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Sarangi J, Das P, Ahmad A, Sulaiman M, Ghosh S, Gupta B, Panwar R, Pal S, Yadav R, Ahuja V, Sen S, Upadhyay AD, Dash NR, Sharma A, Gupta SD. Methylation study of tumor suppressor genes in human aberrant crypt foci, colorectal carcinomas, and normal colon. J Cancer Res Ther 2024; 20:268-274. [PMID: 38554332 DOI: 10.4103/jcrt.jcrt_1573_22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Accepted: 09/22/2022] [Indexed: 04/01/2024]
Abstract
BACKGROUND Aberrant crypt foci (ACF) are the earliest preneoplastic lesions in human colon, identifiable on chromoendoscopic screening. Our objective was to evaluate the %methylation of APC, CDKN2A, MLH1, RASSF1, MGMT, and WIF1 tumor suppressor genes (TSG) in ACF, corresponding colorectal carcinomas (CRC), and normal colonic mucosal controls. METHODS In this study, macroscopically normal-appearing mucosal flaps were sampled 5-10 cm away from the tumor mass from 302 fresh colectomy specimens to identify ACF-like lesions. Thirty-five cases with multiple ACFs were selected (n 35) as the main study group, with corresponding sections from CRC (n 35) as disease controls, and mucosal tissue blocks from 20 colectomy specimens (normal controls), operated for non-neoplastic pathologies. Genomic DNA was extracted, and methylation-specific polymerase chain reaction (PCR) was performed on a customized methylation array model. %Methylation data were compared among the groups and with clinicopathological parameters. Selected target mRNA and protein expression studies were performed. RESULTS %Methylation of TSGs in ACF was intermediate between normal colon and CRC, although a statistically significant difference was observed only for the WIF1 gene (P < 0.01). Also, there was increased nuclear β-catenin expression and upregulation of CD44-positive cancer-stem cells in ACF and CRCs than in controls. Right-sided ACFs and dysplastic ACFs had a higher %methylation of CDKN2A (P < 0.01), whereas hyperplastic ACFs had a higher %methylation of RASSF1 (P 0.04). The topographic characteristics of ACFs did not correlate with TSG %methylation. CONCLUSIONS Early epigenetic methylation of WIF1 gene is one of the mechanisms for ACF development in human colon.
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Affiliation(s)
- Jayati Sarangi
- Department of Pathology, All India Institute of Medical Sciences, New Delhi, India
| | - Prasenjit Das
- Department of Pathology, All India Institute of Medical Sciences, New Delhi, India
| | - Aijaz Ahmad
- Department of Pathology, All India Institute of Medical Sciences, New Delhi, India
| | - Mohamed Sulaiman
- Department of Pathology, All India Institute of Medical Sciences, New Delhi, India
| | - Shouriyo Ghosh
- Department of Pathology, All India Institute of Medical Sciences, New Delhi, India
| | - Brijnandan Gupta
- Department of Pathology, All India Institute of Medical Sciences, New Delhi, India
| | - Rajesh Panwar
- Department of Gastrointestinal Surgery, All India Institute of Medical Sciences, New Delhi, India
| | - Sujoy Pal
- Department of Gastrointestinal Surgery, All India Institute of Medical Sciences, New Delhi, India
| | - Rajni Yadav
- Department of Pathology, All India Institute of Medical Sciences, New Delhi, India
| | - Vineet Ahuja
- Department of Gastroenterology, All India Institute of Medical Sciences, New Delhi, India
| | - Sudip Sen
- Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, India
| | - Asish D Upadhyay
- Department of Biostatistics and, All India Institute of Medical Sciences, New Delhi, India
| | - Nihar R Dash
- Department of Gastrointestinal Surgery, All India Institute of Medical Sciences, New Delhi, India
| | - Atul Sharma
- Department of Medical Oncology, All India Institute of Medical Sciences, New Delhi, India
| | - Siddhartha D Gupta
- Department of Pathology, All India Institute of Medical Sciences, New Delhi, India
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Bai F, Du Q, Zou Q, Xu L, Dong W, Lv X, Han X, Zhou H, Zhang C, Lu T. The association of blood ctDNA levels to mutations of marker genes in colorectal cancer. Cancer Rep (Hoboken) 2023; 6:e1782. [PMID: 36746394 PMCID: PMC10075297 DOI: 10.1002/cnr2.1782] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Revised: 12/06/2022] [Accepted: 01/06/2023] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Colorectal cancer (CRC) is a deadly and commonly diagnosed cancer. Cell-free circulating tumor DNAs (ctDNA) have been used in the diagnosis and treatment of CRC, but there are open questions about the relationship between ctDNAs and CRC. Although mutations of genes detected by ctDNA in CRC have been studied, the quantitative relationship between ctDNA mutations and ctDNA concentration has not been addressed. AIMS We hypothesized that there was an association between mutations of genes identified in ctDNAs and ctDNA concentration. His study examined this association in a population of CRC patients. METHODS In 85 CRC patients, we sampled 282 mutations in 36 genes and conducted an association study based on a Random forest model between mutations and ctDNA concentrations in all patients. RESULTS This association study showed that mutations on five genes, ALK, PMS2, KDR, MAP2K1, and MSH2, were associated with the ctDNA concentrations in CRC patients' blood samples. Because ctDNA mutations correlate with ctDNA level, we can infer the tumor burden or tumor size from ctDNA mutations, as well as the survival time for prognosis. CONCLUSION Our findings shed light on the associations between mutations of genes identified in ctDNAs and ctDNA concentration in the blood of CRC patients. This discovery provides information regarding the tumor burden or tumor size based on ctDNA mutations.
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Affiliation(s)
- Fei Bai
- Hunan Cancer Hospital and The Affiliated cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China
| | - Qian Du
- School of Biological Sciences, University of Nebraska, Lincoln, Nebraska, USA
| | | | - Lin Xu
- Sichuan Cancer Hospital and Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, China
| | - Wei Dong
- Department of oncology, Chengdu Ping-An Hospital, Chengdu, Sichuan, China
| | - Xinlin Lv
- Chengdu Women and Children's Center Hospital, Chengdu, Sichuan, China
| | - Xiaorong Han
- Chengdu Women and Children's Center Hospital, Chengdu, Sichuan, China
| | - Huijun Zhou
- Hunan Cancer Hospital and The Affiliated cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China
| | - Chi Zhang
- School of Biological Sciences, University of Nebraska, Lincoln, Nebraska, USA
| | - Tao Lu
- Chengdu Medical College, Chengdu, Sichuan, China
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Oliver JA, Gómez-Millán J, Medina JA, Cabeza L, Perazzoli G, Jimenez-Luna C, Doello K, Ortiz R. O6-methylguanine-DNA Methyltransferase Promoter Methylation in Patients with Rectal Adenocarcinoma After Chemoradiotherapy Treatment: Clinical Implications. Balkan Med J 2019; 36:283-286. [PMID: 31199091 PMCID: PMC6711248 DOI: 10.4274/balkanmedj.galenos.2019.2018.12.93] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022] Open
Abstract
Aims: To analyze the clinical relevance of O6-methylguanine-DNA methyltransferase in rectal adenocarcinoma treated with chemoradiotherapy followed by surgery. Methods: Tissue samples from 29 rectal adenocarcinoma patients were obtained after chemoradiotherapy. O6-methylguanine-DNA methyltransferase promoter methylation status was established by methylation-specific polymerase chain reaction. O6-methylguanine-DNA methyltransferase protein levels were determined by immunohistochemistry. Clinicopathologic variables, including treatment regression grade, recurrence, lymph node invasion, and stage and differentiation grade of the tumor, were determined. Results: The O6-methylguanine-DNA methyltransferase gene promoter was methylated in 81.5% of samples. Most patients (88.9%) showed low O6-methylguanine-DNA methyltransferase protein expression. O6-methylguanine-DNA methyltransferase methylation status was not correlated with any of the clinicopathological variables determined in rectal adenocarcinomas selected for chemoradiotherapy. Conclusion: O6-methylguanine-DNA methyltransferase methylation status is not correlated with clinicopathologic variables examined in rectal adenocarcinoma selected for chemoradiotherapy, although its role as a biomarker awaits further investigation.
