex, tumor stage, grade, MSI status, and KRAS mutation status. Our findings have important implications to widen our understanding of inflammatory pathogenesis of sporadic CRC. Furthermore, targeting of several of these dysregulated pathways could provide the basis for improved therapies for CRC.
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Affiliation(s)
- Muhammad G. Kibriya
- Institute for Population and Precision Health (IPPH), Biological Sciences Division, University of Chicago, Chicago, IL 60637, USA; (F.J.); (A.M.); (H.A.)
- Department of Public Health Sciences, Biological Sciences Division, University of Chicago, Chicago, IL 60637, USA
| | - Farzana Jasmine
- Institute for Population and Precision Health (IPPH), Biological Sciences Division, University of Chicago, Chicago, IL 60637, USA; (F.J.); (A.M.); (H.A.)
| | - Joel Pekow
- Department of Medicine, Section of Gastroenterology, Hepatology and Nutrition, University of Chicago, Chicago, IL 60637, USA; (J.P.); (M.B.)
| | - Aaron Munoz
- Institute for Population and Precision Health (IPPH), Biological Sciences Division, University of Chicago, Chicago, IL 60637, USA; (F.J.); (A.M.); (H.A.)
| | - Christopher Weber
- Department of Pathology, University of Chicago, Chicago, IL 60637, USA;
| | - Maruf Raza
- Department of Pathology, Jahurul Islam Medical College, Kishoregonj 2336, Bangladesh;
| | - Mohammed Kamal
- Department of Pathology, The Laboratory Dhaka, Dhaka 1205, Bangladesh;
| | - Habibul Ahsan
- Institute for Population and Precision Health (IPPH), Biological Sciences Division, University of Chicago, Chicago, IL 60637, USA; (F.J.); (A.M.); (H.A.)
- Department of Public Health Sciences, Biological Sciences Division, University of Chicago, Chicago, IL 60637, USA
| | - Marc Bissonnette
- Department of Medicine, Section of Gastroenterology, Hepatology and Nutrition, University of Chicago, Chicago, IL 60637, USA; (J.P.); (M.B.)
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3
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Dybska E, Nowak JK, Banaszkiewicz A, Szaflarska-Popławska A, Kierkuś J, Kwiecień J, Grzybowska-Chlebowczyk U, Walkowiak J. Methylation of RUNX3 Promoter 2 in the Whole Blood of Children with Ulcerative Colitis. Genes (Basel) 2022; 13:genes13091568. [PMID: 36140736 PMCID: PMC9498668 DOI: 10.3390/genes13091568] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2022] [Revised: 08/22/2022] [Accepted: 08/30/2022] [Indexed: 12/03/2022] Open
Abstract
Ulcerative colitis (UC) results from a complex interplay between the environment, gut microbiota, host genetics, and immunity. Runt-related transcription factor 3 (RUNX3) regulates Th1/Th2 balance and, thus, the synthesis of cytokines and inflammation. We aimed to analyze the dependence of RUNX3 promoter 2 (P2) methylation level on: age, sex, body mass index (BMI), C-reactive protein (CRP), serum albumin, disease duration, Pediatric Ulcerative Colitis Activity Index (PUCAI), the Paris classification, and exposure to medications. This multicenter, cross-sectional study recruited hospitalized children with UC. Methylation of RUNX3 P2 was measured with methylation-sensitive restriction enzymes in the whole blood DNA. Sixty-four children were enrolled, with a mean age of 14.5 ± 2.8 years. Half of them were female (51.6%), and the average BMI Z-score was −0.44 ± 1.14. The mean methylation of RUNX3 P2 was 54.1 ± 13.3%. The methylation level of RUNX3 P2 did not correlate with age, sex, nutritional status, CRP, albumin, PUCAI, or the extent of colitis (Paris E1–E4). RUNX3 P2 methylation did not differ between patients recruited within two and a half months of diagnosis and children who had UC for at least a year. Current or past exposure to biologics, immunosuppressants, or steroids was not associated with RUNX3 P2 methylation. Methylation of RUNX3 promoter 2 in whole blood DNA does not seem to be associated with the characteristics of UC in children.
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Affiliation(s)
- Emilia Dybska
- Department of Pediatric Gastroenterology and Metabolic Diseases, Poznan University of Medical Sciences, 60-572 Poznan, Poland
| | - Jan Krzysztof Nowak
- Department of Pediatric Gastroenterology and Metabolic Diseases, Poznan University of Medical Sciences, 60-572 Poznan, Poland
| | - Aleksandra Banaszkiewicz
- Department of Pediatric Gastroenterology and Nutrition, Medical University of Warsaw, 02-091 Warsaw, Poland
| | - Anna Szaflarska-Popławska
- Department of Pediatric Endoscopy and Gastrointestinal Function Testing, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, 85-094 Bydgoszcz, Poland
| | - Jarosław Kierkuś
- Department of Gastroenterology, Hepatology, Feeding Disorders and Pediatrics, The Children’s Memorial Health Institute, 04-730 Warsaw, Poland
| | - Jarosław Kwiecień
- Department of Pediatrics, Faculty of Medical Sciences in Zabrze, Medical University of Silesia in Katowice, 41-800 Zabrze, Poland
| | - Urszula Grzybowska-Chlebowczyk
- Department of Pediatrics, Faculty of Medical Sciences, Medical University of Silesia in Katowice, 40-752 Katowice, Poland
| | - Jarosław Walkowiak
- Department of Pediatric Gastroenterology and Metabolic Diseases, Poznan University of Medical Sciences, 60-572 Poznan, Poland
- Correspondence:
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Leite-Gomes E, Dias AM, Azevedo CM, Santos-Pereira B, Magalhães M, Garrido M, Amorim R, Lago P, Marcos-Pinto R, Pinho SS. Bringing to Light the Risk of Colorectal Cancer in Inflammatory Bowel Disease: Mucosal Glycosylation as a Key Player. Inflamm Bowel Dis 2022; 28:947-962. [PMID: 34849933 DOI: 10.1093/ibd/izab291] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Indexed: 02/06/2023]
Abstract
Colitis-associated cancer is a major complication of inflammatory bowel disease remaining an important clinical challenge in terms of diagnosis, screening, and prognosis. Inflammation is a driving factor both in inflammatory bowel disease and cancer, but the mechanism underlying the transition from colon inflammation to cancer remains to be defined. Dysregulation of mucosal glycosylation has been described as a key regulatory mechanism associated both with colon inflammation and colorectal cancer development. In this review, we discuss the major molecular mechanisms of colitis-associated cancer pathogenesis, highlighting the role of glycans expressed at gut epithelial cells, at lamina propria T cells, and in serum proteins in the regulation of intestinal inflammation and its progression to colon cancer, further discussing its potential clinical and therapeutic applications.
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Affiliation(s)
- Eduarda Leite-Gomes
- i3S-Institute for Research and Innovation in Health, University of Porto, Porto, Portugal
| | - Ana M Dias
- i3S-Institute for Research and Innovation in Health, University of Porto, Porto, Portugal
| | - Catarina M Azevedo
- i3S-Institute for Research and Innovation in Health, University of Porto, Porto, Portugal
| | - Beatriz Santos-Pereira
- i3S-Institute for Research and Innovation in Health, University of Porto, Porto, Portugal
| | - Mariana Magalhães
- i3S-Institute for Research and Innovation in Health, University of Porto, Porto, Portugal.,Department of Gastroenterology, Centro Hospitalar e Universitário do Porto, Porto, Portugal
| | - Mónica Garrido
- Department of Gastroenterology, Centro Hospitalar e Universitário do Porto, Porto, Portugal
| | - Rita Amorim
- i3S-Institute for Research and Innovation in Health, University of Porto, Porto, Portugal.,Pediatrics Department, Centro Hospitalar e Universitário São João, Porto, Portugal.,Medical Faculty, University of Porto, Porto, Portugal
| | - Paula Lago
- Department of Gastroenterology, Centro Hospitalar e Universitário do Porto, Porto, Portugal
| | - Ricardo Marcos-Pinto
- Department of Gastroenterology, Centro Hospitalar e Universitário do Porto, Porto, Portugal.,School of Medicine and Biomedical Sciences, University of Porto, Porto, Portugal.,Centre for Research in Health Technologies and Information Systems, University of Porto, Portugal
| | - Salomé S Pinho
- i3S-Institute for Research and Innovation in Health, University of Porto, Porto, Portugal.,School of Medicine and Biomedical Sciences, University of Porto, Porto, Portugal.,Medical Faculty, University of Porto, Porto, Portugal
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5
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Lucafò M, Curci D, Franzin M, Decorti G, Stocco G. Inflammatory Bowel Disease and Risk of Colorectal Cancer: An Overview From Pathophysiology to Pharmacological Prevention. Front Pharmacol 2021; 12:772101. [PMID: 34744751 PMCID: PMC8563785 DOI: 10.3389/fphar.2021.772101] [Citation(s) in RCA: 68] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Accepted: 10/06/2021] [Indexed: 12/14/2022] Open
Abstract
Increased risk of colorectal cancer (CRC) in inflammatory bowel disease (IBD) patients has been attributed to long-standing chronic inflammation, with the contribution of genetic alterations and environmental factors such as the microbiota. Moreover, accumulating data indicate that IBD-associated CRC (IBD-CRC) may initiate and develop through a pathway of tumorigenesis distinct from that of sporadic CRC. This mini-review summarizes the current knowledge of IBD-CRC, focusing on the main mechanisms underlying its pathogenesis, and on the important role of immunomodulators and biologics used to treat IBD patients in interfering with the inflammatory process involved in carcinogenesis.
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Affiliation(s)
- Marianna Lucafò
- Institute for Maternal and Child Health-IRCCS Burlo Garofolo, Trieste, Italy
| | - Debora Curci
- Institute for Maternal and Child Health-IRCCS Burlo Garofolo, Trieste, Italy
| | - Martina Franzin
- Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste, Italy
| | - Giuliana Decorti
- Institute for Maternal and Child Health-IRCCS Burlo Garofolo, Trieste, Italy
- Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste, Italy
| | - Gabriele Stocco
- Department of Life Sciences, University of Trieste, Trieste, Italy
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Liu C, Yuan ZY, Yuan H, Wu KX, Cao B, Ren KY, Cui MJ, Liu JH, Chen HX, Pang YW. Status of Gene Methylation and Polymorphism in Different Courses of Ulcerative Colitis and Their Comparison with Sporadic Colorectal Cancer. Inflamm Bowel Dis 2021; 27:522-529. [PMID: 32793962 DOI: 10.1093/ibd/izaa203] [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: 03/02/2020] [Indexed: 12/09/2022]
Abstract
BACKGROUND The objective of this study is to explore the common genetic and epigenetic mechanism of ulcerative colitis (UC) and sporadic colorectal cancer (SCRC) by observing genes methylation level and single nucleotide polymorphisms (SNPs) of different disease courses in UC and SCRC. METHODS Two hundred subjects were enrolled, including 40 in the healthy control (HC) group, 50 in the short disease course UC group (SUC), 52 in the long disease course UC group (LUC), and 58 in the SCRC group. Methylation-specific polymerase chain reaction was used to detect the methylation of MINT1 and cyclooxygenase 2 (COX-2) gene. Single nucleotide polymorphisms of interleukin (IL)-23R rs10889677 and IL-1β rs1143627 were detected by Sanger sequencing. RESULTS Compared with HCs (32.5%), methylation level of MINT1 was significantly increased in SCRC (67.2%; P = 0.001) and was a risk factor for CRC (odds ratio, [OR] 4.26). The methylation ratios of COX-2 were 95.0%, 58.0%, 23.1%, and 24.1% in HC, SUC, LUC, and SCRC, respectively, which were negatively correlated with the disease course of UC (r = -0.290). Hypermethylation of COX-2 was a protective factor for SUC (OR, 0.11), LUC (OR, 0.02), and SCRC (OR, 0.03; P < 0.05). Compared with HCs, rs10889677 allele A was a risk factor for SUC and LUC, and rs1143627 allele T was a protective factor for SUC and LUC. Genotype TT was a protective factor for SUC. CONCLUSION The hypomethylation of COX-2 gene was a common risk factor and epigenetic modification for UC and SCRC, which might be one of the mechanisms through which UC patients were susceptible to CRC. The hypermethylation of MINT1 was a risk factor for SCRC but not for UC; alleles of IL-23Rrs10889677 and IL-1βrs1143627 were related to UC but not to SCRC.
