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Duan JL, Deng MH, Xiang ZC, Hu JL, Qu CH, Zhu TC, Xu MX, Chen JW, Xie JJ, Xie D, Cai MY, Li M, Liang H. Impact of WTAP in small HCC and paired adjacent non-neoplastic liver tissue on recurrence: A cohort study with external extension analysis. Front Cell Dev Biol 2022; 10:973548. [PMID: 36420139 PMCID: PMC9676468 DOI: 10.3389/fcell.2022.973548] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Accepted: 10/18/2022] [Indexed: 02/03/2024] Open
Abstract
Background: To evaluate prognostic value of WTAP levels in tumor and paired adjacent non-neoplastic liver tissues (PANLT) for cases of hepatitis B virus (HBV)-positive Asian small hepatocellular carcinoma (sHCC) patients who received curative partial hepatectomy. Method: The investigation with two external cohorts were included. Associations between hazard risk of recurrence and continuous WTAP levels were investigated with restricted cubic spline models. Cox and inverse probability weighting models were established for survival analysis. Based on interaction effects, further stratification analysis was performed. Landmark analysis was employed to analyze cases of late recurrence. Finally, sensitivity analysis was performed to assess unmeasured confounders. Findings: In an investigation cohort of 307 patients, restricted cubic spline models indicated that hazard risk of recurrence increases with elevated WTAP levels for sHCC and PANLT. However, using Cox and inverse probability weighting models, no significant differences were observed in recurrence-free survival (RFS) between groups with different WTAP levels in sHCC. Multivariate analysis showed that patients with high PANLT WTAP levels had significantly worse RFS (HR 1.567, 95% CI 1.065-2.307; p = 0.023). Based on the significant interaction effect between WTAP levels in sHCC and PANLT, stratification analysis revealed that recurrence risk is more pronounced in patients with high WTAP levels in both PANLT and sHCC. Landmark analysis showed that late recurrence was more likely to occur in patients with high PANLT WTAP levels (HR 2.058, 95% CI 1.113-3.805; p = 0.021). Moreover, the detrimental effects of elevated PANLT WTAP levels on RFS were validated with two external cohorts. Sensitivity analysis confirmed the robustness of results. Conclusion: Increased PANLT WTAP expression levels independently predict high recurrence risk in HBV-positive Asian sHCC patients. Both tumor tissues and PANLT need to be considered together in future clinical practice to obtain a more comprehensive and accurate evaluation for recurrence risk.
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Affiliation(s)
- Jin-Ling Duan
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China
- Department of Pathology, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Min-Hua Deng
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China
- Department of Surgery, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Zhi-Cheng Xiang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China
- Department of Pathology, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Jin-Long Hu
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China
- Department of Pathology, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Chun-Hua Qu
- Department of Pathology, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Tian-Chen Zhu
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China
- Department of Pathology, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Ming-Xing Xu
- Department of Hepatobiliary Surgery, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Jie-Wei Chen
- Department of Pathology, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Juan-Juan Xie
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Dan Xie
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China
- Department of Pathology, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Mu-Yan Cai
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China
- Department of Pathology, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Mei Li
- Department of Pathology, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Hu Liang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China
- Department of Clinical Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, China
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Possible Earlier Diagnosis of Ulcerative Colitis-Associated Neoplasia: A Retrospective Analysis of Interval Cases during Surveillance. J Clin Med 2021; 10:jcm10091927. [PMID: 33946906 PMCID: PMC8124807 DOI: 10.3390/jcm10091927] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Revised: 04/25/2021] [Accepted: 04/26/2021] [Indexed: 01/08/2023] Open
Abstract
Background: Early detection of ulcerative colitis-associated neoplasia (UCAN) is often difficult. The aim of this study was to clarify the morphology of initial UCAN. Methods: White-light colonoscopy images obtained within the 2 years before UCAN diagnosis were retrospectively reviewed. The primary endpoint was the frequency of visible or invisible neoplasia on the endoscopic images before UCAN diagnosis. The secondary endpoints were comparisons of (1) visible or invisible neoplasia on initial endoscopic images of early-stage and advanced cancers, (2) the clinical backgrounds of patients in whom neoplasia was visible or invisible on initial endoscopic images, and (3) the clinical backgrounds of patients with distinct and indistinct UCAN borders. Results: Of the 27 UCAN lesions (11 early-stage; 16 advanced-stage), 25.9% (n = 7) were initially visible and 74.1% (n = 20) were invisible. The mean interval between the last surveillance colonoscopy and UCAN diagnosis was 14.5 ± 6.7 months. Of early-stage cancers, 18.2% (n = 2) were visible and 81.8% (n = 9) were invisible. Of advanced-stage cancers, 31.3% (n = 5) were visible and 68.8% (n = 11) were invisible. Invisible lesions were significantly more common in the rectum (p = 0.011) and tended to be more common in patients with inflammation and left-sided colitis (p = 0.084, p = 0.068, respectively). Patients with indistinct UCAN borders were significantly more likely to present with inflammation than those with distinct UCAN borders (p = 0.021). Conclusion: More careful surveillance is needed because rectum lesions and inflammation are difficult to identify as neoplasia even within the 2 years before a UCAN diagnosis.
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Azuara D, Aussó S, Rodriguez-Moranta F, Guardiola J, Sanjuan X, Lobaton T, Boadas J, Piqueras M, Monfort D, Guinó E, Moreno V, Capellá G, de Oca J. New Methylation Biomarker Panel for Early Diagnosis of Dysplasia or Cancer in High-Risk Inflammatory Bowel Disease Patients. Inflamm Bowel Dis 2018; 24:2555-2564. [PMID: 30099509 DOI: 10.1093/ibd/izy255] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2017] [Indexed: 02/07/2023]
Abstract
BACKGROUND The risk of developing colorectal cancer (CRC) is increased in patients with inflammatory bowel disease (IBD) of the colon. The aim of the study was to evaluate the effectiveness of selected methylation gene panel for the early detection of CRC in high-risk IBD patients. METHODS In a discovery phase, 73 biopsies of 48 IBD patients (associated or not to CRC) were analyzed from genome-wide DNA methylation analysis using the Illumina Human Methylation 450K BeadChip. The panel of 5 genes selected (EYA4, SLIT2, FLI1, USP44, and SND1) was validated prospectively using methylation-specific melting curve analysis in biopsies of diseased and adjacent healthy tissue of 203 patients: 38 with IBD and associated neoplasia, 81 patients with IBD (25 of them with high risk), 48 with sporadic CRC, and 36 healthy controls. RESULTS The prevalence of methylation was higher in patients with IBD and associated neoplasia (both in diseased and adjacent healthy tissue, 71% and 52%, respectively) than in healthy controls (2/36, 6%; P = 6.72E-05). Methylation in IBD patients at high risk of dysplasia or cancer was more frequently detected than in patients at low risk (92% vs 57%; odds ratio, 8.63; P = 0.001). EYA4 and SLIT2 were the markers most frequently methylated. Differences in methylation levels were more evident in healthy mucosa (82% vs 15% high vs low risk, respectively; P = 1.25E-05). CONCLUSIONS Analysis of this panel of methylation markers may help in the early identification of colorectal dysplasia or cancer in high-risk IBD patients.
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Affiliation(s)
- Daniel Azuara
- Translational Research Laboratory, Catalan Insitute of Oncology (ICO), Bellvitge Biomedical Research Institute (IDIBELL)-CIBERONC, L'Hospitalet de Llobregat, Barcelona, Spain
| | - Susanna Aussó
- Unit of Biomarkers and Susceptibility, Cancer Prevention and Control Program, ICO-IDIBELL and CIBERESP, L'Hospitalet de Llobregat, Barcelona, Spain
| | - Francisco Rodriguez-Moranta
- Department of Gastroenterology, University Hospital Bellvitge (HUB-IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain
| | - Jordi Guardiola
- Department of Gastroenterology, University Hospital Bellvitge (HUB-IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain
| | - Xavier Sanjuan
- Department of Pathology, University Hospital Bellvitge (HUB-IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain
| | - Triana Lobaton
- Department of Gastroenterology, Germans Trias i Pujol University Hospital, Badalona, Barcelona, Spain
| | - Jaume Boadas
- Department of Gastroenterology, Hospital of Terrassa, Terrassa Health Consortium (CST), Terrassa, Barcelona, Spain
| | - Marta Piqueras
- Department of Gastroenterology, Hospital of Terrassa, Terrassa Health Consortium (CST), Terrassa, Barcelona, Spain
| | - David Monfort
- Department of Gastroenterology, Hospital of Terrassa, Terrassa Health Consortium (CST), Terrassa, Barcelona, Spain
| | - Elisabet Guinó
- Unit of Biomarkers and Susceptibility, Cancer Prevention and Control Program, ICO-IDIBELL and CIBERESP, L'Hospitalet de Llobregat, Barcelona, Spain
| | - Victor Moreno
- Unit of Biomarkers and Susceptibility, Cancer Prevention and Control Program, ICO-IDIBELL and CIBERESP, L'Hospitalet de Llobregat, Barcelona, Spain
| | - Gabriel Capellá
- Translational Research Laboratory, Catalan Insitute of Oncology (ICO), Bellvitge Biomedical Research Institute (IDIBELL)-CIBERONC, L'Hospitalet de Llobregat, Barcelona, Spain
| | - Javier de Oca
- Department of General and Digestive Surgery, Colorectal Unit, University Hospital Bellvitge (HUB-IDIBELL)-CIBERONC, L'Hospitalet de Llobregat, Barcelona, Spain
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Toiyama Y, Okugawa Y, Kondo S, Okita Y, Araki T, Kusunoki K, Uchino M, Ikeuchi H, Hirota S, Mitsui A, Takehana K, Umezawa T, Kusunoki M. Comprehensive analysis identifying aberrant DNA methylation in rectal mucosa from ulcerative colitis patients with neoplasia. Oncotarget 2018; 9:33149-33159. [PMID: 30237858 PMCID: PMC6145694 DOI: 10.18632/oncotarget.26032] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2018] [Accepted: 08/10/2018] [Indexed: 12/19/2022] Open
Abstract
Background There are no biomarkers to facilitate the identification of patients with ulcerative colitis (UC) who are at high risk for developing colorectal cancer (CRC). In our current study, we used rectal tissues from UC patients to identify aberrant DNA methylations and evaluated whether they could be used to identify UC patients with coexisting colorectal neoplasia. Results Using a training set, we identified 484 differentially methylated regions (DMRs) with absolute delta beta-values > 0.1 in rectal mucosa by using the ChAMP algorithm. Next, pathway enrichment analysis was performed using 484 DMRs to select coordinately methylated DMRs, resulting in the selection of 187 aberrant DMRs in rectal tissues from UC-CRC. Then, the Elastic Net classification algorithm was performed to narrow down optimal aberrant DMRs, and we finally selected 11 DMRs as biomarkers for identification of UC-CRC patients. The 11 chosen DMRs could discriminate UC patients with or without CRC in a training set (area under the curve, 0.96) and the validation set (area under the curve, 0.81). Conclusions In conclusion, we identified 11 DMRs that could identify UC patients with CRC complications. Prospective studies should further confirm the validity of these biomarkers. Methods We performed genome-wide DNA methylation profiles in rectal mucosal tissues (n = 48) from 24 UC-CRC and 24 UC patients in a training set. Next, we performed comprehensive DNA methylation analysis using rectal mucosal tissues (n = 16) from 8 UC-CRC and 8 UC patients for validation.
