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Lønning PE, Nikolaienko O, Knappskog S. Constitutional Epimutations: From Rare Events Toward Major Cancer Risk Factors? JCO Precis Oncol 2025; 9:e2400746. [PMID: 40179326 PMCID: PMC11995855 DOI: 10.1200/po-24-00746] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2024] [Revised: 01/09/2025] [Accepted: 01/14/2025] [Indexed: 04/05/2025] Open
Abstract
Constitutional epimutations are epigenetic aberrations that arise in normal cells prenatally. Two major forms exist: secondary constitutional epimutations (SCEs), associated with cis-acting genetic aberrations, and primary constitutional epimutations (PCEs), for which no associated genetic aberrations were identified. Some SCEs have been associated with risk of cancer (MLH1 and MSH2 with colon or endometrial cancers, BRCA1 with familial breast and ovarian cancers), although such epimutations are rare, with a total of <100 cases reported. This contrasts recent findings for PCE, where low-level mosaic BRCA1 epimutations are recorded in 5%-10% of healthy females across all age groups, including newborns. BRCA1 PCEs predict an elevated risk of high-grade serous ovarian cancer and triple-negative breast cancer (TNBC) and are estimated to account for about 20% of all TNBCs. A similarly high population frequency is observed for mosaic constitutional epimutations in MGMT, occurring as PCE or SCE, but not in MLH1. Contrasting BRCA1 and MLH1, a potential association with cancer risk for MGMT epimutations is yet unclear. In this review, we provide a summary of findings linking constitutional epimutations to cancer risk with emphasis on PCE. We also highlight challenges in detection of PCE exemplified by low-level mosaic epimutations in BRCA1 and indicate the need for further studies, hypothesizing that improved knowledge about PCE may add significantly to our understanding of cancer risk, carcinogenesis, and potentially development of other diseases as well.
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Affiliation(s)
| | - Oleksii Nikolaienko
- Department of Oncology, Haukeland University Hospital, Bergen, Norway
- Department of Clinical Science, University of Bergen, Bergen, Norway
| | - Stian Knappskog
- Department of Oncology, Haukeland University Hospital, Bergen, Norway
- Department of Clinical Science, University of Bergen, Bergen, Norway
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Rico-Méndez MA, Trujillo-Rojas MA, Ayala-Madrigal MDLL, Hernández-Sandoval JA, González-Mercado A, Gutiérrez-Angulo M, Romero-Quintana JG, Valenzuela-Pérez JA, Ramírez-Ramírez R, Flores-López BA, Moreno-Ortiz JM. MLH1 Methylation Status and Microsatellite Instability in Patients with Colorectal Cancer. Genes (Basel) 2025; 16:182. [PMID: 40004511 PMCID: PMC11854980 DOI: 10.3390/genes16020182] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2025] [Revised: 01/29/2025] [Accepted: 01/30/2025] [Indexed: 02/27/2025] Open
Abstract
Background/Objectives: The purpose of the current study was to compare the methylation of five regions of the CpG island of MLH1 with the presence of microsatellite instability (MSI) in colorectal cancer (CRC) patients. Methods: The study analyzed 138 CRC tumor samples. DNA extraction was performed, followed by bisulfite conversion. MLH1 gene methylation was assessed by methylation-specific PCR (MS-PCR), and the resulting fragments were analyzed using polyacrylamide gels. MSI was evaluated using multiplex PCR, and the fragments were run through capillary electrophoresis. R studio (v4.4.1) and SPSS (v29.0) software were used for the statistical analysis, and values of p < 0.05 were considered statistically significant. Results: The study showed 75.4% unmethylated, 21% partially methylated, and 3.6% fully methylated samples, with region A frequently methylated. MSI was observed in 7.2% of cases (MSI-H: 5.8%, MSI-L: 1.4%). BAT-26 was the most unstable marker. A significant difference between MLH1 methylation and MSI-H (p < 0.01) was identified, but there was no relationship with specific MLH1 regions. Conclusions: No differences were identified when analyzing specific methylation regions in relation to MSI. This study is the first to describe MSI frequency in Mexican patients regardless of age.
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Affiliation(s)
- Manuel Alejandro Rico-Méndez
- Doctorado en Genética Humana e Instituto de Genética Humana “Dr. Enrique Corona Rivera”, Departamento de Biología Molecular y Genómica, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara C.P. 44340, Jalisco, Mexico; (M.A.R.-M.); (M.A.T.-R.); (M.d.l.L.A.-M.); (J.A.H.-S.); (A.G.-M.)
| | - Miguel Angel Trujillo-Rojas
- Doctorado en Genética Humana e Instituto de Genética Humana “Dr. Enrique Corona Rivera”, Departamento de Biología Molecular y Genómica, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara C.P. 44340, Jalisco, Mexico; (M.A.R.-M.); (M.A.T.-R.); (M.d.l.L.A.-M.); (J.A.H.-S.); (A.G.-M.)
| | - María de la Luz Ayala-Madrigal
- Doctorado en Genética Humana e Instituto de Genética Humana “Dr. Enrique Corona Rivera”, Departamento de Biología Molecular y Genómica, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara C.P. 44340, Jalisco, Mexico; (M.A.R.-M.); (M.A.T.-R.); (M.d.l.L.A.-M.); (J.A.H.-S.); (A.G.-M.)
| | - Jesús Arturo Hernández-Sandoval
- Doctorado en Genética Humana e Instituto de Genética Humana “Dr. Enrique Corona Rivera”, Departamento de Biología Molecular y Genómica, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara C.P. 44340, Jalisco, Mexico; (M.A.R.-M.); (M.A.T.-R.); (M.d.l.L.A.-M.); (J.A.H.-S.); (A.G.-M.)
| | - Anahí González-Mercado
- Doctorado en Genética Humana e Instituto de Genética Humana “Dr. Enrique Corona Rivera”, Departamento de Biología Molecular y Genómica, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara C.P. 44340, Jalisco, Mexico; (M.A.R.-M.); (M.A.T.-R.); (M.d.l.L.A.-M.); (J.A.H.-S.); (A.G.-M.)
| | - Melva Gutiérrez-Angulo
- Departamento de Ciencias de la Salud, Centro Universitario de los Altos, Universidad de Guadalajara, Tepatitlán de Morelos C.P. 47600, Jalisco, Mexico;
| | - José Geovanni Romero-Quintana
- Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Sinaloa, Ciudad Universitaria, Culiacán C.P. 80010, Sinaloa, Mexico;
| | | | - Ruth Ramírez-Ramírez
- Departamento de Biología Molecular, Centro Universitario de Ciencias Biológicas y Agropecuarias, Universidad de Guadalajara, Zapopan C.P. 45200, Jalisco, Mexico;
| | - Beatriz Armida Flores-López
- Departamento de Ciclo de Vida, Facultad de Medicina, Universidad Autónoma de Guadalajara, Zapopan C.P. 45129, Jalisco, Mexico
| | - José Miguel Moreno-Ortiz
- Doctorado en Genética Humana e Instituto de Genética Humana “Dr. Enrique Corona Rivera”, Departamento de Biología Molecular y Genómica, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara C.P. 44340, Jalisco, Mexico; (M.A.R.-M.); (M.A.T.-R.); (M.d.l.L.A.-M.); (J.A.H.-S.); (A.G.-M.)