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Affiliation(s)
- Chen Liu
- Departments of School of Clinical Medicine, Weifang Medical University, Weifang, Shandong, China
| | - Zi-Ying Yuan
- Department of Gastroenterology, Peking University Third Hospital, Haidian District, Beijing, China
| | - Hao Yuan
- Department of Gastroenterology, the Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
| | - Ke-Xiang Wu
- Department of Electrophysiology, The Affiliated Hospital of Weifang Medical University, Weifang, Shandong, China
| | - Bin Cao
- Department of Gastroenterology, the Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
| | - Ke-Yu Ren
- Department of Gastroenterology, the Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
| | - Ming-Juan Cui
- Department of Gastroenterology, the Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
| | - Jun-Heng Liu
- Department of Gastroenterology, the Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
| | - Hai-Xing Chen
- Departments of School of Clinical Medicine, Weifang Medical University, Weifang, Shandong, China
| | - Yao-Wei Pang
- Departments of School of Clinical Medicine, Weifang Medical University, Weifang, Shandong, China
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Zhou G, Wu H, Lin J, Lin R, Feng B, Liu Z. TRIM21 Is Decreased in Colitis-associated Cancer and Negatively Regulates Epithelial Carcinogenesis. Inflamm Bowel Dis 2021; 27:458-468. [PMID: 32860065 DOI: 10.1093/ibd/izaa229] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2020] [Indexed: 12/13/2022]
Abstract
BACKGROUND Tripartite motif-containing (TRIM)21 is reported to be associated with the regulation of immune response in gut mucosa. Here we studied the underlying mechanisms of TRIM21 in the pathogenesis of colitis-associated cancer (CAC). METHODS We analyzed TRIM21 expression in tumor tissues from patients with colorectal cancer (CRC) and ulcerative colitis (UC)-associated cancer by immunohistochemistry and real-time polymerase chain reaction and established a CAC model in TRIM21-∕- and wild type mice by azoxymethane (AOM) and dextran sodium sulfate (DSS). Associated gene expression of tumor cell proliferation, adhesion, tissue remodeling and angiogenesis, and inflammatory cytokines were examined in normal colon and CAC by immunohistochemistry and real-time polymerase chain reaction. RESULTS Expression of TRIM21 was found to be decreased in tumor tissues from patients with CRC and UC-associated cancer than that in controls, and TRIM21-∕- deficiency promoted AOM/DSS-induced CAC, characterized by more weight loss and multiple, large colon tumors in TRIM21-∕- mice. Moreover, associated gene expression of tumor cell proliferation (eg, Ki67), tissue remodeling and angiogenesis (eg, MMP10, HIF1-α, COX2, Ang4), and pro-inflammatory cytokines (eg, IL-6, TNF-α, IL-1β) markedly upregulated, whereas associated gene expression of tumor cell adhesion (E-cadherin) and inflammatory cytokines (eg, IL-10, TGF-β, Foxp3, IFN-γ) downregulated in tumor tissues from TRIM21-/- mice compared with controls. CONCLUSIONS TRIM21 is decreased in colitis-associated cancer and negatively regulates intestinal epithelial carcinogenesis by modulating epithelial cell proliferation, adhesion, tissue remodeling and angiogenesis, and pro-inflammatory responses. Therefore, TRIM21 may serve as a novel therapeutic target for CAC therapy.
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Affiliation(s)
- Guangxi Zhou
- Department of Gastroenterology, The Shanghai Tenth People's Hospital of Tongji University, Shanghai, China.,Department of Gastroenterology, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, China
| | - Huili Wu
- Department of Gastroenterology, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou, China
| | - Jian Lin
- Department of Gastroenterology, The Shanghai Tenth People's Hospital of Tongji University, Shanghai, China
| | - Ritian Lin
- Department of Gastroenterology, The Shanghai Tenth People's Hospital of Tongji University, Shanghai, China
| | - Baisui Feng
- Department of Gastroenterology, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Zhanju Liu
- Department of Gastroenterology, The Shanghai Tenth People's Hospital of Tongji University, Shanghai, China.,Department of Gastroenterology, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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Fernández-Ponce C, Navarro Quiroz R, Díaz Perez A, Aroca Martinez G, Cadena Bonfanti A, Acosta Hoyos A, Gómez Escorcia L, Hernández Agudelo S, Orozco Sánchez C, Villarreal Camacho J, Atencio Ibarra L, Consuegra Machado J, Espinoza Garavito A, García-Cózar F, Navarro Quiroz E. MicroRNAs overexpressed in Crohn's disease and their interactions with mechanisms of epigenetic regulation explain novel aspects of Crohn's disease pathogenesis. Clin Epigenetics 2021; 13:39. [PMID: 33602320 PMCID: PMC7890887 DOI: 10.1186/s13148-021-01022-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Accepted: 02/02/2021] [Indexed: 12/14/2022] Open
Abstract
Background In this review, we were interested to identify the wide universe of enzymes associated with epigenetic modifications, whose gene expression is regulated by miRNAs with a high relative abundance in Crohn's disease (CD) affected tissues, with the aim to determine their impact in the pathogenesis and evolution of the disease. Methods We used HMDD and Bibliometrix R-package in order to identify the miRNAs overexpressed in CD. The identified enzymes associated with epigenetic mechanisms and post-translational modifications, regulated by miRNAs upregulated in CD, were analyzed using String v11 database. Results We found 190 miRNAs with great abundance in patients with CD, of which 26 miRNAs regulate the gene expression of enzymes known to catalyze epigenetic modifications involved in essentials pathophysiological processes, such as chromatin architecture reorganization, immune response regulation including CD4+ T cells polarization, integrity of gut mucosa, gut microbiota composition and tumorigenesis. Conclusion The integrated analysis of miRNAs with a high relative abundance in patients with CD showed a combined and superimposed gene expression regulation of enzymes associated with relevant epigenetic mechanisms and that could explain, in part, the pathogenesis of CD. Supplementary Information The online version contains supplementary material available at 10.1186/s13148-021-01022-8.
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Affiliation(s)
- Cecilia Fernández-Ponce
- Department of Biomedicine, Biotechnology and Public Health, University of Cadiz, Cadiz, Spain
| | - Roberto Navarro Quiroz
- CMCC-Centro de Matemática, Computação E Cognição, Laboratório do Biología Computacional e Bioinformática-LBCB, Universidade Federal Do ABC, Sao Paulo, 01023, Brazil
| | - Anderson Díaz Perez
- Facultad de Ciencias Básicas y Biomédicas, Universidad Simon Bolivar, 080001, Barranquilla, Colombia.,Universidad Rafael Nuñez, 130001, Cartagena, Colombia
| | - Gustavo Aroca Martinez
- Facultad de Ciencias Básicas y Biomédicas, Universidad Simon Bolivar, 080001, Barranquilla, Colombia.,Department of Nephrology, Clinica de La Costa, 080001, Barranquilla, Colombia
| | - Andrés Cadena Bonfanti
- Facultad de Ciencias Básicas y Biomédicas, Universidad Simon Bolivar, 080001, Barranquilla, Colombia.,Department of Nephrology, Clinica de La Costa, 080001, Barranquilla, Colombia
| | - Antonio Acosta Hoyos
- Facultad de Ciencias Básicas y Biomédicas, Universidad Simon Bolivar, 080001, Barranquilla, Colombia
| | - Lorena Gómez Escorcia
- Facultad de Ciencias Básicas y Biomédicas, Universidad Simon Bolivar, 080001, Barranquilla, Colombia.,Universidad Rafael Nuñez, 130001, Cartagena, Colombia
| | - Sandra Hernández Agudelo
- Facultad de Ciencias Básicas y Biomédicas, Universidad Simon Bolivar, 080001, Barranquilla, Colombia.,Department of Nephrology, Clinica de La Costa, 080001, Barranquilla, Colombia
| | - Christian Orozco Sánchez
- Facultad de Ciencias Básicas y Biomédicas, Universidad Simon Bolivar, 080001, Barranquilla, Colombia
| | | | | | | | - Alberto Espinoza Garavito
- Facultad de Ciencias Básicas y Biomédicas, Universidad Simon Bolivar, 080001, Barranquilla, Colombia
| | - Francisco García-Cózar
- Department of Biomedicine, Biotechnology and Public Health, University of Cadiz, Cadiz, Spain
| | - Elkin Navarro Quiroz
- Facultad de Ciencias Básicas y Biomédicas, Universidad Simon Bolivar, 080001, Barranquilla, Colombia. .,Centro de Investigación E Innovación en Biomoléculas, C4U S.A.S, 080001, Barranquilla, Colombia.
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C8orf48 inhibits the tumorigenesis of colorectal cancer by regulating the MAPK signaling pathway. Life Sci 2020; 266:118872. [PMID: 33309715 DOI: 10.1016/j.lfs.2020.118872] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2020] [Revised: 11/27/2020] [Accepted: 12/01/2020] [Indexed: 11/22/2022]
Abstract
AIMS Colorectal cancer (CRC) is a leading cause of cancer-related death globally. Thus, in this study, we aimed to investigate chromosome 8 open reading frame 48 (C8orf48) as a biomarker for early detection of CRC. MAIN METHODS RNA expression and methylation profiles were downloaded from The Cancer Genome Atlas (TCGA) database. Cell proliferation, migration and invasion assays were performed to confirm the function of C8orf48 in CRC cells. Dual-luciferase reporter assay was used to identify that C8orf48 was the direct target of miR-556. Genomics of Drug Sensitivity in Cancer (GDSC) database, gene set enrichment analysis (GSEA) and western blot analysis were performed to explore the mechanism of C8orf48. KEY FINDINGS we found that C8orf48 is down-regulated in clinical samples of CRC tissues. Enrichment analysis showed that C8orf48 is associated with methylation biomarkers in CRC, and TCGA database confirmed that the methylation of C8orf48 is up-regulated in the early stage of CRC. We further revealed that the overexpression of C8orf48 decreased CRC cell proliferation, migration and invasion. Luciferase reporter indicated that C8orf48 was the direct target of the oncogene miR-556. Additionally, we used GDSC database, GSEA database and western blot analysis to demonstrate that C8orf48 plays a suppressor role in CRC by inhibiting MAPK signaling pathway. SIGNIFICANCE C8orf48 was identified as a biomarker for early detection of CRC for the first time, and might provide novel information for CRC prediction and therapy.
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10
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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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11
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Muller M, Hansmannel F, Arnone D, Choukour M, Ndiaye NC, Kokten T, Houlgatte R, Peyrin-Biroulet L. Genomic and molecular alterations in human inflammatory bowel disease-associated colorectal cancer. United European Gastroenterol J 2020; 8:675-684. [PMID: 32268844 DOI: 10.1177/2050640620919254] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
Patients with inflammatory bowel disease are at increased risk of colorectal cancer, which has worse prognosis than sporadic colorectal cancer. Until recently, understanding of pathogenesis in inflammatory bowel disease-associated colorectal cancer was restricted to the demonstration of chromosomic/microsatellite instabilities and aneuploidy. The advance of high-throughput sequencing technologies has highlighted the complexity of the pathobiology and revealed recurrently mutated genes involved in the RTK/RAS, PI3K, WNT, and TGFβ pathways, leading to potentially new targetable mutations. Moreover, alterations of mitochondrial DNA and the dysregulation of non-coding sequences have also been described, as well as several epigenetic modifications. Although recent studies have brought new insights into pathobiology and raised the prospect of innovative therapeutic approaches, the understanding of colorectal carcinogenesis in inflammatory bowel disease and how it differs from sporadic colorectal cancer remains not fully elucidated. Further studies are required to better understand the pathogenesis and molecular alterations leading to human inflammatory bowel disease-associated colorectal cancer.