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Affiliation(s)
- Yuji Toiyama
- Department of Gastrointestinal and Pediatric Surgery, Division of Reparative Medicine, Institute of Life Sciences, Graduate School of Medicine, Mie University, Mie, Japan
| | - Yoshinaga Okugawa
- Department of Gastrointestinal and Pediatric Surgery, Division of Reparative Medicine, Institute of Life Sciences, Graduate School of Medicine, Mie University, Mie, Japan
| | - Satoru Kondo
- Department of Gastrointestinal and Pediatric Surgery, Division of Reparative Medicine, Institute of Life Sciences, Graduate School of Medicine, Mie University, Mie, Japan
| | - Yoshiki Okita
- Department of Gastrointestinal and Pediatric Surgery, Division of Reparative Medicine, Institute of Life Sciences, Graduate School of Medicine, Mie University, Mie, Japan
| | - Toshimitsu Araki
- Department of Gastrointestinal and Pediatric Surgery, Division of Reparative Medicine, Institute of Life Sciences, Graduate School of Medicine, Mie University, Mie, Japan
| | - Kurando Kusunoki
- Department of Inflammatory Bowel Disease, Hyogo College of Medicine, Hyogo, Japan
| | - Motoi Uchino
- Department of Inflammatory Bowel Disease, Hyogo College of Medicine, Hyogo, Japan
| | - Hiroki Ikeuchi
- Department of Inflammatory Bowel Disease, Hyogo College of Medicine, Hyogo, Japan
| | - Seiichi Hirota
- Department of Surgical Pathology, Hyogo College of Medicine, Hyogo, Japan
| | - Akira Mitsui
- Institute for Innovation, Ajinomoto Co., Inc., Kawasaki, Japan
| | - Kenji Takehana
- R&D Planning Department, EA Pharma Co., Ltd., Tokyo, Japan
| | | | - Masato Kusunoki
- Department of Gastrointestinal and Pediatric Surgery, Division of Reparative Medicine, Institute of Life Sciences, Graduate School of Medicine, Mie University, Mie, Japan
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Toiyama Y, Okugawa Y, Tanaka K, Araki T, Uchida K, Hishida A, Uchino M, Ikeuchi H, Hirota S, Kusunoki M, Boland CR, Goel A. A Panel of Methylated MicroRNA Biomarkers for Identifying High-Risk Patients With Ulcerative Colitis-Associated Colorectal Cancer. Gastroenterology 2017; 153:1634-1646.e8. [PMID: 28847750 PMCID: PMC5748293 DOI: 10.1053/j.gastro.2017.08.037] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2017] [Revised: 07/27/2017] [Accepted: 08/18/2017] [Indexed: 01/16/2023]
Abstract
BACKGROUND & AIMS Methylation of specific microRNAs (miRNAs) often occurs in an age-dependent manner, as a field defect in some instances, and may be an early event in colitis-associated carcinogenesis. We aimed to determine whether specific mRNA signature patterns (MIR1, MIR9, MIR124, MIR137, MIR34B/C) could be used to identify patients with ulcerative colitis (UC) who are at increased risk for colorectal neoplasia. METHODS We obtained 387 colorectal tissue specimens collected from 238 patients with UC (152 without neoplasia, 17 with dysplasia, and 69 with UC-associated colorectal cancer [UC-CRC]), from 2 independent cohorts in Japan between 2005 and 2015. We quantified methylation of miRNAs by bisulfite pyrosequencing analysis. We analyzed clinical data to determine whether miRNA methylation patterns were associated with age, location, or segment of the colorectum (cecum, transverse colon, and rectum). Differences in tissue miRNA methylation and expression levels were compared among samples and associated with cancer risk using the Wilcoxon, Mann-Whitney, and Kruskal-Wallis tests as appropriate. We performed a validation study of samples from 90 patients without UC and 61 patients with UC-associated dysplasia or cancer to confirm the association between specific methylation patterns of miRNAs in non-tumor rectal mucosa from patients with UC at risk of UC-CRC. RESULTS Among patients with UC without neoplasia, rectal tissues had significantly higher levels of methylation levels of MIR1, MIR9, MIR124, and MIR137 than in proximal mucosa; levels of methylation were associated with age and duration of UC in rectal mucosa. Methylation of all miRNAs was significantly higher in samples from patients with dysplasia or CRC compared with samples from patients without neoplasia. Receiver operating characteristic analysis revealed that methylation levels of miRNAs in rectal mucosa accurately differentiated patients with CRC from those without. Methylation of MIR137 in rectal mucosa was an independent risk factor for UC-CRC. Methylation patterns of a set of miRNAs (panel) could discriminate discriminate UC patients with or without dysplasia or CRC in the evaluation cohort (area under the curve, 0.81) and the validation cohort (area under the curve, 0.78). CONCLUSIONS In evaluation and validation cohorts, we found specific miRNAs to be methylated in rectal mucosal samples from patients with UC with dysplasia or CRC compared with patients without neoplasms. This pattern also associated with patient age and might be used to identify patients with UC at greatest risk for developing UC-CRC. Our findings provide evidence for a field defect in rectal mucosa from patients with UC-CRC.
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Affiliation(s)
- Yuji Toiyama
- Center for Gastrointestinal Research, Center for Translational Genomics and Oncology, Baylor Scott & White Research Institute and Charles A. Sammons Cancer Center, Baylor Research Institute and Sammons Cancer Center, Baylor University Medical Center, Dallas, Texas,Department of Gastrointestinal and Pediatric Surgery, Division of Reparative Medicine, Institute of Life Sciences, Graduate School of Medicine, Mie University, Mie, Japan
| | - Yoshinaga Okugawa
- Center for Gastrointestinal Research, Center for Translational Genomics and Oncology, Baylor Scott & White Research Institute and Charles A. Sammons Cancer Center, Baylor Research Institute and Sammons Cancer Center, Baylor University Medical Center, Dallas, Texas,Department of Gastrointestinal and Pediatric Surgery, Division of Reparative Medicine, Institute of Life Sciences, Graduate School of Medicine, Mie University, Mie, Japan
| | - Koji Tanaka
- Department of Gastrointestinal and Pediatric Surgery, Division of Reparative Medicine, Institute of Life Sciences, Graduate School of Medicine, Mie University, Mie, Japan
| | - Toshimitsu Araki
- Department of Gastrointestinal and Pediatric Surgery, Division of Reparative Medicine, Institute of Life Sciences, Graduate School of Medicine, Mie University, Mie, Japan
| | - Keiichi Uchida
- Department of Gastrointestinal and Pediatric Surgery, Division of Reparative Medicine, Institute of Life Sciences, Graduate School of Medicine, Mie University, Mie, Japan
| | - Asahi Hishida
- Department of Preventive Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Motoi Uchino
- Department of Inflammatory Bowel Disease, Hyogo College of Medicine, Hyogo, Japan
| | - Hiroki Ikeuchi
- Department of Inflammatory Bowel Disease, Hyogo College of Medicine, Hyogo, Japan
| | - Seiichi Hirota
- Department of Surgical Pathology, Hyogo College of Medicine, Hyogo, Japan
| | - Masato Kusunoki
- Department of Gastrointestinal and Pediatric Surgery, Division of Reparative Medicine, Institute of Life Sciences, Graduate School of Medicine, Mie University, Mie, Japan
| | - C. Richard Boland
- Center for Gastrointestinal Research, Center for Translational Genomics and Oncology, Baylor Scott & White Research Institute and Charles A. Sammons Cancer Center, Baylor Research Institute and Sammons Cancer Center, Baylor University Medical Center, Dallas, Texas,School of Medicine, University of California, San Diego, La Jolla, California
| | - Ajay Goel
- Center for Gastrointestinal Research, Center for Translational Genomics and Oncology, Baylor Scott & White Research Institute and Charles A. Sammons Cancer Center, Baylor Research Institute and Sammons Cancer Center, Baylor University Medical Center, Dallas, Texas.
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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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Zhang HJZ, Yang H, Hu YS, Wang X, Wu QF. Progress in epigenetic research of ulcerative colitis. Shijie Huaren Xiaohua Zazhi 2016; 24:4584-4588. [DOI: 10.11569/wcjd.v24.i34.4584] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Ulcerative colitis (UC) is a nonspecific chronic disease that may relapse again and again and be associated with the risk of cancer. At present, the precise pathogenesis and etiology of UC are unclear. Research suggests that epigenetic modifications can mediate the mutual influence between susceptibility genes for ulcerative colitis and the internal and external environment of the body, and thus play an important part in the initial and sustainable development of UC. Regulation of expression of related genes by epigenetic modifications is closely linked to colonic mucosa immunity and defense in UC patients. In this paper, we will summarize the epigenetic mechanisms that may influence the pathogenesis of UC and discuss the role of epigenetic modifications in the pathogenesis of this disease.
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Baba Y, Ishimoto T, Kurashige J, Iwatsuki M, Sakamoto Y, Yoshida N, Watanabe M, Baba H. Epigenetic field cancerization in gastrointestinal cancers. Cancer Lett 2016; 375:360-366. [PMID: 26971491 DOI: 10.1016/j.canlet.2016.03.009] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2016] [Revised: 03/04/2016] [Accepted: 03/04/2016] [Indexed: 02/06/2023]
Abstract
Epigenetic alterations, including aberrant DNA methylation, play an important role in human cancer development. Importantly, epigenetic alterations are reversible and can be targets for therapy or chemoprevention for various types of human cancers. A field for cancerization, or a field defect, is formed by the accumulation of genetic and/or epigenetic alterations in normal-appearing tissues and can correlate with risk of cancer development. Thus, a better understanding of epigenetic field cancerization may represent a useful translational opportunity for cancer risk assessment, including previous history and exposure to carcinogenic factors, and for cancer prevention. In this article, we summarize current knowledge regarding epigenetic field cancerization and its clinical implications in gastrointestinal cancers, including colorectal cancer, gastric cancer and esophageal cancer.