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Parmar S, Easwaran H. Genetic and epigenetic dependencies in colorectal cancer development. Gastroenterol Rep (Oxf) 2022; 10:goac035. [PMID: 35975243 PMCID: PMC9373935 DOI: 10.1093/gastro/goac035] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Revised: 04/24/2022] [Accepted: 05/22/2022] [Indexed: 11/12/2022] Open
Abstract
Recent studies have mapped key genetic changes in colorectal cancer (CRC) that impact important pathways contributing to the multistep models for CRC initiation and development. In parallel with genetic changes, normal and cancer tissues harbor epigenetic alterations impacting regulation of critical genes that have been shown to play profound roles in the tumor initiation. Cumulatively, these molecular changes are only loosely associated with heterogenous transcriptional programs, reflecting the heterogeneity in the various CRC molecular subtypes and the paths to CRC development. Studies from mapping molecular alterations in early CRC lesions and use of experimental models suggest that the intricate dependencies of various genetic and epigenetic hits shape the early development of CRC via different pathways and its manifestation into various CRC subtypes. We highlight the dependency of epigenetic and genetic changes in driving CRC development and discuss factors affecting epigenetic alterations over time and, by extension, risk for cancer.
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Affiliation(s)
- Sehej Parmar
- Cancer Genetics and Epigenetics, Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Hariharan Easwaran
- Cancer Genetics and Epigenetics, Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
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Krasteva N, Georgieva M. Promising Therapeutic Strategies for Colorectal Cancer Treatment Based on Nanomaterials. Pharmaceutics 2022; 14:pharmaceutics14061213. [PMID: 35745786 PMCID: PMC9227901 DOI: 10.3390/pharmaceutics14061213] [Citation(s) in RCA: 56] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2022] [Revised: 05/18/2022] [Accepted: 05/26/2022] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) is a global health problem responsible for 10% of all cancer incidences and 9.4% of all cancer deaths worldwide. The number of new cases increases per annum, whereas the lack of effective therapies highlights the need for novel therapeutic approaches. Conventional treatment methods, such as surgery, chemotherapy and radiotherapy, are widely applied in oncology practice. Their therapeutic success is little, and therefore, the search for novel technologies is ongoing. Many efforts have focused recently on the development of safe and efficient cancer nanomedicines. Nanoparticles are among them. They are uniquewith their properties on a nanoscale and hold the potential to exploit intrinsic metabolic differences between cancer and healthy cells. This feature allows them to induce high levels of toxicity in cancer cells with little damage to the surrounding healthy tissues. Graphene oxide is a promising 2D material found to play an important role in cancer treatments through several strategies: direct killing and chemosensitization, drug and gene delivery, and phototherapy. Several new treatment approaches based on nanoparticles, particularly graphene oxide, are currently under research in clinical trials, and some have already been approved. Here, we provide an update on the recent advances in nanomaterials-based CRC-targeted therapy, with special attention to graphene oxide nanomaterials. We summarise the epidemiology, carcinogenesis, stages of the CRCs, and current nanomaterials-based therapeutic approaches for its treatment.
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Affiliation(s)
- Natalia Krasteva
- Institute of Biophysics and Biomedical Engineering, Bulgarian Academy of Sciences, “Acad. Georgi Bonchev” Str., bl. 21, 1113 Sofia, Bulgaria
- Correspondence: (N.K.); (M.G.); Tel.: +359-889-577-074 (N.K.); +359-896-833-604 (M.G.)
| | - Milena Georgieva
- Institute of Molecular Biology “Acad. R. Tsanev”, Bulgarian Academy of Sciences, “Acad. Georgi Bonchev” Str., bl. 21, 1113 Sofia, Bulgaria
- Correspondence: (N.K.); (M.G.); Tel.: +359-889-577-074 (N.K.); +359-896-833-604 (M.G.)
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Ruiz de la Cruz M, de la Cruz Montoya AH, Rojas Jiménez EA, Martínez Gregorio H, Díaz Velásquez CE, Paredes de la Vega J, de la Cruz Hernández-Hernández F, Vaca Paniagua F. Cis-Acting Factors Causing Secondary Epimutations: Impact on the Risk for Cancer and Other Diseases. Cancers (Basel) 2021; 13:cancers13194807. [PMID: 34638292 PMCID: PMC8508567 DOI: 10.3390/cancers13194807] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2021] [Revised: 08/09/2021] [Accepted: 08/15/2021] [Indexed: 12/25/2022] Open
Abstract
Epigenetics affects gene expression and contributes to disease development by alterations known as epimutations. Hypermethylation that results in transcriptional silencing of tumor suppressor genes has been described in patients with hereditary cancers and without pathogenic variants in the coding region of cancer susceptibility genes. Although somatic promoter hypermethylation of these genes can occur in later stages of the carcinogenic process, constitutional methylation can be a crucial event during the first steps of tumorigenesis, accelerating tumor development. Primary epimutations originate independently of changes in the DNA sequence, while secondary epimutations are a consequence of a mutation in a cis or trans-acting factor. Secondary epimutations have a genetic basis in cis of the promoter regions of genes involved in familial cancers. This highlights epimutations as a novel carcinogenic mechanism whose contribution to human diseases is underestimated by the scarcity of the variants described. In this review, we provide an overview of secondary epimutations and present evidence of their impact on cancer. We propose the necessity for genetic screening of loci associated with secondary epimutations in familial cancer as part of prevention programs to improve molecular diagnosis, secondary prevention, and reduce the mortality of these diseases.
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Affiliation(s)
- Miguel Ruiz de la Cruz
- Laboratorio Nacional en Salud, Diagnóstico Molecular y Efecto Ambiental en Enfermedades Crónico-Degenerativas, Facultad de Estudios Superiores Iztacala, Tlalnepantla 54090, Mexico; (M.R.d.l.C.); (E.A.R.J.); (H.M.G.); (C.E.D.V.); (J.P.d.l.V.)
- Avenida Instituto Politécnico Nacional # 2508, Colonia San Pedro Zacatenco, Delegación Gustavo A. Madero, C.P. Departamento de Infectómica y Patogénesis Molecular, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (CINVESTAV-IPN), Mexico City 07360, Mexico;
| | | | - Ernesto Arturo Rojas Jiménez
- Laboratorio Nacional en Salud, Diagnóstico Molecular y Efecto Ambiental en Enfermedades Crónico-Degenerativas, Facultad de Estudios Superiores Iztacala, Tlalnepantla 54090, Mexico; (M.R.d.l.C.); (E.A.R.J.); (H.M.G.); (C.E.D.V.); (J.P.d.l.V.)
- Unidad de Biomedicina, Facultad de Estudios Superiores Iztacala, UNAM, Tlalnepantla 54090, Mexico;
| | - Héctor Martínez Gregorio
- Laboratorio Nacional en Salud, Diagnóstico Molecular y Efecto Ambiental en Enfermedades Crónico-Degenerativas, Facultad de Estudios Superiores Iztacala, Tlalnepantla 54090, Mexico; (M.R.d.l.C.); (E.A.R.J.); (H.M.G.); (C.E.D.V.); (J.P.d.l.V.)