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Affiliation(s)
- Marie Muller
- Department of Gastroenterology, Nancy University Hospital, University of Lorraine, France
| | - Franck Hansmannel
- Inserm U1256 "Nutrition - Genetics and exposure to environmental risks - NGERE", Nancy, France
| | - Djesia Arnone
- Inserm U1256 "Nutrition - Genetics and exposure to environmental risks - NGERE", Nancy, France
| | - Myriam Choukour
- Department of Gastroenterology, Nancy University Hospital, University of Lorraine, France
| | - Ndeye Coumba Ndiaye
- Inserm U1256 "Nutrition - Genetics and exposure to environmental risks - NGERE", Nancy, France
| | - Tunay Kokten
- Inserm U1256 "Nutrition - Genetics and exposure to environmental risks - NGERE", Nancy, France
| | - Rémi Houlgatte
- Inserm U1256 "Nutrition - Genetics and exposure to environmental risks - NGERE", Nancy, France
| | - Laurent Peyrin-Biroulet
- Department of Gastroenterology, Nancy University Hospital, University of Lorraine, France.,Inserm U1256 "Nutrition - Genetics and exposure to environmental risks - NGERE", Nancy, France
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12
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Circulating methylated RUNX3 and SFRP1 genes as a noninvasive panel for early detection of colorectal cancer. Eur J Gastroenterol Hepatol 2019; 31:1342-1349. [PMID: 31524773 DOI: 10.1097/meg.0000000000001532] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
OBJECTIVE This study was conducted to assess the methylation status of runt-related transcription factor 3 (RUNX3) and secreted frizzled-related protein 1 (SFRP1) genes in paired tissue and serum samples of colorectal cancer (CRC), adenomatous, and control subjects and elucidate the association between methylation status on RUNX3 and SFRP1 mRNA expression. METHODS Methylation status of RUNX3 and SFRP1 in paired tissue and serum samples and RUNX3 and SFRP1 mRNA expression in tissue from 85 patients with CRC, 40 with adenoma, and 40 healthy controls were determined using methylation-specific PCR and reverse transcription PCR. RESULTS The frequency RUNX3 and SFRP1 genes methylation was significantly higher in both tissues and serum of CRC patients and was significantly associated with absence of its corresponding mRNA expression. The concordance between tissue and serum methylation status was 94.4% for RUNX3 and 94.3% for SFRP1. Tissue RUNX3 methylation status detected CRC with 63.53% sensitivity and 80.00% specificity, while serum RUNX3 methylation status detected CRC with 60.00% sensitivity and 82.50% specificity. Tissue SFRP1 methylation status showed a sensitivity of 82.35% and specificity of 65.00%, while serum SFRP1 methylation status showed a sensitivity of 77.65% and specificity of 70.00% in detection of CRC. RUNX3/SFRP1/carcinoembryonic antigen (CEA) panel identified CRC with sensitivity of 89.41% in tissue and 84.71% in serum. CONCLUSION Our results verified the reliability of using serum RUNX3 and SFRP1 methylation status as a noninvasive biomarker for diagnosis of CRC and that combined detection of RUNX3/SFRP1/CEA panel might be a promising strategy for early detection of CRC.
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13
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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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14
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Kotsafti A, D'Incà R, Scarpa M, Fassan M, Angriman I, Mescoli C, Bortoli N, Brun P, Bardini R, Rugge M, Savarino E, Zingone F, Castoro C, Castagliuolo I, Scarpa M. Weak Cytotoxic T Cells Activation Predicts Low-Grade Dysplasia Persistence in Ulcerative Colitis. Clin Transl Gastroenterol 2019; 10:e00061. [PMID: 31343468 PMCID: PMC6708661 DOI: 10.14309/ctg.0000000000000061] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2019] [Accepted: 05/16/2019] [Indexed: 12/12/2022] Open
Abstract
INTRODUCTION In patients with ulcerative colitis (UC), dysplasia develops in 10%-20% of cases. The persistence of low-grade dysplasia (LGD) in UC in 2 consecutive observations is still an indication for restorative proctocolectomy. Our hypothesis is that in the case of weak cytotoxic activation, dysplasia persists. We aimed to identify possible immunological markers of LGD presence and persistence. METHODS We prospectively enrolled 112 UC patients who underwent screening colonoscopy (T0) who had biopsies taken from their sigmoid colon. Ninety of them had at least a second colonoscopy (T1) with biopsies taken in the sigmoid colon and 8 patients had dysplasia in both examinations suggesting a persistence of LGD in their colon. Immunohistochemistry and real time polymerase chain reaction for CD4, CD69, CD107, and CD8β messenger RNA (mRNA) expression and flow cytometry for epithelial cells expressing CD80 or HLA avidin-biotin complex were performed. Non-parametric statistics, receiver operating characteristic curves analysis, and logistic multiple regression analysis were used. RESULTS Thirteen patients had LGD diagnosed at T0. The mucosal mRNA expression of CD4, CD69, and CD8β was significantly lower than in patients without dysplasia (P = 0.033, P = 0.046 and P = 0.007, respectively). A second colonoscopy was performed in 90 patients after a median follow-up of 17 (12-25) months and 14 of the patients were diagnosed with LGD. In these patients, CD8β mRNA expression at T0 was significantly lower in patients without dysplasia (P = 0.004). A multivariate survival analysis in a model including CD8β mRNA levels and age >50 demonstrated that both items were independent predictors of dysplasia at follow-up (hazard ratio [HR] = 0.47 [95% confidence interval [CI]: 0.26-0.86], P = 0.014, and HR = 13.32 [95% CI: 1.72-102.92], P = 0.013). DISCUSSION These data suggest a low cytotoxic T cell activation in the colonic mucosa of UC patients who do not manage to clear dysplasia. Thus, low level of CD8β mRNA expression in non-dysplastic colonic mucosa might be considered in future studies about the decision making of management of LGD in UC.
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MESH Headings
- Adult
- Antigens, CD/metabolism
- Antigens, Differentiation, T-Lymphocyte/metabolism
- B7-1 Antigen/metabolism
- Biopsy
- CD4 Antigens/metabolism
- CD8 Antigens/metabolism
- Colitis, Ulcerative/diagnostic imaging
- Colitis, Ulcerative/pathology
- Colon, Sigmoid/pathology
- Colonoscopy/methods
- Female
- Humans
- Hyperplasia/classification
- Hyperplasia/pathology
- Immunohistochemistry/instrumentation
- Intestinal Mucosa/metabolism
- Intestinal Mucosa/pathology
- Lectins, C-Type/metabolism
- Lysosomal-Associated Membrane Protein 1/metabolism
- Lysosomal-Associated Membrane Protein 2/metabolism
- Male
- Middle Aged
- Proctocolectomy, Restorative/standards
- Prospective Studies
- RNA, Messenger/metabolism
- Survival Analysis
- T-Lymphocytes, Cytotoxic/metabolism
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Affiliation(s)
- Andromachi Kotsafti
- Laboratory of Advanced Translational Research, Veneto Institute of Oncology IOV - IRCCS, Padova, Italy
| | - Renata D'Incà
- Gastroenterology Unit, Azienda Ospedaliera di Padova, Padova, Italy
| | - Melania Scarpa
- Laboratory of Advanced Translational Research, Veneto Institute of Oncology IOV - IRCCS, Padova, Italy
| | - Matteo Fassan
- Department of Medicine, University of Padova, Padova, Italy
| | - Imerio Angriman
- Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy
| | | | - Nicolò Bortoli
- Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy
| | - Paola Brun
- Department of Molecular Medicine, University of Padova, Padova, Italy
| | - Romeo Bardini
- Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy
| | - Massimo Rugge
- Department of Medicine, University of Padova, Padova, Italy
| | - Edoardo Savarino
- Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy
| | - Fabiana Zingone
- Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy
| | - Carlo Castoro
- Upper GI Surgery Unit, Istituto Humanitas, Rozzano, Italy
| | | | - Marco Scarpa
- General Surgery Unit, Azienda Ospedaliera di Padova, Padova, Italy
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15
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Salama RH, Sayed ZEAA, Ashmawy AM, Elsewify WA, Ezzat GM, Mahmoud MA, Alsanory AA, Alsanory TA. Interrelations of Apoptotic and Cellular Senescence Genes Methylation in Inflammatory Bowel Disease Subtypes and Colorectal Carcinoma in Egyptians Patients. Appl Biochem Biotechnol 2019; 189:330-343. [PMID: 30989570 DOI: 10.1007/s12010-019-03017-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2019] [Accepted: 03/27/2019] [Indexed: 12/24/2022]
Abstract
Ras-related domain family member 1 transcript variant A (RASSF1A) controls apoptosis and cell proliferation while p14/ARF gene has a regulatory role in cellular senescence. Failure of apoptosis and cellular senescence occurs during inflammatory bowel disease (IBD) and colorectal cancer (CRC). To reveal the role of peripheral leukocyte promoter methylation of RASSF1A and p14/ARF in the pathogenesis of IBD subtypes and CRC we investigated the methylation state of the two genes by methylation-specific polymerase chain reaction (MSP-PCR) in 60 CRC patients, 60 patients with IBD; 27 with ulcerative colitis and 33 had Crohn's disease and also in 30 healthy subjects. Methylated RASSF1A and p14/ARF genes were detected in 55% and 60% of CRC, while the frequency of the methylated RASSF1A and p14/ARF genes was 23.3% and 43.3% in IBD patients and 3.3% and 13.3% in the control group (P = 0.000 each). Also, the frequency of methylated RASSF1A gene was significantly higher in ulcerative colitis than in Crohn's disease, while a non-significant frequency of methylated p14/ARF was detected between ulcerative colitis and Crohn's disease. Furthermore, methylated RASSF1A and p14/ARF were associated with the grade of CRC but not associated with the age of patients, family history, or tumor location. Results suggest that methylated RASSF1A and p14/ARF are related to CRC and IBD pathogenesis and may be used as molecular biomarkers for early detection of CRC and IBD.
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Affiliation(s)
- Ragaa H Salama
- Department of Medical Biochemistry, Faculty of Medicine, Assiut University, Assiut, Egypt
| | | | - Ahmed M Ashmawy
- Department of Internal Medicine, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Wael A Elsewify
- Department of Internal Medicine, Faculty of Medicine, Aswan University, Aswan, Egypt
| | - Ghada M Ezzat
- Department of Medical Biochemistry, Faculty of Medicine, Assiut University, Assiut, Egypt.
| | - Mahmoud A Mahmoud
- Department of Internal Medicine, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Aya A Alsanory
- Students at Faculty of Medicine, Faculty of Pharmacy, Assiut University, Assiut, Egypt
| | - Tasneem A Alsanory
- Students at Faculty of Medicine, Faculty of Pharmacy, Assiut University, Assiut, Egypt
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16
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Chen HX, Yuan ZY, Wu KX, Liu C, Mao QD, He BG, Yuan H. The study of methylation and single nucleotide polymorphisms of cancer-related genes in patients with early-stage ulcerative colitis. Scand J Gastroenterol 2019; 54:427-431. [PMID: 31046486 DOI: 10.1080/00365521.2019.1594355] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Aim: To investigate the methylation status and single nucleotide polymorphisms (SNPs) of cancer-associated genes in ulcerative colitis (UC) patients and explore the potential mechanism for high cancer risk of UC. Methods: A total of 103 patients were enrolled in our study, which included 30 healthy subjects, 41 patients with early-stage UC, and 32 patients with colorectal cancer (CRC). Methylation status of cyclooxygenase 2 (COX2) and human RUNT-related transcription factor 3 (RUNX3) genes in colonic mucosa from 3 groups of subjects were detected by methylation-specific polymerase chain reaction (PCR). The SNPs TNF-α rs1800629 and IL-1 rs1143627 were genotyped by PCR and direct sequencing. Results: The methylation rate of RUNX3 gene within CRC group was 35.7%, which was significantly higher than the other two groups (Healthy control 5.9%, UC 15.4%, p = .040). There was no significant difference in the methylation rate of RUNX3 between early-stage UC group and healthy control group (p = .633). The methylation rate of COX2 gene, the genotypes (GG, AG) and alleles (A, G) of rs1800629, and the genotypes (CC,CT,TT) and alleles (C,T) of rs1143627 were not statistically different among three groups. Conclusion: In the early stage of UC, the methylation rate of cancer-related genes RUNX3 and COX2 and SNPs TNF-α rs1800629 and IL-1 rs1143627 were not significantly different compared with healthy subjects. The methylation rate of RUNX3 in CRC increased, while the methylation rate of COX2 and SNPs TNF-α rs1800629 and IL-1 rs1143627 did not change significantly compared with the other two groups.