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Affiliation(s)
- Yoshifumi Baba
- Department of Gastroenterological Surgery, Graduate School of Medical Science, Kumamoto University, Japan
| | - Takatsugu Ishimoto
- Department of Gastroenterological Surgery, Graduate School of Medical Science, Kumamoto University, Japan
| | - Junji Kurashige
- Department of Gastroenterological Surgery, Graduate School of Medical Science, Kumamoto University, Japan
| | - Masaaki Iwatsuki
- Department of Gastroenterological Surgery, Graduate School of Medical Science, Kumamoto University, Japan
| | - Yasuo Sakamoto
- Department of Gastroenterological Surgery, Graduate School of Medical Science, Kumamoto University, Japan
| | - Naoya Yoshida
- Department of Gastroenterological Surgery, Graduate School of Medical Science, Kumamoto University, Japan
| | - Masayuki Watanabe
- Department of Gastroenterological Surgery, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Japan
| | - Hideo Baba
- Department of Gastroenterological Surgery, Graduate School of Medical Science, Kumamoto University, Japan.
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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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Principi M, Scavo MP, Piscitelli D, Villanacci V, Lovero R, Losurdo G, Girardi B, Ierardi E, Di Leo A. The sharp decline of beta estrogen receptors expression in long-lasting ulcerative-associated carcinoma. Scand J Gastroenterol 2015; 50:1002-10. [PMID: 25862314 DOI: 10.3109/00365521.2014.978817] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVE Colorectal carcinoma is an important cause of death in inflammatory bowel diseases, thus requiring surveillance for dysplasia in long-standing ulcerative colitis (UC). Females show a lower incidence probably related to hormonal factors; therefore, a role of estrogen receptors (ERs) has been supposed in carcinoma-associated colitis (CAC) development. Our aim was to identify ER beta/alpha expression in long-lasting pancolitis through each grade of dysplasia to carcinoma and, furthermore, to investigate the simultaneous epithelial apoptosis/proliferation. MATERIALS AND METHODS Forty-eight patients affected by long-lasting pancolitis were retrospectively investigated. Samples were divided into four groups: UC, low-grade dysplasia/high-grade dysplasia (UC-HGD), and CAC. Normal colon samples were used as controls. ER-beta, ER-alpha, Ki-67, and TUNEL expression (labeling/H index) were evaluated by immunohistochemistry. RESULTS ER-beta expression revealed an impressive reduction in CAC (10.4 ± 5.1; p < 0.001) compared to controls and UC (34.3 ± 3.1 and 26.8 ± 7.8, respectively), meanwhile ER-beta level in LGD (29.4 ± 3.7) was comparable to UC. As far ER-beta/ER-alpha mean value ratio revealed a progressive reduction. Ki67 demonstrated a progressive significant increase from UC until CAC (37.9 ± 6.4 < 45.7 ± 6.2 < 60.6 ± 5.2 < 71.1 ± 5.1; p < 0.001). Apoptotic index (TUNEL) revealed a strong fall in UC-HGD and CAC. CONCLUSIONS ER-beta fall could be considered as a biomarker of UC-dysplasia progression. It occurs in HGD and overt neoplasia, while in LGD shows a normal expression. At the moment, we are unable to use this tool in the clinical practice to predict tumor progression, but it would be appropriate to encourage ER expression investigations in large samples for the interesting perspectives of application.
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Affiliation(s)
- Mariabeatrice Principi
- Department of Emergency and Organ Transplantation, Gastroenterology Section, University of Bari , Bari , Italy
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11
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Mokarram P, Estiar MA, Ashktorab H. Methylation in Colorectal Cancer. EPIGENETICS TERRITORY AND CANCER 2015:373-455. [DOI: 10.1007/978-94-017-9639-2_13] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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12
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Park JM, Han NY, Han YM, Chung MK, Lee HK, Ko KH, Kim EH, Hahm KB. Predictive proteomic biomarkers for inflammatory bowel disease-associated cancer: Where are we now in the era of the next generation proteomics? World J Gastroenterol 2014; 20:13466-13476. [PMID: 25309077 PMCID: PMC4188898 DOI: 10.3748/wjg.v20.i37.13466] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2013] [Revised: 03/10/2014] [Accepted: 06/17/2014] [Indexed: 02/06/2023] Open
Abstract
Recent advances in genomic medicine have opened up the possibility of tailored medicine that may eventually replace traditional “one-size-fits all” approaches to the treatment of inflammatory bowel disease (IBD). In addition to exploring the interactions between hosts and microbes, referred to as the microbiome, a variety of strategies that can be tailored to an individual in the coming era of personalized medicine in the treatment of IBD are being investigated. These include prompt genomic screening of patients at risk of developing IBD, the utility of molecular discrimination of IBD subtypes among patients diagnosed with IBD, and the discovery of proteome biomarkers to diagnose or predict cancer risks. Host genetic factors influence the etiology of IBD, as do microbial ecosystems in the human bowel, which are not uniform, but instead represent many different microhabitats that can be influenced by diet and might affect processes essential to bowel metabolism. Further advances in basic research regarding intestinal inflammation may reveal new insights into the role of inflammatory mediators, referred to as the inflammasome, and the macromolecular complex of metabolites formed by intestinal bacteria. Collectively, knowledge of the inflammasome and metagenomics will lead to the development of biomarkers for IBD that target specific pathogenic mechanisms involved in the spontaneous progress of IBD. In this review article, our recent results regarding the discovery of potential proteomic biomarkers using a label-free quantification technique are introduced and on-going projects contributing to either the discrimination of IBD subtypes or to the prediction of cancer risks are accompanied by updated information from IBD biomarker research.
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13
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Principi M, Barone M, Pricci M, De Tullio N, Losurdo G, Ierardi E, Di Leo A. Ulcerative colitis: From inflammation to cancer. Do estrogen receptors have a role? World J Gastroenterol 2014; 20:11496-11504. [PMID: 25206257 PMCID: PMC4155343 DOI: 10.3748/wjg.v20.i33.11496] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2014] [Revised: 03/29/2014] [Accepted: 05/26/2014] [Indexed: 02/06/2023] Open
Abstract
Ulcerative colitis (UC) is a condition at increased risk for colorectal carcinoma (CRC) development. Nowadays, screening and follow-up programs are routinely performed worldwide to promote the early detection of CRCs in subjects with well known risk factors (extent, duration and severity of the disorder). The diffusion of these procedures is presumably the main reason for the marked reduction of cancer incidence and mortality in the course of UC. In addition, chemoprevention has been widely investigated and developed in many medical fields, and aspirin has shown a preventive effect against CRC, while mesalazine has been strongly invoked as a potential chemopreventive agent in UC. However, available studies show some limitations due to the obvious ethical implications of drug withdrawal in UC in order to design a control group. The estrogen receptors (ER) alpha/beta balance seems to have a relevant influence on colorectal carcinogenesis and ER beta appears to parallel apoptosis, and hence an anti-carcinogenic effect. Phytoestrogens are compounds acting as ER beta agonists and have shown a promising chemopreventive effect on sporadic as well as genetically inherited CRC. There is evidence suggesting a role for ERs in UC-related carcinogenesis. In this perspective, since these substances can be considered as dietary supplements and are completely free from side effects, phytoestrogens could be an interesting option for CRC prevention, even when the disease is a consequence of long-term chronic inflammation, as in the course of UC. Further studies of their effects are warranted in both the basic research and clinical fields.
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Sakurai T, Kashida H, Watanabe T, Hagiwara S, Mizushima T, Iijima H, Nishida N, Higashitsuji H, Fujita J, Kudo M. Stress Response Protein Cirp Links Inflammation and Tumorigenesis in Colitis-Associated Cancer. Cancer Res 2014; 74:6119-28. [DOI: 10.1158/0008-5472.can-14-0471] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
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15
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Shigaki K, Mitomi H, Fujimori T, Ichikawa K, Tomita S, Imura J, Fujii S, Itabashi M, Kameoka S, Sahara R, Takenoshita S. Immunohistochemical analysis of chromogranin A and p53 expressions in ulcerative colitis-associated neoplasia: neuroendocrine differentiation as an early event in the colitis-neoplasia sequence. Hum Pathol 2013; 44:2393-9. [PMID: 24029705 DOI: 10.1016/j.humpath.2013.06.008] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2013] [Revised: 06/14/2013] [Accepted: 06/21/2013] [Indexed: 12/17/2022]
Abstract
Pancellular dysplasia involving neuroendocrine cells has been shown to be comparatively rare but crucially implicated in the development of neuroendocrine tumors in ulcerative colitis (UC). We attempted to clarify the prevalence of chromogranin A expression as a marker of neuroendocrine differentiation in UC-associated neoplasia by immunohistochemical analyses of 26 lesions of low-grade dysplasia (LGD), 32 high-grade dysplasias (HGDs) and 27 invasive cancers (INVs), along with p53 expression. We additionally assessed the utility of these proteins for differential diagnosis between LGD and HGD. Chromogranin A was considered positive when immunoreactive cells were more than 5% of neoplastic lesions, and the positivity tended to be higher in HGDs (57.7%) or INVs (46.7%) than LGDs (32.0%). Focal or diffuse nuclear staining for p53 was defined as positive. The positive rate for p53 was also higher in HGDs (59.4%; P = 0.037) or INVs (59.3%) than LGDs (30.8%). A similar trend was found in co-positivity for both proteins (HGDs, 30.7%/INVs, 26.7% versus LGDs, 12.0%). No positivity for both proteins was identified in the non-neoplastic mucosa. The combination of the two proteins improved the sensitivity (66.7%), specificity (80.0%), positive predictive value (72.7%) and negative predictive value (75.0%) for HGD as compared to p53 alone (sensitivity, 57.7%; specificity 68.0%; positive predictive value, 65.2%; negative predictive value, 60.7%). In conclusion, we show here that neuroendocrine differentiation is relatively common and represents an early event in the UC-neoplasia pathway in which p53 and chromogranin A are coordinately up-regulated. Immunohistochemical assessment of their expression might provide a useful adjunct tool for grading dysplasia in UC.
