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Ghimire B, Kurlberg G, Falk P, Singh Y, Wettergren Y. Epigenetic differences in the tumor suppressor genes MLH1 and p16INK4a between Nepalese and Swedish patients with colorectal cancer. Innov Surg Sci 2024; 9:153-163. [PMID: 39309195 PMCID: PMC11416036 DOI: 10.1515/iss-2023-0039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Accepted: 06/02/2024] [Indexed: 09/25/2024] Open
Abstract
Objectives Colorectal cancer (CRC) is one of the most prevalent cancer types worldwide, exhibiting significant variance in incidence rates across different ethnicities and geographical regions. Notably, there is a rising incidence of CRC among younger adults, particularly evident in advanced stages, with a more pronounced trend observed in developing nations. Epigenetic alterations potentially play a role in the early onset of CRC and could elucidate interpopulation disparities. This study aimed to examine DNA methylation levels in the tumor suppressor genes MLH1 and p16INK4a, comparing Nepalese and Swedish patients with CRC. Methods Patients who underwent CRC surgery at Tribhuvan University Teaching Hospital, Nepal (n=39), and Sahlgrenska University Hospital, Sweden (n=39) were included. Demographic and clinicopathological data were analyzed, and pyrosequencing was employed to determine methylation levels in the MLH1 promoter region and the first exon of p16INK4a in tumor tissues and adjacent mucosa located 10 cm from the tumor site. Subsequently, methylation status was compared between Nepalese and Swedish patients and correlated with clinicopathological parameters. Results Nepalese and Swedish patients displayed equal levels of MLH1 and p16INK4a methylation in tumors, but Nepalese patients exhibited a significantly higher level of MLH1 methylation in mucosa compared to Swedish patients (p=0.0008). Moreover, a greater proportion of Nepalese patients showed MLH1 methylation in mucosa compared to Swedish patients (31 vs. 2.6 %). Aberrant methylation of p16INK4a was also observed in the mucosa of Nepalese patients, characterized by high methylation at specific sites rather than uniform methylation across CpG sites. There were no significant differences in methylation levels based on tumor location among Nepalese patients, whereas Swedish patients exhibited higher methylation in right- compared to left-sided colon tumors. Swedish patients showed an increase in p16INK4a methylation in tumors with advancing age. Conclusions Nepalese and Swedish patients displayed equal levels of MLH1 and p16INK4a methylation in tumors. In contrast, Nepalese patients had a higher level of MLH1 methylation as well as aberrant methylation of p16INK4a in mucosa compared to Swedish patients. These epigenetic differences may be linked to environmental and lifestyle factors. Ongoing research will further explore whether hypermethylation in the mucosa of Nepalese patients is associated with tumorigenesis and its potential utility in screening high-risk patients or predicting recurrence.
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Affiliation(s)
- Bikal Ghimire
- Department of GI and General Surgery, Maharajgung Medical Campus, Institute of Medicine, Tribhuvan University, Kathmandu, Nepal
| | - Göran Kurlberg
- Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Peter Falk
- Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Department of Surgery, Region Västra Götaland, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Yogendra Singh
- Department of GI and General Surgery, Maharajgung Medical Campus, Institute of Medicine, Tribhuvan University, Kathmandu, Nepal
| | - Yvonne Wettergren
- Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Department of Surgery, Region Västra Götaland, Sahlgrenska University Hospital, Gothenburg, Sweden
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He C, Huang Q, Zhong S, Chen LS, Xiao H, Li L. Screening and identifying of biomarkers in early colorectal cancer and adenoma based on genome-wide methylation profiles. World J Surg Oncol 2023; 21:312. [PMID: 37779184 PMCID: PMC10544418 DOI: 10.1186/s12957-023-03189-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2023] [Accepted: 09/17/2023] [Indexed: 10/03/2023] Open
Abstract
BACKGROUND Colorectal cancer is one of the most common malignant tumors worldwide with high morbidity and mortality. This study aimed to identify different methylation sites as new methylation markers in CRC and colorectal adenoma through tissue detection. METHODS DNA extraction and bisulfite modification as well as Infinium 450K methylation microarray detection were performed in 46 samples of sporadic colorectal cancer tissue, nine samples of colorectal adenoma, and 20 normal samples, and bioinformatic analysis was conducted involving genes enrichments of GO and KEGG. Pyrosequencing methylation detection was further performed in 68 sporadic colorectal cancer tissues, 31 samples of colorectal adenoma, and 49 normal colorectal mucosae adjacent to carcinoma to investigate the differentially methylated genes obtained from methylation microarray. RESULTS There were 65,535 differential methylation marker probes, among which 25,464 were hypermethylated markers and 40,071 were hypomethylated markers in the adenoma compared with the normal group, and 395,571 were differentially methylated markers in patients with sporadic colorectal cancer compared with the normal group, including 21,710 hypermethylated markers and 17,861 hypomethylated markers. Five hypermethylated genes including ZNF471, SND1, SPOCK1, FBLIM1, and OTX1 were detected and confirmed in 68 cases of colorectal cancer, 31 cases of adenoma, and 49 cases of normal control group. CONCLUSIONS Hypermethylated genes of ZNF471, SND1, SPOCK1, FBLIM1, and OTX1 were obtained from methylation chip detection and further confirm analysis in colorectal cancer and adenoma compared with normal tissue, which may be promising diagnostic markers of colorectal cancer and colorectal adenoma.