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Affiliation(s)
- Hai-Xing Chen
- a School of clinical medicine , Weifang Medical University , Weifang , Shandong , China
| | - Zi-Ying Yuan
- b Department of Gastroenterology , Peking University Third Hospital , Beijing , China
| | - Ke-Xiang Wu
- c Department of Electrophysiology , The Affiliated Hospital of Weifang Medical College , Weifang , Shandong , China
| | - Chen Liu
- a School of clinical medicine , Weifang Medical University , Weifang , Shandong , China
| | - Qing-Dong Mao
- d Department of Gastroenterology , The Affiliated Hospital Of Qingdao University , Qingdao , Shandong , China
| | - Bao-Guo He
- d Department of Gastroenterology , The Affiliated Hospital Of Qingdao University , Qingdao , Shandong , China
| | - Hao Yuan
- d Department of Gastroenterology , The Affiliated Hospital Of Qingdao University , Qingdao , Shandong , China
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17
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Beggs AD, Mehta S, Deeks JJ, James JD, Caldwell GM, Dilworth MP, Stockton JD, Blakeway D, Pestinger V, Vince A, Taniere P, Iqbal T, Magill L, Matthews G, Morton DG. Validation of epigenetic markers to identify colitis associated cancer: Results of module 1 of the ENDCAP-C study. EBioMedicine 2019; 39:265-271. [PMID: 30473377 PMCID: PMC6355942 DOI: 10.1016/j.ebiom.2018.11.034] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2018] [Revised: 10/04/2018] [Accepted: 11/16/2018] [Indexed: 01/27/2023] Open
Abstract
BACKGROUND Chronic inflammation caused by ulcerative colitis (UC) causes a pro-neoplastic drive in the inflamed colon, leading to a markedly greater risk of invasive malignancy compared to the general population. Despite surveillance protocols, 50% of cases proceed to cancer before neoplasia is detected. The Enhanced Neoplasia Detection and Cancer Prevention in Chronic Colitis (ENDCaP-C) trial is an observational multi-centre test accuracy study to ascertain the role of molecular markers in improving the detection of dysplasia. We aimed to validate previously identified biomarkers of neoplasia in a retrospective cohort and create predictive models for later validation in a prospective cohort. METHODS A retrospective analysis using bisulphite pyrosequencing of an 11 marker panel (SFRP1, SFRP2, SRP4, SRP5, WIF1, TUBB6, SOX7, APC1A, APC2, MINT1, RUNX3) in samples from 35 patients with cancer, 78 with dysplasia and 343 without neoplasia undergoing surveillance for UC associated neoplasia across 6 medical centres. Predictive models for UC associated cancer/dysplasia were created in the setting of neoplastic and non-neoplastic mucosa. FINDINGS For neoplastic mucosa a five marker panel (SFRP2, SFRP4, WIF1, APC1A, APC2) was accurate in detecting pre-cancerous and invasive neoplasia (AUC = 0.83; 95% CI: 0.79, 0.88), and dysplasia (AUC = 0.88; (0.84, 0.91). For non-neoplastic mucosa a four marker panel (APC1A, SFRP4, SFRP5, SOX7) had modest accuracy (AUC = 0.68; 95% CI: 0.62,0.73) in predicting associated bowel neoplasia through the methylation signature of distant non-neoplastic colonic mucosa. INTERPRETATION This multiplex methylation marker panel is accurate in the detection of ulcerative colitis associated dysplasia and neoplasia and is currently being validated in a prospective clinical trial. FUNDING The ENDCAP-C study was funded by the National Institute for Health Research Efficacy and Mechanism Evaluation (EME) Programme (11/100/29).
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Affiliation(s)
- Andrew D Beggs
- Institute of Cancer & Genomic Science, University of Birmingham, UK.
| | - Samir Mehta
- Birmingham Clinical Trials Unit, University of Birmingham, UK
| | - Jonathan J Deeks
- Birmingham Clinical Trials Unit, University of Birmingham, UK; National Institute for Health Research (NIHR), Birmingham Inflammation Biomedical Research Centre, UK
| | - Jonathan D James
- Institute of Cancer & Genomic Science, University of Birmingham, UK
| | | | - Mark P Dilworth
- Institute of Cancer & Genomic Science, University of Birmingham, UK
| | | | - Daniel Blakeway
- Institute of Cancer & Genomic Science, University of Birmingham, UK
| | | | - Alexandra Vince
- Birmingham Clinical Trials Unit, University of Birmingham, UK
| | | | - Tariq Iqbal
- Institute of Cancer & Genomic Science, University of Birmingham, UK
| | - Laura Magill
- Birmingham Clinical Trials Unit, University of Birmingham, UK
| | - Glenn Matthews
- Institute of Cancer & Genomic Science, University of Birmingham, UK
| | - Dion G Morton
- Institute of Cancer & Genomic Science, University of Birmingham, UK
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18
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Promoter methylation cooperates with SNPs to modulate RAGE transcription and alter UC risk. Biochem Biophys Rep 2018; 17:17-22. [PMID: 30519644 PMCID: PMC6260414 DOI: 10.1016/j.bbrep.2018.11.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2018] [Revised: 10/07/2018] [Accepted: 11/09/2018] [Indexed: 12/28/2022] Open
Abstract
Single-nucleotide polymorphisms (SNPs) located in the promoter region of the receptor for advanced glycation end products (RAGE) gene have been linked to the activity of RAGE. However, contrary to our expectation, we previously detected no correlation between SNPs within the RAGE promoter and ulcerative colitis (UC) risk in a case-control study. Here, we investigated the methylation of the RAGE promoter and analyzed the collective contribution of methylation and SNPs to UC risk. We found that RAGE promoter hypomethylation was more common in UC patients compared to controls (70% vs. 30%, respectively), as determined via bisulfite sequencing PCR (BSP) and methylation-specific PCR (MSP). Furthermore, we investigated the cooperativity of promoter methylation and SNPs and found that either of two SNPs (rs1800624 or rs1800625) and promoter methylation jointly contributed to UC risk (30 UC patients vs. 30 controls, P < 0.05). There was no correlation between UC risk and either methylation or SNPs when analyzed separately. This lack of correlation is likely due to promoter methylation repressing gene transcription, whereas SNPs in the RAGE promoter region activate RAGE transcription. We found that variant allele carriers with promoter hypomethylation were at an increased risk for UC (rs1800624, OR = 10, 95% CI: 1.641-60.21, P = 0.009; rs1800625, OR = 4.8, 95% CI: 1.074-21.447, P = 0.039). Furthermore, our data revealed that the RAGE mRNA levels in variant allele carriers with promoter hypomethylation were significantly higher compared to those with promoter hypermethylation (P < 0.05) as well as to those in wild-type allele individuals exhibiting promoter hypomethylation (P < 0.05). We therefore speculate that the methylation status and SNPs present in the RAGE promoter region alter RAGE transcription, thereby impacting UC risk. We also propose that the methylation status and RAGE promoter genotype could jointly serve as clinical biomarkers to assist in UC risk assessment.
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19
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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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20
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Nieto T, Tomlinson CL, Dretzke J, Bayliss S, Price MJ, Dilworth M, Beggs AD, Tucker O. A systematic review of epigenetic biomarkers in progression from non-dysplastic Barrett's oesophagus to oesophageal adenocarcinoma. BMJ Open 2018; 8:e020427. [PMID: 29961009 PMCID: PMC6042533 DOI: 10.1136/bmjopen-2017-020427] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2017] [Revised: 04/16/2018] [Accepted: 05/03/2018] [Indexed: 12/22/2022] Open
Abstract
OBJECTIVES The objective of this systematic review is to identify and summarise studies which examine epigenetic biomarkers in patients with Barrett's oesophagus (BO) and their association with progression to oesophageal adenocarcinoma (OADC). BO is a precursor lesion for OADC. There is no clinical test to predict patients who are likely to progress to OADC. An epigenetic biomarker could predict patients who are at high risk of progression from BO to OADC which could facilitate earlier diagnosis and spare those unlikely to develop cancer from regular invasive surveillance endoscopy. SETTING A systematic search was conducted of the following databases: MEDLINE, MEDLINE in Process, EMBASE, Cochrane Central, ISI Conference Proceedings Citation Index and the British Library's ZETOC. Studies were conducted in secondary and tertiary care settings. PARTICIPANTS All studies measuring epigenetic change in patients over 18 years old who progressed from non-dysplastic BO to OADC were included. Genetic, in vitro and studies which did not measure progression in the same patient cohort were excluded. Study inclusion and risk of bias of individual eligible studies were assessed in duplicate by two reviewers using a modified Quality in Prognostic Studies tool. RESULTS 14 studies met the inclusion criteria. 42 epigenetic markers were identified, and 5 studies developed models aiming to predict progression to OADC. CONCLUSIONS The evidence from this systematic review is suggestive of a role for p16 as an epigenetic biomarker for the progression of BO to OADC. PROSPERO NUMBER CRD42016038654.
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Affiliation(s)
- Tom Nieto
- Department of Surgery, University of Birmingham, Birmingham, UK
| | - Claire L Tomlinson
- Birmingham Clinical Trials Unit, Institute of Applied Health Research, University of Birmingham, Birmingham, UK
| | - Janine Dretzke
- Institute of Applied Health Research, University of Birmingham, Birmingham, UK
| | - Susan Bayliss
- Institute of Applied Health Research, University of Birmingham, Birmingham, UK
| | - Malcolm James Price
- Institute of Applied Health Research, University of Birmingham, Birmingham, UK
| | - Mark Dilworth
- Department of Surgery, Heart of England Foundation Trust and Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK
| | - Andrew D Beggs
- Department of Surgery, University of Birmingham, Birmingham, UK
| | - Olga Tucker
- Department of Surgery, University of Birmingham, Birmingham, UK
- Department of Surgery, Heart of England Foundation Trust and Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK
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21
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Porcellini E, Laprovitera N, Riefolo M, Ravaioli M, Garajova I, Ferracin M. Epigenetic and epitranscriptomic changes in colorectal cancer: Diagnostic, prognostic, and treatment implications. Cancer Lett 2018; 419:84-95. [PMID: 29360561 DOI: 10.1016/j.canlet.2018.01.049] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2017] [Revised: 01/07/2018] [Accepted: 01/12/2018] [Indexed: 12/12/2022]
Abstract
A cancer cell is the final product of a complex mixture of genetic, epigenetic and epitranscriptomic alterations, whose final interplay contribute to cancer onset and progression. This is specifically true for colorectal cancer, a tumor with a strong epigenetic component, which acts earlier than any other genetic alteration in promoting cancer cell malignant transformation. The pattern of progressive, and usually subtype-specific, DNA and histone modifications that occur in colorectal cancer has been extensively studied in the last decade, providing plenty of data to explore. For this tumor, it became recently evident that also RNA modifications play a relevant role in the activation of oncogenes or repression of tumor suppressor genes. In this review we provide a brief overview of all epigenetic and epitranscriptomic changes that have been found associated to colorectal cancer till now. We explore the impact of these alterations in cancer prognosis and response to treatment and discuss their potential use as cancer biomarkers.
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Affiliation(s)
- Elisa Porcellini
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy
| | - Noemi Laprovitera
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy
| | - Mattia Riefolo
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy; Sant'Orsola-Malpighi Hospital, Bologna, Italy
| | | | - Ingrid Garajova
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy; Sant'Orsola-Malpighi Hospital, Bologna, Italy
| | - Manuela Ferracin
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy.
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22
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Chandrasinghe P, Cereser B, Moorghen M, Al Bakir I, Tabassum N, Hart A, Stebbing J, Warusavitarne J. Role of SMAD proteins in colitis-associated cancer: from known to the unknown. Oncogene 2017; 37:1-7. [DOI: 10.1038/onc.2017.300] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2017] [Revised: 07/14/2017] [Accepted: 07/19/2017] [Indexed: 02/07/2023]
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Emmett RA, Davidson KL, Gould NJ, Arasaradnam RP. DNA methylation patterns in ulcerative colitis-associated cancer: a systematic review. Epigenomics 2017; 9:1029-1042. [PMID: 28621161 DOI: 10.2217/epi-2017-0025] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2016] [Accepted: 04/19/2017] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Evidence points to the role of DNA methylation in ulcerative colitis (UC)-associated cancer (UCC), the most serious complication of ulcerative colitis. A better understanding of the etiology of UCC may facilitate the development of new therapeutic targets and help to identify biomarkers of the disease risk. METHODS A search was performed in three databases following PRISMA protocol. DNA methylation in UCC was compared with sporadic colorectal cancer (SCRC), and individual genes differently methylated in UCC identified. RESULTS While there were some similarities in the methylation patterns of UCC compared with SCRC, generally lower levels of hypermethylation in promoter regions of individual genes was evident in UCC. Certain individual genes are, however, highly methylated in colitis-associated cancer: RUNX3, MINT1, MYOD and p16 exon1 and the promoter regions of EYA4 and ESR. CONCLUSION Patterns of DNA methylation differ between UCC and SCRC. Seven genes appear to be promising putative biomarkers.
