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Ozawa S, Miura T, Terashima J, Habano W. Cellular irinotecan resistance in colorectal cancer and overcoming irinotecan refractoriness through various combination trials including DNA methyltransferase inhibitors: a review. CANCER DRUG RESISTANCE (ALHAMBRA, CALIF.) 2022; 4:946-964. [PMID: 35582377 PMCID: PMC8992440 DOI: 10.20517/cdr.2021.82] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Revised: 09/27/2021] [Accepted: 10/26/2021] [Indexed: 12/28/2022]
Abstract
Treatment with pharmacological drugs for colorectal cancer (CRC) remains unsatisfactory. A major cause of failure in pharmacotherapy is the resistance of colon cancer cells to the drugs, creating an urgent issue. In this review, we summarize previous studies on the resistance of CRC cells to irinotecan and discuss possible reasons for refractoriness. Our review presents the following five major causes of irinotecan resistance in human CRC: (1) cellular irinotecan resistance is induced mainly through the increased expression of the drug efflux transporter, ABCG2; (2) cellular irinotecan resistance is also induced in association with a nuclear receptor, pregnane/steroid X receptor (PXR/SXR), which is enriched in the CYP3A4 gene enhancer region in CRC cells by exposing the cells to SN-38; (3) irinotecan-resistant cells possess either reduced DNA topoisomerase I (Top1) expression at both the mRNA and protein levels or Top1 missense mutations; (4) alterations in the tumor microenvironment lead to drug resistance through intercellular vesicle-mediated transmission of miRNAs; and (5) CRC stem cells are the most difficult targets to successfully treat CRC. In the clinical setting, CRC gradually develops resistance to initially effective irinotecan-based therapy. To solve this problem, several clinical trials, such as irinotecan plus cetuximab vs. cetuximab monotherapy, have been conducted. Another clinical trial on irinotecan plus guadecitabine, a DNA-methyltransferase inhibitor, has also been conducted.
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Affiliation(s)
- Shogo Ozawa
- Division of Pharmacodynamics and Molecular Genetics, School of Pharmacy, Iwate Medical University, Yahaba, Iwate 028-3694, Japan
| | - Toshitaka Miura
- Division of Pharmacodynamics and Molecular Genetics, School of Pharmacy, Iwate Medical University, Yahaba, Iwate 028-3694, Japan
| | - Jun Terashima
- Division of Pharmacodynamics and Molecular Genetics, School of Pharmacy, Iwate Medical University, Yahaba, Iwate 028-3694, Japan
| | - Wataru Habano
- Division of Pharmacodynamics and Molecular Genetics, School of Pharmacy, Iwate Medical University, Yahaba, Iwate 028-3694, Japan
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Guo L, Lee YT, Zhou Y, Huang Y. Targeting epigenetic regulatory machinery to overcome cancer therapy resistance. Semin Cancer Biol 2021; 83:487-502. [PMID: 33421619 PMCID: PMC8257754 DOI: 10.1016/j.semcancer.2020.12.022] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2020] [Revised: 12/28/2020] [Accepted: 12/29/2020] [Indexed: 02/07/2023]
Abstract
Drug resistance, either intrinsic or acquired, represents a major hurdle to achieving optimal therapeutic outcomes during cancer treatment. In addition to acquisition of resistance-conferring genetic mutations, accumulating evidence suggests an intimate involvement of the epigenetic machinery in this process as well. Recent studies have revealed that epigenetic reprogramming, such as altered expression or relocation of DNA/histone modulators accompanied with chromatin structure remodeling, can lead to transcriptional plasticity in tumor cells, thereby driving their transformation towards a persistent state. These "persisters" represent a pool of slow-growing cells that can either re-expand when treatment is discontinued or acquire permanent resistance. Targeting epigenetic reprogramming or plasticity represents a new strategy to prevent the emergence of drug-refractory populations and to enable more consistent clinical responses. With the growing numbers of drugs or drug candidates developed to target epigenetic regulators, more and more epigenetic therapies are under preclinical evaluation, early clinical trials or approved by FDA as single agent or in combination with existing antitumor drugs. In this review, we highlight latest discoveries in the mechanistic understanding of epigenetically-induced drug resistance. In parallel, we discuss the potential of combining epigenetic drugs with existing anticancer regimens as a promising strategy for overcoming cancer drug resistance.