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Affiliation(s)
- Kotaro Shigaki
- Department of Surgical and Molecular Pathology, Dokkyo Medical University School of Medicine, 880 Kitakobayashi, Mibu, Shimotsuga, Tochigi 321-0293, Japan; Department of Coloproctology, Social Health Insurance Hospital, 22-1 Hyakunincho, Shinjuku, Tokyo 169-0073, Japan; Department of Organ Regulatory Surgery, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima 960-1295, Japan
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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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17
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Kim TO, Park J, Kang MJ, Lee SH, Jee SR, Ryu DY, Yang K, Yi JM. DNA hypermethylation of a selective gene panel as a risk marker for colon cancer in patients with ulcerative colitis. Int J Mol Med 2013; 31:1255-61. [PMID: 23546389 DOI: 10.3892/ijmm.2013.1317] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2012] [Accepted: 02/26/2013] [Indexed: 11/05/2022] Open
Abstract
Patients with inflammatory bowel disease (IBD) which includes ulcerative colitis (UC) and Crohn's disease (CD) of the colon are at risk of developing colorectal cancer (CRC). Here, we analyzed the methylation status of selected genes as a risk marker in UC patients. We assessed methylation frequency of 4 genes [secreted frizzled-related protein 1 (SFRP1), transcription elongation regulator 1-like (TCERG1L), fibrillin 2 (FBN2) and tissue factor pathway inhibitor 2 (TFPI2)] in biopsies of 36 UC patients. SFRP1 and TCERG1L genes showed high methylation frequencies but FBN2 and TFPI2 genes showed methylation frequencies of 50% in UC patients which suggests that our sensitive selective markers could detect half of the UC patients. We also confirmed the methylation status in UC tissues by bisulfite sequencing analysis. We compared the levels of methylation in terms of quantification between UC patients and CRC tumors. Importantly, methylation levels of these 4 genes were found to be significantly higher in CRC compared to UC patients, even though we noted a frequent methylation pattern in UC patients. Our data suggest that sensitive DNA methylation markers are able to identify UC patients and this would implicate the risk of CRC. Therefore, assessing the methylation of these 4 genes in UC patients could contribute to prevent the progression of severe disease with regular colonoscopic surveillance.
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Affiliation(s)
- Tae-Oh Kim
- Department of Internal Medicine, Inje University Haeundae Paik Hospital, Busan, Republic of Korea
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18
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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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20
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Gao Y, Killian K, Zhang H, Yu K, Li QZ, Weinstein S, Virtamo J, Tucker M, Taylor P, Albanes D, Meltzer P, Caporaso N. Leukocyte DNA methylation and colorectal cancer among male smokers. World J Gastrointest Oncol 2012; 4:193-201. [PMID: 22912915 PMCID: PMC3423510 DOI: 10.4251/wjgo.v4.i8.193] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2012] [Revised: 07/13/2012] [Accepted: 07/20/2012] [Indexed: 02/05/2023] Open
Abstract
AIM: To explore the association between methylation in leukocyte DNA and colorectal cancer (CRC) risk in male smokers using the α-tocopherol, β-carotene cancer prevention study.
METHODS: About 221 incident CRC cases, and 219 controls, frequency-matched on age and smoking intensity were included. DNA methylation of 1505 CpG sites selected from 807 genes were evaluated using Illumina GoldenGate Methylation Cancer Panel I in pre-diagnostic blood leukocytes of study subjects. Tertiles of methylation level classified according to the distribution in controls for each CpG site were used to analyze the association between methylation level and CRC risk with logistic regression. The time between blood draw to cancer diagnosis (classifying cases according to latency) was incorporated in further analyses using proportional odds regression.
RESULTS: We found that methylation changes of 31 CpG sites were associated with CRC risk at P < 0.01 level. Though none of these 31 sites remained statistically significant after Bonferroni correction, the most statistically significant CpG site associated with CRC risk achieved a P value of 1.0 × 10-4. The CpG site is located in DSP gene, and the risk estimate was 1.52 (95% CI: 0.91-2.53) and 2.62 (95% CI: 1.65-4.17) for the second and third tertile comparing with the lowest tertile respectively. Taking the latency information into account strengthened some associations, suggesting that the methylation levels of corresponding sites might change over time with tumor progression.
CONCLUSION: The results suggest that the methylation level of some genes were associated with cancer susceptibility and some were related to tumor development over time. Further studies are warranted to confirm and refine our results.
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Affiliation(s)
- Ying Gao
- Ying Gao, Kai Yu, Stephanie Weinstein, Margaret Tucker, Philip Taylor, Demetrius Albanes, Neil Caporaso, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20852, United States
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21
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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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22
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Olaru AV, Cheng Y, Agarwal R, Yang J, David S, Abraham JM, Yu W, Lazarev M, Brant SR, Marohn MR, Hutcheon DF, Harpaz N, Meltzer SJ, Mori Y, Mori Y. Unique patterns of CpG island methylation in inflammatory bowel disease-associated colorectal cancers. Inflamm Bowel Dis 2012; 18:641-8. [PMID: 21830278 PMCID: PMC3214229 DOI: 10.1002/ibd.21826] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2011] [Accepted: 06/20/2011] [Indexed: 12/20/2022]
Abstract
BACKGROUND CpG island (CGI) hypermethylation at discrete loci is a prevalent cancer-promoting abnormality in sporadic colorectal carcinomas (S-CRCs). We investigated genome-wide CGI methylation in inflammatory bowel disease (IBD)-associated CRCs (IBD-CRCs). METHODS Methylation microarray analyses were conducted on seven IBD-CRCs, 17 S-CRCs, and eight normal control colonic tissues from patients without CRC or IBD. CGI methylator phenotype (CIMP), a surrogate marker for widespread cancer-specific CGI hypermethylation, was examined in 30 IBD-CRCs and 43 S-CRCs. RESULTS The genome-wide CGI methylation pattern of IBD-CRCs was CIMP status-dependent. Based on methylation array data profiling of all autosomal loci, CIMP(+) IBD-CRCs grouped together with S-CRCs, while CIMP(-) IBD-CRCs grouped together with control tissues. CIMP(-) IBD-CRCs demonstrated less methylation than did age-matched CIMP(-) S-CRCs at autosomal CGIs (z-score -0.17 vs. 0.09, P = 3 × 10(-3)) and CRC-associated hypermethylation target CGIs (z-score -0.43 vs. 0.68, P = 1 × 10(-4)). Age-associated hypermethylation target CGIs were significantly overrepresented in CGIs that were hypermethylated in S-CRCs (P = 1 × 10(-192)), but not in CGIs that were hypermethylated in IBD-CRCs (P = 0.11). In contrast, KRAS mutation prevalence was similar between IBD-CRCs and S-CRCs. Notably, CIMP(+) prevalence was significantly higher in older than in younger IBD-CRC cases (50.0 vs. 4.2, P = 0.02), but not in S-CRC cases (9.7 vs. 16.7, P = 0.92). CONCLUSIONS Cancer-specific CGI hypermethylation and age-associated CGI hypermethylation are diminished in IBD-CRCs relative to S-CRCs, while the KRAS mutation rate is comparable between these cancers. CGI hypermethylation appears to play only a minor role in IBD-associated carcinogenesis. We speculate that aging, rather than inflammation per se, promotes CIMP(+) CRCs in IBD patients.
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Affiliation(s)
- Alexandru V. Olaru
- Department of Medicine, Division of Gastroenterology, Johns Hopkins University School of Medicine; 720 Rutland Avenue, Baltimore, Maryland 21205
| | - Yulan Cheng
- Department of Medicine, Division of Gastroenterology, Johns Hopkins University School of Medicine; 720 Rutland Avenue, Baltimore, Maryland 21205
| | - Rachana Agarwal
- Department of Medicine, Division of Gastroenterology, Johns Hopkins University School of Medicine; 720 Rutland Avenue, Baltimore, Maryland 21205
| | - Jian Yang
- Department of Medicine, Division of Gastroenterology, Johns Hopkins University School of Medicine; 720 Rutland Avenue, Baltimore, Maryland 21205
| | - Stefan David
- Department of Medicine, Division of Gastroenterology, Johns Hopkins University School of Medicine; 720 Rutland Avenue, Baltimore, Maryland 21205
| | - John M. Abraham
- Department of Medicine, Division of Gastroenterology, Johns Hopkins University School of Medicine; 720 Rutland Avenue, Baltimore, Maryland 21205
| | - Wayne Yu
- Sidney Kimmel Comprehensive Cancer Center, DNA Microarray Core Facility, Johns Hopkins University School of Medicine; 1503 E. Jefferson Street, Baltimore, Maryland 21287
| | - Mark Lazarev
- Department of Medicine, Division of Gastroenterology, Johns Hopkins University School of Medicine; 720 Rutland Avenue, Baltimore, Maryland 21205
| | - Steven R. Brant
- Department of Medicine, Division of Gastroenterology, Johns Hopkins University School of Medicine; 720 Rutland Avenue, Baltimore, Maryland 21205
| | - Michael R. Marohn
- Department of Surgery, Johns Hopkins University School of Medicine; 600 N. Wolfe Street, Baltimore MD 21207
| | - David F. Hutcheon
- Department of Medicine, Division of Gastroenterology, Johns Hopkins University School of Medicine; 720 Rutland Avenue, Baltimore, Maryland 21205
| | - Noam Harpaz
- Department of Pathology, Mount Sinai School of Medicine; One Gustave L. Levy Place, New York, New York 10029
| | - Stephen J. Meltzer
- Department of Medicine, Division of Gastroenterology, Johns Hopkins University School of Medicine; 720 Rutland Avenue, Baltimore, Maryland 21205, Department of Oncology, Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center; 1503 E. Jefferson Street, Baltimore, Maryland 21287
| | - Yuriko Mori
- Department of Medicine, Division of Gastroenterology, Johns Hopkins University School of Medicine; 720 Rutland Avenue, Baltimore, Maryland 21205
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Koizumi K, Alonso S, Miyaki Y, Okada S, Ogura H, Shiiya N, Konishi F, Taya T, Perucho M, Suzuki K. Array-based identification of common DNA methylation alterations in ulcerative colitis. Int J Oncol 2011; 40:983-94. [PMID: 22159500 PMCID: PMC3584616 DOI: 10.3892/ijo.2011.1283] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2011] [Accepted: 11/02/2011] [Indexed: 12/22/2022] Open
Abstract
Patients with long-standing ulcerative colitis (UC) have higher risk of developing colorectal cancer. Albeit the causes remain to be understood, epigenetic alterations have been suggested to play a role in the long-term cancer risk of these patients. In this work, we developed a novel microarray platform based on methylation-sensitive amplified fragment length polymorphism (MS-AFLP) DNA fingerprinting. The over 10,000 NotI sites of the human genome were used to generate synthetic primers covering these loci that are equally distributed into CpG rich regions (promoters and CpG islands) and outside the CpG islands, providing a panoramic view of the methylation alterations in the genome. The arrays were first tested using the colon cancer cell line CW-2 showing the reproducibility and sensitivity of the approach. We next investigated DNA methylation alterations in the colonic mucosa of 14 UC patients. We identified epigenetic alterations affecting genes putatively involved in UC disease, and in susceptibility to develop colorectal cancer. There was a strong concordance of methylation alterations (both hypermethylation and hypomethylation) shared by the cancer cells of the CW-2 cell line and the non-cancer UC samples. To the best of our knowledge, this work defines the first high-throughput aberrant DNA methylation profiles of the colonic mucosa of UC patients. These epigenetic profiles provide novel and relevant knowledge on the molecular alterations associated to the UC pathology. Some of the detected alterations could be exploited as cancer risk predictors underlying a field defect for cancerization in UC-associated carcinogenesis.