- Unidad de Biomedicina, Facultad de Estudios Superiores Iztacala, UNAM, Tlalnepantla 54090, Mexico;
| | - Clara Estela Díaz Velásquez
- Laboratorio Nacional en Salud, Diagnóstico Molecular y Efecto Ambiental en Enfermedades Crónico-Degenerativas, Facultad de Estudios Superiores Iztacala, Tlalnepantla 54090, Mexico; (M.R.d.l.C.); (E.A.R.J.); (H.M.G.); (C.E.D.V.); (J.P.d.l.V.)
| | - Jimena Paredes de la Vega
- Laboratorio Nacional en Salud, Diagnóstico Molecular y Efecto Ambiental en Enfermedades Crónico-Degenerativas, Facultad de Estudios Superiores Iztacala, Tlalnepantla 54090, Mexico; (M.R.d.l.C.); (E.A.R.J.); (H.M.G.); (C.E.D.V.); (J.P.d.l.V.)
- Unidad de Biomedicina, Facultad de Estudios Superiores Iztacala, UNAM, Tlalnepantla 54090, Mexico;
| | - Fidel de la Cruz Hernández-Hernández
- Avenida Instituto Politécnico Nacional # 2508, Colonia San Pedro Zacatenco, Delegación Gustavo A. Madero, C.P. Departamento de Infectómica y Patogénesis Molecular, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (CINVESTAV-IPN), Mexico City 07360, Mexico;
| | - Felipe Vaca Paniagua
- Laboratorio Nacional en Salud, Diagnóstico Molecular y Efecto Ambiental en Enfermedades Crónico-Degenerativas, Facultad de Estudios Superiores Iztacala, Tlalnepantla 54090, Mexico; (M.R.d.l.C.); (E.A.R.J.); (H.M.G.); (C.E.D.V.); (J.P.d.l.V.)
- Unidad de Biomedicina, Facultad de Estudios Superiores Iztacala, UNAM, Tlalnepantla 54090, Mexico;
- Subdirección de Investigación Básica, Instituto Nacional de Cancerología, Ciudad de México 14080, Mexico
- Correspondence: ; Tel.: +52-55-5623-1333 (ext. 39788)
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Advani SM, Advani PS, Brown DW, DeSantis SM, Korphaisarn K, VonVille HM, Bressler J, Lopez DS, Davis JS, Daniel CR, Sarshekeh AM, Braithwaite D, Swartz MD, Kopetz S. Global differences in the prevalence of the CpG island methylator phenotype of colorectal cancer. BMC Cancer 2019; 19:964. [PMID: 31623592 PMCID: PMC6796359 DOI: 10.1186/s12885-019-6144-9] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2019] [Accepted: 09/10/2019] [Indexed: 02/07/2023] Open
Abstract
Background CpG Island Methylator Phenotype (CIMP) is an epigenetic phenotype in CRC characterized by hypermethylation of CpG islands in promoter regions of tumor suppressor genes, leading to their transcriptional silencing and loss of function. While the prevalence of CRC differs across geographical regions, no studies have compared prevalence of CIMP-High phenotype across regions. The purpose of this project was to compare the prevalence of CIMP across geographical regions after adjusting for variations in methodologies to measure CIMP in a meta-analysis. Methods We searched PubMed, Medline, and Embase for articles focusing on CIMP published from 2000 to 2018. Two reviewers independently identified 111 articles to be included in final meta-analysis. We classified methods used to quantify CIMP into 4 categories: a) Classical (MINT marker) Panel group b) Weisenberg-Ogino (W-O) group c) Human Methylation Arrays group and d) Miscellaneous group. We compared the prevalence of CIMP across geographical regions after correcting for methodological variations using meta-regression techniques. Results The pooled prevalence of CIMP-High across all studies was 22% (95% confidence interval:21–24%; I2 = 94.75%). Pooled prevalence of CIMP-H across Asia, Australia, Europe, North America and South America was 22, 21, 21, 27 and 25%, respectively. Meta-regression analysis identified no significant differences in the prevalence of CIMP-H across geographical regions after correction for methodological variations. In exploratory analysis, we observed variations in CIMP-H prevalence across countries. Conclusion Although no differences were found for CIMP-H prevalence across countries, further studies are needed to compare the influence of demographic, lifestyle and environmental factors in relation to the prevalence of CIMP across geographical regions.
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Affiliation(s)
- Shailesh Mahesh Advani
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 0426, Houston, TX, 77030, USA. .,Cancer Prevention and Control Program, Lombardi Comprehensive Cancer Center, Georgetown University, Washington DC, 20007, USA. .,Social Behavioral Research Branch, National Human Genome Research Institute, National Institute of Health, Bethesda, MD, 20892, USA.
| | - Pragati Shailesh Advani
- Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Institutes of Health, National Cancer Institute, Rockville, MD, 20850, USA
| | - Derek W Brown
- Department of Biostatistics and Data Science, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA
| | - Stacia M DeSantis
- Department of Biostatistics and Data Science, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA
| | - Krittiya Korphaisarn
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 0426, Houston, TX, 77030, USA
| | - Helena M VonVille
- Library, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA
| | - Jan Bressler
- Department of Epidemiology, Human Genetics and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA
| | - David S Lopez
- Division of Urology- UTHealth McGovern Medical School, Houston, TX, 77030, USA.,Department of Preventive Medicine and Community Health, UTMB Health-School of Medicine, Galveston, TX, 77555-1153, USA
| | - Jennifer S Davis
- Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Carrie R Daniel
- Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Amir Mehrvarz Sarshekeh
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 0426, Houston, TX, 77030, USA
| | - Dejana Braithwaite
- Cancer Prevention and Control Program, Lombardi Comprehensive Cancer Center, Georgetown University, Washington DC, 20007, USA
| | - Michael D Swartz
- Department of Biostatistics and Data Science, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA
| | - Scott Kopetz
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 0426, Houston, TX, 77030, USA.
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Kim Y, Lee K, Jeong S, Wen X, Cho NY, Kang GH. DLEC1 methylation is associated with a better clinical outcome in patients with intrahepatic cholangiocarcinoma of the small duct subtype. Virchows Arch 2019; 475:49-58. [DOI: 10.1007/s00428-018-02511-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2018] [Revised: 12/07/2018] [Accepted: 12/12/2018] [Indexed: 12/13/2022]
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Gao D, Pinello N, Nguyen TV, Thoeng A, Nagarajah R, Holst J, Rasko JEJ, Wong JJL. DNA methylation/hydroxymethylation regulate gene expression and alternative splicing during terminal granulopoiesis. Epigenomics 2019; 11:95-109. [DOI: 10.2217/epi-2018-0050] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
Aim: To determine whether epigenetic modifications of DNA regulate gene expression and alternative splicing during terminal granulopoiesis. Materials & methods: Using whole genome bisulfite sequencing, reduced representation hydroxymethylation profiling and mRNA sequencing, we compare changes in DNA methylation, DNA hydroxymethylation, gene expression and alternative splicing in mouse promyelocytes and granulocytes. Results & conclusion: We show reduced DNA methylation at the promoters and enhancers of key granulopoiesis genes, indicating a regulatory role in the activation of lineage-specific genes during differentiation. Notably, increased DNA hydroxymethylation in exons is associated with preferential inclusion of specific exons in granulocytes. Overall, DNA methylation and hydroxymethylation changes at particular genomic loci may play specific roles in gene regulation or alternative splicing during terminal granulopoiesis. Data deposition: Whole genome bisulfite sequencing of mouse promyelocytes and granulocytes: Gene Expression Omnibus (GSE85517); mRNA sequencing of mouse promyelocytes and granulocytes: Gene Expression Omnibus (GSE48307); reduced representation 5-hydroxymethylation profiling of mouse promyelocytes and granulocytes: Bioproject (PRJNA495696).