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Affiliation(s)
- Chungang He
- Department of Colorectal and Anal Surgery, the People's Hospital of Guangxi Zhuang Autonomous Region, Tao Yuan Road No.6, Nanning, 530021, Guangxi, China.
| | - Qinyuan Huang
- Nursing College of Guangxi Medical University, Nanning, 530021, Guangxi, China
| | - Shibiao Zhong
- Department of Gastrointestinal Surgery, Ruikang Hospital Affiliated to Guangxi University of Traditional Chinese Medicine, Nanning, 530011, Guangxi, China
| | - Li Sheng Chen
- Department of Colorectal and Anal Surgery, the First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi, China
| | - Hewei Xiao
- Office of Academic Research, the People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, 530021, Guangxi, China
| | - Lei Li
- Department of Gastrointestinal Surgery, the People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, 530021, Guangxi, China
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Hernandez-Meza G, von Felden J, Gonzalez-Kozlova EE, Garcia-Lezana T, Peix J, Portela A, Craig AJ, Sayols S, Schwartz M, Losic B, Mazzaferro V, Esteller M, Llovet JM, Villanueva A. DNA Methylation Profiling of Human Hepatocarcinogenesis. Hepatology 2021; 74:183-199. [PMID: 33237575 PMCID: PMC8144238 DOI: 10.1002/hep.31659] [Citation(s) in RCA: 63] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2020] [Revised: 10/28/2020] [Accepted: 10/30/2020] [Indexed: 12/24/2022]
Abstract
BACKGROUND AND AIMS Mutations in TERT (telomerase reverse transcriptase) promoter are established gatekeepers in early hepatocarcinogenesis, but little is known about other molecular alterations driving this process. Epigenetic deregulation is a critical event in early malignancies. Thus, we aimed to (1) analyze DNA methylation changes during the transition from preneoplastic lesions to early HCC (eHCC) and identify candidate epigenetic gatekeepers, and to (2) assess the prognostic potential of methylation changes in cirrhotic tissue. APPROACH AND RESULTS Methylome profiling was performed using Illumina HumanMethylation450 (485,000 cytosine-phosphateguanine, 96% of known cytosine-phosphateguanine islands), with data available for a total of 390 samples: 16 healthy liver, 139 cirrhotic tissue, 8 dysplastic nodules, and 227 HCC samples, including 40 eHCC below 2cm. A phylo-epigenetic tree derived from the Euclidean distances between differentially DNA-methylated sites (n = 421,997) revealed a gradient of methylation changes spanning healthy liver, cirrhotic tissue, dysplastic nodules, and HCC with closest proximity of dysplasia to HCC. Focusing on promoter regions, we identified epigenetic gatekeeper candidates with an increasing proportion of hypermethylated samples (beta value > 0.5) from cirrhotic tissue (<1%), to dysplastic nodules (≥25%), to eHCC (≥50%), and confirmed inverse correlation between DNA methylation and gene expression for TSPYL5 (testis-specific Y-encoded-like protein 5), KCNA3 (potassium voltage-gated channel, shaker-related subfamily, member 3), LDHB (lactate dehydrogenase B), and SPINT2 (serine peptidase inhibitor, Kunitz type 2) (all P < 0.001). Unsupervised clustering of genome-wide methylation profiles of cirrhotic tissue identified two clusters, M1 and M2, with 42% and 58% of patients, respectively, which correlates with survival (P < 0.05), independent of etiology. CONCLUSIONS Genome-wide DNA-methylation profiles accurately discriminate the different histological stages of human hepatocarcinogenesis. We report on epigenetic gatekeepers in the transition between dysplastic nodules and eHCC. DNA-methylation changes in cirrhotic tissue correlate with clinical outcomes.
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Affiliation(s)
- Gabriela Hernandez-Meza
- Division of Liver Diseases, Liver Cancer Program, Tisch Cancer Institute, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Johann von Felden
- Division of Liver Diseases, Liver Cancer Program, Tisch Cancer Institute, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.,I. Department of Internal Medicine, University Medical Center Hamburg Eppendorf, Hamburg, Germany
| | - Edgar E. Gonzalez-Kozlova
- Department of Genetics and Genomic Sciences, Cancer Immunology Program, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Teresa Garcia-Lezana
- Division of Liver Diseases, Liver Cancer Program, Tisch Cancer Institute, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Judit Peix
- Translational Research in Hepatic Oncology, Liver Unit, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)-Hospital Clínic, Universitat De Barcelona, Catalonia, Spain
| | - Anna Portela
- Cancer Epigenetics and Biology Program, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain
| | - Amanda J. Craig
- Division of Liver Diseases, Liver Cancer Program, Tisch Cancer Institute, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Sergi Sayols
- Cancer Epigenetics and Biology Program, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain.,Institute of Molecular Biology, Mainz, Germany
| | - Myron Schwartz
- Department of Surgery, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Bojan Losic
- Department of Genetics and Genomic Sciences, Cancer Immunology Program, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.,Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.,Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Vincenzo Mazzaferro
- Gastrointestinal Surgery and Liver Transplantation Unit, National Cancer Institute, Milan, Italy
| | - Manel Esteller
- Josep Carreras Leukemia Research Institute (IJC), Badalona, Barcelona, Catalonia, Spain,Centro de Investigacion Biomedica en Red Cancer (CIBERONC), Madrid, Spain.,Institucio Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain.,Physiological Sciences Department, School of Medicine and Health Sciences, University of Barcelona (UB), Barcelona, Catalonia, Spain
| | - Josep M. Llovet
- Division of Liver Diseases, Liver Cancer Program, Tisch Cancer Institute, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.,Translational Research in Hepatic Oncology, Liver Unit, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)-Hospital Clínic, Universitat De Barcelona, Catalonia, Spain,Institució Catalana de Recerca i Estudis Avançats, Barcelona, Catalonia, Spain
| | - Augusto Villanueva
- Division of Liver Diseases, Liver Cancer Program, Tisch Cancer Institute, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.,Division of Hematology and Medical Oncology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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Coppedè F, Stoccoro A, Lazzarotti A, Spisni R, Migliore L. Investigation of GHSR and GHRL methylation in colorectal cancer. Epigenomics 2018; 10:1525-1539. [PMID: 29963901 DOI: 10.2217/epi-2018-0030] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
AIM To investigate GHSR and GHRL methylation in 73 pairs of colorectal cancer (CRC) tissues and healthy adjacent mucosa. METHODS Methylation was assessed with methylation-sensitive high-resolution melting. RESULTS GHSR was significantly hypermethylated in CRC tissues than in healthy mucosa (p < 1 × 10-5), but no significant changes of GHRL methylation were observed. GHSR hypermethylation was already detectable at the adenoma stage and maintained in later stages independently of age, gender, anatomical location, histological grading, MLH1 deficiency, as well as of major polymorphisms in folate-pathway genes, yielding an area under the curve of 0.824 for discriminating cancers from respective non-neoplastic mucosa specimens. CONCLUSION GHSR hypermethylation occurs early in CRC, but is not paralleled by significant changes of GHRL methylation.