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Affiliation(s)
- Ruth A Emmett
- Warwick Medical School, University of Warwick, Coventry, UK
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24
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Barnicle A, Seoighe C, Greally JM, Golden A, Egan LJ. Inflammation-associated DNA methylation patterns in epithelium of ulcerative colitis. Epigenetics 2017; 12:591-606. [PMID: 28557546 DOI: 10.1080/15592294.2017.1334023] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Aberrant DNA methylation patterns have been reported in inflamed tissues and may play a role in disease. We studied DNA methylation and gene expression profiles of purified intestinal epithelial cells from ulcerative colitis patients, comparing inflamed and non-inflamed areas of the colon. We identified 577 differentially methylated sites (false discovery rate <0.2) mapping to 210 genes. From gene expression data from the same epithelial cells, we identified 62 differentially expressed genes with increased expression in the presence of inflammation at prostate cancer susceptibility genes PRAC1 and PRAC2. Four genes showed inverse correlation between methylation and gene expression; ROR1, GXYLT2, FOXA2, and, notably, RARB, a gene previously identified as a tumor suppressor in colorectal adenocarcinoma as well as breast, lung and prostate cancer. We highlight targeted and specific patterns of DNA methylation and gene expression in epithelial cells from inflamed colon, while challenging the importance of epithelial cells in the pathogenesis of chronic inflammation.
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Affiliation(s)
- Alan Barnicle
- a Clinical Pharmacology, School of Medicine, National University of Ireland , Galway , Ireland.,b School of Mathematics, Statistics and Applied Mathematics, National University of Ireland , Galway , Ireland
| | - Cathal Seoighe
- b School of Mathematics, Statistics and Applied Mathematics, National University of Ireland , Galway , Ireland
| | - John M Greally
- c Center of Epigenomics and Department of Genetics (Division of Computational Genetics) , Albert Einstein College of Medicine, Morris Park Avenue , Bronx , NY , USA
| | - Aaron Golden
- b School of Mathematics, Statistics and Applied Mathematics, National University of Ireland , Galway , Ireland.,c Center of Epigenomics and Department of Genetics (Division of Computational Genetics) , Albert Einstein College of Medicine, Morris Park Avenue , Bronx , NY , USA.,d Department of Mathematical Sciences , Yeshiva University , 2495 Amsterdam Avenue, New York , NY , USA
| | - Laurence J Egan
- a Clinical Pharmacology, School of Medicine, National University of Ireland , Galway , Ireland
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25
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Targeted sequencing-based analyses of candidate gene variants in ulcerative colitis-associated colorectal neoplasia. Br J Cancer 2017; 117:136-143. [PMID: 28524162 PMCID: PMC5520210 DOI: 10.1038/bjc.2017.148] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2016] [Revised: 04/25/2017] [Accepted: 04/26/2017] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Long-standing ulcerative colitis (UC) leading to colorectal cancer (CRC) is one of the most serious and life-threatening consequences acknowledged globally. Ulcerative colitis-associated colorectal carcinogenesis showed distinct molecular alterations when compared with sporadic colorectal carcinoma. METHODS Targeted sequencing of 409 genes in tissue samples of 18 long-standing UC subjects at high risk of colorectal carcinoma (UCHR) was performed to identify somatic driver mutations, which may be involved in the molecular changes during the transformation of non-dysplastic mucosa to high-grade dysplasia. Findings from the study are also compared with previously published genome wide and exome sequencing data in inflammatory bowel disease-associated and sporadic colorectal carcinoma. RESULTS Next-generation sequencing analysis identified 1107 mutations in 275 genes in UCHR subjects. In addition to TP53 (17%) and KRAS (22%) mutations, recurrent mutations in APC (33%), ACVR2A (61%), ARID1A (44%), RAF1 (39%) and MTOR (61%) were observed in UCHR subjects. In addition, APC, FGFR3, FGFR2 and PIK3CA driver mutations were identified in UCHR subjects. Recurrent mutations in ARID1A (44%), SMARCA4 (17%), MLL2 (44%), MLL3 (67%), SETD2 (17%) and TET2 (50%) genes involved in histone modification and chromatin remodelling were identified in UCHR subjects. CONCLUSIONS Our study identifies new oncogenic driver mutations which may be involved in the transition of non-dysplastic cells to dysplastic phenotype in the subjects with long-standing UC with high risk of progression into colorectal neoplasia.
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26
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Abstract
Optimizing the management of colorectal cancer (CRC) risk in IBD requires a fundamental understanding of the evolutionary process underpinning tumorigenesis. In IBD, clonal evolution begins long before the development of overt neoplasia, and is probably accelerated by the repeated cycles of epithelial wounding and repair that are characteristic of the condition. Here, we review the biological drivers of mutant clone selection in IBD with particular reference to the unique histological architecture of the intestinal epithelium coupled with the inflammatory microenvironment in IBD, and the unique mutation patterns seen in IBD-driven neoplasia when compared with sporadic adenomas and CRC. How these data can be leveraged as evolutionary-based biomarkers to predict cancer risk is discussed, as well as how the efficacy of CRC surveillance programmes and the management of dysplasia can be improved. From a research perspective, the longitudinal surveillance of patients with IBD provides an under-exploited opportunity to investigate the biology of the human gastrointestinal tract over space and time.
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Affiliation(s)
- Chang-Ho R Choi
- Evolution and Cancer Laboratory, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK
- Inflammatory Bowel Disease Unit, Level 4 St Mark's Hospital, Watford Road, London HA1 3UJ, UK
| | - Ibrahim Al Bakir
- Evolution and Cancer Laboratory, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK
- Inflammatory Bowel Disease Unit, Level 4 St Mark's Hospital, Watford Road, London HA1 3UJ, UK
| | - Ailsa L Hart
- Inflammatory Bowel Disease Unit, Level 4 St Mark's Hospital, Watford Road, London HA1 3UJ, UK
| | - Trevor A Graham
- Evolution and Cancer Laboratory, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK
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27
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Alexander M, Burch JB, Steck SE, Chen CF, Hurley TG, Cavicchia P, Shivappa N, Guess J, Zhang H, Youngstedt SD, Creek KE, Lloyd S, Jones K, Hébert JR. Case-control study of candidate gene methylation and adenomatous polyp formation. Int J Colorectal Dis 2017; 32:183-192. [PMID: 27771773 PMCID: PMC5288296 DOI: 10.1007/s00384-016-2688-1] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/12/2016] [Indexed: 02/04/2023]
Abstract
PURPOSE Colorectal cancer (CRC) is one of the most common and preventable forms of cancer but remains the second leading cause of cancer-related death. Colorectal adenomas are precursor lesions that develop in 70-90 % of CRC cases. Identification of peripheral biomarkers for adenomas would help to enhance screening efforts. This exploratory study examined the methylation status of 20 candidate markers in peripheral blood leukocytes and their association with adenoma formation. METHODS Patients recruited from a local endoscopy clinic provided informed consent and completed an interview to ascertain demographic, lifestyle, and adenoma risk factors. Cases were individuals with a histopathologically confirmed adenoma, and controls included patients with a normal colonoscopy or those with histopathological findings not requiring heightened surveillance (normal biopsy, hyperplastic polyp). Methylation-specific polymerase chain reaction was used to characterize candidate gene promoter methylation. Odds ratios (ORs) and 95 % confidence intervals (95% CIs) were calculated using unconditional multivariable logistic regression to test the hypothesis that candidate gene methylation differed between cases and controls, after adjustment for confounders. RESULTS Complete data were available for 107 participants; 36 % had adenomas (men 40 %, women 31 %). Hypomethylation of the MINT1 locus (OR 5.3, 95% CI 1.0-28.2) and the PER1 (OR 2.9, 95% CI 1.1-7.7) and PER3 (OR 11.6, 95% CI 1.6-78.5) clock gene promoters was more common among adenoma cases. While specificity was moderate to high for the three markers (71-97 %), sensitivity was relatively low (18-45 %). CONCLUSION Follow-up of these epigenetic markers is suggested to further evaluate their utility for adenoma screening or surveillance.
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Affiliation(s)
- M Alexander
- South Carolina Statewide Cancer Prevention and Control Program, University of South Carolina, Columbia, SC, USA
- Department of Epidemiology and Biostatistics, Arnold School of Public Health, University of South Carolina, 915 Greene St, Room 228, Columbia, SC, 29209, USA
| | - J B Burch
- South Carolina Statewide Cancer Prevention and Control Program, University of South Carolina, Columbia, SC, USA.
- Department of Epidemiology and Biostatistics, Arnold School of Public Health, University of South Carolina, 915 Greene St, Room 228, Columbia, SC, 29209, USA.
- William Jennings Bryant Dorn Department of Veterans Affairs Medical Center, Columbia, SC, USA.
| | - S E Steck
- South Carolina Statewide Cancer Prevention and Control Program, University of South Carolina, Columbia, SC, USA
- Department of Epidemiology and Biostatistics, Arnold School of Public Health, University of South Carolina, 915 Greene St, Room 228, Columbia, SC, 29209, USA
| | - C-F Chen
- Center for Molecular Studies, Greenwood Genetic Center, Greenwood, SC, USA
| | - T G Hurley
- South Carolina Statewide Cancer Prevention and Control Program, University of South Carolina, Columbia, SC, USA
| | - P Cavicchia
- South Carolina Statewide Cancer Prevention and Control Program, University of South Carolina, Columbia, SC, USA
- Department of Epidemiology and Biostatistics, Arnold School of Public Health, University of South Carolina, 915 Greene St, Room 228, Columbia, SC, 29209, USA
- Division of Community Health Promotion, Florida Department of Health, Tallahassee, FL, USA
| | - N Shivappa
- South Carolina Statewide Cancer Prevention and Control Program, University of South Carolina, Columbia, SC, USA
- Department of Epidemiology and Biostatistics, Arnold School of Public Health, University of South Carolina, 915 Greene St, Room 228, Columbia, SC, 29209, USA
| | - J Guess
- South Carolina Statewide Cancer Prevention and Control Program, University of South Carolina, Columbia, SC, USA
- Department of Epidemiology and Biostatistics, Arnold School of Public Health, University of South Carolina, 915 Greene St, Room 228, Columbia, SC, 29209, USA
| | - H Zhang
- Division of Epidemiology, Biostatistics, and Environmental Health, School of Public Health, University of Memphis, Memphis, TN, USA
| | - S D Youngstedt
- College of Nursing and Health Innovation, College of Health Solutions, Arizona State University and Phoenix VA Health Care System, Phoenix, AZ, USA
| | - K E Creek
- Department of Drug Discovery and Biomedical Sciences, South Carolina College of Pharmacy, University of South Carolina, Columbia, SC, USA
| | - S Lloyd
- South Carolina Medical Endoscopy Center, and Department of Family Medicine, University of South Carolina School of Medicine, Columbia, SC, USA
| | - K Jones
- Center for Molecular Studies, Greenwood Genetic Center, Greenwood, SC, USA
| | - J R Hébert
- South Carolina Statewide Cancer Prevention and Control Program, University of South Carolina, Columbia, SC, USA
- Department of Epidemiology and Biostatistics, Arnold School of Public Health, University of South Carolina, 915 Greene St, Room 228, Columbia, SC, 29209, USA
- Department of Family and Preventive Medicine, School of Medicine, University of South Carolin, Columbia, SC, USA
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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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Nieto T, Tomlinson CL, Dretzke J, Bayliss S, Dilworth M, Beggs AD, Tucker O. Epigenetic biomarkers in progression from non-dysplastic Barrett's oesophagus to oesophageal adenocarcinoma: a systematic review protocol. BMJ Open 2016; 6:e013361. [PMID: 27927666 PMCID: PMC5168625 DOI: 10.1136/bmjopen-2016-013361] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
INTRODUCTION Barrett's oesophagus (BO), a metaplastic condition affecting the lower oesophagus due to long-standing gastro-oesophageal reflux and chronic inflammation, is a precursor lesion for oesophageal adenocarcinoma (OADC). There is no clinical test to predict which patients with BO will progress to OADC. The British Society of Gastroenterology recommends endoscopic surveillance of patients with BO. Epigenetic changes have been well characterised in the neoplastic progression of ulcerative colitis to colonic carcinoma, another gastrointestinal cancer associated with chronic inflammation. This systematic review protocol aims to identify and evaluate studies which examine epigenetic biomarkers in BO and their association with progression to OADC. METHODS AND ANALYSIS All prospective and retrospective primary studies, and existing systematic reviews investigating epigenetic markers including DNA methylation, histone modification, chromatin remodelling, micro and non-coding RNAs of all types will be eligible for inclusion. Eligible patients are those over the age of 18 with BO, BO with dysplasia, OADC or unspecified oesophageal cancer. A comprehensive search of bibliographic databases using combinations of text and index words relating to the population, prognostic markers and outcome will be undertaken with no language restrictions. Results will be screened by 2 independent reviewers and data extracted using a standardised proforma. The quality and risk of bias of individual studies will be assessed using the Quality in Prognostic Studies (QUIPS) tool. A narrative synthesis of all evidence will be performed with key findings tabulated. Meta-analysis will be considered where studies and reported outcomes are considered sufficiently homogeneous, both clinically and methodologically. Findings will be interpreted in the context of the quality of included studies. The systematic review will be reported according to PRISMA guidelines. ETHICS AND DISSEMINATION This is a systematic review of completed studies and no ethical approval is required. Findings from the full systematic review will be submitted for publication and presentation at national and international conferences which will inform future research on risk stratification in patients with BO. REVIEW REGISTRATION NUMBER CRD42016038654.