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Affiliation(s)
- Dadi Gao
- Gene & Stem Cell Therapy Program Centenary Institute, University of Sydney, Camperdown 2050, Australia
- Bioinformatics Laboratory Centenary Institute, University of Sydney, Camperdown 2050, Australia
- Sydney Medical School, University of Sydney, NSW 2006, Australia
- Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA
- Department of Neurology, Harvard Medical School, Boston, MA 02115, USA
| | - Natalia Pinello
- Gene & Stem Cell Therapy Program Centenary Institute, University of Sydney, Camperdown 2050, Australia
- Sydney Medical School, University of Sydney, NSW 2006, Australia
- Gene Regulation in Cancer Laboratory Centenary Institute, University of Sydney, Camperdown 2050, Australia
| | - Trung V Nguyen
- Gene & Stem Cell Therapy Program Centenary Institute, University of Sydney, Camperdown 2050, Australia
- Sydney Medical School, University of Sydney, NSW 2006, Australia
- Gene Regulation in Cancer Laboratory Centenary Institute, University of Sydney, Camperdown 2050, Australia
| | - Annora Thoeng
- Gene & Stem Cell Therapy Program Centenary Institute, University of Sydney, Camperdown 2050, Australia
- Sydney Medical School, University of Sydney, NSW 2006, Australia
| | - Rajini Nagarajah
- Gene & Stem Cell Therapy Program Centenary Institute, University of Sydney, Camperdown 2050, Australia
- Sydney Medical School, University of Sydney, NSW 2006, Australia
| | - Jeff Holst
- Sydney Medical School, University of Sydney, NSW 2006, Australia
- Origins of Cancer Program Centenary Institute, University of Sydney, Camperdown 2050, Australia
| | - John EJ Rasko
- Gene & Stem Cell Therapy Program Centenary Institute, University of Sydney, Camperdown 2050, Australia
- Sydney Medical School, University of Sydney, NSW 2006, Australia
- Cell & Molecular Therapies, Royal Prince Alfred Hospital, Camperdown 2050, Australia
| | - Justin J-L Wong
- Gene & Stem Cell Therapy Program Centenary Institute, University of Sydney, Camperdown 2050, Australia
- Sydney Medical School, University of Sydney, NSW 2006, Australia
- Gene Regulation in Cancer Laboratory Centenary Institute, University of Sydney, Camperdown 2050, Australia
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Sánchez-Vega F, Gotea V, Chen YC, Elnitski L. CpG island methylator phenotype in adenocarcinomas from the digestive tract: Methods, conclusions, and controversies. World J Gastrointest Oncol 2017; 9:105-120. [PMID: 28344746 PMCID: PMC5348626 DOI: 10.4251/wjgo.v9.i3.105] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2016] [Revised: 10/01/2016] [Accepted: 01/03/2017] [Indexed: 02/05/2023] Open
Abstract
Over the last two decades, cancer-related alterations in DNA methylation that regulate transcription have been reported for a variety of tumors of the gastrointestinal tract. Due to its relevance for translational research, great emphasis has been placed on the analysis and molecular characterization of the CpG island methylator phenotype (CIMP), defined as widespread hypermethylation of CpG islands in clinically distinct subsets of cancer patients. Here, we present an overview of previous work in this field and also explore some open questions using cross-platform data for esophageal, gastric, and colorectal adenocarcinomas from The Cancer Genome Atlas. We provide a data-driven, pan-gastrointestinal stratification of individual samples based on CIMP status and we investigate correlations with oncogenic alterations, including somatic mutations and epigenetic silencing of tumor suppressor genes. Besides known events in CIMP such as BRAF V600E mutation, CDKN2A silencing or MLH1 inactivation, we discuss the potential role of emerging actors such as Wnt pathway deregulation through truncating mutations in RNF43 and epigenetic silencing of WIF1. Our results highlight the existence of molecular similarities that are superimposed over a larger backbone of tissue-specific features and can be exploited to reduce heterogeneity of response in clinical trials.
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Zhuo C, Li Q, Wu Y, Li Y, Nie J, Li D, Peng J, Lian P, Li B, Cai G, Li X, Cai S. LINE-1 hypomethylation in normal colon mucosa is associated with poor survival in Chinese patients with sporadic colon cancer. Oncotarget 2016; 6:23820-36. [PMID: 26172297 PMCID: PMC4695154 DOI: 10.18632/oncotarget.4450] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2015] [Accepted: 06/19/2015] [Indexed: 12/20/2022] Open
Abstract
Genetic and epigenetic pathways are not independent in colorectal cancer (CRC) carcinogenesis. We aimed to determine the influence of various molecular features on Chinese patients' colon cancer-specific survival (CCSS). Various genetic and epigenetic modifications were detected in paired tumor and normal mucosa tissue samples. The prognostic variables regarding patient CCSS were determined. Overall, 127 patients, including 83 males and 44 females, completed a median follow-up of 65 (3–85) months. A mean LINE-1 methylation rate of 64.62% (range, 9.45–86.93) was observed. Hypermethylation at the hMLH1 gene promoter was detected in 26 (20.47%) patients. KRAS was mutated in 52 (40.94%) patients. Sixteen (12.60%) patients were confirmed as microsatellite instability (MSI)-High, and 76 (59.84%) were found to have loss of heterozygosity at 18q. The LINE-1 methylation level, MSI status, perineural invasion and distant metastases were confirmed as independent prognostic factors for patient CCSS. A stratified survival analysis further revealed that certain subgroups of patients with LINE-1 hypomethylation had significantly worse survival (all p < 0.05). Our data revealed that both genetic and epigenetic abnormalities can concurrently exist during colonic tumorigenesis. As a global epigenetic change, LINE-1 hypomethylation in normal colon mucosa might be associated with a worse outcome in certain Chinese patients with colon cancer.