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Affiliation(s)
- Fabio Coppedè
- Department of Translational Research & New Technologies in Medicine & Surgery, Medical Genetics Laboratory, University of Pisa, Pisa, Italy
| | - Andrea Stoccoro
- Department of Translational Research & New Technologies in Medicine & Surgery, Medical Genetics Laboratory, University of Pisa, Pisa, Italy
| | - Alessandro Lazzarotti
- Department of Translational Research & New Technologies in Medicine & Surgery, Medical Genetics Laboratory, University of Pisa, Pisa, Italy
| | - Roberto Spisni
- Department of Surgery, Medical, Molecular, & Critical Area Pathology, University of Pisa, Pisa, Italy
| | - Lucia Migliore
- Department of Translational Research & New Technologies in Medicine & Surgery, Medical Genetics Laboratory, University of Pisa, Pisa, Italy
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Zhang HF, Lu YW, Xie ZR, Wang KH. Relationship Between Human mutL Homolog 1 (hMLH1) Hypermethylation and Colorectal Cancer: A Meta-Analysis. Med Sci Monit 2017. [PMID: 28635682 PMCID: PMC6179171 DOI: 10.12659/msm.895643] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Background Hypermethylation of CpG islands in gene promoter regions is an important mechanism of gene inactivation in cancers. Promoter hypermethylation of human mutL homolog 1 (hMLH1) has been implicated in a subset of colorectal cancers that show microsatellite instability (MSI), while the connection of the epigenetic inactivation of hMLH1 in colorectal cancers remains unknown. The aim of this study was to evaluate the relationship between the promoter hypermethylation of hMLH1 and colorectal cancers by performing a meta-analysis. Material/Methods Eligible studies were identified through searching PubMed, Cochrane Library, Web of Science, and Google Scholar databases. R Software including meta packages was used to calculate the pooled and odds ratios (ORs) with corresponding confidence intervals (CIs). Funnel plots were also performed to evaluate publication bias. Results This meta-analysis obtained 45 articles, including 4096 colorectal cancer patients, and identified a significant association between hMLH1 hypermethylation and colorectal cancer risk using the fixed-effects model (OR=8.3820; 95% CI, 6.9202~10.1527; z=21.7431; P<0.0001) and random effects model pooled (OR=10.0963; 95% CI, 6.1919~16.4626; z=9.2688; P<0.0001). The significant relationship was found in subgroup analyses. Conclusions The results of this meta-analysis show a significant association between hMLH1 hypermethylation and colorectal cancer risk.
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Affiliation(s)
- Hui-Feng Zhang
- Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, Yunnan, China (mainland).,Faculty of Environmental Science and Engineering, Kunming University of Science and Technology, Kunming, Yunnan, China (mainland).,The First People's Hospital of Yunnan Province, Kunming, Yunnan, China (mainland)
| | - You-Wang Lu
- Faculty of Environmental Science and Engineering, Kunming University of Science and Technology, Kunming, Yunnan, China (mainland)
| | - Zhen-Rong Xie
- Yunnan Institute of Digestive Disease, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China (mainland)
| | - Kun-Hua Wang
- Yunnan Institute of Digestive Disease, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China (mainland)
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Sugai T, Yoshida M, Eizuka M, Uesugii N, Habano W, Otsuka K, Sasaki A, Yamamoto E, Matsumoto T, Suzuki H. Analysis of the DNA methylation level of cancer-related genes in colorectal cancer and the surrounding normal mucosa. Clin Epigenetics 2017; 9:55. [PMID: 28533824 PMCID: PMC5437595 DOI: 10.1186/s13148-017-0352-4] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2016] [Accepted: 05/05/2017] [Indexed: 12/17/2022] Open
Abstract
Background Two molecular pathways promote the development of colorectal cancer (CRC). One is termed “microsatellite stable” (MSS) whereas the other is characterized by “microsatellite instability” (MSI or MIN). In addition, the CpG island methylation phenotype is known to be an important alteration as a third molecular type. Thus, DNA methylation is thought to provide potential biomarkers for assessment of cancer risk in normal mucosa. In addition, it is also known that colonic location is an important parameter in the development of CRC. Methods We examined the surrounding normal mucosa in three parts of the colon. Next, we quantified DNA methylation levels of SFRP1, SFRP2, SFRP5, DKK2, DKK3, mir34b/c, RASSF1A, IGFBP7, CDKN2A, and MLH1 in isolated cancerous glands and crypts of normal colorectal mucosa adjacent to CRCs using a pyrosequencer. Results DNA methylation levels of SFRP1, SFRP2, DKK2, and mir34b/c were significantly higher in CRCs with an MSS phenotype than in those with an MSI phenotype. The average level of methylation in normal crypts did not decrease with the distance from the tumor, irrespective of microsatellite status or the tumor location. DNA methylation levels in SFRP1 and SFRP2 genes in normal crypts were significantly higher in left-side than right-side CRC with an MSS phenotype. Finally, the genes were classified into three types based on the methylation frequencies in normal crypts, including type I (SFRP1 and SFRP2I), type II (DKK2 and mir34b/c), and type III (others). Conclusions Our results showed that DNA methylation of SFRP1 and SFRP2 might be useful to predict cancer risk of surrounding normal mucosa. In addition, a field effect may be present in CRC, affecting both adjacent and non-adjacent normal mucosa. Electronic supplementary material The online version of this article (doi:10.1186/s13148-017-0352-4) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Tamotsu Sugai
- Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, 19-1, Morioka, 020-8505 Japan
| | - Masakazu Yoshida
- Department of Surgery, School of Medicine, Iwate Medical University, 19-1, Morioka, 020-8505 Japan
| | - Makoto Eizuka
- Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, 19-1, Morioka, 020-8505 Japan
| | - Noriyuki Uesugii
- Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, 19-1, Morioka, 020-8505 Japan
| | - Wataru Habano
- Department of Pharmacodynamics and Molecular Genetics, School of Pharmacy, Iwate Medical University, 19-1, Morioka, 020-8505 Japan
| | - Kouki Otsuka
- Department of Surgery, School of Medicine, Iwate Medical University, 19-1, Morioka, 020-8505 Japan
| | - Akira Sasaki
- Department of Surgery, School of Medicine, Iwate Medical University, 19-1, Morioka, 020-8505 Japan
| | - Eiichiro Yamamoto
- Department of Molecular Biology, Sapporo Medical University, Chuo-ku, Sapporo, 060-8556 Japan
| | - Takayuki Matsumoto