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Affiliation(s)
- Jaime A. Oliver
- Center for Cancer Research and Cell Biology, Queen’s University Belfast, Belfast, UK,Institute of Biopathology and Regenerative Medicine, Center of Biomedical Research, University of Granada, Granada, Spain
| | - Jaime Gómez-Millán
- Department of Radiation Oncology, Universitary Hospital Virgen de la Victoria, Málaga, Spain
| | - Jose A. Medina
- Department of Radiation Oncology, Universitary Hospital Virgen de la Victoria, Málaga, Spain
| | - Laura Cabeza
- Institute of Biopathology and Regenerative Medicine, Center of Biomedical Research, University of Granada, Granada, Spain,Department of Anatomy and Embryology, University of Granada, Granada, Spain,Biosanitary Institute of Granada (ibs. GRANADA), SAS-Universidad de Granada, Granada, Spain
| | - Gloria Perazzoli
- Institute of Biopathology and Regenerative Medicine, Center of Biomedical Research, University of Granada, Granada, Spain,Biosanitary Institute of Granada (ibs. GRANADA), SAS-Universidad de Granada, Granada, Spain
| | - Cristina Jimenez-Luna
- Institute of Biopathology and Regenerative Medicine, Center of Biomedical Research, University of Granada, Granada, Spain
| | - Kevin Doello
- Medical Oncology Service, Universitary Hospital Virgen de las Nieves, Granada, Spain
| | - Raúl Ortiz
- Institute of Biopathology and Regenerative Medicine, Center of Biomedical Research, University of Granada, Granada, Spain,Department of Anatomy and Embryology, University of Granada, Granada, Spain,Biosanitary Institute of Granada (ibs. GRANADA), SAS-Universidad de Granada, Granada, Spain
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Kojima K, Nakamura T, Ohbu M, Katoh H, Ooizumi Y, Igarashi K, Ishii S, Tanaka T, Yokoi K, Nishizawa N, Yokota K, Kosaka Y, Sato T, Watanabe M, Yamashita K. Cysteine dioxygenase type 1 (CDO1) gene promoter methylation during the adenoma-carcinoma sequence in colorectal cancer. PLoS One 2018; 13:e0194785. [PMID: 29746493 PMCID: PMC5944981 DOI: 10.1371/journal.pone.0194785] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2017] [Accepted: 03/10/2018] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Progression of colorectal cancer (CRC) has been explained by genomic abnormalities along with the adenoma-carcinoma sequence theory (ACS). The aim of our study is to elucidate whether the promoter DNA methylation of the cancer-specific methylation gene, cysteine dioxygenase 1 (CDO1), contributes to the carcinogenic process in CRC. METHODS The study group comprised 107 patients with CRC who underwent surgical resection and 90 adenomas treated with endoscopic resection in the Kitasato University Hospital in 2000. We analyzed the extent of methylation in each tissue using quantitative TaqMan methylation-specific PCR for CDO1. RESULTS The methylation level increased along with the ACS process (p < 0.0001), and statistically significant differences were found between normal-appearing mucosa (NAM) and low-grade adenoma (p < 0.0001), and between low-grade adenoma and high-grade adenoma (p = 0.01), but not between high-grade adenoma and cancer with no liver metastasis. Furthermore, primary CRC cancers with liver metastasis harbored significantly higher methylation of CDO1 than those without liver metastasis (p = 0.02). As a result, the area under the curve by CDO1 promoter methylation was 0.96, 0.80, and 0.67 to discriminate cancer from NAM, low-grade adenoma from NAM, and low-grade adenoma from high-grade adenoma, respectively. CONCLUSIONS CDO1 methylation accumulates during the ACS process, and consistently contributes to CRC progression.
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Affiliation(s)
- Keita Kojima
- Department of Surgery, Kitasato University School of Medicine, Minami-ku, Sagamihara, Kanagawa, Japan
| | - Takatoshi Nakamura
- Department of Surgery, Kitasato University School of Medicine, Minami-ku, Sagamihara, Kanagawa, Japan
| | - Makoto Ohbu
- Department of Pathology, Kitasato University School of Allied Health Sciences, Minami-ku, Sagamihara, Kanagawa, Japan
| | - Hiroshi Katoh
- Department of Surgery, Kitasato University School of Medicine, Minami-ku, Sagamihara, Kanagawa, Japan
| | - Yosuke Ooizumi
- Department of Surgery, Kitasato University School of Medicine, Minami-ku, Sagamihara, Kanagawa, Japan
| | - Kazuharu Igarashi
- Department of Surgery, Kitasato University School of Medicine, Minami-ku, Sagamihara, Kanagawa, Japan
| | - Satoru Ishii
- Department of Surgery, Kitasato University School of Medicine, Minami-ku, Sagamihara, Kanagawa, Japan
| | - Toshimichi Tanaka
- Department of Surgery, Kitasato University School of Medicine, Minami-ku, Sagamihara, Kanagawa, Japan
| | - Keigo Yokoi
- Department of Surgery, Kitasato University School of Medicine, Minami-ku, Sagamihara, Kanagawa, Japan
| | - Nobuyuki Nishizawa
- Department of Surgery, Kitasato University School of Medicine, Minami-ku, Sagamihara, Kanagawa, Japan
| | - Kazuko Yokota
- Department of Surgery, Kitasato University School of Medicine, Minami-ku, Sagamihara, Kanagawa, Japan
| | - Yoshimasa Kosaka
- Department of Surgery, Kitasato University School of Medicine, Minami-ku, Sagamihara, Kanagawa, Japan
| | - Takeo Sato
- Department of Surgery, Kitasato University School of Medicine, Minami-ku, Sagamihara, Kanagawa, Japan
| | - Masahiko Watanabe
- Department of Surgery, Kitasato University School of Medicine, Minami-ku, Sagamihara, Kanagawa, Japan
- * E-mail:
| | - Keishi Yamashita
- Department of Surgery, Kitasato University School of Medicine, Minami-ku, Sagamihara, Kanagawa, Japan
- Division of Advanced Surgical Oncology, Department of Research and Development Center for New Medical Frontiers, Minami-ku, Sagamihara, Kanagawa, Japan
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Baretti M, Azad NS. The role of epigenetic therapies in colorectal cancer. Curr Probl Cancer 2018; 42:530-547. [PMID: 29625794 DOI: 10.1016/j.currproblcancer.2018.03.001] [Citation(s) in RCA: 47] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2017] [Revised: 02/21/2018] [Accepted: 03/08/2018] [Indexed: 12/14/2022]
Abstract
Although developments in the diagnosis and therapy of colorectal cancer (CRC) have been made in the last decade, much work remains to be done as it remains the second leading cause of cancer death. It is now well established that epigenetic events, together with genetic alterations, are key events in initiation and progression of CRC. Epigenetics refers to heritable alterations in gene expression that do not involve changes in the DNA sequence. These alterations include DNA methylation, histone alterations, chromatin remodelers, and noncoding RNAs. In CRC, aberrations in epigenome may also involve in the development of drug resistance to conventional drugs such as 5-fluorouracil, oxaliplatin, and irinotecan. Thus, it has been suggested that combined therapies with epigenetic agents may reverse drug resistance. In this regard, DNA methyltransferase inhibitors and histone deacetylase inhibitors have been extensively investigated in CRC. The aim of this review is to provide a brief overview of the preclinical data that represent a proof of principle for the employment of epigenetic agents in CRC with a focus on the advantages of combinatorial therapy over single-drug treatment. We will also critically discuss the results and limitations of initial clinical experiences of epigenetic-based therapy in CRC and summarize ongoing clinical trials. Nevertheless, since recent translational research suggest that epigenetic modulators play a key role in augmenting immunogenicity of the tumor microenvironment and in restoring immune recognition, we will also highlight the recent developments of combinations strategies of immunotherapies and epigenetic therapies in CRC, summarizing preclinical, and clinical data to signify this evolving and promising field for CRC treatment.