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Affiliation(s)
- Changhua Zhuo
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, People's Republic of China.,Department of Surgical Oncology, Fujian Provincial Cancer Hospital, Teaching Hospital of Fujian Medical University, Fuzhou 350014, People's Republic of China
| | - Qingguo Li
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, People's Republic of China
| | - Yuchen Wu
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, People's Republic of China
| | - Yiwei Li
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, People's Republic of China
| | - Jia Nie
- Key Laboratory of Molecular Virology & Immunology, Unit of Molecular Immunology, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, People's Republic of China
| | - Dawei Li
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, People's Republic of China
| | - Junjie Peng
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, People's Republic of China
| | - Peng Lian
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, People's Republic of China
| | - Bin Li
- Key Laboratory of Molecular Virology & Immunology, Unit of Molecular Immunology, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, People's Republic of China
| | - Guoxiang Cai
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, People's Republic of China
| | - Xinxiang Li
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, People's Republic of China
| | - Sanjun Cai
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, People's Republic of China
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11
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Zong L, Abe M, Ji J, Zhu WG, Yu D. Tracking the Correlation Between CpG Island Methylator Phenotype and Other Molecular Features and Clinicopathological Features in Human Colorectal Cancers: A Systematic Review and Meta-Analysis. Clin Transl Gastroenterol 2016; 7:e151. [PMID: 26963001 PMCID: PMC4822093 DOI: 10.1038/ctg.2016.14] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2015] [Accepted: 01/21/2016] [Indexed: 01/08/2023] Open
Abstract
OBJECTIVES The controversy of CpG island methylator phenotype (CIMP) in colorectal cancers (CRCs) persists, despite many studies that have been conducted on its correlation with molecular and clinicopathological features. To drive a more precise estimate of the strength of this postulated relationship, a meta-analysis was performed. METHODS A comprehensive search for studies reporting molecular and clinicopathological features of CRCs stratified by CIMP was performed within the PubMed, EMBASE, and Cochrane Library. CIMP was defined by either one of the three panels of gene-specific CIMP markers (Weisenberger panel, classic panel, or a mixture panel of the previous two) or the genome-wide DNA methylation profile. The associations of CIMP with outcome parameters were estimated using odds ratio (OR) or weighted mean difference (WMD) or hazard ratios (HRs) with 95% confidence interval (CI) for each study using a fixed effects or random effects model. RESULTS A total of 29 studies involving 9,393 CRC patients were included for analysis. We observed more BRAF mutations (OR 34.87; 95% CI, 22.49-54.06) and microsatellite instability (MSI) (OR 12.85 95% CI, 8.84-18.68) in CIMP-positive vs. -negative CRCs, whereas KRAS mutations were less frequent (OR 0.47; 95% CI, 0.30-0.75). Subgroup analysis showed that only the genome-wide methylation profile-defined CIMP subset encompassed all BRAF-mutated CRCs. As expected, CIMP-positive CRCs displayed significant associations with female (OR 0.64; 95% CI, 0.56-0.72), older age at diagnosis (WMD 2.77; 95% CI, 1.15-4.38), proximal location (OR 6.91; 95% CI, 5.17-9.23), mucinous histology (OR 3.81; 95% CI, 2.93-4.95), and poor differentiation (OR 4.22; 95% CI, 2.52-7.08). Although CIMP did not show a correlation with tumor stage (OR 1.10; 95% CI, 0.82-1.46), it was associated with shorter overall survival (HR 1.73; 95% CI, 1.27-2.37). CONCLUSIONS The meta-analysis highlights that CIMP-positive CRCs take their own molecular feature, especially overlapping with BRAF mutations, and clinicopathological features and worse prognosis from CIMP-negative CRCs, suggesting CIMP could be used as an independent prognostic marker for CRCs.
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Affiliation(s)
- Liang Zong
- Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan
- Department of Gastrointestinal Surgery, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
- Department of Gastrointestinal Surgery, Su Bei People's Hospital of Jiangsu Province, Yangzhou University, Yangzhou, China
| | - Masanobu Abe
- Division for Health Service Promotion, University of Tokyo Hospital, Tokyo, Japan
| | - Jiafu Ji
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Surgery, Peking University Cancer Hospital and Institute, Beijing, China
| | - Wei-Guo Zhu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing, China
- Peking-Tsinghua University Center for Life Sciences, Peking University, Beijing, China
| | - Duonan Yu
- Non-coding RNA Center, Yangzhou University, Yangzhou, China
- Jiangsu Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Treatment of Senile Disease, Yangzhou, China
- Institute of Comparative Medicine, Yangzhou University, Yangzhou, China
- Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Disease and Zoonosis, Yangzhou, China
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12
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Hitchins MP. Finding the needle in a haystack: identification of cases of Lynch syndrome with MLH1 epimutation. Fam Cancer 2016; 15:413-22. [DOI: 10.1007/s10689-016-9887-3] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
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13
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Yamagishi H, Kuroda H, Imai Y, Hiraishi H. Molecular pathogenesis of sporadic colorectal cancers. CHINESE JOURNAL OF CANCER 2016; 35:4. [PMID: 26738600 PMCID: PMC4704376 DOI: 10.1186/s40880-015-0066-y] [Citation(s) in RCA: 111] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/24/2015] [Accepted: 09/01/2015] [Indexed: 02/07/2023]
Abstract
Colorectal cancer (CRC) results from the progressive accumulation of genetic and epigenetic alterations that lead to the transformation of normal colonic mucosa to adenocarcinoma. Approximately 75% of CRCs are sporadic and occur in people without genetic predisposition or family history of CRC. During the past two decades, sporadic CRCs were classified into three major groups according to frequently altered/mutated genes. These genes have been identified by linkage analyses of cancer-prone families and by individual mutation analyses of candidate genes selected on the basis of functional data. In the first half of this review, we describe the genetic pathways of sporadic CRCs and their clinicopathologic features. Recently, large-scale genome analyses have detected many infrequently mutated genes as well as a small number of frequently mutated genes. These infrequently mutated genes are likely described in a limited number of pathways. Gene-oriented models of CRC progression are being replaced by pathway-oriented models. In the second half of this review, we summarize the present knowledge of this research field and discuss its prospects.
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Affiliation(s)
- Hidetsugu Yamagishi
- Department of Diagnostic Pathology, Dokkyo Medical University, 880 Kita-Kobayashi, Mibu, Shimotsuga, Tochigi, 321-0293, Japan.
| | - Hajime Kuroda
- Department of Pathology, International University of Health and Welfare Hospital, 537-3 Iguchi, Nasushiobara, Tochigi, 329-2763, Japan.
| | - Yasuo Imai
- Department of Diagnostic Pathology, Dokkyo Medical University, 880 Kita-Kobayashi, Mibu, Shimotsuga, Tochigi, 321-0293, Japan.
- Department of Diagnostic Pathology, Ota Memorial Hospital, Fuji Heavy Industries Health Insurance Society, 455-1 Oshima, Ota, Gunma, 373-8585, Japan.
| | - Hideyuki Hiraishi
- Department of Gastroenterology, Dokkyo Medical University, 880 Kita-Kobayashi, Mibu, Shimotsuga, Tochigi, 321-0293, Japan.
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14
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Abstract
Constitutional epimutation, which is an aberration in gene expression due to an altered epigenotype that is widely distributed in normal tissues (albeit frequently mosaic), provides an alternative mechanism to genetic mutation for cancer predisposition. Observational studies in cancer-affected families have revealed intergenerational inheritance of constitutional epimutation, providing unique insights into the heritability of epigenetic traits in humans. In this Opinion article, the potential contribution of constitutional epimutation to the 'missing' causality and heritability of cancer is explored.