- Department of Internal Medicine, Division of Gastrointestinal Tract, School of Medicine, Iwate Medical University, 19-1, Morioka, 020-8505 Japan
| | - Hiromu Suzuki
- Department of Molecular Biology, Sapporo Medical University, Chuo-ku, Sapporo, 060-8556 Japan
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Patel A, Tripathi G, Gopalakrishnan K, Williams N, Arasaradnam RP. Field cancerisation in colorectal cancer: A new frontier or pastures past? World J Gastroenterol 2015; 21:3763-3772. [PMID: 25852261 PMCID: PMC4385523 DOI: 10.3748/wjg.v21.i13.3763] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2014] [Revised: 01/09/2015] [Accepted: 02/13/2015] [Indexed: 02/07/2023] Open
Abstract
Despite considerable advances in our understanding of cancer biology, early diagnosis of colorectal cancer remains elusive. Based on the adenoma-carcinoma sequence, cancer develops through the progressive accumulation of mutations in key genes that regulate cell growth. However, recent mathematical modelling suggests that some of these genetic events occur prior to the development of any discernible histological abnormality. Cells acquire pro-tumourigenic mutations that are not able to produce morphological change but predispose to cancer formation. These cells can grow to form large patches of mucosa from which a cancer arises. This process has been termed “field cancerisation”. It has received little attention in the scientific literature until recently. Several studies have now demonstrated cellular, genetic and epigenetic alterations in the macroscopically normal mucosa of colorectal cancer patients. In some reports, these changes were effectively utilised to identify patients with a neoplastic lesion suggesting potential application in the clinical setting. In this article, we present the scientific evidence to support field cancerisation in colorectal cancer and discuss important limitations that require further investigation. Characterisation of the field defect is necessary to enable early diagnosis of colorectal cancer and identify molecular targets for chemoprevention. Field cancerisation offers a promising prospect for experimental cancer research and has potential to improve patient outcomes in the clinical setting.
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Abstract
Colorectal cancer (CRC) results from a stepwise accumulation of genetic and epigenetic alterations that transform the normal colonic epithelium into cancer. DNA methylation represents one of the most studied epigenetic marks in CRC, and three common epigenotypes have been identified characterized by high, intermediate and low methylation profiles, respectively. Combining DNA methylation data with gene mutations and cytogenetic alterations occurring in CRC is nowadays allowing the characterization of different CRC subtypes, but the crosstalk between DNA methylation and other epigenetic mechanisms, such as histone tail modifications and the deregulated expression of non-coding RNAs is not yet clearly defined. Epigenetic biomarkers are increasingly recognized as promising diagnostic and prognostic tools in CRC, and the potential of therapeutic applications aimed at targeting the epigenome is under investigation.
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Affiliation(s)
- Fabio Coppedè
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Medical School, Via Roma 55, 56126 Pisa, Italy
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9
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Deb S, Fox SB. Molecular profiling in colorectal cancer: current state of play and future directions. COLORECTAL CANCER 2014. [DOI: 10.2217/crc.13.82] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
SUMMARY In the era of molecular scientific discovery, there is a continuing gap between our growing scientific knowledge and its utility at the bedside. This phenomenon probably occurs more frequently in colorectal cancer than in other cancer streams, with thousands of scientific studies having produced only a handful of molecular interventions. This review examines our current practices of molecular profiling in colorectal cancer and the scientific research that may impact on this area in the future.
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Affiliation(s)
- Siddhartha Deb
- Department of Anatomical Pathology, Peter MacCallum Cancer Centre, East Melbourne 3002, Australia
- Department of Pathology, University of Melbourne, Parkville 3052, Australia
| | - Stephen B Fox
- Department of Pathology, University of Melbourne, Parkville 3052, Australia
- Department of Anatomical Pathology, Peter MacCallum Cancer Centre, East Melbourne 3002, Australia.
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Coppedè F, Migheli F, Lopomo A, Failli A, Legitimo A, Consolini R, Fontanini G, Sensi E, Servadio A, Seccia M, Zocco G, Chiarugi M, Spisni R, Migliore L. Gene promoter methylation in colorectal cancer and healthy adjacent mucosa specimens: correlation with physiological and pathological characteristics, and with biomarkers of one-carbon metabolism. Epigenetics 2014; 9:621-33. [PMID: 24500500 DOI: 10.4161/epi.27956] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
We evaluated the promoter methylation levels of the APC, MGMT, hMLH1, RASSF1A and CDKN2A genes in 107 colorectal cancer (CRC) samples and 80 healthy adjacent tissues. We searched for correlation with both physical and pathological features, polymorphisms of folate metabolism pathway genes (MTHFR, MTRR, MTR, RFC1, TYMS, and DNMT3B), and data on circulating folate, vitamin B12 and homocysteine, which were available in a subgroup of the CRC patients. An increased number of methylated samples were found in CRC respect to adjacent healthy tissues, with the exception of APC, which was also frequently methylated in healthy colonic mucosa. Statistically significant associations were found between RASSF1A promoter methylation and tumor stage, and between hMLH1 promoter methylation and tumor location. Increasing age positively correlated with both hMLH1 and MGMT methylation levels in CRC tissues, and with APC methylation levels in the adjacent healthy mucosa. Concerning gender, females showed higher hMLH1 promoter methylation levels with respect to males. In CRC samples, the MTR 2756AG genotype correlated with higher methylation levels of RASSF1A, and the TYMS 1494 6bp ins/del polymorphism correlated with the methylation levels of both APC and hMLH1. In adjacent healthy tissues, MTR 2756AG and TYMS 1494 6bp del/del genotypes correlated with APC and MGMT promoter methylation, respectively. Low folate levels were associated with hMLH1 hypermethylation. Present results support the hypothesis that DNA methylation in CRC depends from both physiological and environmental factors, with one-carbon metabolism largely involved in this process.