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Affiliation(s)
- Lei Guo
- Center for Epigenetics & Disease Prevention, Institute of Biosciences and Technology, Texas A&M University, Houston, TX, 77030, USA; Center for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&M University, Houston, TX, 77030, USA
| | - Yi-Tsang Lee
- Center for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&M University, Houston, TX, 77030, USA
| | - Yubin Zhou
- Center for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&M University, Houston, TX, 77030, USA; Department of Translational Medical Sciences, College of Medicine, Texas A&M University, Houston, TX, 77030, USA.
| | - Yun Huang
- Center for Epigenetics & Disease Prevention, Institute of Biosciences and Technology, Texas A&M University, Houston, TX, 77030, USA; Department of Translational Medical Sciences, College of Medicine, Texas A&M University, Houston, TX, 77030, USA.
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Dos Santos RS, Marroqui L, Velayos T, Olazagoitia-Garmendia A, Jauregi-Miguel A, Castellanos-Rubio A, Eizirik DL, Castaño L, Santin I. DEXI, a candidate gene for type 1 diabetes, modulates rat and human pancreatic beta cell inflammation via regulation of the type I IFN/STAT signalling pathway. Diabetologia 2019; 62:459-472. [PMID: 30478640 DOI: 10.1007/s00125-018-4782-0] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2018] [Accepted: 10/29/2018] [Indexed: 01/09/2023]
Abstract
AIMS/HYPOTHESIS The initial stages of type 1 diabetes are characterised by an aberrant islet inflammation that is in part regulated by the interaction between type 1 diabetes susceptibility genes and environmental factors. Chromosome 16p13 is associated with type 1 diabetes and CLEC16A is thought to be the aetiological gene in the region. Recent gene expression analysis has, however, indicated that SNPs in CLEC16A modulate the expression of a neighbouring gene with unknown function named DEXI, encoding dexamethasone-induced protein (DEXI). We therefore evaluated the role of DEXI in beta cell responses to 'danger signals' and determined the mechanisms involved. METHODS Functional studies based on silencing or overexpression of DEXI were performed in rat and human pancreatic beta cells. Beta cell inflammation and apoptosis, driven by a synthetic viral double-stranded RNA, were evaluated by real-time PCR, western blotting and luciferase assays. RESULTS DEXI-silenced beta cells exposed to a synthetic double-stranded RNA (polyinosinic:polycytidylic acid [PIC], a by-product of viral replication) showed reduced activation of signal transducer and activator of transcription (STAT) 1 and lower production of proinflammatory chemokines that was preceded by a reduction in IFNβ levels. Exposure to PIC increased chromatin-bound DEXI and IFNβ promoter activity. This effect on IFNβ promoter was inhibited in DEXI-silenced beta cells, suggesting that DEXI is implicated in the regulation of IFNβ transcription. In a mirror image of knockdown experiments, DEXI overexpression led to increased levels of STAT1 and proinflammatory chemokines. CONCLUSIONS/INTERPRETATION These observations support DEXI as the aetiological gene in the type 1 diabetes-associated 16p13 genomic region, and provide the first indication of a link between this candidate gene and the regulation of local antiviral immune responses in beta cells. Moreover, our results provide initial information on the function of DEXI.
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Affiliation(s)
- Reinaldo S Dos Santos
- ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles (ULB), Brussels, Belgium
- Instituto de Biología Molecular y Celular (IBMC), and Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Universitas Miguel Hernández, Elche, Spain
- CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain
| | - Laura Marroqui
- ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles (ULB), Brussels, Belgium
- Instituto de Biología Molecular y Celular (IBMC), and Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Universitas Miguel Hernández, Elche, Spain
- CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain
| | - Teresa Velayos
- CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain
- Biocruces Bizkaia Health Research Institute, Barakaldo, Spain
- Department of Pediatrics, University of the Basque Country, Leioa, Spain
| | - Ane Olazagoitia-Garmendia
- Biocruces Bizkaia Health Research Institute, Barakaldo, Spain
- Department of Genetics, Physical Anthropology and Animal Fisiology, University of the Basque Country, Leioa, Spain
| | - Amaia Jauregi-Miguel
- Biocruces Bizkaia Health Research Institute, Barakaldo, Spain
- Department of Genetics, Physical Anthropology and Animal Fisiology, University of the Basque Country, Leioa, Spain
| | - Ainara Castellanos-Rubio
- CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain
- Biocruces Bizkaia Health Research Institute, Barakaldo, Spain
- Department of Genetics, Physical Anthropology and Animal Fisiology, University of the Basque Country, Leioa, Spain
| | - Decio L Eizirik
- ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles (ULB), Brussels, Belgium
| | - Luis Castaño
- CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain
- Biocruces Bizkaia Health Research Institute, Barakaldo, Spain
- Department of Pediatrics, University of the Basque Country, Leioa, Spain
- CIBER de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Madrid, Spain
| | - Izortze Santin
- CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain.