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Affiliation(s)
- Marina Baretti
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University.
| | - Nilofer Saba Azad
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University
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Guo H, Zeng W, Feng L, Yu X, Li P, Zhang K, Zhou Z, Cheng S. Integrated transcriptomic analysis of distance-related field cancerization in rectal cancer patients. Oncotarget 2017; 8:61107-61117. [PMID: 28977850 PMCID: PMC5617410 DOI: 10.18632/oncotarget.17864] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2017] [Accepted: 04/07/2017] [Indexed: 12/18/2022] Open
Abstract
Field cancerization (FC) occurs in various epithelial carcinomas, including colorectal cancer, which indicates that the molecular events in carcinogenesis might occur in normal tissues extending from tumors. However, the transcriptomic characteristics of FC in colorectal cancer (CRC) remain largely unexplored. To investigate the changes in gene expression associated with proximity to the tumor, we analyzed the global gene expression profiles of cancer tissues and histologically normal tissues taken at various distances from the tumor (1 cm, 5 cm and the proximal end of the resected sample) from 32 rectal cancer patients. Significantly differentially expressed genes related to the distance from the tumor were screened by linear mixed effects analysis using the lme4 package in R. The distance-related differentially expressed genes that were gradually up-regulated (n=302) or gradually down-regulated (n=568) from normal tissues to the tumor were used to construct protein-protein interaction (PPI) networks. Three subnetworks among the gradually up-regulated genes and four subnetworks among the gradually down-regulated genes were identified using the MCODE plugin in the Cytoscape software program. The most significantly enriched Gene Ontology (GO) biological process terms were "ribosome biogenesis", "mRNA splicing via spliceosome", and "positive regulation of leukocyte migration" for the gradually up-regulated subnetworks and "cellular calcium ion homeostasis", "cell separation after cytokinesis", "cell junction assembly", and "fatty acid metabolic process" for the gradually down-regulated subnetworks. Combined with the previously constructed multistep carcinogenesis model used for the analysis, 50.59% of the genes in the subnetworks (43/85) displayed identical changes in expression from normal colon tissues to adenoma and colon cancer. We focused on the 7 genes associated with fatty acid metabolic processes in the distance-related down-regulated subnetwork. Survival analysis of patients in the CRC dataset from The Cancer Genome Atlas (TCGA) revealed that higher expression of these 7 genes, especially CPT2, ACAA2 and ACADM, was associated with better prognosis (p = 0.034, p = 0.00058, p = 0.039, p = 0.04). Cox proportional hazards regression analysis revealed that CPT2 was an independent prognostic factor (p = 0.004131). Our results demonstrate that field cancerization occurs in CRC and affects gene expression in normal tissues extending from the tumor, which may provide new insights into CRC oncogenesis and patient progression.
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Affiliation(s)
- Honglin Guo
- State Key Laboratory of Molecular Oncology, Department of Etiology and Carcinogenesis, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Weigen Zeng
- Department of General Surgery, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China
| | - Lin Feng
- State Key Laboratory of Molecular Oncology, Department of Etiology and Carcinogenesis, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Xuexin Yu
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150081, China
| | - Ping Li
- State Key Laboratory of Molecular Oncology, Department of Etiology and Carcinogenesis, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Kaitai Zhang
- State Key Laboratory of Molecular Oncology, Department of Etiology and Carcinogenesis, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Zhixiang Zhou
- Department of Colorectal Surgery, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Shujun Cheng
- State Key Laboratory of Molecular Oncology, Department of Etiology and Carcinogenesis, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
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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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Chatterjee N, Walker GC. Mechanisms of DNA damage, repair, and mutagenesis. ENVIRONMENTAL AND MOLECULAR MUTAGENESIS 2017; 58:235-263. [PMID: 28485537 PMCID: PMC5474181 DOI: 10.1002/em.22087] [Citation(s) in RCA: 1148] [Impact Index Per Article: 143.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/15/2016] [Accepted: 03/16/2017] [Indexed: 05/08/2023]
Abstract
Living organisms are continuously exposed to a myriad of DNA damaging agents that can impact health and modulate disease-states. However, robust DNA repair and damage-bypass mechanisms faithfully protect the DNA by either removing or tolerating the damage to ensure an overall survival. Deviations in this fine-tuning are known to destabilize cellular metabolic homeostasis, as exemplified in diverse cancers where disruption or deregulation of DNA repair pathways results in genome instability. Because routinely used biological, physical and chemical agents impact human health, testing their genotoxicity and regulating their use have become important. In this introductory review, we will delineate mechanisms of DNA damage and the counteracting repair/tolerance pathways to provide insights into the molecular basis of genotoxicity in cells that lays the foundation for subsequent articles in this issue. Environ. Mol. Mutagen. 58:235-263, 2017. © 2017 Wiley Periodicals, Inc.