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Affiliation(s)
- Kei Koizumi
- First Department of Surgery, Hamamatsu University School of Medicine, 1-20-1 Handa-yama, Higashi-ku, Hamamatsu, Shizuoka 431-3192, Japan
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Yasuda H, Tanaka K, Okita Y, Araki T, Saigusa S, Toiyama Y, Yokoe T, Yoshiyama S, Kawamoto A, Inoue Y, Miki C, Kusunoki M. CD133, OCT4, and NANOG in ulcerative colitis-associated colorectal cancer. Oncol Lett 2011; 2:1065-1071. [PMID: 22848268 DOI: 10.3892/ol.2011.415] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2011] [Accepted: 08/26/2011] [Indexed: 12/23/2022] Open
Abstract
Stem cells are thought to contribute to tissue regeneration as well as carcinogenesis. Ulcerative colitis-associated colorectal cancer (UC-CRC) has shown distinct characteristics compared with those of sporadic CRC. The aim of this study was to evaluate the expression of stem cell markers CD133, OCT4 and NANOG in UC-CRC and the inflamed colonic epithelium of UC patients. Total RNAs of UC-CRC (n=6), inflamed colonic epithelium (n=24), sporadic CRC (n=37) and adjacent normal colonic epithelium (n=37) were isolated from formalin-fixed, paraffin-embedded specimens using microdissection techniques in order to purify colonic epithelial cells. Relative mRNA levels of CD133 (PROM), OCT4 (POU5F1) and NANOG were measured using real-time reverse transcription polymerase chain reaction. Three stem cell markers were also investigated immunohistochemically. PROM, POU5F1 and NANOG levels were found to be significantly lower in UC-CRC than in inflamed colonic epithelium of UC patients. By contrast, sporadic CRC showed a significantly higher expression of PROM, POU5F1 and NANOG compared with adjacent normal colonic epithelium. POU5F1 and NANOG levels were significantly lower in UC-CRC than in sporadic CRC. PROM and NANOG levels in inflamed colonic epithelium were significantly higher among younger UC patients (P<0.05). Longer disease duration was significantly associated with lower PROM expression (P=0.0117). No significant difference was found in PROM levels between UC-CRC and inflamed colonic epithelium in patients with longer disease duration. UC-CRC showed different expression profiles of stem cell markers compared with sporadic CRC. Decreases in PROM expression of inflamed colonic epithelium may identify UC patients at high risk for the development of UC-CRC.
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Affiliation(s)
- Hiromi Yasuda
- Department of Gastrointestinal and Pediatric Surgery, Division of Reparative Medicine, Institute of Life Sciences, Mie University Graduate School of Medicine, Tsu, Mie 514-5807, Japan
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Lv H, Ma X, Che T, Chen Y. Methylation of the promoter A of estrogen receptor alpha gene in hBMSC and osteoblasts and its correlation with homocysteine. Mol Cell Biochem 2011; 355:35-45. [PMID: 21523370 DOI: 10.1007/s11010-011-0836-z] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2011] [Accepted: 04/15/2011] [Indexed: 01/16/2023]
Abstract
Recent studies have shown that adult osteoporosis could be induced by ageing and estrogen deficiency and homocysteine (Hcy) is an independent risk factor of fracture in osteoporosis patients. In this study, we found hypermethylation of the promoter A region in the estrogen receptor alpha (ERα) gene, and methylation in 70.59% of 68 post-menopausal women, whose methylation degree was significantly higher than the pre-menopausal women (P < 0.05). Their methylation frequency was detected only 26.67% in 30 subjects. An obvious correlation between the degree of methylation in ERα gene and the level of Hcy (r = 0.809, P < 0.05) was explored. The cultured human bone marrow strom cells (hBMSC) and osteoblasts treated by Hcy resulted in de novo methylation of the promoter A region in the ERα gene and suppressed proliferation and differentiation with time and dose dependence. Meanwhile, ERα gene mRNA in osteoblast-like cells treated by Hcy was much lower than the control group (P < 0.05). Thus, both in vivo and in vitro data showed that Hcy could promote hypermethylation of the promoter A region and reduce ERα mRNA transcription, which may be an important mechanism for the pathogenesis of postmenopausal osteoporosis.
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Affiliation(s)
- Haihong Lv
- Department of Biochemistry and Molecular Biology, School of Life Sciences, Lanzhou University, Lanzhou 730000, People's Republic of China
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Watanabe T, Kobunai T, Yamamoto Y, Ikeuchi H, Matsuda K, Ishihara S, Nozawa K, Iinuma H, Kanazawa T, Tanaka T, Yokoyama T, Konishi T, Eshima K, Ajioka Y, Hibi T, Watanabe M, Muto T, Nagawa H. Predicting ulcerative colitis-associated colorectal cancer using reverse-transcription polymerase chain reaction analysis. Clin Colorectal Cancer 2011; 10:134-41. [PMID: 21859567 DOI: 10.1016/j.clcc.2011.03.011] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2010] [Revised: 08/02/2010] [Accepted: 08/27/2010] [Indexed: 01/01/2023]
Abstract
BACKGROUND Widespread genetic alterations are present not only in ulcerative colitis (UC)-associated neoplastic lesions but also in the adjacent normal colonic mucosa. This suggests that genetic changes in nonneoplastic mucosa might be effective markers for predicting the development of UC-associated cancer (UC-Ca). This study aimed to build a predictive model for the development of UC-Ca based on gene expression levels measured by reverse-transcription polymerase chain reaction (RT-PCR) analysis in nonneoplastic rectal mucosa. PATIENTS AND METHODS Fifty-three UC patients were examined, of which 10 had UC-Ca and 43 did not (UC-NonCa). In addition to the 40 genes and transcripts previously shown to be predictive for developing UC-Ca in our microarray studies, 149 new genes, reported to be important in carcinogenesis, were selected for low density array (LDA) analysis. The expression of a total of 189 genes was examined by RT-PCR in nonneoplastic rectal mucosa. RESULTS We identified 20 genes showing differential expression in UC-Ca and UC-NonCa patients, including cancer-related genes such as CYP27B1, RUNX3, SAMSN1, EDIL3, NOL3, CXCL9, ITGB2, and LYN. Using these 20 genes, we were able to build a predictive model that distinguished patients with and without UC-Ca with a high accuracy rate of 83% and a negative predictive value of 100%. CONCLUSION This predictive model suggests that it is possible to identify UC patients at a high risk of developing cancer. These results have important implications for improving the efficacy of surveillance by colonoscopy and suggest directions for future research into the molecular mechanisms of UC-associated cancer.
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Affiliation(s)
- Toshiaki Watanabe
- Department of Surgery, Teikyo University School of Medicine, Tokyo, Japan.
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Bronner MP, Skacel M, Crispin DA, Hoff PD, Emond MJ, Lai LA, Tubbs RR, Rabinovitch PS, Brentnall TA, Brentnall TA. Array-based comparative genomic hybridization in ulcerative colitis neoplasia: single non-dysplastic biopsies distinguish progressors from non-progressors. Mod Pathol 2010; 23:1624-33. [PMID: 20802465 PMCID: PMC2932629 DOI: 10.1038/modpathol.2010.161] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Approximately 10% of ulcerative colitis patients develop colorectal neoplasia. At present, identification of this subset is markedly limited and necessitates lifelong colonoscopic surveillance for the entire ulcerative colitis population. Better risk markers are needed to focus surveillance onto the patients who are most likely to benefit. Using array-based comparative genomic hybridization, we analyzed single, non-dysplastic biopsies from three patient groups: ulcerative colitis progressors (n=9) with cancer or high-grade dysplasia at a mean distance of 18 cm from the analyzed site; ulcerative colitis non-progressors (n=8) without dysplasia during long-term surveillance; and non-ulcerative colitis normal controls (n=2). Genomic DNA from fresh colonic epithelium purified from stroma was hybridized to 287 (low-density) and 4342 (higher-density) feature bacterial artificial chromosome arrays. Sample-to-reference fluorescence ratios were calculated for individual chromosomal targets and globally across the genome. The low-density arrays yielded pronounced genomic gains and losses in 3 of 9 (33%) ulcerative colitis progressors but in none of the 10 control patients. Identical DNA samples analyzed on the higher-density arrays, using a combination of global and individual high variance assessments, distinguished all nine progressors from all 10 controls. These data confirm that genomic alterations in ulcerative colitis progressors are widespread, even involving single non-dysplastic biopsies that are far distant from neoplasia. They therefore show promise toward eliminating full colonoscopic surveillance with extensive biopsy sampling in the majority of ulcerative colitis patients.