- Biocruces Bizkaia Health Research Institute, Barakaldo, Spain.
- CIBER de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Madrid, Spain.
- Department of Biochemistry and Molecular Biology, University of the Basque Country, Barrio Sarriena, S/N, 48940, Leioa, Bizkaia, Spain.
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Abdelfatah E, Kerner Z, Nanda N, Ahuja N. Epigenetic therapy in gastrointestinal cancer: the right combination. Therap Adv Gastroenterol 2016; 9:560-79. [PMID: 27366224 PMCID: PMC4913338 DOI: 10.1177/1756283x16644247] [Citation(s) in RCA: 57] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
Epigenetics is a relatively recent field of molecular biology that has arisen over the past 25 years. Cancer is now understood to be a disease of widespread epigenetic dysregulation that interacts extensively with underlying genetic mutations. The development of drugs targeting these processes has rapidly progressed; with several drugs already FDA approved as first-line therapy in hematological malignancies. Gastrointestinal (GI) cancers possess high degrees of epigenetic dysregulation, exemplified by subtypes such as CpG island methylator phenotype (CIMP), and the potential benefit of epigenetic therapy in these cancers is evident. The application of epigenetic drugs in solid tumors, including GI cancers, is just emerging, with increased understanding of the cancer epigenome. In this review, we provide a brief overview of cancer epigenetics and the epigenetic targets of therapy including deoxyribonucleic acid (DNA) methylation, histone modifications, and chromatin remodeling. We discuss the epigenetic drugs currently in use, with a focus on DNA methyltransferase (DNMT) and histone deacetylase (HDAC) inhibitors, and explain the pharmacokinetic and mechanistic challenges in their application. We present the strategies employed in incorporating these drugs into the treatment of GI cancers, and explain the concept of the cancer stem cell in epigenetic reprogramming and reversal of chemo resistance. We discuss the most promising combination strategies in GI cancers including: (1) epigenetic sensitization to radiotherapy, (2) epigenetic sensitization to cytotoxic chemotherapy, and (3) epigenetic immune modulation and priming for immune therapy. Finally, we present preclinical and clinical trial data employing these strategies thus far in various GI cancers including colorectal, esophageal, gastric, and pancreatic cancer.
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Affiliation(s)
- Eihab Abdelfatah
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Zachary Kerner
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Nainika Nanda
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- West Virginia University School of Medicine, Morgantown, WV, USA
| | - Nita Ahuja
- Department of Surgery and Oncology, Johns Hopkins University, 1650 Orleans St. Room 342, Baltimore, MD 21231, USA
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Tomlinson MJ, Pitsillides A, Pickin R, Mika M, Keene KL, Hou X, Mychaleckyj J, Chen WM, Concannon P, Onengut-Gumuscu S. Fine mapping and functional studies of risk variants for type 1 diabetes at chromosome 16p13.13. Diabetes 2014; 63:4360-8. [PMID: 25008175 PMCID: PMC4237999 DOI: 10.2337/db13-1785] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2013] [Accepted: 06/27/2014] [Indexed: 12/11/2022]
Abstract
Single nucleotide polymorphisms (SNPs) located in the chromosomal region 16p13.13 have been previously associated with risk for several autoimmune diseases, including type 1 diabetes. To identify and localize specific risk variants for type 1 diabetes in this region and understand the mechanism of their action, we resequenced a 455-kb region in type 1 diabetic patients and unaffected control subjects, identifying 93 novel variants. A panel of 939 SNPs that included 46 of these novel variants was genotyped in 3,070 multiplex families with type 1 diabetes. Forty-eight SNPs, all located in CLEC16A, provided a statistically significant association (P < 5.32 × 10(-5)) with disease, with rs34306440 being most significantly associated (P = 5.74 × 10(-6)). The panel of SNPs used for fine mapping was also tested for association with transcript levels for each of the four genes in the region in B lymphoblastoid cell lines. Significant associations were observed only for transcript levels of DEXI, a gene with unknown function. We examined the relationship between the odds ratio for type 1 diabetes and the magnitude of the effect of DEXI transcript levels for each SNP in the region. Among SNPs significantly associated with type 1 diabetes, the common allele conferred an increased risk for disease and corresponded to lower DEXI expression. Our results suggest that the primary mechanism by which genetic variation at CLEC16A contributes to the risk for type 1 diabetes is through reduced expression of DEXI.