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Mori H, Kobara H, Nishiyama N, Fujihara S, Kobayashi N, Ayaki M, Masaki T. Surgical margin-negative endoscopic mucosal resection with simple three-clipping technique: a randomized prospective study (with video). Surg Endosc 2016; 30:4827-4834. [PMID: 26902618 DOI: 10.1007/s00464-016-4816-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2015] [Accepted: 02/03/2016] [Indexed: 10/22/2022]
Abstract
BACKGROUND Although endoscopic mucosal resection is an established colorectal polyp treatment, local recurrence occurs in 13 % of cases due to inadequate snaring. We evaluated whether pre-clipping to the muscularis propria resulted in resected specimens with negative surgical margins without thermal denaturation. METHODS Of 245 polyps from 114 patients with colorectal polyps under 20 mm, we included 188 polyps from 81 patients. We randomly allocated polyps to the conventional injection group (CG) (97 polyps) or the pre-clipping injection group (PG) (91 polyps). The PG received three-point pre-clipping to ensure ample gripping to the muscle layer on the oral and both sides of the tumor with 4 mL local injection. Endoscopic ultrasonography was performed to measure the resulting bulge. Outcomes included the number of instances of thermal denaturation of the horizontal/vertical margin (HMX/VMX) or positive horizontal/vertical margins (HM+/VM+), the shortest distance from tumor margins to resected edges, and the maximum bulge distances from tumor surface to the muscularis propria. RESULTS The numbers of HMX and HM+ in the CG and PG were 27 and 6, and 9 and 2 (P = 0.001), and VMX and VM+ were 8 and 5, and 0 and 0 (P = 0.057). The shortest distance from tumor margin to resected edge [median (range), mm] in polyps in the CG and PG was 0.6 (0-2.7) and 4.7 (2.1-8.9) (P = 0.018). The maximum bulge distances were 4.6 (3.0-8.0) and 11.0 (6.8-17.0) (P = 0.005). CONCLUSIONS Pre-clipping enabled surgical margin-negative resection without thermal denaturation.
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Affiliation(s)
- Hirohito Mori
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa, 761-0793, Japan. .,Department of Gastroenterological Surgery, Ehime Rosai Hospital, Niihama, Ehime, Japan.
| | - Hideki Kobara
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa, 761-0793, Japan
| | - Noriko Nishiyama
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa, 761-0793, Japan
| | - Shintaro Fujihara
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa, 761-0793, Japan
| | - Nobuya Kobayashi
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa, 761-0793, Japan
| | - Maki Ayaki
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa, 761-0793, Japan
| | - Tsutomu Masaki
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa, 761-0793, Japan
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Sensitivity Analysis of the MGMT-STP27 Model and Impact of Genetic and Epigenetic Context to Predict the MGMT Methylation Status in Gliomas and Other Tumors. J Mol Diagn 2016; 18:350-361. [PMID: 26927331 DOI: 10.1016/j.jmoldx.2015.11.009] [Citation(s) in RCA: 81] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2015] [Revised: 11/12/2015] [Accepted: 11/24/2015] [Indexed: 11/24/2022] Open
Abstract
The methylation status of the O(6)-methylguanine-DNA methyltransferase (MGMT) gene is an important predictive biomarker for benefit from alkylating agent therapy in glioblastoma. Our model MGMT-STP27 allows prediction of the methylation status of the MGMT promoter using data from the Illumina's Human Methylation BeadChips (HM-27K and HM-450K) that is publically available for many cancer data sets. Here, we investigate the impact of the context of genetic and epigenetic alterations and tumor type on the classification and report on technical aspects, such as robustness of cutoff definition and preprocessing of the data. The association between gene copy number variation, predicted MGMT methylation, and MGMT expression revealed a gene dosage effect on MGMT expression in lower grade glioma (World Health Organization grade II/III) that in contrast to glioblastoma usually carry two copies of chromosome 10 on which MGMT resides (10q26.3). This implies some MGMT expression, potentially conferring residual repair function blunting the therapeutic effect of alkylating agents. A sensitivity analyses corroborated the performance of the original cutoff for various optimization criteria and for most data preprocessing methods. Finally, we propose an R package mgmtstp27 that allows prediction of the methylation status of the MGMT promoter and calculation of appropriate confidence and/or prediction intervals. Overall, MGMT-STP27 is a robust model for MGMT classification that is independent of tumor type and is adapted for single sample prediction.
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Li Y, Melnikov AA, Levenson V, Guerra E, Simeone P, Alberti S, Deng Y. A seven-gene CpG-island methylation panel predicts breast cancer progression. BMC Cancer 2015; 15:417. [PMID: 25986046 PMCID: PMC4438505 DOI: 10.1186/s12885-015-1412-9] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2014] [Accepted: 05/01/2015] [Indexed: 12/31/2022] Open
Abstract
Background DNA methylation regulates gene expression, through the inhibition/activation of gene transcription of methylated/unmethylated genes. Hence, DNA methylation profiling can capture pivotal features of gene expression in cancer tissues from patients at the time of diagnosis. In this work, we analyzed a breast cancer case series, to identify DNA methylation determinants of metastatic versus non-metastatic tumors. Methods CpG-island methylation was evaluated on a 56-gene cancer-specific biomarker microarray in metastatic versus non-metastatic breast cancers in a multi-institutional case series of 123 breast cancer patients. Global statistical modeling and unsupervised hierarchical clustering were applied to identify a multi-gene binary classifier with high sensitivity and specificity. Network analysis was utilized to quantify the connectivity of the identified genes. Results Seven genes (BRCA1, DAPK1, MSH2, CDKN2A, PGR, PRKCDBP, RANKL) were found informative for prognosis of metastatic diffusion and were used to calculate classifier accuracy versus the entire data-set. Individual-gene performances showed sensitivities of 63–79 %, 53–84 % specificities, positive predictive values of 59–83 % and negative predictive values of 63–80 %. When modelled together, these seven genes reached a sensitivity of 93 %, 100 % specificity, a positive predictive value of 100 % and a negative predictive value of 93 %, with high statistical power. Unsupervised hierarchical clustering independently confirmed these findings, in close agreement with the accuracy measurements. Network analyses indicated tight interrelationship between the identified genes, suggesting this to be a functionally-coordinated module, linked to breast cancer progression. Conclusions Our findings identify CpG-island methylation profiles with deep impact on clinical outcome, paving the way for use as novel prognostic assays in clinical settings. Electronic supplementary material The online version of this article (doi:10.1186/s12885-015-1412-9) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Yan Li
- Rush University Medical Center, 653 W Congress Pkwy, Chicago, IL, 60612, USA.
| | | | - Victor Levenson
- US Biomarkers, Inc, 29 Buckingham Ln., Buffalo Grove, IL, 60089, USA. .,Currently at Center for Translational Research, Catholic Health Initiatives, Englewood, USA.
| | - Emanuela Guerra
- Unit of Cancer Pathology, CeSI, 'G. d'Annunzio' University Foundation, Via L. Polacchi 11, 66100, Chieti, Italy.
| | - Pasquale Simeone
- Unit of Cancer Pathology, CeSI, 'G. d'Annunzio' University Foundation, Via L. Polacchi 11, 66100, Chieti, Italy.
| | - Saverio Alberti
- Unit of Cancer Pathology, CeSI, 'G. d'Annunzio' University Foundation, Via L. Polacchi 11, 66100, Chieti, Italy. .,Department of Neuroscience, Imaging and Clinical Sciences, Unit of Physiology and Physiopathology, 'G. d'Annunzio' University, Via dei Vestini, 66100, Chieti, Italy.
| | - Youping Deng
- Rush University Medical Center, 653 W Congress Pkwy, Chicago, IL, 60612, USA.