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Affiliation(s)
- Mary P. Bronner
- Division of Pathology and Laboratory Medicine, Cleveland Clinic, Cleveland, Ohio, USA
| | - Marek Skacel
- Dahl-Chase Pathology Associates, Bangor, Maine, USA
| | - David A. Crispin
- Department of Medicine in the Division of Gastroenterology; University of Washington, Seattle, Washington, USA
| | - Peter D. Hoff
- Department of Biostatistics, University of Washington, Seattle, Washington, USA
| | - Mary J. Emond
- Department of Biostatistics, University of Washington, Seattle, Washington, USA
| | - Lisa A. Lai
- Department of Medicine in the Division of Gastroenterology; University of Washington, Seattle, Washington, USA
| | - Raymond R. Tubbs
- Division of Pathology and Laboratory Medicine, Cleveland Clinic, Cleveland, Ohio, USA
| | | | - Teresa A. Brentnall
- Department of Medicine in the Division of Gastroenterology; University of Washington, Seattle, Washington, USA
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Azuara D, Rodriguez-Moranta F, de Oca J, Soriano-Izquierdo A, Mora J, Guardiola J, Biondo S, Blanco I, Peinado MA, Moreno V, Esteller M, Capellá G. Novel methylation panel for the early detection of colorectal tumors in stool DNA. Clin Colorectal Cancer 2010; 9:168-76. [PMID: 20643622 DOI: 10.3816/ccc.2010.n.023] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
BACKGROUND Previous studies showed that the assessment of promoter hypermethylation of a limited number of genes in tumor biopsies may identify the majority of colorectal tumors. This study aimed to assess the clinical usefulness of a panel of methylation biomarkers in stool DNA in the identification of colorectal tumors, using methylation-specific melting curve analysis (MS-MCA), a technique that simultaneously analyzes all cytosine-phosphate-guanine (CpG) residues within a promoter. MATERIALS AND METHODS The promoter methylation status of 4 tumor-related genes (RARB2, p16INK4a, MGMT, and APC) was analyzed in DNA stool samples and corresponding tissues in an initial set of 12 patients with newly diagnosed primary colorectal carcinomas and 20 patients with newly diagnosed colorectal adenomas, using methylation-specific polymerase chain reaction. Results were replicated in a set of 82 patients (20 healthy subjects, 16 patients with inflammatory bowel disease (IBD), 20 patients with adenomas, and 26 patients with carcinomas), using MS-MCA analyses. RESULTS In the initial set, >or= 1 positive methylation marker was detected in the stools of 9 of 12 patients (75%) with carcinomas and 12 of 20 patients (60%) with adenomas, with no false-positive results. Stool analyses missed 7 methylated lesions (25%). In the replication set, stool DNA testing detected 16 of 26 carcinomas (62%) and 8 of 20 adenomas (40%). The MS-MCAs missed 14 methylated tumors (37%). No aberrant methylation was evident in healthy subjects, but the RARB2 marker was positive in 2 of 15 stool samples (13%) of patients with IBD. CONCLUSION Analysis via MS-MCA of a panel of methylation markers in stool DNA may offer a good alternative in the early, noninvasive detection of colorectal tumors.
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Affiliation(s)
- Daniel Azuara
- Translational Research Laboratory, Institut Català d'Oncologia-IDIBELL, Barcelona, Spain
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Lin Z, Hegarty JP, Cappel JA, Yu W, Chen X, Faber P, Wang Y, Kelly AA, Poritz LS, Peterson BZ, Schreiber S, Fan JB, Koltun WA. Identification of disease-associated DNA methylation in intestinal tissues from patients with inflammatory bowel disease. Clin Genet 2010; 80:59-67. [PMID: 20950376 DOI: 10.1111/j.1399-0004.2010.01546.x] [Citation(s) in RCA: 60] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Overwhelming evidence supports the theory that inflammatory bowel disease (IBD) is caused by a complex interplay between genetic predispositions of multiple genes, combined with an abnormal interaction with environmental factors. It is becoming apparent that epigenetic factors can have a significant contribution in the pathogenesis of disease. Changes in the methylation state of IBD-associated genes could significantly alter levels of gene expression, potentially contributing to disease onset and progression. We have explored the role of DNA methylation in IBD pathogenesis. DNA methylation profiles (1505 CpG sites of 807 genes) of matched diseased (n = 26) and non-diseased (n = 26) intestinal tissues from 26 patients with IBD [Crohn's disease (CD) n = 9, ulcerative colitis (UC) n = 17] were profiled using the GoldenGate™ methylation assay. After an initial identification of a panel of 50 differentially methylated CpG sites from a training set (14 non-diseased and 14 diseased tissues) and subsequent validation with a testing set (12 non-diseased and 12 diseased tissues), we identified seven CpG sites that are differentially methylated in intestinal tissues of IBD patients. We have also identified changes in DNA methylation associated with the two major IBD subtypes, CD and UC. This study reports IBD-associated changes in DNA methylation in intestinal tissue, which may be disease subtype-specific.
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Affiliation(s)
- Z Lin
- Department of Surgery, The Pennsylvania State University College of Medicine, Hershey, PA17033, USA.
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Harpaz N, Polydorides AD. Colorectal dysplasia in chronic inflammatory bowel disease: pathology, clinical implications, and pathogenesis. Arch Pathol Lab Med 2010; 134:876-95. [PMID: 20524866 DOI: 10.5858/134.6.876] [Citation(s) in RCA: 62] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
CONTEXT Colorectal cancer, the most lethal long-term complication of chronic inflammatory bowel disease (IBD), is the culmination of a complex sequence of molecular and histologic derangements of the intestinal epithelium that are initiated and at least partially sustained by chronic inflammation. Dysplasia, the earliest histologic manifestation of this process, plays an important role in cancer prevention by providing the first clinical alert that this sequence is underway and serving as an endpoint in colonoscopic surveillance of patients at high risk for colorectal cancer. OBJECTIVE To review the histology, nomenclature, clinical implications, and molecular pathogenesis of dysplasia in IBD. DATA SOURCE Literature review and illustrations from case material. CONCLUSIONS The diagnosis and grading of dysplasia in endoscopic surveillance biopsies play a decisive role in the management of patients with IBD. Although interpathologist variation, endoscopic sampling problems, and incomplete information regarding the natural history of dysplastic lesions are important limiting factors, indirect evidence that surveillance may be an effective means of reducing cancer-related mortality in the population with IBD has helped validate the histologic criteria, nomenclature, and clinical recommendations that are the basis of current practice among pathologists and clinicians. Emerging technologic advances in endoscopy may permit more effective surveillance, but ultimately the greatest promise for cancer prevention in IBD lies in expanding our thus far limited understanding of the molecular pathogenetic relationships between neoplasia and chronic inflammation.
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Affiliation(s)
- Noam Harpaz
- Department of Pathology, The Mount Sinai School of Medicine, New York, New York 10092, USA.
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31
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Kuester D, Guenther T, Biesold S, Hartmann A, Bataille F, Ruemmele P, Peters B, Meyer F, Schubert D, Bohr UR, Malfertheiner P, Lippert H, Silver ARJ, Roessner A, Schneider-Stock R. Aberrant methylation of DAPK in long-standing ulcerative colitis and ulcerative colitis-associated carcinoma. Pathol Res Pract 2010; 206:616-24. [PMID: 20630662 DOI: 10.1016/j.prp.2010.05.004] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2010] [Accepted: 05/19/2010] [Indexed: 02/08/2023]
Abstract
Death-associated protein kinase (DAPK) has pro-apoptotic functions and participates in various apoptotic systems. DAPK acts as a tumor suppressor, and its inactivation by promoter hypermethylation has been frequently observed in various human cancers. As alterations of pro-apoptotic genes might cause instability in the balance of cell-turnover during chronic inflammatory processes, epigenetic silencing of DAPK might be involved in the carcinogenesis of ulcerative colitis-associated carcinoma (UCC). To evaluate the role of DAPK in the inflammation-driven carcinogenesis of ulcerative colitis (UC), we analyzed promoter hypermethylation and protein expression of DAPK using methylation-specific PCR and immunohistochemistry in 43 UCCs and paired UC-background mucosa, as well as in UC-background mucosa of 50 patients without UCC. The frequency of methylation of DAPK in UCCs was low (27.6%) compared to overall non-neoplastic UC-background mucosa (48.3%; p=0.02) and sporadic colorectal carcinoma (57.4%, p=0.019). The difference in the methylation frequency in UC-background mucosa in patients without UCC (54.2%), compared to those with UCC (40.0%), was not significant (p=0.141). Promoter methylation correlated significantly with decreased DAPK protein expression (p<0.001) and severity of inflammatory activity (p=0.024). In unmethylated UC-background mucosa, DAPK protein expression increased with activity of UC-associated inflammation, suggesting a protective role of the pro-apoptotic DAPK during the chronic inflammatory process of UC. Thus, inactivation of DAPK by promoter hypermethylation might be crucial for accumulation of DNA damage in inflamed mucosa of UC, and might therefore contribute to the initiation of the neoplastic process and development of UC-associated carcinoma.
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Affiliation(s)
- Doerthe Kuester
- Department of Pathology, Hepatology and Infectious Diseases, Otto-von-Guericke-University, 39120 Magdeburg, Germany.
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Methylation status of genes in non-neoplastic mucosa from patients with ulcerative colitis-associated colorectal cancer. Am J Gastroenterol 2010; 105:1610-9. [PMID: 20160714 DOI: 10.1038/ajg.2010.22] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Patients with ulcerative colitis (UC) are at increased risk for developing colorectal cancer (CRC). Surveillance in this at-risk population remains challenging. We assessed the methylation status of genes in the non-neoplastic mucosa of UC-CRC patients and controls to identify potential biomarkers of CRC. METHODS We evaluated the methylation status of 10 genes (p16, p14, runt-related transcript factor-3 (RUNX3), cyclooxygenase-2 (COX-2), E-cadherin, methylated-in-tumor-1 (MINT1), MINT31, HPP1, estrogen receptor, SLC5A8) in UC-CRC tumors and non-neoplastic sections from both UC-CRC cases and UC controls (n=114 for each) using methylation-specific PCR. RESULTS Amplification was successful for 96 UC controls, 83 tumors, and 66 non-adjacent, non-neoplastic samples. The prevalence of methylation was significantly greater in UC-CRC tumors for p16, RUNX3, MINT1, MINT31, and HPP1. Methylation of COX-2 and E-cadherin was greater in UC controls than in tumors. Univariate testing of these genes using non-adjacent, non-neoplastic sections from UC-CRC cases indicated that associations between p16, RUNX3, MINT1, MINT31, E-cadherin, and COX-2 and UC-CRC remained significant. In multivariable analysis of the six genes, only RUNX3, MINT1, and COX-2 remained significantly associated with the UC-CRC cases (odds ratio=12.6, 9.0, and 0.2, respectively). The results remained unaffected by the presence of PSC or severity of inflammation. Logistic regression modeling with the three genes showed interactions that increased the odds ratio for each gene. CONCLUSIONS RUNX3, MINT1, and COX-2 are potential biomarkers for detecting the presence of CRC in patients with UC. These genes should be evaluated as biomarkers for colorectal dysplasia.