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Affiliation(s)
- Megan P Hitchins
- Department of Medicine (Oncology), Stanford Cancer Institute, Stanford University, Grant Building S169, 1291 Welch Road, Stanford, California 94305, USA
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15
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Wong JJL, Lau KA, Pinello N, Rasko JEJ. Epigenetic modifications of splicing factor genes in myelodysplastic syndromes and acute myeloid leukemia. Cancer Sci 2014; 105:1457-63. [PMID: 25220401 PMCID: PMC4462368 DOI: 10.1111/cas.12532] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2014] [Revised: 08/28/2014] [Accepted: 09/01/2014] [Indexed: 12/19/2022] Open
Abstract
Somatic mutations in splicing factor genes have frequently been reported in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Although aberrant epigenetic changes are frequently implicated in blood cancers, their direct role in suppressing one or both alleles of critical splicing factors has not been previously examined. Here, we examined promoter DNA hypermethylation of nine splicing factors, SF3B1, SRSF2, U2AF1, ZRSR2, SF3A1, HNRNPR, MATR3, ZFR, and YBX3 in 10 leukemic cell lines and 94 MDS or AML patient samples from the Australasian Leukemia and Lymphoma Group Tissue Bank. The only evidence of epigenetic effects was hypermethylation of the YBX3 promoter in U937 cells in conjunction with an enrichment of histone marks associated with gene silencing. In silico analysis of DNA methylation data for 173 AML samples generated by the Cancer Genome Atlas Research Network revealed promoter hypermethylation of the gene encoding Y box binding protein 3, YBX3, in 11/173 (6.4%) AML cases, which was significantly associated with reduced mRNA expression (P < 0.0001). Hypermethylation of the ZRSR2 promoter was also detected in 7/173 (4%) cases but was not associated with decreased mRNA expression (P = 0.1204). Hypermethylation was absent at the promoter of seven other splicing factor genes in all cell lines and patient samples examined. We conclude that DNA hypermethylation does not frequently silence splicing factors in MDS and AML. However, in the case of YBX3, promoter hypermethylation-induced downregulation may contribute to the pathogenesis or maintenance of AML.
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Affiliation(s)
- Justin J-L Wong
- Gene and Stem Cell Therapy Program, Centenary Institute, Camperdown, New South Wales, Australia; Sydney Medical School, University of Sydney, Camperdown, New South Wales, Australia
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16
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Nizam ZM, Abdul Aziz AA, Kaur G, Abu Hassan MR, Mohd Sidek AS, Yeh LY, Mazuwin M, Ankathil R. Contribution of the MLH1 -93G>a promoter polymorphism in modulating susceptibility risk in Malaysian colorectal cancer patients. Asian Pac J Cancer Prev 2014; 14:619-24. [PMID: 23621208 DOI: 10.7314/apjcp.2013.14.2.619] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Colorectal cancer (CRC) exists in a more common sporadic form and less common hereditary forms, associated with the Lynch syndrome, familial adenomatous polyposis (FAP) and other rare syndromes. Sporadic CRC is believed to arise as a result of close interaction between environmental factors, including dietary and lifestyle habits, and genetic predisposition factors. In contrast, hereditary forms such as those related to the Lynch syndrome result from inheritance of germline mutations of mismatch repair (MMR) genes. However, in certain cases, the influence of low penetrance alleles in familial colorectal cancer susceptibility is also undeniable. AIM To investigate the genotype frequencies of MLH1 promoter polymorphism -93G>A and to determine whether it could play any role in modulating familial and sporadic CRC susceptibility risk. METHODS A case-control study comprising of 104 histopathologically confirmed CRC patients as cases (52 sporadic CRC and 52 Lynch syndrome patients) and 104 normal healthy individuals as controls was undertaken. DNA was extracted from peripheral blood and the polymorphism was genotyped employing PCR-RFLP methods. The genotypes were categorized into homozygous wild type, heterozygous and homozygous variants. The risk association between these polymorphisms and CRC susceptibility risk was calculated using binary logistic regression analysis and deriving odds ratios (ORs). RESULTS When risk association was investigated for all CRC patients as a single group, the heterozygous (G/A) genotype showed a significantly higher risk for CRC susceptibility with an OR of 2.273, (95%CI: 1.133-4.558 and p-value=0.021). When analyzed specifically for the 2 types of CRC, the heterozygous (G/A) genotype showed significantly higher risk for sporadic CRC susceptibility with and OR of 3.714, (95%CI: 1.416-9.740 and p-value=0.008). Despite high OR value was observed for Lynch syndrome (OR: 1.600, 95%CI: 0.715-3.581), the risk was not statistically significant (P=0.253). CONCLUSION Our results suggest an influence of MLH1 promoter polymorphism -93G>A in modulating susceptibility risk in Malaysian CRC patients, especially those with sporadic disease.
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17
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Suzuki H, Yamamoto E, Maruyama R, Niinuma T, Kai M. Biological significance of the CpG island methylator phenotype. Biochem Biophys Res Commun 2014; 455:35-42. [PMID: 25016183 DOI: 10.1016/j.bbrc.2014.07.007] [Citation(s) in RCA: 64] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2014] [Revised: 06/25/2014] [Accepted: 07/01/2014] [Indexed: 12/12/2022]
Abstract
Cancers exhibiting the CpG island methylator phenotype (CIMP) are found among a wide variety of human malignancies and represent a subclass of tumors showing concurrent hypermethylation of multiple CpG islands. These CIMP-positive tumors often exhibit characteristic molecular and clinicopathological features, suggesting CIMP represents a distinct carcinogenic pathway. However, marker genes to define CIMP have been largely inconsistent among studies, which has caused results to vary. Nonetheless, recent advances in genome-wide methylation analysis have enabled the existence of CIMP to be confirmed, and large-scale cancer genome analyses have begun to unravel the previously unknown molecular basis of CIMP tumors. CIMP is strongly associated with clinical outcome, suggesting it may be a predictive biomarker.
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Affiliation(s)
- Hiromu Suzuki
- Department of Molecular Biology, Sapporo Medical University, Sapporo, Japan.
| | - Eiichiro Yamamoto
- Department of Molecular Biology, Sapporo Medical University, Sapporo, Japan
| | - Reo Maruyama
- Department of Molecular Biology, Sapporo Medical University, Sapporo, Japan
| | - Takeshi Niinuma
- Department of Molecular Biology, Sapporo Medical University, Sapporo, Japan
| | - Masahiro Kai
- Department of Molecular Biology, Sapporo Medical University, Sapporo, Japan
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18
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Zoratto F, Rossi L, Verrico M, Papa A, Basso E, Zullo A, Tomao L, Romiti A, Lo Russo G, Tomao S. Focus on genetic and epigenetic events of colorectal cancer pathogenesis: implications for molecular diagnosis. Tumour Biol 2014; 35:6195-206. [PMID: 25051912 DOI: 10.1007/s13277-014-1845-9] [Citation(s) in RCA: 84] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2013] [Accepted: 03/12/2014] [Indexed: 12/15/2022] Open
Abstract
Originally, colorectal cancer (CRC) tumorigenesis was understood as a multistep process that involved accumulation of tumor suppressor genes and oncogenes mutations, such as APC, TP53 and KRAS. However, this assumption proposed a relatively limited repertoire of genetic alterations. In the last decade, there have been major advances in knowledge of multiple molecular pathways involved in CRC pathogenesis, particularly regarding cytogenetic and epigenetic events. Microsatellite instability, chromosomal instability and CpG island methylator phenotype are the most analyzed cytogenetic changes, while DNA methylation, modifications in histone proteins and microRNAs (miRNAs) were analyzed in the field of epigenetic alterations. Therefore, CRC development results from interactions at many levels between genetic and epigenetic amendments. Furthermore, hereditary cancer syndrome and individual or environmental risk factors should not be ignored. The difficulties in this setting are addressed to understand the molecular basis of individual susceptibility to CRC and to determine the roles of genetic and epigenetic alterations, in order to yield more effective prevention strategies in CRC patients and directing their treatment. This review summarizes the most investigated biomolecular pathways involved in CRC pathogenesis, their role as biomarkers for early CRC diagnosis and their possible use to stratify susceptible patients into appropriate screening or surveillance programs.