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12
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Bernstein C, Bernstein H. Epigenetic reduction of DNA repair in progression to gastrointestinal cancer. World J Gastrointest Oncol 2015; 7:30-46. [PMID: 25987950 PMCID: PMC4434036 DOI: 10.4251/wjgo.v7.i5.30] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2014] [Revised: 03/18/2015] [Accepted: 04/20/2015] [Indexed: 02/05/2023] Open
Abstract
Deficiencies in DNA repair due to inherited germ-line mutations in DNA repair genes cause increased risk of gastrointestinal (GI) cancer. In sporadic GI cancers, mutations in DNA repair genes are relatively rare. However, epigenetic alterations that reduce expression of DNA repair genes are frequent in sporadic GI cancers. These epigenetic reductions are also found in field defects that give rise to cancers. Reduced DNA repair likely allows excessive DNA damages to accumulate in somatic cells. Then either inaccurate translesion synthesis past the un-repaired DNA damages or error-prone DNA repair can cause mutations. Erroneous DNA repair can also cause epigenetic alterations (i.e., epimutations, transmitted through multiple replication cycles). Some of these mutations and epimutations may cause progression to cancer. Thus, deficient or absent DNA repair is likely an important underlying cause of cancer. Whole genome sequencing of GI cancers show that between thousands to hundreds of thousands of mutations occur in these cancers. Epimutations that reduce DNA repair gene expression and occur early in progression to GI cancers are a likely source of this high genomic instability. Cancer cells deficient in DNA repair are more vulnerable than normal cells to inactivation by DNA damaging agents. Thus, some of the most clinically effective chemotherapeutic agents in cancer treatment are DNA damaging agents, and their effectiveness often depends on deficient DNA repair in cancer cells. Recently, at least 18 DNA repair proteins, each active in one of six DNA repair pathways, were found to be subject to epigenetic reduction of expression in GI cancers. Different DNA repair pathways repair different types of DNA damage. Evaluation of which DNA repair pathway(s) are deficient in particular types of GI cancer and/or particular patients may prove useful in guiding choice of therapeutic agents in cancer therapy.
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Michailidi C, Theocharis S, Tsourouflis G, Pletsa V, Kouraklis G, Patsouris E, Papavassiliou AG, Troungos C. Expression and promoter methylation status of hMLH1, MGMT, APC, and CDH1 genes in patients with colon adenocarcinoma. Exp Biol Med (Maywood) 2015; 240:1599-605. [PMID: 25908636 DOI: 10.1177/1535370215583800] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2014] [Accepted: 03/12/2015] [Indexed: 01/14/2023] Open
Abstract
Colorectal cancer (CRC) is the third most common cancer in men and the second in women worldwide. CRC development is the result of genetic and epigenetic alterations accumulation in the epithelial cells of colon mucosa. In the present study, DNA methylation, an epigenetic event, was evaluated in tumoral and matching normal epithelium in a cohort of 61 CRC patients. The results confirmed and expanded knowledge for the tumor suppressor genes hMLH1, MGMT, APC, and CDH1. Promoter methylation was observed for all the examined genes in different percentage. A total of 71% and 10% of the examined cases were found to be methylated in two or more and in all genes, respectively. mRNA and protein levels were also evaluated. Promoter methylation of hMLH1, MGMT, APC, and CDH1 genes was present at the early stages of tumor's formation and it could also be detected in the normal mucosa. Correlations of the methylated genes with patient's age and tumor's clinicopathological characteristics were also observed. Our findings suggest that DNA methylation is a useful marker for tumor progression monitoring and that promoter methylation in certain genes is associated with more advanced tumor stage, poor differentiation, and metastasis.
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Affiliation(s)
- Christina Michailidi
- Department of Biological Chemistry, University of Athens Medical School, Athens 11527, Greece
| | - Stamatios Theocharis
- First Department of Pathology, University of Athens Medical School, Athens 11527, Greece
| | - Gerasimos Tsourouflis
- Second Department of Propedeutic Surgery, University of Athens Medical School, Athens 11527, Greece
| | - Vasiliki Pletsa
- Institute of Biology, Medicinal Chemistry and Biotechnology, Division of Biological Research & Biotechnology, National Hellenic Research Foundation, Athens 11635, Greece
| | - Gregorios Kouraklis
- Second Department of Propedeutic Surgery, University of Athens Medical School, Athens 11527, Greece
| | - Efstratios Patsouris
- First Department of Pathology, University of Athens Medical School, Athens 11527, Greece
| | | | - Constantinos Troungos
- Department of Biological Chemistry, University of Athens Medical School, Athens 11527, Greece
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Zheng CG, Jin C, Ye LC, Chen NZ, Chen ZJ. Clinicopathological significance and potential drug target of O6-methylguanine-DNA methyltransferase in colorectal cancer: a meta-analysis. Tumour Biol 2015; 36:5839-48. [PMID: 25716203 DOI: 10.1007/s13277-015-3254-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2015] [Accepted: 02/10/2015] [Indexed: 12/18/2022] Open
Abstract
Emerging evidence indicates that O(6)-methylguanine-DNA methyltransferase (MGMT) is a candidate for tumor suppression in several types of human tumors including colorectal cancer (CRC). However, the correlation between MGMT hypermethylation and clinicopathological characteristics of CRC remains unclear. In this study, we conducted a systematic review and meta-analysis to quantitatively evaluate the effects of MGMT hypermethylation on the incidence of CRC and clinicopathological characteristics. A comprehensive literature search was done from Web of Science, the Cochrane Library Database, PubMed, EMBASE, CINAHL, and the Chinese Biomedical Database for related research publications written in English and Chinese. Methodological quality of the studies was also evaluated. Analyses of pooled data were performed with Review Manager 5.2. Odds ratio (OR) and hazard ratio (HR) were calculated and summarized, respectively. Final analysis from 28 eligible studies was performed. MGMT hypermethylation is found to be significantly higher in CRC than in normal colorectal mucosa, the pooled OR from 13 studies including 1085 CRC and 899 normal colorectal mucosa, OR = 6.04, 95 % confidence interval (CI) = 4.69-7.77, p < 0.00001. MGMT hypermethylation is also significantly higher in colorectal adenoma than in normal colorectal mucosa, but it is significantly less compared to that in CRC patients. Interestingly, MGMT hypermethylation is correlated with sex status and is significantly higher in female than in male. MGMT hypermethylation is also associated with high levels of microsatellite instability (MSI). The pooled HR for overall survival (OS) shows that MGMT hypermethylation is not associated with worse survival in CRC patients. The results of this meta-analysis suggest that MGMT hypermethylation is associated with an increased risk and high levels of MSI and may play an important role in CRC initiation. However, MGMT hypermethylation may play an important role in the early stage of CRC progression and development, as well as having limited value in prediction of prognosis in CRC patients. We also discussed that MGMT may serve as a potential drug target of CRC.