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Affiliation(s)
- Fabio Coppedè
- Department of Translational Research and New Technologies in Medicine and Surgery; Division of Medical Genetics; University of Pisa; Pisa, Italy; Istituto Toscano Tumori (ITT); Florence, Italy; Research Center Nutraceuticals and Food for Health-Nutrafood; University of Pisa; Pisa, Italy
| | - Francesca Migheli
- Department of Translational Research and New Technologies in Medicine and Surgery; Division of Medical Genetics; University of Pisa; Pisa, Italy; Istituto Toscano Tumori (ITT); Florence, Italy
| | - Angela Lopomo
- Department of Translational Research and New Technologies in Medicine and Surgery; Division of Medical Genetics; University of Pisa; Pisa, Italy; Doctoral School in Genetics, Oncology, and Clinical Medicine; University of Siena; Siena, Italy
| | - Alessandra Failli
- Istituto Toscano Tumori (ITT); Florence, Italy; Department of Clinical and Experimental Medicine; University of Pisa; Pisa, Italy
| | - Annalisa Legitimo
- Department of Clinical and Experimental Medicine; University of Pisa; Pisa, Italy
| | - Rita Consolini
- Department of Clinical and Experimental Medicine; University of Pisa; Pisa, Italy
| | - Gabriella Fontanini
- Department of Surgery, Medical, Molecular, and Critical Area Pathology; University of Pisa; Pisa, Italy
| | - Elisa Sensi
- Department of Surgery, Medical, Molecular, and Critical Area Pathology; University of Pisa; Pisa, Italy
| | - Adele Servadio
- Department of Surgery, Medical, Molecular, and Critical Area Pathology; University of Pisa; Pisa, Italy
| | - Massimo Seccia
- Department of Surgery, Medical, Molecular, and Critical Area Pathology; University of Pisa; Pisa, Italy
| | - Giuseppe Zocco
- Department of Surgery, Medical, Molecular, and Critical Area Pathology; University of Pisa; Pisa, Italy
| | - Massimo Chiarugi
- Department of Surgery, Medical, Molecular, and Critical Area Pathology; University of Pisa; Pisa, Italy
| | - Roberto Spisni
- Department of Surgery, Medical, Molecular, and Critical Area Pathology; University of Pisa; Pisa, Italy
| | - Lucia Migliore
- Department of Translational Research and New Technologies in Medicine and Surgery; Division of Medical Genetics; University of Pisa; Pisa, Italy; Istituto Toscano Tumori (ITT); Florence, Italy; Research Center Nutraceuticals and Food for Health-Nutrafood; University of Pisa; Pisa, Italy
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Baker AM, Graham TA, Wright NA. Pre-tumour clones, periodic selection and clonal interference in the origin and progression of gastrointestinal cancer: potential for biomarker development. J Pathol 2013; 229:502-14. [PMID: 23288692 DOI: 10.1002/path.4157] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2012] [Revised: 12/17/2012] [Accepted: 12/18/2012] [Indexed: 12/18/2022]
Abstract
Classically, the risk of cancer progression in premalignant conditions of the gastrointestinal tract is assessed by examining the degree of histological dysplasia. However, there are many putative pro-cancer genetic changes that have occurred in histologically normal tissue well before the onset of dysplasia. Here we summarize the evidence for such pre-tumour clones and the existing technology that can be used to locate these clones and characterize them at the genetic level. We also discuss the mechanisms by which pre-tumour clones may spread through large areas of normal tissue, and highlight emerging theories on how multiple clones compete and interact within the gastrointestinal mucosa. It is important to gain an understanding of these processes, as it is envisaged that certain pre-tumour changes may be powerful predictive markers, with the potential to identify patients at high risk of developing cancer at a much earlier stage.
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Affiliation(s)
- Ann-Marie Baker
- Centre for Tumour Biology, Barts and the London School of Medicine and Dentistry, London, UK.
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12
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Subramaniam MM, Loh M, Chan JY, Liem N, Lim PL, Peng YW, Lim XY, Yeoh KG, Iacopetta B, Soong R, Salto-Tellez M. The topography of DNA methylation in the non-neoplastic colonic mucosa surrounding colorectal cancers. Mol Carcinog 2012; 53:98-108. [PMID: 22911899 DOI: 10.1002/mc.21951] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2012] [Revised: 07/20/2012] [Accepted: 07/27/2012] [Indexed: 12/17/2022]
Abstract
The degree of gene hypermethylation in non-neoplastic colonic mucosa (NNCM) is a potentially important event in the development of colorectal cancer (CRC), particularly for the subgroup with a CpG island methylator phenotype (CIMP). In this study, we aimed to use an unbiased and high-throughput approach to evaluate the topography of DNA methylation in the non-neoplastic colonic mucosa (NNCM) surrounding colorectal cancer (CRC). A total of 61 tissue samples comprising 53 NNCM and 8 tumor samples were obtained from hemicolectomy specimens of two CRC patients (Cases 1 and 2). NNCM was stripped from the underlying colonic wall and samples taken at varying distances from the tumor. The level of DNA methylation in NNCM and tumor tissues was assessed at 1,505 CpG sites in 807 cancer-related genes using Illumina GoldenGate® methylation arrays. Case 1 tumor showed significantly higher levels of methylation compared to surrounding NNCM samples (P < 0.001). The average level of methylation in NNCM decreased with increasing distance from the tumor (r = -0.418; P = 0.017), however this was not continuous and "patches" with higher levels of methylation were observed. Case 2 tumor was less methylated than Case 1 tumor (average β-value 0.181 vs. 0.415) and no significant difference in the level of methylation was observed in comparison to the surrounding NNCM. No evidence was found for a diminishing gradient of methylation in the NNCM surrounding CRC with a high level of methylation. Further work is required to determine whether CIMP+ CRC develop from within "patches" of NCCM that display high levels of methylation.