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Abstract
Colorectal cancer (CRC) arises as a consequence of the accumulation of genetic and epigenetic alterations in colonic epithelial cells during neoplastic transformation. Epigenetic modifications, particularly DNA methylation in selected gene promoters, are recognized as common molecular alterations in human tumors. Substantial efforts have been made to determine the cause and role of aberrant DNA methylation ("epigenomic instability") in colon carcinogenesis. In the colon, aberrant DNA methylation arises in tumor-adjacent, normal-appearing mucosa. Aberrant methylation also contributes to later stages of colon carcinogenesis through simultaneous methylation in key specific genes that alter specific oncogenic pathways. Hypermethylation of several gene clusters has been termed CpG island methylator phenotype and appears to define a subgroup of colon cancer distinctly characterized by pathological, clinical, and molecular features. DNA methylation of multiple promoters may serve as a biomarker for early detection in stool and blood DNA and as a tool for monitoring patients with CRC. DNA methylation patterns may also be predictors of metastatic or aggressive CRC. Therefore, the aim of this review is to understand DNA methylation as a driving force in colorectal neoplasia and its emerging value as a molecular marker in the clinic.
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Affiliation(s)
- Myoung Sook Kim
- Department of Otolaryngology, Head and Neck Surgery, The Johns Hopkins University School of Medicine, 1550 Orleans Street, CRB II-5M, Baltimore, MD, 21231, USA
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Ally MS, Al-Ghnaniem R, Pufulete M. The relationship between gene-specific DNA methylation in leukocytes and normal colorectal mucosa in subjects with and without colorectal tumors. Cancer Epidemiol Biomarkers Prev 2009; 18:922-8. [PMID: 19258481 DOI: 10.1158/1055-9965.epi-08-0703] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
CpG island methylation in the promoter regions of tumor suppressor genes has been shown to occur in normal colonic tissue and can distinguish between subjects with and without colorectal neoplasms. It is unclear whether this relationship exists in other tissues such as blood. We report the relationship between estrogen receptor gene (estrogen receptor alpha) methylation in leukocyte and normal colonic tissue DNA in subjects with and without colorectal neoplasia. DNA was extracted from frozen stored whole blood samples of 27 subjects with cancer, 30 with adenoma, 16 with hyperplastic polyps, and 57 disease-free subjects. DNA methylation in seven CpG sites close to the transcription start of estrogen receptor alpha was quantitated using pyrosequencing and expressed as a methylation index (average methylation across all CpG sites analyzed). Estrogen receptor alpha methylation in leukocyte DNA was compared with estrogen receptor alpha methylation in normal colonic mucosa DNA that had been previously determined in the same subjects. Estrogen receptor alpha was partially methylated (median, 4.3%; range, 0.0-12.6%) in leukocyte DNA in all subjects, with no significant difference between disease groups (P>0.05). Estrogen receptor alpha methylation in leukocytes was 60% lower than estrogen receptor alpha methylation in normal colonic tissue (P<0.001). Estrogen receptor alpha methylation in colonic tissue (P<0.001) and smoking (P=0.016) were determinants of estrogen receptor alpha methylation in leukocytes, independent of age, body mass index, gender, and disease status. In conclusion, there was a positive relationship between estrogen receptor alpha methylation in leukocytes and colonic tissue in subjects with and without colorectal tumors. However, unlike in colonic tissue, estrogen receptor alpha methylation in leukocytes was unable to distinguish between disease groups.
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Affiliation(s)
- Mina Sarah Ally
- Diet and Gastrointestinal Health Group, Department of Nutrition and Dietetics, King's College London, Franklin Wilkins Building, 150 Stamford Street, London SE1 9NH, United Kingdom
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Nittke T, Selig S, Kallay E, Cross HS. Nutritional calcium modulates colonic expression of vitamin D receptor and pregnane X receptor target genes. Mol Nutr Food Res 2008; 52 Suppl 1:S45-51. [PMID: 18327873 DOI: 10.1002/mnfr.200700200] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Low nutritional calcium contributes to disruption of the intestinal epithelial barrier function, to hyperproliferation of colonocytes and increased occurrence of aggressive secondary bile acids in the gut lumen. These mechanisms are also known to be involved in the etiology of colonic inflammation and cancer. We studied in mice and human adenocarcinoma-derived Caco-2 cells the impact of low calcium on markers of inflammation (cyclooxygenase-2; COX-2), of detoxification (pregnane and xenobiotic receptor (PXR)/steroid and xenobiotic receptor (SXR), cytochrome P450 steroid-inducible 3a11 (CYP3A11)), and on expression of the vitamin D system as a protection against tumorigenesis. Caco-2 cells express high COX-2 and low SXR mRNA levels when subconfluent. During differentiation this is reversed, while low calcium enhanced COX-2 protein expression. In vivo low dietary calcium significantly increased the expression of the PXR target gene CYP3A11 in the proximal colon, suggesting compensatory defense mechanisms. In comparison with males, low nutritional calcium elicits a better protective response in females: both the vitamin D synthesizing 25-hydroxyvitamin D(3 )1alpha hydroxylase (CYP27B1) mRNA and the detoxifying CYP3A11 mRNA are augmented more. While it is recognized that colonic vitamin D synthesis may prevent tumor progression, low dietary calcium also elevates the 1,25-(OH)(2)-D(3) catabolic 25-hydroxyvitamin D(3) 24 hydroxylase (CYP24) expression primarily in the proximal colon. Our data suggest the proximal colon as the primary site of response to insufficient calcium intake.
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Affiliation(s)
- Thomas Nittke
- Department of Pathophysiology, Medical University of Vienna, Vienna, Austria
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Tanemura A, van Hoesel AQ, Mori T, Yu T, Hoon DSB. The role of estrogen receptor in melanoma. Expert Opin Ther Targets 2008; 11:1639-48. [PMID: 18020983 DOI: 10.1517/14728222.11.12.1639] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
The estrogen receptor (ER) belongs to the group of sex hormone receptors and binds the biologically active form of estrogen, 17beta-estradiol. Expression of ER in tumor tissue is a well-established prognostic marker in breast cancer. The role of ER has been extensively studied in several other types of human cancers. This report investigates the potential role of ER as a surrogate marker for predicting melanoma progression, response to therapy, and patient survival. In addition, the authors review what is known, so far, about ER signaling pathways and their potential role in carcinogenesis and progression of cutaneous melanoma. Possibilities and limitations of using ER as a therapeutic target in the treatment of melanoma is also discussed.
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Affiliation(s)
- Atsushi Tanemura
- John Wayne Cancer Institute, Department of Molecular Oncology, 2200 Santa Monica Blvd., Santa Monica, CA 90404, USA
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Al-Ghnaniem R, Peters J, Foresti R, Heaton N, Pufulete M. Methylation of estrogen receptor alpha and mutL homolog 1 in normal colonic mucosa: association with folate and vitamin B-12 status in subjects with and without colorectal neoplasia. Am J Clin Nutr 2007; 86:1064-72. [PMID: 17921385 DOI: 10.1093/ajcn/86.4.1064] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023] Open
Abstract
BACKGROUND Greater promoter methylation in some tumor-suppressor genes underlies most sporadic colorectal cancers and increases with age in the colon. OBJECTIVE We tested the hypothesis that biomarkers of folate and vitamin B-12 status are associated with estrogen receptor alpha (ERalpha) and mutL homolog 1 (MLH1) promoter methylation in subjects with and without neoplasia. DESIGN Biopsies of normal-appearing colorectal mucosa from 156 subjects with and without colorectal neoplasia (disease free, n = 76; cancer, n = 28; adenoma, n = 35; hyperplastic polyps, n = 17) were obtained at colonoscopy and used to evaluate methylation in 7 CpG sites in the ERalpha promoter and 13 CpG sites in the MLH1 promoter. Blood samples were obtained for the measurement of serum and red cell folate, serum vitamin B-12, and plasma homocysteine concentrations. Methylation indexes were generated to reflect an average methylation value across all CpG dinucleotides in both ERalpha and MLH1. RESULTS The methylation indexes for ERalpha and MLH1 generally were significantly (P < 0.05) higher in subjects with neoplasia than in disease-free subjects. The ERalpha methylation index correlated negatively with serum vitamin B-12 (r = -0.239, P = 0.003) and positively with plasma homocysteine (r = 0.188, P = 0.021). Disease status (P < 0.005), age (P < 0.001), and serum vitamin B-12 concentrations (P = 0.006) were independent determinants of ERalpha promoter methylation. Serum and red cell folate concentrations had no influence on ERalpha promoter methylation. CONCLUSION Serum vitamin B-12 but not folate status may be associated with ERalpha promoter methylation in normal-appearing colorectal mucosa.
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Affiliation(s)
- Reyad Al-Ghnaniem
- Nutritional Sciences Research Division, King's College London, London, United Kingdom
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Moriyama T, Matsumoto T, Nakamura S, Jo Y, Mibu R, Yao T, Iida M. Hypermethylation of p14 (ARF) may be predictive of colitic cancer in patients with ulcerative colitis. Dis Colon Rectum 2007; 50:1384-92. [PMID: 17665255 DOI: 10.1007/10350-007-0302-x] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
PURPOSE The microsatellite instability and CpG island hypermethylation of p14 ( ARF ) and p16 ( INK4a ) are related to the pathogenesis of neoplasia in ulcerative colitis. This study was designed to assess the significance of those genetic or epigenetic alterations for cancer surveillance in ulcerative colitis. METHODS During surveillance colonoscopy in 39 patients with ulcerative colitis, biopsy specimens were obtained from the cecum and the rectum as well as from any other areas suspected of being neoplasia by chromoscopy. Using DNA extracts, the methylation status of p14 ( ARF ) and p16 ( INK4a ) and the microsatellite status were determined. RESULTS Microsatellite instability was positive in one of five dysplasias, but it was negative in the cecum and the rectum. The incidence of hypermethylation of p14 ( ARF ) was 0 percent in the cecum, 26 percent in the rectum, and 100 percent in dysplasia, whereas that of p16 ( INK4a ) was 10, 10, and 0 percent, respectively. Patients who were positive for the hypermethylation of p14 ( ARF )in the rectum had a longer duration of ulcerative colitis than those who were negative for such hypermethylation. Two of 10 patients who were positive for p14 ( ARF ) hypermethylation in the rectum and 1 of 29 patients who were negative for the hypermethylation had dysplasia. During the subsequent surveillance of 36 patients, dysplasia was detected in 2 of 8 patients with p14 ( ARF ) hypermethylation and in none of 28 patients without hypermethylation (P = 0.044). CONCLUSIONS In patients with ulcerative colitis, hypermethylation of p14 ( ARF ) seems to be associated with an early stage of dysplasia. The hypermethylation may be one of candidates for potential biomarker to identify patients at a high risk of dysplasia.
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Affiliation(s)
- Tomohiko Moriyama
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Fukuoka, Japan.