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Affiliation(s)
- T Nieto
- Department of Surgery, University of Birmingham, Birmingham, UK
| | - C L Tomlinson
- Birmingham Clinical Trials Unit, Institute of Applied Health Research, University of Birmingham, Birmingham, UK
| | - J Dretzke
- Institute of Applied Health Research, University of Birmingham, Birmingham, UK
| | - S Bayliss
- Institute of Applied Health Research, University of Birmingham, Birmingham, UK
| | - M Dilworth
- Department of Surgery, Heart of England Foundation Trust and Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK
| | - A D Beggs
- Department of Surgery, University of Birmingham, Birmingham, UK
| | - O Tucker
- Department of Surgery, University of Birmingham, Birmingham, UK
- Department of Surgery, Heart of England Foundation Trust and Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK
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Chen R, Lai LA, Brentnall TA, Pan S. Biomarkers for colitis-associated colorectal cancer. World J Gastroenterol 2016; 22:7882-7891. [PMID: 27672285 PMCID: PMC5028804 DOI: 10.3748/wjg.v22.i35.7882] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2016] [Revised: 06/30/2016] [Accepted: 08/01/2016] [Indexed: 02/06/2023] Open
Abstract
Patients with extensive ulcerative colitis (UC) of more than eight years duration have an increased risk of colorectal cancer. Molecular biomarkers for dysplasia and cancer could have a great clinical value in managing cancer risk in these UC patients. Using a wide range of molecular techniques - including cutting-edge OMICS technologies - recent studies have identified clinically relevant biomarker candidates from a variety of biosamples, including colonic biopsies, blood, stool, and urine. While the challenge remains to validate these candidate biomarkers in multi-center studies and with larger patient cohorts, it is certain that accurate biomarkers of colitis-associated neoplasia would improve clinical management of neoplastic risk in UC patients. This review highlights the ongoing avenues of research in biomarker development for colitis-associated colorectal cancer.
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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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Scarpa M, Scarpa M, Castagliuolo I, Erroi F, Kotsafti A, Basato S, Brun P, D'Incà R, Rugge M, Angriman I, Castoro C. Aberrant gene methylation in non-neoplastic mucosa as a predictive marker of ulcerative colitis-associated CRC. Oncotarget 2016; 7:10322-31. [PMID: 26862732 PMCID: PMC4891122 DOI: 10.18632/oncotarget.7188] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2015] [Accepted: 01/23/2016] [Indexed: 12/31/2022] Open
Abstract
UNLABELLED BACKGROUND PROMOTER: hypermethylation plays a major role in cancer through transcriptional silencing of critical genes. The aim of our study is to evaluate the methylation status of these genes in the colonic mucosa without dysplasia or adenocarcinoma at the different steps of sporadic and UC-related carcinogenesis and to investigate the possible role of genomic methylation as a marker of CRC. RESULTS The expression of Dnmts 1 and 3A was significantly increased in UC-related carcinogenesis compared to non inflammatory colorectal carcinogenesis. In non-neoplastic colonic mucosa, the number of methylated genes resulted significantly higher in patients with CRC and in those with UC-related CRC compared to the HC and UC patients and patients with dysplastic lesion of the colon. The number of methylated genes in non-neoplastic colonic mucosa predicted the presence of CRC with good accuracy either in non inflammatory and inflammatory related CRC. METHODS Colonic mucosal samples were collected from healthy subjects (HC) (n = 30) and from patients with ulcerative colitis (UC) (n = 29), UC and dysplasia (n = 14), UC and cancer (n = 10), dysplastic adenoma (n = 14), and colon adenocarcinoma (n = 10). DNA methyltransferases-1, -3a, -3b, mRNA expression were quantified by real time qRT-PCR. The methylation status of CDH13, APC, MLH1, MGMT1 and RUNX3 gene promoters was assessed by methylation-specific PCR. CONCLUSIONS Methylation status of APC, CDH13, MGMT, MLH1 and RUNX3 in the non-neoplastic mucosa may be used as a marker of CRC: these preliminary results could allow for the adjustment of a patient's surveillance interval and to select UC patients who should undergo intensive surveillance.
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Affiliation(s)
- Marco Scarpa
- Surgical Oncology Unit, Veneto Institute of Oncology IOV - IRCCS, Padova, Italy
| | - Melania Scarpa
- Surgical Oncology Unit, Veneto Institute of Oncology IOV - IRCCS, Padova, Italy
| | | | - Francesca Erroi
- Department of Surgery Oncology and Gastroenterology DISCOG, University of Padova, Padova, Italy
| | - Andromachi Kotsafti
- Surgical Oncology Unit, Veneto Institute of Oncology IOV - IRCCS, Padova, Italy
| | - Silvia Basato
- Department of Surgery Oncology and Gastroenterology DISCOG, University of Padova, Padova, Italy
| | - Paola Brun
- Department of Molecular Medicine, University of Padova, Padova, Italy
| | - Renata D'Incà
- Department of Surgery Oncology and Gastroenterology DISCOG, University of Padova, Padova, Italy
| | - Massimo Rugge
- Department of Medicine, University of Padova, Padova, Italy
| | - Imerio Angriman
- Department of Surgery Oncology and Gastroenterology DISCOG, University of Padova, Padova, Italy
| | - Carlo Castoro
- Surgical Oncology Unit, Veneto Institute of Oncology IOV - IRCCS, Padova, Italy
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Barnicle A, Seoighe C, Golden A, Greally JM, Egan LJ. Differential DNA methylation patterns of homeobox genes in proximal and distal colon epithelial cells. Physiol Genomics 2016; 48:257-73. [PMID: 26812987 DOI: 10.1152/physiolgenomics.00046.2015] [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: 05/04/2015] [Accepted: 01/13/2016] [Indexed: 12/24/2022] Open
Abstract
Region and cell-type specific differences in the molecular make up of colon epithelial cells have been reported. Those differences may underlie the region-specific characteristics of common colon epithelial diseases such as colorectal cancer and inflammatory bowel disease. DNA methylation is a cell-type specific epigenetic mark, essential for transcriptional regulation, silencing of repetitive DNA and genomic imprinting. Little is known about any region-specific variations in methylation patterns in human colon epithelial cells. Using purified epithelial cells and whole biopsies (n= 19) from human subjects, we generated epigenome-wide DNA methylation data (using the HELP-tagging assay), comparing the methylation signatures of the proximal and distal colon. We identified a total of 125 differentially methylated sites (DMS) mapping to transcription start sites of protein-coding genes, most notably several members of the homeobox (HOX) family of genes. Patterns of differential methylation were validated with MassArray EpiTYPER. We also examined DNA methylation in whole biopsies, applying a computational technique to deconvolve variation in methylation within cell types and variation in cell-type composition across biopsies. Including inferred epithelial proportions as a covariate in differential methylation analysis applied to the whole biopsies resulted in greater overlap with the results obtained from purified epithelial cells compared with when the covariate was not included. Results obtained from both approaches highlight region-specific methylation patterns of HOX genes in colonic epithelium. Regional variation in methylation patterns has implications for the study of diseases that exhibit regional expression patterns in the human colon, such as inflammatory bowel disease and colorectal cancer.
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Affiliation(s)
- Alan Barnicle
- Clinical Pharmacology, School of Medicine, National University of Ireland, Galway, Ireland; School of Mathematics, Statistics and Applied Mathematics, National University of Ireland, Galway, Ireland; and
| | - Cathal Seoighe
- School of Mathematics, Statistics and Applied Mathematics, National University of Ireland, Galway, Ireland; and
| | - Aaron Golden
- Center of Epigenomics and Department of Genetics (Division of Computational Genetics), Albert Einstein College of Medicine, Bronx, New York
| | - John M Greally
- Center of Epigenomics and Department of Genetics (Division of Computational Genetics), Albert Einstein College of Medicine, Bronx, New York
| | - Laurence J Egan
- Clinical Pharmacology, School of Medicine, National University of Ireland, Galway, Ireland;
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Gerecke C, Scholtka B, Löwenstein Y, Fait I, Gottschalk U, Rogoll D, Melcher R, Kleuser B. Hypermethylation of ITGA4, TFPI2 and VIMENTIN promoters is increased in inflamed colon tissue: putative risk markers for colitis-associated cancer. J Cancer Res Clin Oncol 2015; 141:2097-107. [PMID: 25902909 DOI: 10.1007/s00432-015-1972-8] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2014] [Accepted: 04/13/2015] [Indexed: 12/18/2022]
Abstract
PURPOSE Epigenetic silencing of tumor suppressor genes is involved in early transforming events and has a high impact on colorectal carcinogenesis. Likewise, colon cancers that derive from chronically inflamed bowel diseases frequently exhibit epigenetic changes. But there is little data about epigenetic aberrations causing colorectal cancer in chronically inflamed tissue. The aim of the present study was to evaluate the aberrant gain of methylation in the gene promoters of VIM, TFPI2 and ITGA4 as putative early markers in the development from inflamed tissue via precancerous lesions toward colorectal cancer. METHODS Initial screening of different cancer cell lines by using methylation-specific PCR revealed a putative colon cancer-specific methylation pattern. Additionally, a demethylation assay was performed to investigate the methylation-dependent gene silencing of ITGA4. The candidate markers were analyzed in colonic tissue specimens from patients with colorectal cancer (n = 15), adenomas (n = 76), serrated lesions (n = 13), chronic inflammation (n = 10) and normal mucosal samples (n = 9). RESULTS A high methylation frequency of VIM (55.6 %) was observed in normal colon tissue, whereas ITGA4 and TFPI2 were completely unmethylated in controls. A significant gain of methylation frequency with progression of disease as well as an age-dependent effect was detectable for TFPI2. ITGA4 methylation frequency was high in precancerous and cancerous tissues as well as in inflammatory bowel diseases (IBD). CONCLUSION The already established methylation marker VIM does not permit a specific and sensitive discrimination of healthy and neoplastic tissue. The methylation markers ITGA4 and TFPI2 seem to be suitable risk markers for inflammation-associated colon cancer.
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Affiliation(s)
- Christian Gerecke
- Department of Nutritional Toxicology, Institute of Nutritional Science, University of Potsdam, Arthur-Scheunert-Allee 114-116, 14558, Nuthetal, Germany
| | - Bettina Scholtka
- Department of Nutritional Toxicology, Institute of Nutritional Science, University of Potsdam, Arthur-Scheunert-Allee 114-116, 14558, Nuthetal, Germany
| | - Yvonne Löwenstein
- Department of Nutritional Toxicology, Institute of Nutritional Science, University of Potsdam, Arthur-Scheunert-Allee 114-116, 14558, Nuthetal, Germany
| | - Isabel Fait
- Department of Nutritional Toxicology, Institute of Nutritional Science, University of Potsdam, Arthur-Scheunert-Allee 114-116, 14558, Nuthetal, Germany
| | - Uwe Gottschalk
- Department of Internal Medicine, Gastroenterology and Interventional Endoscopy, Vivantes-Klinikum im Friedrichshain, Berlin, Germany
| | - Dorothee Rogoll
- Division of Gastroenterology, Department of Medicine II, University of Würzburg, Würzburg, Germany
| | - Ralph Melcher
- Division of Gastroenterology, Department of Medicine II, University of Würzburg, Würzburg, Germany
| | - Burkhard Kleuser
- Department of Nutritional Toxicology, Institute of Nutritional Science, University of Potsdam, Arthur-Scheunert-Allee 114-116, 14558, Nuthetal, Germany.