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Affiliation(s)
- Manish Mani Subramaniam
- Department of Pathology, National University Health System, National University of Singapore, Singapore, Singapore; Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
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13
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Nyiraneza C, Sempoux C, Detry R, Kartheuser A, Dahan K. Hypermethylation of the 5' CpG island of the p14ARF flanking exon 1β in human colorectal cancer displaying a restricted pattern of p53 overexpression concomitant with increased MDM2 expression. Clin Epigenetics 2012; 4:9. [PMID: 22703554 PMCID: PMC3470942 DOI: 10.1186/1868-7083-4-9] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2012] [Accepted: 05/07/2012] [Indexed: 01/10/2023] Open
Abstract
Background It has been suggested that inactivation of p14ARF, a tumor suppressor central to regulating p53 protein stability through interaction with the MDM2 oncoprotein, abrogates p53 activity in human tumors retaining the wild-type TP53 gene. Differences in expression of tumor suppressor genes are frequently associated with cancer. We previously reported on a pattern of restricted p53 immunohistochemical overexpression significantly associated with microsatellite instability (MSI), low TP53 mutation frequency, and MDM2 overexpression in colorectal cancers (CRCs). In this study, we investigated whether p14ARF alterations could be a mechanism for disabling the p53 pathway in this subgroup of CRCs. Results Detailed maps of the alterations in the p14ARF gene were determined in a cohort of 98 CRCs to detect both nucleotide and copy-number changes. Methylation-specific PCR combined with bisulfite sequencing was used to evaluate the prevalence and distribution of p14ARF methylation. p14ARF alterations were then correlated with MSI status, TP53 mutations, and immunohistochemical expression of p53 and MDM2. The frequency of p14ARF mutations was extremely low (1/98; 1%), whereas coexistence of methylated and unmethylated alleles in both tumors and normal colon mucosa was common (91/98; 93%). Only seven of ninety-eight tumors (7%) had a distinct pattern of methylation compared with normal colon mucosa. Evaluation of the prevalence and distribution of p14ARF promoter methylation in a region containing 27 CpG sites in 35 patients showed a range of methylated CpG sites in tumors (0 to 25 (95% CI 1 to 13) versus 0 to 17 (95% CI 0 to 2)) in adjacent colon mucosa (P = 0.004). Hypermethylation of the p14ARF promoter was significantly correlated with the restricted p53 overexpression pattern (P = 0.03), and MDM2 overexpression (P = 0.02), independently of MSI phenotype. Although no significant correlation between p14ARF methylation and TP53 mutational status was seen (P = 0.23), methylation involving the proximal CpG sites within the 5′ CpG flanking exon 1β was present more frequently in tumors with restricted p53 overexpression than in those with diffuse p53 overexpression (range of methylated clones 17 to 36% (95% CI 24 to 36%) versus range 0 to 3% (95% CI 0 to 3%), P = 0. 0003). Conclusion p14ARF epigenetic silencing may represent an important deregulating mechanism of the p53-MDM2-p14ARF pathway in CRCs exhibiting a restricted p53 overexpression pattern.
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Affiliation(s)
- Christine Nyiraneza
- Center for Human Genetics, Université Catholique de Louvain, Cliniques universitaires Saint-Luc, Avenue Hippocrate 10, Brussels, B-1200, Belgium.
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14
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Hao XW, Zhu ST, He YL, Li P, Wang YJ, Zhang ST. Epigenetic inactivation of secreted frizzled-related protein 2 in esophageal squamous cell carcinoma. World J Gastroenterol 2012; 18:532-40. [PMID: 22363119 PMCID: PMC3280398 DOI: 10.3748/wjg.v18.i6.532] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2011] [Revised: 09/22/2011] [Accepted: 10/28/2011] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the expression and methylation status of the secreted frizzled-related protein 2 (SFRP2) in esophageal squamous cell carcinoma (ESCC) and explore its role in ESCC carcinogenesis.
METHODS: Seven ESCC cell lines (KYSE 30, KYSE150, KYSE410, KYSE510, EC109, EC9706 and TE-1) and one immortalized human esophageal epithelial cell line (Het-1A), 20 ESCC tissue samples and 20 paired adjacent non-tumor esophageal epithelial tissues were analyzed in this study. Reverse-transcription polymerase chain reaction (RT-PCR) was employed to investigate the expression of SFRP2 in cell lines, primary ESCC tumor tissue, and paired adjacent normal tissue. Methylation status was evaluated by methylation-specific PCR and bisulfite sequencing. The correlation between expression and promoter methylation of the SFRP2 gene was confirmed with treatment of 5-aza-2’-deoxycytidine. To assess the potential role of SFRP2 in ESCC, we established stable SFRP2-transfected cells and examined them with regard to cell proliferation, colony formation, apoptosis and cell cycle in vivo and in vitro.
RESULTS: SFRP2 mRNA was expressed in the immortalized normal esophageal epithelial cell line but not in seven ESCC cell lines. By methylation-specific PCR, complete methylation was detected in three cell lines with silenced SFRP2 expression, and extensive methylation was observed in the other four ESCC cell lines. 5-aza-2’-deoxycytidine could restore the expression of SFRP2 mRNA in the three ESCC cell lines lacking SFRP2 expression. SFRP2 mRNA expression was obviously lower in primary ESCC tissue than in adjacent normal tissue (0.939 ± 0.398 vs 1.51 ± 0.399, P < 0.01). SFRP2 methylation was higher in tumor tissue than in paired normal tissue (95% vs 65%, P < 0.05). The DNA methylation status of the SFRP2 correlated inversely with the SFRP2 expression. To assess the potential role of SFRP2 in ESCC, we established stable SFRP2 transfectants and control counterparts by introducing pcDNA3.1/v5 hisA -SFRP2 or pcDNA3.1/v5 hisA -empty vector into KYSE30 cells lacking SFRP2 expression. After transfection, the forced-expression of SFRP2 was confirmed by the RT-PCR. In comparison with the control groups, stably-expressed SFRP2 in KYSE 30 cells significantly reduced colony formation in vitro (47.17% ± 15.61% vs 17% ± 3.6%, P = 0.031) and tumor growth in nude mice (917.86 ± 249.35 mm3vs 337.23 ± 124.43 mm3, P < 0.05). Using flow cytometry analysis, we found a significantly higher number of early apoptotic cells in SFRP2-transfected cells than in the control cells (P = 0.025). The mean cell number in the S and G2-M phases of the cell cycle was also significantly lower in SFRP2-transfected KYSE30 cells compared with mock transfected counterparts.
CONCLUSION: Silencing of SFRP2 expression through promoter hypermethylation may be a factor in ESCC carcinogenesis through loss of its tumor-suppressive activity.