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Affiliation(s)
- Chen-Guo Zheng
- Department of Coloproctology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, People's Republic of China
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Prognostic value of MGMT methylation in colorectal cancer: a meta-analysis and literature review. Tumour Biol 2015; 36:1595-601. [PMID: 25596081 DOI: 10.1007/s13277-014-2752-9] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2014] [Accepted: 10/20/2014] [Indexed: 10/24/2022] Open
Abstract
The development of colorectal cancer (CRC) spans about 5-10 years, making early detection and prevention beneficial to the survival of CRC patients. To address inconsistencies in evidence regarding O(6)-methylguanine-DNA-methyltransferase (MGMT) methylation as a potential prognostic factor in CRC, we conducted a meta-analysis to evaluate MGMT methylation in CRC patients. Fourteen studies were included in the meta-analysis after screening 120 articles. The following items were collected from each study: author, published year, country, patient gender, MGMT methylation status, and patients' disease progression. Pooled hazard ratios and odd ratios with 95% confidence intervals (CIs) were calculated using fixed or random effect models depending on the heterogeneity between studies. The overall survival of CRC patients was found not to be significantly associated with MGMT methylation. Further subgroup analysis showed that the frequency of MGMT methylation was significantly higher in CRC than in normal tissues (p < 0.00001). MGMT promoter in CRC patients was more frequently methylated than in adenoma patients. In addition, MGMT methylation was significantly increased in adenoma than in normal tissues (p < 0.0001). In conclusion, MGMT methylation is central to the development of cancer that involves a stepwise carcinogenesis of normal adenoma carcinoma cascade. However, MGMT methylation is not associated with the prognosis of CRC.
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16
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Yan ZH, Cui LH, Wang XH, Li C, He X. Comparative study of mutations in SNP loci of K-RAS, hMLH1 and hMSH2 genes in neoplastic intestinal polyps and colorectal cancer. World J Gastroenterol 2014; 20:18338-18345. [PMID: 25561800 PMCID: PMC4277970 DOI: 10.3748/wjg.v20.i48.18338] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2014] [Revised: 07/12/2014] [Accepted: 08/28/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To clarify the molecular mechanism involved in pathogenesis of colorectal cancer as well as clinical significance of genetic analysis of histological samples.
METHODS: A total of 480 blood and tissue specimens were collected in our hospital from January 2011 to October 2012. In the observation group, there were 120 blood specimens and 120 intestinal tract tissue specimens collected from patients with neoplastic intestinal polyps. In the control group I there were 80 blood specimens and 80 intestinal tract tissue specimens collected from patients with colorectal cancer. In the control group II there were 40 blood specimens and 40 intestinal tract tissue specimens collected from healthy individuals. The gene segments were amplified using PCR and DNA gel electrophoresis along with DNA sequence analysis were employed for the detection of the following single nucleotide polymorphisms (SNPs): K-RAS codons 12 and 13; hMLH1 (human mutS homolog 1) gene missense mutation at Va1384Asp; hMSH2 (human mutS homolog 2) gene missense mutation at 2783C/A.
RESULTS: The mutation rate of the SNP at Va1384Asp locus of the hMLH1 gene from blood and tissue specimens in the observation group showed no statistical difference from those in the control group I. The mutation rates of SNPs in codons 12 and 13 of K-RAS and at 2783C/A locus of the hMSH2 gene were significantly lower in the observation group than in the control group I (χ2 = 15.476, 29.670, 10.811, 16.618, 33.538, 7.898, P < 0.05). The mutation rate of SNP at Va1384Asp locus of the hMLH1 gene was significantly higher in the observation group when compared to the control group II (χ2 = 10.486, 4.876, P < 0.05). The mutation rates of SNPs in codons 12 and 13 of K-RAS and at 2783C/A locus of the hMSH2 gene did not show any statistical difference from those in the control group II.
CONCLUSION: There may be important clinical significance and relevance between neoplastic intestinal polyps and colorectal cancer in terms of the mechanisms involved in the pathogenesis.
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Barrow TM, Michels KB. Epigenetic epidemiology of cancer. Biochem Biophys Res Commun 2014; 455:70-83. [PMID: 25124661 DOI: 10.1016/j.bbrc.2014.08.002] [Citation(s) in RCA: 63] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2014] [Revised: 07/15/2014] [Accepted: 08/01/2014] [Indexed: 02/06/2023]
Abstract
Epigenetic epidemiology includes the study of variation in epigenetic traits and the risk of disease in populations. Its application to the field of cancer has provided insight into how lifestyle and environmental factors influence the epigenome and how epigenetic events may be involved in carcinogenesis. Furthermore, it has the potential to bring benefit to patients through the identification of diagnostic markers that enable the early detection of disease and prognostic markers that can inform upon appropriate treatment strategies. However, there are a number of challenges associated with the conduct of such studies, and with the identification of biomarkers that can be applied to the clinical setting. In this review, we delineate the challenges faced in the design of epigenetic epidemiology studies in cancer, including the suitability of blood as a surrogate tissue and the capture of genome-wide DNA methylation. We describe how epigenetic epidemiology has brought insight into risk factors associated with lung, breast, colorectal and bladder cancer and review relevant research. We discuss recent findings on the identification of epigenetic diagnostic and prognostic biomarkers for these cancers.
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Affiliation(s)
- Timothy M Barrow
- Institute for Prevention and Tumor Epidemiology, Freiburg Medical Center, University of Freiburg, 79106, Germany; German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany.
| | - Karin B Michels
- Institute for Prevention and Tumor Epidemiology, Freiburg Medical Center, University of Freiburg, 79106, Germany; Obstetrics and Gynecology Epidemiology Center, Department of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Epidemiology, Harvard School of Public Health, Boston, MA 02115, USA.
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18
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Oliver JA, Ortiz R, Melguizo C, Álvarez PJ, Gómez-Millán J, Prados J. Prognostic impact of MGMT promoter methylation and MGMT and CD133 expression in colorectal adenocarcinoma. BMC Cancer 2014; 14:511. [PMID: 25015560 PMCID: PMC4227111 DOI: 10.1186/1471-2407-14-511] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2014] [Accepted: 07/07/2014] [Indexed: 01/21/2023] Open
Abstract
BACKGROUND New biomarkers are needed for the prognosis of advanced colorectal cancer, which remains incurable by conventional treatments. O6-methylguanine DNA methyltransferase (MGMT) methylation and protein expression have been related to colorectal cancer treatment failure and tumor progression. Moreover, the presence in these tumors of cancer stem cells, which are characterized by CD133 expression, has been associated with chemoresistance, radioresistance, metastasis, and local recurrence. The objective of this study was to determine the prognostic value of CD133 and MGMT and their possible interaction in colorectal cancer patients. METHODS MGMT and CD133 expression was analyzed by immunohistochemistry in 123 paraffin-embedded colorectal adenocarcinoma samples, obtaining the percentage staining and intensity. MGMT promoter methylation status was obtained by using bisulfite modification and methylation-specific PCR (MSP). These values were correlated with clinical data, including overall survival (OS), disease-free survival (DFS), tumor stage, and differentiation grade. RESULTS Low MGMT expression intensity was significantly correlated with shorter OS and was a prognostic factor independently of treatment and histopathological variables. High percentage of CD133 expression was significantly correlated with shorter DFS but was not an independent factor. Patients with low-intensity MGMT expression and ≥50% CD133 expression had the poorest DFS and OS outcomes. CONCLUSIONS Our results support the hypothesis that MGMT expression may be an OS biomarker as useful as tumor stage or differentiation grade and that CD133 expression may be a predictive biomarker of DFS. Thus, MGMT and CD133 may both be useful for determining the prognosis of colorectal cancer patients and to identify those requiring more aggressive adjuvant therapies. Future studies will be necessary to determine its clinical utility.