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Affiliation(s)
- M Joseph Tomlinson
- Department of Biochemistry and Molecular Genetics, UVA School of Medicine, University of Virginia, Charlottesville, VA Center for Public Health Genomics, UVA School of Medicine, University of Virginia, Charlottesville, VA
| | - Achilleas Pitsillides
- Department of Biochemistry and Molecular Genetics, UVA School of Medicine, University of Virginia, Charlottesville, VA Center for Public Health Genomics, UVA School of Medicine, University of Virginia, Charlottesville, VA
| | - Rebecca Pickin
- Center for Public Health Genomics, UVA School of Medicine, University of Virginia, Charlottesville, VA Department of Public Health Sciences, UVA School of Medicine, University of Virginia, Charlottesville, VA
| | - Matthew Mika
- Department of Biochemistry and Molecular Genetics, UVA School of Medicine, University of Virginia, Charlottesville, VA Center for Public Health Genomics, UVA School of Medicine, University of Virginia, Charlottesville, VA
| | - Keith L Keene
- Department of Biochemistry and Molecular Genetics, UVA School of Medicine, University of Virginia, Charlottesville, VA Center for Public Health Genomics, UVA School of Medicine, University of Virginia, Charlottesville, VA
| | - Xuanlin Hou
- Center for Public Health Genomics, UVA School of Medicine, University of Virginia, Charlottesville, VA Department of Public Health Sciences, UVA School of Medicine, University of Virginia, Charlottesville, VA
| | - Josyf Mychaleckyj
- Center for Public Health Genomics, UVA School of Medicine, University of Virginia, Charlottesville, VA Department of Public Health Sciences, UVA School of Medicine, University of Virginia, Charlottesville, VA
| | - Wei-Min Chen
- Center for Public Health Genomics, UVA School of Medicine, University of Virginia, Charlottesville, VA Department of Public Health Sciences, UVA School of Medicine, University of Virginia, Charlottesville, VA
| | - Patrick Concannon
- Department of Biochemistry and Molecular Genetics, UVA School of Medicine, University of Virginia, Charlottesville, VA Center for Public Health Genomics, UVA School of Medicine, University of Virginia, Charlottesville, VA Genetics Institute and Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL
| | - Suna Onengut-Gumuscu
- Center for Public Health Genomics, UVA School of Medicine, University of Virginia, Charlottesville, VA Department of Public Health Sciences, UVA School of Medicine, University of Virginia, Charlottesville, VA
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Nakamura J, Tanaka T, Kitajima Y, Noshiro H, Miyazaki K. Methylation-mediated gene silencing as biomarkers of gastric cancer: A review. World J Gastroenterol 2014; 20:11991-12006. [PMID: 25232236 PMCID: PMC4161787 DOI: 10.3748/wjg.v20.i34.11991] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2013] [Revised: 01/29/2014] [Accepted: 04/09/2014] [Indexed: 02/06/2023] Open
Abstract
Despite a decline in the overall incidence of gastric cancer (GC), the disease remains the second most common cause of cancer-related death worldwide and is thus a significant global health problem. The best means of improving the survival of GC patients is to screen for and treat early lesions. However, GC is often diagnosed at an advanced stage and is associated with a poor prognosis. Current diagnostic and therapeutic strategies have not been successful in decreasing the global burden of the disease; therefore, the identification of reliable biomarkers for an early diagnosis, predictive markers of recurrence and survival and markers of drug sensitivity and/or resistance is urgently needed. The initiation and progression of GC depends not only on genetic alterations but also epigenetic changes, such as DNA methylation and histone modification. Aberrant DNA methylation is the most well-defined epigenetic change in human cancers and is associated with inappropriate gene silencing. Therefore, an increasing number of genes methylated at the promoter region have been targeted as possible biomarkers for different purposes, including early detection, classification, the assessment of the tumor prognosis, the development of therapeutic strategies and patient follow-up. This review article summarizes the current understanding and recent evidence regarding DNA methylation markers in GC with a focus on the clinical potential of these markers.