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15
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Buda A, Pignatelli M. E-cadherin and the cytoskeletal network in colorectal cancer development and metastasis. ACTA ACUST UNITED AC 2011; 18:133-43. [PMID: 22176698 DOI: 10.3109/15419061.2011.636465] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Abnormalities in the expression and functional activity of cell adhesion molecules are implicated in the development and progression of the majority of colorectal cancers (CRC). Cell-cell adhesion molecule E-cadherin regulates cell polarity, differentiation, proliferation and migration through its intimate association to the actin cytoskeletal network. During colorectal carcinogenesis changes in intercellular adhesion and dynamic rearrangements in the actin cytoskeleton result in altered signalling and migration with loss of contact inhibition. The adenomatous polyposis coli (APC) protein, besides its established role in the β catenin/Wnt signalling pathway, can coordinate microtubule and actin organization during cell migration. The actin-bundling protein Fascin promotes cell motility and is overexpressed in CRC. Based on recent molecular and pathological studies, this review focusses on the role of these molecules sharing the common feature of being associated with the cytoskeletal network during colorectal carcinogenesis and metastasis. The potential use of these molecules as prognostic markers and/or therapeutic targets will also be discussed.
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Affiliation(s)
- Andrea Buda
- School of Clinical Sciences, University of Bristol, Bristol, UK
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16
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Abstract
The widely accepted paradigm for tumorigenesis begins with rate-limiting mutations in a key growth control gene resulting in immediate lesion growth. Tumor progression occurs as cells within the tumor acquire additional carcinogenic mutations. However, there is clear evidence that the road to cancer can begin long before the growth of a clinically detectable lesion - indeed, long before any of the usual morphological correlates of preneoplasia are recognizable. Field cancerization, the replacement of the normal cell population by a histologically nondysplastic but protumorigenic mutant cell clone, underlies the development of many cancer types, and in this article we review field cancerization in the GI tract. We present the evidence that field cancerization can underpin tumorigenesis in all gastrointestinal compartments, discuss the homeostatic mechanisms that could permit clone spread and highlight how an understanding of the mechanisms driving field cancerization is a means to study human stem cell biology. Finally, we discuss how appropriate recognition of the role of field cancerization in tumorigenesis could impact patient care.
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Affiliation(s)
- Trevor A Graham
- Histopathology Laboratory, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London, WC2A 3LY, UK.
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17
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Abstract
Colorectal cancer (CRC) is a leading cause of cancer deaths worldwide. It results from an accumulation of genetic and epigenetic changes in colon epithelial cells, which transforms them into adenocarcinomas. Over the past decade, major advances have been made in understanding cancer epigenetics, particularly regarding aberrant DNA methylation. Assessment of the colon cancer epigenome has revealed that virtually all CRCs have aberrantly methylated genes and that the average CRC methylome has hundreds to thousands of abnormally methylated genes. As with gene mutations in the cancer genome, a subset of these methylated genes, called driver genes, is presumed to have a functional role in CRC. The assessment of methylated genes in CRCs has also revealed a unique molecular subgroup of CRCs called CpG island methylator phenotype (CIMP) cancers; these tumors have a particularly high frequency of methylated genes. These advances in our understanding of aberrant methylation in CRC have led to epigenetic alterations being developed as clinical biomarkers for diagnostic, prognostic and therapeutic applications. Progress in this field suggests that these epigenetic alterations will be commonly used in the near future to direct the prevention and treatment of CRC.
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Affiliation(s)
- Victoria Valinluck Lao
- Department of Surgery, University of Washington, Seattle, WA,Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA
| | - William M. Grady
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA,Department of Medicine, University of Washington Medical School, Seattle, WA
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18
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Aberrant methylation of hMLH1 and p16INK4a in Tunisian patients with sporadic colorectal adenocarcinoma. Biosci Rep 2011; 31:257-64. [DOI: 10.1042/bsr20100023] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
The methylation of CpG islands in the promoters is associated with loss of protein via repression of gene transcription. Several studies have demonstrated that tumour suppressor and DNA repair genes are often aberrantly hypermethylated in colorectal cancer. The present study was conducted to examine whether the methylation profile of p16INK4a and hMLH1 (human mutL homologue 1) promoters was associated with clinical features and patients’ survival in CRC (colorectal carcinoma). Aberrant methylation of p16INK4a and hMLH1 promoters was found in 47.2 and 53.4% of tumours respectively. For adjacent non-tumoral mucosa, p16INK4a was fully unmethylated in 30% of the cases, whereas hMLH1 was predominantly unmethylated (76%). Methylation of p16INK4a correlated with gender and tumour size (P=0.005 and 0.035 respectively), whereas those of hMLH1 significantly correlated with overall survival (P log rank = 0.007). Concomitant methylation of p16INK4a and hMLH1 was associated with TNM (tumour, lymph node and metastases) stage and tumour size (P=0.024 and 0.021 respectively). Our data show that loss of hMLH1 expression through aberrant methylation could be used as a marker of poor prognosis in CRC.
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19
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Migliore L, Migheli F, Spisni R, Coppedè F. Genetics, cytogenetics, and epigenetics of colorectal cancer. J Biomed Biotechnol 2011; 2011:792362. [PMID: 21490705 PMCID: PMC3070260 DOI: 10.1155/2011/792362] [Citation(s) in RCA: 172] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2010] [Accepted: 12/14/2010] [Indexed: 12/17/2022] Open
Abstract
Most of the colorectal cancer (CRC) cases are sporadic, only 25% of the patients have a family history of the disease, and major genes causing syndromes predisposing to CRC only account for 5-6% of the total cases. The following subtypes can be recognized: MIN (microsatellite instability), CIN (chromosomal instability), and CIMP (CpG island methylator phenotype). CIN occurs in 80-85% of CRC. Chromosomal instability proceeds through two major mechanisms, missegregation that results in aneuploidy through the gain or loss of whole chromosomes, and unbalanced structural rearrangements that lead to the loss and/or gain of chromosomal regions. The loss of heterozygosity that occur in the first phases of the CRC cancerogenesis (in particular for the genes on 18q) as well as the alteration of methylation pattern of multiple key genes can drive the development of colorectal cancer by facilitating the acquisition of multiple tumor-associated mutations and the instability phenotype.
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Affiliation(s)
- Lucia Migliore
- Department of Human and Environmental Sciences, University of Pisa, Street S. Giuseppe 22, 56126 Pisa, Italy.