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Abstract
BACKGROUND Mucosal abnormalities are potentially important in the primary pathogenesis of ulcerative colitis (UC). We investigated the mucosal transcriptomic expression profiles of biopsies from patients with UC and healthy controls, taken from macroscopically noninflamed tissue from the terminal ileum and 3 colonic locations with the objective of identifying abnormal molecules that might be involved in disease development. METHODS Whole-genome transcriptional analysis was performed on intestinal biopsies taken from 24 patients with UC, 26 healthy controls, and 14 patients with Crohn's disease. Differential gene expression analysis was performed at each tissue location separately, and results were then meta-analyzed. Significantly, differentially expressed genes were validated using quantitative polymerase chain reaction. The location of gene expression within the colon was determined using immunohistochemistry, subcellular fractionation, electron and confocal microscopy. DNA methylation was quantified by pyrosequencing. RESULTS Only 4 probes were abnormally expressed throughout the colon in patients with UC with Bone morphogenetic protein/Retinoic acid Inducible Neural-specific 3 (BRINP3) being the most significantly underexpressed. Attenuated expression of BRINP3 in UC was independent of current inflammation, unrelated to phenotype or treatment, and remained low at rebiopsy an average of 22 months later. BRINP3 is localized to the brush border of the colonic epithelium and expression is influenced by DNA methylation within its promoter. CONCLUSIONS Genome-wide expression analysis of noninflamed mucosal biopsies from patients with UC identified BRINP3 as significantly underexpressed throughout the colon in a large subset of patients with UC. Low levels of this gene could predispose or contribute to the maintenance of the characteristic mucosal inflammation seen in this condition.
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DNA methylation of microRNA-124a is a potential risk marker of colitis-associated cancer in patients with ulcerative colitis. Dig Dis Sci 2014; 59:2444-51. [PMID: 24825593 DOI: 10.1007/s10620-014-3193-4] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2014] [Accepted: 04/28/2014] [Indexed: 02/07/2023]
Abstract
BACKGROUND Colitis-associated cancer (CAC) is the serious complication of ulcerative colitis (UC), and molecular markers to evaluate the individual risk are required. MicroRNA-124a (miR - 124a) is known to have tumor-suppressive function and be methylation-silenced during exposure to chronic inflammation. AIM We analyzed whether higher methylation levels of miR-124a genes correlated with the higher epidemiologic risk of CAC development in UC patients. METHODS Forty UC patients without CAC, four patients with CAC or dysplasia, eight sporadic colorectal cancer (S-CRC) patients, and 12 healthy volunteers (HV) were studied. Methylation status of miR-124a genes (miR-124a-1, -2, and -3) was analyzed by methylation-specific polymerase chain reaction (MSP), and methylation levels were quantified by real-time MSP. Expression of cyclin-dependent kinase 6 (CDK6), a target of miR-124a, was analyzed by immunohistochemistry. RESULTS Three miR-124a genes were methylated in all neoplastic tissues (CAC, dysplasia, and S-CRC), and CDK6 was highly expressed in those tissues. Regarding disease extent, mean methylation levels of miR-124a-3 in HV, non-pancolitis, and pancolitis were 2.0, 5.3, and 12.3%, respectively, and were significantly higher in pancolitis than in HV (p < 0.01). Regarding disease duration, mean methylation levels in short-term and long-standing UC patients were 2.5 and 13.2%, respectively. Long-standing UC patients had significantly higher methylation levels than HV (p < 0.01). Moreover, UC patients with both pancolitis and long-standing had 7.4-fold higher methylation levels than those without these risk factors. CONCLUSIONS MiR-124a genes are methylated during carcinogenesis in UC patients. The methylation level of miR-124a-3 is a promising marker for estimating individual risk for CAC.
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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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Scarpa M, Castagliuolo I, Castoro C, Pozza A, Scarpa M, Kotsafti A, Angriman I. Inflammatory colonic carcinogenesis: A review on pathogenesis and immunosurveillance mechanisms in ulcerative colitis. World J Gastroenterol 2014; 20:6774-6785. [PMID: 24944468 PMCID: PMC4051917 DOI: 10.3748/wjg.v20.i22.6774] [Citation(s) in RCA: 74] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2013] [Accepted: 02/27/2014] [Indexed: 02/06/2023] Open
Abstract
Ulcerative colitis (UC) is characterized by repeated flare-ups of inflammation that can lead to oncogenic insults to the colonic epithelial. UC-associated carcinogenesis presents a different sequence of tumorigenic events compared to those that contribute to the development of sporadic colorectal cancer. In fact, in UC, the early events are represented by oxidative DNA damage and DNA methylation that can produce an inhibition of oncosuppressor genes, mutation of p53, aneuploidy, and microsatellite instability. Hypermethylation of tumor suppressor and DNA mismatch repair gene promoter regions is an epigenetic mechanism of gene silencing that contribute to tumorigenesis and may represent the first step in inflammatory carcinogenesis. Moreover, p53 is frequently mutated in the early stages of UC-associated cancer. Aneuploidy is an independent risk factor for forthcoming carcinogenesis in UC. Epithelial cell-T-cell cross-talk mediated by CD80 is a key factor in controlling the progression from low to high grade dysplasia in UC-associated carcinogenesis.
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MESH Headings
- Cell Transformation, Neoplastic/genetics
- Cell Transformation, Neoplastic/immunology
- Cell Transformation, Neoplastic/metabolism
- Cell Transformation, Neoplastic/pathology
- Colitis, Ulcerative/complications
- Colitis, Ulcerative/genetics
- Colitis, Ulcerative/immunology
- Colitis, Ulcerative/metabolism
- Colitis, Ulcerative/pathology
- Colonic Neoplasms/etiology
- Colonic Neoplasms/genetics
- Colonic Neoplasms/immunology
- Colonic Neoplasms/metabolism
- Colonic Neoplasms/pathology
- DNA Damage
- DNA Methylation
- Disease Progression
- Epigenesis, Genetic
- Gene Expression Regulation, Neoplastic
- Humans
- Inflammation Mediators/metabolism
- Neoplasm Grading
- Oncogenes
- Oxidative Stress
- Risk Factors
- T-Lymphocytes/immunology
- T-Lymphocytes/metabolism
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Li YX, Lu Y, Li CY, Yuan P, Lin SS. Role of CDH1 promoter methylation in colorectal carcinogenesis: a meta-analysis. DNA Cell Biol 2014; 33:455-62. [PMID: 24684676 DOI: 10.1089/dna.2013.2291] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
This meta-analysis was performed to evaluate the role of CDH1 promoter methylation in colorectal carcinogenesis. The PubMed, CISCOM, CINAHL, Web of Science, Google Scholar, EBSCO, Cochrane Library, and CBM databases were searched for relevant articles published before November 1st, 2013 without any language restrictions. Meta-analysis was conducted using the STATA 12.0 software. Crude odds ratios (ORs) with 95% confidence intervals (95% CIs) were calculated. Nine clinical cohort studies met all our inclusion criteria and were included in this meta-analysis. A total of 883 colorectal cancer (CRC) patients were assessed. Our meta-analysis results revealed that the frequencies of CDH1 promoter methylation in CRC tissues were higher than those in control tissues (OR=2.61, 95% CI=1.24-5.50, p=0.012). A subgroup analysis by ethnicity showed that CDH1 promoter methylation was closely linked to the pathogenesis of CRC among Asians and Africans (Asians: OR=2.90, 95% CI=1.26-6.67, p=0.012; Africans: OR=3.81, 95% CI=1.56-9.34, p=0.003; respectively), but not among Caucasians (OR=1.68, 95% CI=0.24-11.72, p=0.598). A further subgroup analysis by type of control tissues suggested that CRC tissues also exhibited higher frequencies of CDH1 promoter methylation than those of normal and adjacent tissues (normal: OR=1.57, 95% CI=1.12-2.21, p=0.009; adjacent: OR=5.07, 95% CI=2.91-8.82, p<0.001; respectively). However, we found no evidence for any significant difference in the frequencies of CDH1 promoter methylation between CRC tissues and adenomas tissues (OR=1.18, 95% CI=0.74-1.90, p=0.485). Our findings provide empirical evidence that CDH1 promoter methylation may play an important role in colorectal carcinogenesis. Thus, CDH1 promoter methylation may be a useful biomarker for the early diagnosis of CRC.
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Affiliation(s)
- Yu-Xi Li
- Department of Coloproctological, The Fourth Affiliated Hospital of China Medical University , Shenyang, People's Republic of China
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41
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Kisiel JB, Ahlquist DA. Stool DNA testing for cancer surveillance in inflammatory bowel disease: an early view. Therap Adv Gastroenterol 2013; 6:371-80. [PMID: 24003338 PMCID: PMC3756632 DOI: 10.1177/1756283x13487941] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
Patients with inflammatory bowel disease (IBD) are at increased risk for colorectal cancer (CRC). Despite weak supporting evidence, important logistic barriers and high cost, colonoscopy is currently the only recommended approach to CRC surveillance in patients with IBD. As such, there is imperative to explore alternative or complementary strategies with potential to improve the efficiency and effectiveness of surveillance in IBD. Given our increasing understanding of tumorigenesis in IBD and the accompanying cascade of molecular alterations, there is a strong rationale to pursue biomarker assays for this application. Stool-based DNA testing with advanced technology has been shown to be highly discriminatory for detection of sporadic colorectal cancer and advanced precancers. In early observations, stool DNA testing also shows promise for the accurate detection of IBD-associated colorectal neoplasms. These findings raise important clinical and translational questions about how to best evaluate and develop this technology, and devise clinical algorithms that will complement colonoscopy to improve patient outcomes.
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Affiliation(s)
- John B Kisiel
- Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First Street Southwest, Rochester, MN 55905, USA
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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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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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Kisiel JB, Yab TC, Hussain FTN, Taylor WR, Garrity-Park MM, Sandborn WJ, Loftus EV, Wolff BG, Smyrk TC, Itzkowitz SH, Rubin DT, Zou H, Mahoney DW, Ahlquist DA. Stool DNA testing for the detection of colorectal neoplasia in patients with inflammatory bowel disease. Aliment Pharmacol Ther 2013; 37:546-54. [PMID: 23347191 PMCID: PMC3869396 DOI: 10.1111/apt.12218] [Citation(s) in RCA: 63] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2012] [Revised: 12/29/2012] [Accepted: 01/02/2013] [Indexed: 12/12/2022]
Abstract
BACKGROUND Current approaches to the detection of colorectal neoplasia associated with inflammatory bowel disease (IBD-CRN) are suboptimal. AIM To test the feasibility of using stool assay of exfoliated DNA markers to detect IBD-CRN. METHODS This investigation comprised tissue and stool studies. In the tissue study, gene sequencing and methylation assays were performed on candidate genes using tissue DNA from 25 IBD-CRNs and from 25 IBD mucosae without CRN. Mutations on p53, APC, KRAS, BRAF or PIK3CA genes were insufficiently informative, but several aberrantly methylated genes were highly discriminant. In the stool study, we evaluated candidate methylated genes (vimentin, EYA4, BMP3, NDRG4) in a prospective blinded study on buffered stools from 19 cases with known IBD-CRN and 35 age- and sex-matched IBD controls without CRN. From stool-extracted DNA, target genes were assayed using quantitative allele-specific real-time target and signal amplification method. RESULTS IBD-CRN cases included 17 with ulcerative colitis (UC) and two with Crohn's disease (CD); nine had cancer and 10 had dysplasia. Controls included 25 with UC and 10 with CD. Individually, BMP3, vimentin, EYA4 and NDRG4 markers showed high discrimination in stools with respective areas under the ROC curve of 0.91, 0.91, 0.85 and 0.84 for total IBD-CRN and of 0.97, 0.97, 0.95 and 0.85 for cancer. At 89% specificity, the combination of BMP3 and mNDRG4 detected 9/9 (100%) of CRC and 80% of dysplasia, 4/4 (100%) of high grade and 4/6 (67%) of low grade. CONCLUSION These findings demonstrate the feasibility of stool DNA testing for non-invasive detection of colorectal neoplasia associated with inflammatory bowel disease.