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Affiliation(s)
- Federica Zoratto
- Oncology Unit 2, Azienda Ospedaliera-Universitaria Pisana, Ospedale Santa Chiara, Pisa, 56126, Italy,
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19
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Abstract
Recognition by Warthin of the familial clustering of colorectal and gynaecological cancers a century ago laid the foundation for the recognition of familial cancer. By tracking afflicted pedigrees, Lynch defined the clinical characteristics and argued for a heritable genetic component to this autosomal dominant cancer susceptibility condition, now termed Lynch syndrome. This was proven in the 1990s, with the discovery of deleterious germline mutations of the mismatch repair genes as its cause. Yet despite the genetic revolution at the turn of the twenty-first century, no pathogenic mutation was identifiable in approximately one-third of cases with suspected Lynch syndrome. In the past decade, the alternative mechanism of constitutional epimutation of the two major mismatch repair genes, MLH1 and MSH2, was identified in a proportion of these outstanding cases. This epigenetic defect, characterized by methylation and transcriptional inactivation of a single genetic allele within normal tissues, predisposes to the development of Lynch-type cancers. MSH2 and some MLH1 epimutations have been linked to genetic alterations within their vicinity and demonstrate dominant inheritance, whilst other MLH1 epimutations are reversible between generations and demonstrate non-Mendelian inheritance. This review charts the discovery of mismatch repair epimutations, their aetiological role in Lynch syndrome and the mechanistic basis for their variable inheritance patterns.
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Affiliation(s)
- Megan P Hitchins
- Adult Cancer Program, Medical Epigenetics Laboratory, Lowy Cancer Research Centre, Prince of Wales Clinical School, University of New South Wales, Randwick, NSW, Australia.
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20
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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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21
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Kim HS. [Site-specific colorectal cancer; how is it different?]. THE KOREAN JOURNAL OF GASTROENTEROLOGY 2013; 61:63-70. [PMID: 23458982 DOI: 10.4166/kjg.2013.61.2.63] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
One of the most critical characteristics of colorectal cancer (CRC) is the difference between proximal (right-sided colon cancer, RCC) and distal (left-sided colon cancer, LCC) disease. The recent CRC studies showed the unique characteristics of RCC; RCCs were more prevalent in women than men and old patients, and the age difference between RCC and LCC was more apparent in women. Moreover, relatively poor protection against RCC by colonoscopy is a clearly hot issue for alarm. Thus, the left and right colon have been considered as dichotomous or even different organs in the view of molecular, histopathological, epidemiologic and clinical bases for over three decades. However, the evolutionary data suggesting linearity from the rectum to ascending colon beyond the simple right-left dichotomization in the views of cancer molecular features and site-specific clinicopathological differences, support the need for a paradigm shift to the colorectal continuum model rather than the traditional two-colon concept. This new multi-segmental or colorectal continuum hypothesis would provide both the better understanding of the complex etiology of colorectal carcinogenesis and the tailored preventive and therapeutic strategies for CRC including individualized CRC screening programs.
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Affiliation(s)
- Hyun-Soo Kim
- Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea.
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22
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Kersten C, Louhimo J, Ålgars A, Lahdesmaki A, Cvancerova M, Stenstedt K, Haglund C, Gunnarsson U. Increased C-reactive protein implies a poorer stage-specific prognosis in colon cancer. Acta Oncol 2013; 52:1691-8. [PMID: 24102179 DOI: 10.3109/0284186x.2013.835494] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
BACKGROUND To characterize the stage-specific prognostic relevance of preoperative systemic inflammatory response, defined by C-reactive protein (CRP), in colon cancer (CC) patients. MATERIAL AND METHODS Data from CC patients operated on from 1998 to 2007 at three hospitals from three different Nordic countries were collected retrospectively from national registries, local databases and/or patient records. Patients with emergency surgery, infection or auto-immune disease were excluded. Associations between clinical or histopathological variables and CRP were assessed. Patients were followed from the date of surgery to death or end of follow-up. Disease-specific survival (DSS) was the main endpoint. RESULTS In total, 525 patients with age and stage distributions which were representative for CC patients were included. None of the patients was lost to follow-up. Age, TNM Stage, WHO differentiation grade and right-sided tumor location significantly associated with elevated CRP values, in contrast to postoperative morbidity, which did not. CRP levels were found to be a strong prognostic factor for DSS in CC. The risk of death due to CC was augmented with increasing levels of CRP in every stage of operated CC. Both short- and long-term DSS were impaired. The sub-hazard ratios for CRP-levels above 60 mg/L were 7.37 (CI 2.65-20.5) for stage I+ II, compared to 3.29 (CI 1.30-8.29) for stage III and 2.24 (CI 1.16-4.35) for stage IV. CONCLUSION Increase of CRP concentrations correlate with clinically relevant poorer disease-specific survival in each stage of CC.
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Affiliation(s)
- Christian Kersten
- Department of Oncology, Southern Hospital Trust , Kristiansand , Norway
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23
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Lochhead P, Kuchiba A, Imamura Y, Liao X, Yamauchi M, Nishihara R, Qian ZR, Morikawa T, Shen J, Meyerhardt JA, Fuchs CS, Ogino S. Microsatellite instability and BRAF mutation testing in colorectal cancer prognostication. J Natl Cancer Inst 2013; 105:1151-6. [PMID: 23878352 PMCID: PMC3735463 DOI: 10.1093/jnci/djt173] [Citation(s) in RCA: 346] [Impact Index Per Article: 28.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2012] [Revised: 03/09/2013] [Accepted: 05/30/2013] [Indexed: 02/07/2023] Open
Abstract
BRAF mutation in colorectal cancer is associated with microsatellite instability (MSI) through its relationship with high-level CpG island methylator phenotype (CIMP) and MLH1 promoter methylation. MSI and BRAF mutation analyses are routinely used for familial cancer risk assessment. To clarify clinical outcome associations of combined MSI/BRAF subgroups, we investigated survival in 1253 rectal and colon cancer patients within the Nurses' Health Study and Health Professionals Follow-up Study with available data on clinical and other molecular features, including CIMP, LINE-1 hypomethylation, and KRAS and PIK3CA mutations. Compared with the majority subtype of microsatellite stable (MSS)/BRAF-wild-type, MSS/BRAF-mutant, MSI-high/BRAF-mutant, and MSI-high/BRAF-wild-type subtypes showed multivariable colorectal cancer-specific mortality hazard ratios of 1.60 (95% confidence interval [CI] =1.12 to 2.28; P = .009), 0.48 (95% CI = 0.27 to 0.87; P = .02), and 0.25 (95% CI = 0.12 to 0.52; P < .001), respectively. No evidence existed for a differential prognostic role of BRAF mutation by MSI status (P(interaction) > .50). Combined BRAF/MSI status in colorectal cancer is a tumor molecular biomarker for prognosic risk stratification.