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20
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Tessem MB, Selnæs KM, Sjursen W, Tranø G, Giskeødegård GF, Bathen TF, Gribbestad IS, Hofsli E. Discrimination of Patients with Microsatellite Instability Colon Cancer using 1H HR MAS MR Spectroscopy and Chemometric Analysis. J Proteome Res 2010; 9:3664-70. [DOI: 10.1021/pr100176g] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Affiliation(s)
- May-Britt Tessem
- Department of Circulation and Medical Imaging, Norwegian University of Science and Technology (NTNU), Trondheim, Norway, Department of Laboratory Medicine Children’s and Women’s Health, NTNU, Trondheim, Norway, Department of Pathology and Medical Genetics, St. Olavs University Hospital, Trondheim, Norway, Department of Surgery, Levanger Hospital, Sykehuset Innherred, Levanger, Norway, and Department of Oncology, St. Olavs University Hospital, Trondheim, Norway
| | - Kirsten M. Selnæs
- Department of Circulation and Medical Imaging, Norwegian University of Science and Technology (NTNU), Trondheim, Norway, Department of Laboratory Medicine Children’s and Women’s Health, NTNU, Trondheim, Norway, Department of Pathology and Medical Genetics, St. Olavs University Hospital, Trondheim, Norway, Department of Surgery, Levanger Hospital, Sykehuset Innherred, Levanger, Norway, and Department of Oncology, St. Olavs University Hospital, Trondheim, Norway
| | - Wenche Sjursen
- Department of Circulation and Medical Imaging, Norwegian University of Science and Technology (NTNU), Trondheim, Norway, Department of Laboratory Medicine Children’s and Women’s Health, NTNU, Trondheim, Norway, Department of Pathology and Medical Genetics, St. Olavs University Hospital, Trondheim, Norway, Department of Surgery, Levanger Hospital, Sykehuset Innherred, Levanger, Norway, and Department of Oncology, St. Olavs University Hospital, Trondheim, Norway
| | - Gerd Tranø
- Department of Circulation and Medical Imaging, Norwegian University of Science and Technology (NTNU), Trondheim, Norway, Department of Laboratory Medicine Children’s and Women’s Health, NTNU, Trondheim, Norway, Department of Pathology and Medical Genetics, St. Olavs University Hospital, Trondheim, Norway, Department of Surgery, Levanger Hospital, Sykehuset Innherred, Levanger, Norway, and Department of Oncology, St. Olavs University Hospital, Trondheim, Norway
| | - Guro F. Giskeødegård
- Department of Circulation and Medical Imaging, Norwegian University of Science and Technology (NTNU), Trondheim, Norway, Department of Laboratory Medicine Children’s and Women’s Health, NTNU, Trondheim, Norway, Department of Pathology and Medical Genetics, St. Olavs University Hospital, Trondheim, Norway, Department of Surgery, Levanger Hospital, Sykehuset Innherred, Levanger, Norway, and Department of Oncology, St. Olavs University Hospital, Trondheim, Norway
| | - Tone F. Bathen
- Department of Circulation and Medical Imaging, Norwegian University of Science and Technology (NTNU), Trondheim, Norway, Department of Laboratory Medicine Children’s and Women’s Health, NTNU, Trondheim, Norway, Department of Pathology and Medical Genetics, St. Olavs University Hospital, Trondheim, Norway, Department of Surgery, Levanger Hospital, Sykehuset Innherred, Levanger, Norway, and Department of Oncology, St. Olavs University Hospital, Trondheim, Norway
| | - Ingrid S. Gribbestad
- Department of Circulation and Medical Imaging, Norwegian University of Science and Technology (NTNU), Trondheim, Norway, Department of Laboratory Medicine Children’s and Women’s Health, NTNU, Trondheim, Norway, Department of Pathology and Medical Genetics, St. Olavs University Hospital, Trondheim, Norway, Department of Surgery, Levanger Hospital, Sykehuset Innherred, Levanger, Norway, and Department of Oncology, St. Olavs University Hospital, Trondheim, Norway
| | - Eva Hofsli
- Department of Circulation and Medical Imaging, Norwegian University of Science and Technology (NTNU), Trondheim, Norway, Department of Laboratory Medicine Children’s and Women’s Health, NTNU, Trondheim, Norway, Department of Pathology and Medical Genetics, St. Olavs University Hospital, Trondheim, Norway, Department of Surgery, Levanger Hospital, Sykehuset Innherred, Levanger, Norway, and Department of Oncology, St. Olavs University Hospital, Trondheim, Norway
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21
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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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22
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Gallardo E, Navarro A, Viñolas N, Marrades RM, Diaz T, Gel B, Quera A, Bandres E, Garcia-Foncillas J, Ramirez J, Monzo M. miR-34a as a prognostic marker of relapse in surgically resected non-small-cell lung cancer. Carcinogenesis 2009; 30:1903-9. [PMID: 19736307 DOI: 10.1093/carcin/bgp219] [Citation(s) in RCA: 271] [Impact Index Per Article: 16.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
MicroRNAs (miRNAs) have been identified as promising prognostic markers in non-small-cell lung cancer (NSCLC) since they play an important role in oncogenesis. The miR-34 family is composed of three miRNAs (miR-34a, miR-34b and miR-34c) that are part of the p53 network and whose expression is directly induced by p53 in response to DNA damage or oncogenic stress. We have analyzed the impact of miR-34 expression on relapse and overall survival in surgically resected NSCLC patients. For this purpose, we used stem-loop reverse transcription-polymerase chain reaction to analyze the expression of the miR-34 family in paired tumor and normal tissue from 70 surgically resected NSCLC patients who received no postsurgical treatment until relapse. In addition, in patients with sufficient tumor tissue, we assessed p53 mutations and the methylation status of the MIRN34A gene promoter region and correlated these findings with miR-34a expression. Molecular findings were correlated with relapse and overall survival. The miR-34 family was downregulated in tumor compared with normal tissue, and low levels of miR-34a expression were correlated with a high probability of relapse (P = 0.04). A relation was also found between MIRN34A methylation and miR-34a expression (P = 0.008). Patients with both p53 mutations and low miR-34a levels had the highest probability of relapse (P = 0.001). In the multivariate analysis, miR-34a expression emerged as an independent prognostic marker for relapse. In summary, we have identified miR-34a as a novel prognostic marker in NSCLC patients, providing a potential mechanism for estimating a patient's risk of disease recurrence and a useful tool to help guide treatment decisions.
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Affiliation(s)
- Elena Gallardo
- Department of Medical Oncology, Hospital Clinic, Institut d'Investigacions Biomèdiques, Agust Pi i Sunyer, 08036 Barcelona, Spain
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