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Affiliation(s)
- John B. Kisiel
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester Minnesota, USA
| | - Tracy C. Yab
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester Minnesota, USA
| | | | - William R. Taylor
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester Minnesota, USA
| | - Megan M. Garrity-Park
- Division of Experimental Pathology and Lab Medicine, Mayo Clinic, Rochester Minnesota, USA
| | - William J. Sandborn
- Division of Gastroenterology, University of California San Diego, La Jolla California, USA
| | - Edward V. Loftus
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester Minnesota, USA
| | - Bruce G. Wolff
- Division of Colon and Rectal Surgery, Mayo Clinic, Rochester Minnesota, USA
| | - Thomas C. Smyrk
- Division of Anatomic Pathology, Mayo Clinic, Rochester Minnesota, USA
| | - Steven H. Itzkowitz
- Dr. Henry D. Janowitz Division of Gastroenterology, Mount Sinai School of Medicine, New York New York, USA
| | - David T. Rubin
- University of Chicago Inflammatory Bowel Disease Center, Chicago Illinois, USA
| | - Hongzhi Zou
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester Minnesota, USA
| | - Douglas W. Mahoney
- Biomedical Statistics and Informatics, Mayo Clinic, Rochester Minnesota, USA
| | - David A. Ahlquist
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester Minnesota, USA
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Azuara D, Rodriguez-Moranta F, de Oca J, Sanjuan X, Guardiola J, Lobaton T, Wang A, Boadas J, Piqueras M, Monfort D, Galter S, Esteller M, Moreno V, Capellá G. Novel methylation panel for the early detection of neoplasia in high-risk ulcerative colitis and Crohn's colitis patients. Inflamm Bowel Dis 2013; 19:165-73. [PMID: 22532293 DOI: 10.1002/ibd.22994] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND Patients with ulcerative colitis and Crohn's colonic disease are at increased risk of developing colorectal cancer (CRC). The aim of the study was to analyze the methylation status of selected genes as a risk marker for CRC in inflammatory bowel disease (IBD) patients. METHODS We evaluated the methylation status of four genes (TGFB2, SLIT2, HS3ST2, and TMEFF2) in biopsies of four groups of patients: 60 patients with sporadic CRC, 32 patients with IBD-associated neoplasia, 85 patients with IBD without associated neoplasia (20 at high risk and 65 at low risk), and 28 healthy controls. Methylation-specific melting curve analysis (MS-MCA) was used. Methylation status of these genes was also assessed in stool DNA from 60 IBD patients without neoplasia. RESULTS Methylation of the panel of genes analyzed was a very common phenomenon (78%) in IBD-associated neoplasia. The prevalence of methylation in adjacent nonneoplastic mucosa was also high (12/30). This prevalence was higher than in mucosa from healthy controls (2/28;7.1%; P < 0.05). Methylation of SLIT2 and TMEFF2 was more frequently detected in the mucosa of IBD patients at high risk of dysplasia or cancer (15/20) than patients at low risk (32/63) (P = 0.05 and P = 0.03, respectively). When stool samples were assessed, only SLIT2 gene methylation was more frequently methylated in the group of patients at high risk of dysplasia or cancer (4/16) compared to low risk (0/37) (P = 0.006). CONCLUSIONS Analysis of a 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 Institute of Oncology, IDIBELL, Hospitalet de Llobregat, Barcelona, Spain
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Tahara T, Arisawa T. Potential usefulness of DNA methylation as a risk marker for digestive cancer associated with inflammation. Expert Rev Mol Diagn 2012; 12:489-97. [PMID: 22702365 DOI: 10.1586/erm.12.38] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
DNA methylation has been deeply involved in the development and progression of digestive cancer, while aberrant DNA methylation has also often been observed in aged and inflammatory digestive tissues. Helicobacter pylori-related chronic gastritis, ulcerative colitis, and hepatitis B virus- and hepatitis C virus-related chronic hepatitis, are significant risk factors for developing cancer. A number of studies have revealed the specific methylation patterns for specific tissue types. DNA methylation status is stably transmitted to daughter cells. Also, unlike genetic mutations, it is possible to detect very tiny amounts of methylated DNA among tissues. Therefore, the use of aberrant methylation as a marker could be applicable to risk estimation of cancer development. We discuss the potential usefulness of DNA methylation as a risk marker for inflammation-associated digestive cancer, especially with attempts on gastric cancer, ulcerative colitis-associated cancer, and hepatitis B virus- and hepatitis C virus-related hepatocellular carcinoma.
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Affiliation(s)
- Tomomitsu Tahara
- Department of Gastroenterology, Fujita Health University School of Medicine, Toyoake, 1-98 Dengakugakubo Kutsukake-cho, Toyoake, Aichi, 470-1192, Japan.
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47
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Rubin DC, Shaker A, Levin MS. Chronic intestinal inflammation: inflammatory bowel disease and colitis-associated colon cancer. Front Immunol 2012; 3:107. [PMID: 22586430 PMCID: PMC3347037 DOI: 10.3389/fimmu.2012.00107] [Citation(s) in RCA: 281] [Impact Index Per Article: 21.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2012] [Accepted: 04/17/2012] [Indexed: 12/13/2022] Open
Abstract
The inflammatory bowel diseases (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), are chronic inflammatory disorders of the intestine. The prevalence in the United States is greater than 200 cases per 100,000, with the total number of IBD patients between 1 and 1.5 million. CD may affect all parts of the gastrointestinal tract, from mouth to anus, but most commonly involves the distal part of the small intestine or ileum, and colon. UC results in colonic inflammation that can affect the rectum only, or can progress proximally to involve part of or the entire colon. Clinical symptoms include diarrhea, abdominal pain, gastrointestinal bleeding, and weight loss. A serious long-term complication of chronic inflammation is the development of colorectal cancer. A genetic basis for IBD had long been recognized based on the increased familial risk. However, significant discordance for CD in twins, and a much less robust phenotypic concordance for UC, suggested additional factors play a role in disease pathogenesis, including environmental factors. In the past several years, progress in understanding the molecular basis of IBD has accelerated, beginning with the generation of animal models of colitis and progressing to the identification of specific genetic markers from candidate gene, gene linkage, and genome-wide association analyses. Genetic studies have also resulted in the recognition of the importance of environmental factors, particularly the crucial role of the gut microbiota in CD and UC. Altered immune responses to the normal intestinal flora are key factors in IBD pathogenesis. In this research topic, the genetic basis of IBD, the genetic and cellular alterations associated with colitis-associated colon cancer, and the emerging role of the intestinal microbiota and other environmental factors will be reviewed.
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Affiliation(s)
- Deborah C Rubin
- Division of Gastroenterology, Department of Internal Medicine, Washington University School of Medicine, Saint Louis, MO, USA
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Kisiel JB, Loftus EV, Harmsen WS, Zinsmeister AR, Sandborn WJ. Outcome of sporadic adenomas and adenoma-like dysplasia in patients with ulcerative colitis undergoing polypectomy. Inflamm Bowel Dis 2012; 18:226-35. [PMID: 21416564 DOI: 10.1002/ibd.21687] [Citation(s) in RCA: 55] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2011] [Accepted: 01/20/2011] [Indexed: 12/14/2022]
Abstract
BACKGROUND Ulcerative colitis (UC) patients are at increased risk of colorectal dysplasia and cancer. Few studies have examined the clinical outcomes of dysplastic polyps resembling sporadic adenomas that are removed with endoscopic polypectomy. METHODS A centralized diagnostic index identified patients evaluated between 1994 and 2004 with UC and polypoid dysplasia who were followed from the time of polypectomy until the most recent colonoscopy. They were stratified into two groups by polyp occurrence, either within (adenoma-like dysplasia) or outside (sporadic adenoma) the most proximal endoscopic or histologic extent of colitis. The endpoints of interest were the development of subsequent colorectal neoplasia, flat dysplasia, or cancer. The cumulative probabilities of these endpoints were estimated using the Kaplan-Meier method, and the association with clinical factors assessed using Cox proportional hazards regression. RESULTS Ninety-five patients were found to have polypoid dysplasia; of these, 77 underwent polypectomy. The cumulative probability of subsequent colorectal neoplasia in polypectomy patients was 18% at 1 year and 69% at 5 years. After polypectomy, cumulative incidence of cancer or flat dysplasia was 2% at 1 year and 13% at 5 years. The proportional hazards models indicated that these outcomes were not significantly associated with polyp type, primary sclerosing cholangitis, family history of colorectal cancer, 5-aminosalicylate use, extent of colitis, or duration of disease. CONCLUSIONS While polypectomy may be safe for the management of adenomas occurring in most UC patients, the 5-year cumulative incidence of a combined endpoint (cancer or flat dysplasia) was 13%. Such patients should be followed closely.
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Affiliation(s)
- John B Kisiel
- Division of Gastroenterology & Hepatology, Rochester, Minnesota 55905, USA
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Garrity-Park M, Loftus EV, Sandborn WJ, Smyrk TC. Myeloperoxidase immunohistochemistry as a measure of disease activity in ulcerative colitis: association with ulcerative colitis-colorectal cancer, tumor necrosis factor polymorphism and RUNX3 methylation. Inflamm Bowel Dis 2012; 18:275-83. [PMID: 21425209 DOI: 10.1002/ibd.21681] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2010] [Accepted: 01/17/2011] [Indexed: 12/12/2022]
Abstract
BACKGROUND Patients with extensive, longstanding ulcerative colitis (UC), a disease of chronic colonic inflammation, are at risk for colorectal cancer (CRC). Elucidating the mechanism and fully characterizing the nature of this chronic inflammation offers the potential to identify those at greatest risk. We performed a case-control study comparing histologic disease activity (HDA; neutrophils on hematoxylin and eosin [H&E]-stained slides) with immunohistochemistry (IHC) directed against specific cell types. We correlated IHC results with data previously generated on methylation status of RUNX3 and single nucleotide polymorphisms (SNPs) in tumor necrosis factor alpha (TNF-α). METHODS A nonadjacent, nonneoplastic section of bowel wall was identified for each UC-CRC case. HDA was assessed for UC-CRC cases (n = 50) and UC-controls (n = 50). Sections were immunostained using antibodies against macrophages (CD68), neutrophils/monocytes (myeloperoxidase, MPO), and T cells (CD3). Slides were scored using ImageJ and results reported as the percent area positive for each marker. RESULTS HDA did not correlate with infiltrate levels as measured by IHC and increasing HDA was inversely related to UC-CRC risk. Conversely, the percent area positive for CD68 and MPO was significantly elevated in UC-CRC cases versus controls (P = 0.04 and < 0.0001, respectively). In areas designated inactive, MPO staining remained significantly higher in UC-CRC cases versus controls (P = 0.002). Increased MPO staining was associated with methylation of RUNX3 and the TNF-α -308G>A SNP. CONCLUSIONS HDA is less sensitive than IHC and may underestimate inflammatory cell populations associated with UC-CRC. The epigenetic/genetic associations related to elevated MPO staining in UC-CRC may offer new methods for risk stratification and adjunctive screening tools.
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Affiliation(s)
- Megan Garrity-Park
- Division of Experimental Pathology and Lab Medicine, Mayo Clinic, Rochester, Minnesota, USA.
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Abstract
The widely accepted paradigm for tumorigenesis begins with rate-limiting mutations in a key growth control gene resulting in immediate lesion growth. Tumor progression occurs as cells within the tumor acquire additional carcinogenic mutations. However, there is clear evidence that the road to cancer can begin long before the growth of a clinically detectable lesion - indeed, long before any of the usual morphological correlates of preneoplasia are recognizable. Field cancerization, the replacement of the normal cell population by a histologically nondysplastic but protumorigenic mutant cell clone, underlies the development of many cancer types, and in this article we review field cancerization in the GI tract. We present the evidence that field cancerization can underpin tumorigenesis in all gastrointestinal compartments, discuss the homeostatic mechanisms that could permit clone spread and highlight how an understanding of the mechanisms driving field cancerization is a means to study human stem cell biology. Finally, we discuss how appropriate recognition of the role of field cancerization in tumorigenesis could impact patient care.
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Affiliation(s)
- Trevor A Graham
- Histopathology Laboratory, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London, WC2A 3LY, UK.
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