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Affiliation(s)
- Jaime Antonio Oliver
- Institute of Biopathology and Regenerative Medicine (IBIMER), University of Granada, Granada 18100, Spain
| | - Raúl Ortiz
- Institute of Biopathology and Regenerative Medicine (IBIMER), University of Granada, Granada 18100, Spain
- Department of Health Sciences, University of Jaén, Jaén 23071, Spain
- Biosanitary Institute of Granada (ibs.GRANADA), SAS-Universidad de Granada, Granada, Spain
| | - Consolación Melguizo
- Institute of Biopathology and Regenerative Medicine (IBIMER), University of Granada, Granada 18100, Spain
- Biosanitary Institute of Granada (ibs.GRANADA), SAS-Universidad de Granada, Granada, Spain
- Department of Anatomy and Embryology, University of Granada, Granada 18012, Spain
| | - Pablo Juan Álvarez
- Institute of Biopathology and Regenerative Medicine (IBIMER), University of Granada, Granada 18100, Spain
- Biosanitary Institute of Granada (ibs.GRANADA), SAS-Universidad de Granada, Granada, Spain
| | - Jaime Gómez-Millán
- Radiation Oncology Department, Hospital Clinico Universitario Virgen de la Victoria, Málaga 29010, Spain
| | - Jose Prados
- Institute of Biopathology and Regenerative Medicine (IBIMER), University of Granada, Granada 18100, Spain
- Biosanitary Institute of Granada (ibs.GRANADA), SAS-Universidad de Granada, Granada, Spain
- Department of Anatomy and Embryology, University of Granada, Granada 18012, Spain
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Wang CX, Wang X, Liu HB, Zhou ZH. Aberrant DNA methylation and epigenetic inactivation of hMSH2 decrease overall survival of acute lymphoblastic leukemia patients via modulating cell cycle and apoptosis. Asian Pac J Cancer Prev 2014; 15:355-62. [PMID: 24528056 DOI: 10.7314/apjcp.2014.15.1.355] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
OBJECTIVE Altered regulation of many transcription factors has been shown to play important roles in the development of leukemia. hMSH2 can modulate the activity of some important transcription factors and is known to be a regulator of hematopoietic differentiation. Herein, we investigated epigenetic regulation of hMSH2 and its influence on cell growth and overall survival of acute lymphoblastic leukemia (ALL) patients. METHODS hMSH2 promoter methylation status was assessed by COBRA and pyrosequencing in 60 ALL patients and 30 healthy volunteers. mRNA and protein expression levels of hMSH2, PCNA, CyclinD1, Bcl-2 and Bax were determined by real time PCR and Western blotting, respectively. The influence of hMSH2 on cell proliferation and survival was assessed in transient and stable expression systems. RESULTS mRNA and protein expression of hMSH2 and Bcl-2 was decreased, and that of PCNA, CyclinD1 and Bax was increased in ALL patients as compared to healthy volunteers (P<0.05). hMSH2 was inactivated in ALL patients through promoter hypermethylation. Furthermore, hMSH2 hypermethylation was found in relapsed ALL patients (85.7% of all cases). The median survival of patients with hMSH2 methylation was shorter than that of patients without hMSH2 methylation (log-rank test, P=0.0035). Over-expression of hMSH2 in cell lines resulted in a significant reduction in growth and induction of apoptosis. CONCLUSIONS This study suggests that aberrant DNA methylation and epigenetic inactivation of hMSH2 play an important role in the development of ALL through altering cell growth and survival.
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Affiliation(s)
- Cai-Xia Wang
- Department of Internal Medicine, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, China E-mail :
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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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Zeng JR, Ruan ZM, Mo LF, Chen H. Relationship between MLH1 promoter methylation and colorectal cancer: A meta-analysis. Shijie Huaren Xiaohua Zazhi 2013; 21:4204-4209. [DOI: 10.11569/wcjd.v21.i36.4204] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [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
AIM: To investigate the relationship between mutL homolog 1 (MLH1) promoter hy-permethylation and colorectal cancer (CRC).
METHODS: Relevant trials were identified by searching electronic databases including PubMed, Embase, Web of Science, Cochrane Library, CBM, CNKI, WANGFANG and VIP database updated to July 2013. The English search terms included MLH1, mutL homolog 1, promoter methylation, colon cancer and CRC, and the Chinese search terms included MLH1 gene promoter methylation and colorectal cancer. Stata11.0 software was used for statistical analysis.
RESULTS: A total of 11 articles involving 1496 CRC cases and 382 controls were analyzed in the study. Statistically significant odds ratios (OR) of MLH1 promoter methylation were obtained between total cases and controls (OR = 7.863, 95%CI: 4.537-13.627, P < 0.05), between tumor tissues of CRC patients and those of healthy persons (OR = 8.246, 95%CI: 3.522-19.307, P < 0.05), and between tumor tissues and non-tumorous tissues of CRC patients (OR = 7.549, 95%CI: 3.685-15.464, P < 0.05).
CONCLUSION: MLH1 promoter hypermethylation may contribute to the development of colon cancer and has appreciated value in the diagnosis of this malignancy.
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Li X, Wang Y, Zhang Z, Yao X, Ge J, Zhao Y. Correlation of MLH1 and MGMT methylation levels between peripheral blood leukocytes and colorectal tissue DNA samples in colorectal cancer patients. Oncol Lett 2013; 6:1370-1376. [PMID: 24179526 PMCID: PMC3813787 DOI: 10.3892/ol.2013.1543] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2013] [Accepted: 08/07/2013] [Indexed: 02/06/2023] Open
Abstract
CpG island methylation in the promoter regions of the DNA mismatch repair gene mutator L homologue 1 (MLH1) and DNA repair gene O6-methylguanine-DNA methyltransferase (MGMT) genes has been shown to occur in the leukocytes of peripheral blood and colorectal tissue. However, it is unclear whether the methylation levels in the blood leukocytes and colorectal tissue are correlated. The present study analyzed and compared the levels of MGMT and MLH1 gene methylation in the leukocytes of peripheral blood and colorectal tissues obtained from patients with colorectal cancer (CRC). The methylation levels of MGMT and MLH1 were examined using methylation-sensitive high-resolution melting (MS-HRM) analysis. A total of 44 patients with CRC were selected based on the MLH1 and MGMT gene methylation levels in the leukocytes of the peripheral blood. Corresponding colorectal tumor and normal tissues were obtained from each patient and the DNA methylation levels were determined. The correlation coefficients were evaluated using Spearman's rank test. Agreement was determined by generalized κ-statistics. Spearman's rank correlation coefficients (r) for the methylation levels of the MGMT and MLH1 genes in the leukocytes of the peripheral blood and normal colorectal tissue were 0.475 and 0.362, respectively (P=0.001 and 0.016, respectively). The agreement of the MGMT and MLH1 gene methylation levels in the leukocytes of the peripheral blood and normal colorectal tissue were graded as fair and poor (κ=0.299 and 0.126, respectively). The methylation levels of MGMT and MLH1 were moderately and weakly correlated between the patient-matched leukocytes and the normal colorectal tissue, respectively. Blood-derived DNA methylation measurements may not always represent the levels of normal colorectal tissue methylation.