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Arisawa T, Tahara T, Shibata T, Nagasaka M, Nakamura M, Kamiya Y, Fujita H, Takagi T, Hasegawa S, Wang FY, Hirata I, Nakano H. Promoter hypomethylation of protease-activated receptor 2 associated with carcinogenesis in the stomach. J Gastroenterol Hepatol 2007; 22:943-8. [PMID: 17517084 DOI: 10.1111/j.1440-1746.2007.04847.x] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
BACKGROUND AND AIM Trypsin acting at protease-activated receptor 2 (PAR2) contributes to a progression of malignant tumors. An abnormal DNA methylation has been recognized as an important molecular mechanism for the genesis of various types of cancers. We attempted to clarify the relationship between the promoter methylation of PAR2 and gastric cancer. METHOD We estimated the methylation of the PAR2 promoter in both antral non-cancerous mucosa and cancer lesions in 94 patients with gastric cancer. We employed a methylation-specific PCR method. RESULTS Regarding the methylation ratio (MR) of antral-non-cancerous mucosa, no significant difference was despite among gender, age and Helicobacter pylori infection status, whereas MR increased rising inflammation scores. The MR of cancer lesions was significantly lower than that of antral non-cancerous mucosa. This finding was not dependent on tumor staging, but also histological classification. In venous invasion, lymph node metastasis, or peritoneal dissemination negative cases, this significant lower MR was also seen. CONCLUSION The promoter methylation of PAR2 seems to be increased with a progression of chronic inflammation and has an inhibitory effect on carcinogenesis of the stomach.
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Affiliation(s)
- Tomiyasu Arisawa
- Department of Gastroenterology, Fujita Health University, School of Medicine, Toyoake, Aichi, Japan.
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Peyrin-Biroulet L, Rodriguez-Guéant RM, Chamaillard M, Desreumaux P, Xia B, Bronowicki JP, Bigard MA, Guéant JL. Vascular and cellular stress in inflammatory bowel disease: revisiting the role of homocysteine. Am J Gastroenterol 2007; 102:1108-15. [PMID: 17355415 DOI: 10.1111/j.1572-0241.2007.01170.x] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Moderate hyperhomocysteinemia is a complex trait commonly associated with inflammatory bowel disease (IBD). Nutritional deficiencies and genetic determinants have been identified as risk factors for moderate hyperhomocysteinemia, such as folate and vitamin B(12) deprivation and polymorphisms in the 5,10 methylenetetrahydrofolate reductase (MTHFR) encoding gene, respectively. Homocysteine has a crucial role in cellular stress, epigenetic events, inflammatory processes, and host-microbial interactions. Hyperhomocysteinemia might therefore influence the clinical history of IBD, including disease severity, susceptibility to particular enteric infections, and the risk for the development of colorectal cancer. In contrast, homocysteine metabolism does not seem to contribute to the greater risk of thrombosis in IBD subjects. Herein, we review the evidence linking homocysteine metabolism to the pathophysiology of IBD. Furthermore, we discuss the relevance of screening and treating folate and vitamin B(12) deficiencies in IBD subjects. Given the peculiar frequency of such deficiencies in IBD, normalizing vitamin levels should be an integral part of the management of these patients, especially those with active disease, history of intestinal resection, and/or treated with methotrexate.
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Affiliation(s)
- Laurent Peyrin-Biroulet
- Inserm, U724, Laboratory of Cellular and Molecular Pathology in Nutrition, Faculty of Medicine, Nancy-Universitè Vandoeuvre-les-Nancy, F-54511, France
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Watanabe T, Kobunai T, Toda E, Kanazawa T, Kazama Y, Tanaka J, Tanaka T, Yamamoto Y, Hata K, Kojima T, Yokoyama T, Konishi T, Okayama Y, Sugimoto Y, Oka T, Sasaki S, Ajioka Y, Muto T, Nagawa H. Gene expression signature and the prediction of ulcerative colitis-associated colorectal cancer by DNA microarray. Clin Cancer Res 2007; 13:415-20. [PMID: 17255260 DOI: 10.1158/1078-0432.ccr-06-0753] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
PURPOSE Ulcerative colitis (UC) is associated with a high risk of colorectal cancer. To identify genes that could predict the development of cancer in UC, we conducted a DNA microarray analysis using nonneoplastic rectal mucosa of UC patients. EXPERIMENTAL DESIGN Gene expression in nonneoplastic mucosa of 53 UC patients were examined. Gene expression profiles were examined using human Genome U133 Plus 2.0 gene chip array (Affymetrix). Among 53 UC patients, 10 had UC-associated cancer (UC-Ca group) whereas 43 did not (UC-NonCa group). RESULTS By comparing gene expression profiles of nonneoplastic rectal mucosae between the UC-Ca and UC-NonCa groups, we could identify 40 genes that were differentially expressed between two groups. The list of discriminating genes included low-density lipoprotein receptor-related protein (LRP5 and LRP6). Previous studies suggested that LRP5 and LRP6 expression promotes cancer cell proliferation and tumorigenesis and are considered as candidate oncogenes. In the present study, both LRP5 and LRP6 showed significantly higher expression in the UC-Ca group, which suggests the importance of these genes in the development of UC-associated colorectal cancers. With the 40 selected discriminating genes, we did class prediction of the development of colorectal neoplasms in UC patients. Using the k-nearest neighbor method and the support vector machine, we could predict the development of UC-associated neoplasms with an accuracy of 86.8% and 98.1%, respectively. CONCLUSIONS These findings have important implications for the early detection of malignant lesions in UC and may provide directions for future research into the molecular mechanisms of UC-associated cancer.
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Affiliation(s)
- Toshiaki Watanabe
- Department of Surgery, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo 173-8605, Japan.
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Mori T, Martinez SR, O’Day SJ, Morton DL, Umetani N, Kitago M, Tanemura A, Nguyen SL, Tran AN, Wang HJ, Hoon DS. Estrogen receptor-alpha methylation predicts melanoma progression. Cancer Res 2006; 66:6692-8. [PMID: 16818643 PMCID: PMC2856460 DOI: 10.1158/0008-5472.can-06-0801] [Citation(s) in RCA: 92] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
The role of estrogen receptor alpha (ER-alpha) in melanoma is unknown. ER-alpha expression may be regulated in melanoma via hypermethylation of promoter CpG islands. We assessed ER-alpha hypermethylation in primary and metastatic melanomas and sera as a potential tumor progression marker. ER-alpha methylation status in tumor (n = 107) and sera (n = 109) from American Joint Committee on Cancer (AJCC) stage I to IV melanoma patients was examined by methylation-specific PCR. The clinical significance of serum methylated ER-alpha was assessed among AJCC stage IV melanoma patients receiving biochemotherapy with tamoxifen. Rates of ER-alpha methylation in AJCC stage I, II, and III primary melanomas were 36% (4 of 11), 26% (5 of 19), and 35% (8 of 23), respectively. Methylated ER-alpha was detected in 42% (8 of 19) of stage III and 86% (30 of 35) of stage IV metastatic melanomas. ER-alpha was methylated more frequently in metastatic than primary melanomas (P = 0.0003). Of 109 melanoma patients' sera in AJCC stage I, II, III, and IV, methylated ER-alpha was detected in 10% (2 of 20), 15% (3 of 20), 26% (5 of 19), and 32% (16 of 50), respectively. Serum methylated ER-alpha was detected more frequently in advanced than localized melanomas (P = 0.03) and was the only factor predicting progression-free [risk ratio (RR), 2.64; 95% confidence interval (95% CI), 1.36-5.13; P = 0.004] and overall survival (RR, 2.31; 95% CI, 1.41-5.58; P = 0.003) in biochemotherapy patients. Hypermethylated ER-alpha is a significant factor in melanoma progression. Serum methylated ER-alpha is an unfavorable prognostic factor.
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Affiliation(s)
- Takuji Mori
- Department of Molecular Oncology, John Wayne Cancer Institute, Santa Monica, California
| | - Steve R. Martinez
- Department of Molecular Oncology, John Wayne Cancer Institute, Santa Monica, California
- Division of Surgical Oncology, John Wayne Cancer Institute, Santa Monica, California
| | - Steven J. O’Day
- The Angeles Clinic and Research Institute, Santa Monica, California
| | - Donald L. Morton
- Division of Surgical Oncology, John Wayne Cancer Institute, Santa Monica, California
| | - Naoyuki Umetani
- Department of Molecular Oncology, John Wayne Cancer Institute, Santa Monica, California
| | - Minoru Kitago
- Department of Molecular Oncology, John Wayne Cancer Institute, Santa Monica, California
| | - Atsushi Tanemura
- Department of Molecular Oncology, John Wayne Cancer Institute, Santa Monica, California
| | - Sandy L. Nguyen
- Department of Molecular Oncology, John Wayne Cancer Institute, Santa Monica, California
| | - Andy N. Tran
- Department of Molecular Oncology, John Wayne Cancer Institute, Santa Monica, California
| | - He-Jing Wang
- Division of Biostatistics, John Wayne Cancer Institute, Santa Monica, California
| | - Dave S.B. Hoon
- Department of Molecular Oncology, John Wayne Cancer Institute, Santa Monica, California
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Risques RA, Rabinovitch PS, Brentnall TA. Cancer surveillance in inflammatory bowel disease: new molecular approaches. Curr Opin Gastroenterol 2006; 22:382-90. [PMID: 16760754 DOI: 10.1097/01.mog.0000231812.95525.a7] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
PURPOSE OF REVIEW Patients with chronic inflammatory bowel disease, such as ulcerative colitis and Crohn's disease, have an increased risk of colorectal cancer. Life-long colonoscopy surveillance is performed to detect the presence of dysplasia, but this approach is expensive and time-consuming. Thus, there is intensive research to identify molecular factors with prognostic value. This review summarizes recent research, with a special emphasis on the mechanisms underlying these molecular alterations. RECENT FINDINGS The role of chromosomal instability in the progression to inflammatory bowel disease-associated colorectal cancer is clear and likely relates to chronic cycles of injury, inflammation, repair and telomere shortening. The role of microsatellite instability has been a subject of discussion, and data suggest that microsatellite instability in inflammatory bowel disease might be different from microsatellite instability in sporadic colorectal cancer. Methylation, as a mechanism of gene silencing, also plays a role in ulcerative colitis tumorigenesis. Chronic inflammation has been linked to p53 activation and oxidative stress, contributing to the extensive genomic DNA damage observed in ulcerative colitis. SUMMARY Improved understanding of the molecular biology of cancer progression in inflammatory bowel disease will hopefully lead to the identification of useful prognostic biomarkers. Efforts are needed to prove the clinical utility of the most promising markers now identified.
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