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Panczyk M. Pharmacogenetics research on chemotherapy resistance in colorectal cancer over the last 20 years. World J Gastroenterol 2014; 20:9775-827. [PMID: 25110414 PMCID: PMC4123365 DOI: 10.3748/wjg.v20.i29.9775] [Citation(s) in RCA: 105] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2013] [Revised: 01/17/2014] [Accepted: 04/21/2014] [Indexed: 02/07/2023] Open
Abstract
During the past two decades the first sequencing of the human genome was performed showing its high degree of inter-individual differentiation, as a result of large international research projects (Human Genome Project, the 1000 Genomes Project International HapMap Project, and Programs for Genomic Applications NHLBI-PGA). This period was also a time of intensive development of molecular biology techniques and enormous knowledge growth in the biology of cancer. For clinical use in the treatment of patients with colorectal cancer (CRC), in addition to fluoropyrimidines, another two new cytostatic drugs were allowed: irinotecan and oxaliplatin. Intensive research into new treatment regimens and a new generation of drugs used in targeted therapy has also been conducted. The last 20 years was a time of numerous in vitro and in vivo studies on the molecular basis of drug resistance. One of the most important factors limiting the effectiveness of chemotherapy is the primary and secondary resistance of cancer cells. Understanding the genetic factors and mechanisms that contribute to the lack of or low sensitivity of tumour tissue to cytostatics is a key element in the currently developing trend of personalized medicine. Scientists hope to increase the percentage of positive treatment response in CRC patients due to practical applications of pharmacogenetics/pharmacogenomics. Over the past 20 years the clinical usability of different predictive markers has been tested among which only a few have been confirmed to have high application potential. This review is a synthetic presentation of drug resistance in the context of CRC patient chemotherapy. The multifactorial nature and volume of the issues involved do not allow the author to present a comprehensive study on this subject in one review.
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DNA methylation alterations of AXIN2 in serrated adenomas and colon carcinomas with microsatellite instability. BMC Cancer 2014; 14:466. [PMID: 24964857 PMCID: PMC4099028 DOI: 10.1186/1471-2407-14-466] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2014] [Accepted: 06/16/2014] [Indexed: 12/12/2022] Open
Abstract
Background Recent work led to recognize sessile serrated adenomas (SSA) as precursor to many of the sporadic colorectal cancers with microsatellite instability (MSI). However, comprehensive analyses of DNA methylation in SSA and MSI cancer have not been conducted. Methods With an array-based methylation sensitive amplified fragment length polymorphism (MS-AFLP) method we analyzed 8 tubular (TA) and 19 serrated (SSA) adenomas, and 14 carcinomas with (MSI) and 12 without (MSS) microsatellite instability. MS-AFLP array can survey relative differences in methylation between normal and tumor tissues of 9,654 DNA fragments containing all NotI sequences in the human genome. Results Unsupervised clustering analysis of the genome-wide hypermethylation alterations revealed no major differences between or within these groups of benign and malignant tumors regardless of their location in intergenic, intragenic, promoter, or 3′ end regions. Hypomethylation was less frequent in SSAs compared with MSI or MSS carcinomas. Analysis of variance of DNA methylation between these four subgroups identified 56 probes differentially altered. The hierarchical tree of this subset of probes revealed two distinct clusters: Group 1, mostly composed by TAs and MSS cancers with KRAS mutations; and Group 2 with BRAF mutations, which consisted of cancers with MSI and MLH1 methylation (Group 2A), and SSAs without MLH1 methylation (Group 2B). AXIN2, which cooperates with APC and β-catenin in Wnt signaling, had more methylation alterations in Group 2, and its expression levels negatively correlated with methylation determined by bisulfite sequencing. Within group 2B, low and high AXIN2 expression levels correlated significantly with differences in size (P = 0.01) location (P = 0.05) and crypt architecture (P = 0.01). Conclusions Somatic methylation alterations of AXIN2, associated with changes in its expression, stratify SSAs according to some clinico-pathological differences. We conclude that hypermethylation of MLH1, when occurs in an adenoma cell with BRAF oncogenic mutational activation, drives the pathway for MSI cancer by providing the cells with a mutator phenotype. AXIN2 inactivation may contribute to this tumorigenic pathway either by mutator phenotype driven frameshift mutations or by epigenetic deregulation contemporary with the unfolding of the mutator phenotype.
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