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Affiliation(s)
- Xia Li
- Department of Epidemiology, Public Health College, Harbin Medical University, Harbin, Heilongjiang 150081, P.R. China
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Li X, Yao X, Wang Y, Hu F, Wang F, Jiang L, Liu Y, Wang D, Sun G, Zhao Y. MLH1 promoter methylation frequency in colorectal cancer patients and related clinicopathological and molecular features. PLoS One 2013; 8:e59064. [PMID: 23555617 PMCID: PMC3612054 DOI: 10.1371/journal.pone.0059064] [Citation(s) in RCA: 74] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2012] [Accepted: 02/12/2013] [Indexed: 02/07/2023] Open
Abstract
Purpose To describe the frequency of MLH1 promoter methylation in colorectal cancer (CRC); to explore the associations between MLH1 promoter methylation and clinicopathological and molecular factors using a systematic review and meta-analysis. Methods A literature search of the PubMed and Embase databases was conducted to identify relevant articles published up to September 7, 2012 that described the frequency of MLH1 promoter methylation or its associations with clinicopathological and molecular factors in CRC. The pooled frequency, odds ratio (OR) and 95% confidence intervals (95% CI) were calculated. Results The pooled frequency of MLH1 promoter methylation in unselected CRC was 20.3% (95% CI: 16.8–24.1%). They were 18.7% (95% CI: 14.7–23.6%) and 16.4% (95% CI: 11.9–22.0%) in sporadic and Lynch syndrome (LS) CRC, respectively. Significant associations were observed between MLH1 promoter methylation and gender (pooled OR = 1.641, 95% CI: 1.215–2.215; P = 0.001), tumor location (pooled OR = 3.804, 95% CI: 2.715–5.329; P<0.001), tumor differentiation (pooled OR = 2.131, 95% CI: 1.464–3.102; P<0.001), MSI (OR: 27.096, 95% CI: 13.717–53.526; P<0.001). Significant associations were also observed between MLH1 promoter methylation and MLH1 protein expression, BRAF mutation (OR = 14.919 (95% CI: 6.427–34.631; P<0.001) and 9.419 (95% CI: 2.613–33.953; P = 0.001), respectively). Conclusion The frequency of MLH1 promoter methylation in unselected CRC was 20.3%. They were 18.7% in sporadic CRC and 16.4% in LS CRC, respectively. MLH1 promoter methylation may be significantly associated with gender, tumor location, tumor differentiation, MSI, MLH1 protein expression, and BRAF mutation.
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Affiliation(s)
- Xia Li
- Department of Epidemiology, Public Health College, Harbin Medical University, Harbin, Heilongjiang Province, P.R. China
| | - Xiaoping Yao
- Department of Epidemiology, Public Health College, Harbin Medical University, Harbin, Heilongjiang Province, P.R. China
| | - Yibaina Wang
- Department of Epidemiology, Public Health College, Harbin Medical University, Harbin, Heilongjiang Province, P.R. China
| | - Fulan Hu
- Department of Epidemiology, Public Health College, Harbin Medical University, Harbin, Heilongjiang Province, P.R. China
| | - Fan Wang
- Department of Epidemiology, Public Health College, Harbin Medical University, Harbin, Heilongjiang Province, P.R. China
| | - Liying Jiang
- Department of Epidemiology, Public Health College, Harbin Medical University, Harbin, Heilongjiang Province, P.R. China
| | - Yupeng Liu
- Department of Epidemiology, Public Health College, Harbin Medical University, Harbin, Heilongjiang Province, P.R. China
| | - Da Wang
- Department of Science and Technology Administration, Harbin Medical University, Harbin, Heilongjiang Province, P.R. China
| | - Guizhi Sun
- Department of Surgery, Cancer Hospital of Harbin Medical University, Harbin, Heilongjiang Province, P.R. China
| | - Yashuang Zhao
- Department of Epidemiology, Public Health College, Harbin Medical University, Harbin, Heilongjiang Province, P.R. China
- * E-mail:
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Bernstein C, Nfonsam V, Prasad AR, Bernstein H. Epigenetic field defects in progression to cancer. World J Gastrointest Oncol 2013; 5:43-49. [PMID: 23671730 PMCID: PMC3648662 DOI: 10.4251/wjgo.v5.i3.43] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2012] [Revised: 01/29/2013] [Accepted: 03/07/2013] [Indexed: 02/05/2023] Open
Abstract
A field defect is a field of pre-malignant tissue in which a new cancer is likely to arise. Field defects often appear to be histologically normal under the microscope. Recent research indicates that cells within a field defect characteristically have an increased frequency of epigenetic alterations and these may be fundamentally important as underlying factors in progression to cancer. However, understanding of epigenetic field defects is at an early stage, and the work of Katsurano et al published this year, is a key contribution to this field. One question examined by Katsurano et al was how early could the formation of an epigenetic field defect be detected in a mouse colitis model of tumorigenesis. They highlighted a number of measurable epigenetic alterations, detected very early in normal appearing tissue undergoing histologically invisible tumorigenesis. They also documented the increasing presence of the epigenetic alterations at successive times during progression to cancer. In this commentary, we offer a perspective on the changes they observed within a broader sequence of epigenetic events that occur in progression to cancer. In particular, we highlight the likely central role of epigenetic deficiencies in DNA repair gene expression that arise during progression to cancer.
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Abstract
A large body of evidence indicates that genetic mutations, epigenetic changes, chronic inflammation, diet, and lifestyle are key risk factors for colorectal cancer (CRC). Prevention of CRC has long been considered a plausible approach for the population and individuals at high risk for developing this disease. A significant effort has been made in the development of novel drugs for both prevention and treatment over the past two decades. This review highlights recent advances in our understanding of the role of nonsteroidal anti-inflammatory drugs in CRC prevention and adjuvant treatment. Moreover, we focus on the molecular mechanisms underlying the antitumor effects of these drugs in CRC. The knowledge of how anti-inflammatory agents inhibit cancer formation and progression may provide a rationale for the development of more effective chemopreventive and chemotherapeutic agents with less toxicity.
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Affiliation(s)
- Dingzhi Wang
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030-4009, USA
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