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Affiliation(s)
- Paul Lochhead
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA
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Subsets of microsatellite-unstable colorectal cancers exhibit discordance between the CpG island methylator phenotype and MLH1 methylation status. Mod Pathol 2013; 26:1013-22. [PMID: 23370766 DOI: 10.1038/modpathol.2012.241] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2012] [Revised: 12/11/2012] [Accepted: 12/11/2012] [Indexed: 12/26/2022]
Abstract
Although the presence of MLH1 methylation in microsatellite-unstable colorectal cancer generally indicates involvement of the CpG island methylator phenotype (CIMP) in the development of the tumor, these two conditions do not always correlate. A minority of microsatellite-unstable colorectal cancers exhibit discordance between CIMP and MLH1 methylation statuses. However, the clinicopathological features of such microsatellite-unstable colorectal cancers with discrepant MLH1 methylation and CIMP statuses remain poorly studied. Microsatellite-unstable colorectal cancers (n=220) were analyzed for CIMP and MLH1 methylation statuses using the MethyLight assay. Based on the combinatorial CIMP and MLH1 methylation statuses, the microsatellite-unstable colorectal cancers were grouped into four subtypes (CIMP-high (CIMP-H) MLH1 methylation-positive (MLH1m+), CIMP-H MLH1 methylation-negative, CIMP-low/0 (CIMP-L/0) MLH1m+, and CIMP-L/0 MLH1 methylation-negative), which were compared in terms of their associations with clinicopathological and molecular features. The CIMP-L/0 MLH1 methylation-negative and CIMP-H MLH1m+ subtypes were predominant, comprising 63.6 and 24.1% of total microsatellite-unstable colorectal cancers, respectively. The discordant subtypes, CIMP-H MLH1 methylation-negative and CIMP-L/0 MLH1m+, were found in 5 and 7% of microsatellite-unstable colorectal cancers, respectively. The CIMP-H MLH1 methylation-negative subtype exhibited elevated incidence rates in male patients and was associated with larger tumor size, more frequent loss of MSH2 expression, increased frequency of KRAS mutation, and advanced cancer stage. The CIMP-L/0 MLH1m+ subtype was associated with onset at an earlier age, a predominance of MLH1 loss, and earlier cancer stage. None of the CIMP-L/0 MLH1m+ subtype patients succumbed to death during the follow-up. Our findings suggest that the discordant subtypes of colorectal cancers exhibit distinct clinicopathological and molecular features, although the proportion of discordant subtypes is low. The microsatellite-unstable colorectal cancers of the same CIMP status tended to exhibit different clinicopathological features depending on MLH1 methylation status.
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Nishihara R, Morikawa T, Kuchiba A, Lochhead P, Yamauchi M, Liao X, Imamura Y, Nosho K, Shima K, Kawachi I, Qian ZR, Fuchs CS, Chan AT, Giovannucci E, Ogino S. A prospective study of duration of smoking cessation and colorectal cancer risk by epigenetics-related tumor classification. Am J Epidemiol 2013; 178:84-100. [PMID: 23788674 PMCID: PMC3698990 DOI: 10.1093/aje/kws431] [Citation(s) in RCA: 74] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2012] [Accepted: 10/24/2012] [Indexed: 02/07/2023] Open
Abstract
The effect of duration of cigarette smoking cessation on colorectal cancer risk by molecular subtypes remains unclear. Using duplication-method Cox proportional-hazards regression analyses, we examined associations between duration of smoking cessation and colorectal cancer risk according to status of CpG island methylator phenotype (CIMP), microsatellite instability, v-raf murine sarcoma viral oncogene homolog B1 (BRAF) mutation, or DNA methyltransferase-3B (DNMT3B) expression. Follow-up of 134,204 individuals in 2 US nationwide prospective cohorts (Nurses' Health Study (1980-2008) and Health Professionals Follow-up Study (1986-2008)) resulted in 1,260 incident rectal and colon cancers with available molecular data. Compared with current smoking, 10-19, 20-39, and ≥40 years of smoking cessation were associated with a lower risk of CIMP-high colorectal cancer, with multivariate hazard ratios (95% confidence intervals) of 0.53 (0.29, 0.95), 0.52 (0.32, 0.85), and 0.50 (0.27, 0.94), respectively (Ptrend = 0.001), but not with the risk of CIMP-low/CIMP-negative cancer (Ptrend = 0.25) (Pheterogeneity = 0.02, between CIMP-high and CIMP-low/CIMP-negative cancer risks). Differential associations between smoking cessation and cancer risks by microsatellite instability (Pheterogeneity = 0.02), DNMT3B expression (Pheterogeneity = 0.03), and BRAF (Pheterogeneity = 0.10) status appeared to be driven by the associations of CIMP-high cancer with microsatellite instability-high, DNMT3B-positive, and BRAF-mutated cancers. These molecular pathological epidemiology data suggest a protective effect of smoking cessation on a DNA methylation-related carcinogenesis pathway leading to CIMP-high colorectal cancer.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | | | | | | | - Shuji Ogino
- Correspondence to Dr. Shuji Ogino, Department of Medical Oncology, Dana-Farber Cancer Institute, Department of Epidemiology, Harvard School of Public Health, 450 Brookline Avenue, Room JF-215C, Boston, MA 02215 (e-mail: )
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Ogino S, Lochhead P, Chan AT, Nishihara R, Cho E, Wolpin BM, Meyerhardt JA, Meissner A, Schernhammer ES, Fuchs CS, Giovannucci E. Molecular pathological epidemiology of epigenetics: emerging integrative science to analyze environment, host, and disease. Mod Pathol 2013; 26:465-84. [PMID: 23307060 PMCID: PMC3637979 DOI: 10.1038/modpathol.2012.214] [Citation(s) in RCA: 166] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Epigenetics acts as an interface between environmental/exogenous factors, cellular responses, and pathological processes. Aberrant epigenetic signatures are a hallmark of complex multifactorial diseases (including neoplasms and malignancies such as leukemias, lymphomas, sarcomas, and breast, lung, prostate, liver, and colorectal cancers). Epigenetic signatures (DNA methylation, mRNA and microRNA expression, etc) may serve as biomarkers for risk stratification, early detection, and disease classification, as well as targets for therapy and chemoprevention. In particular, DNA methylation assays are widely applied to formalin-fixed, paraffin-embedded archival tissue specimens as clinical pathology tests. To better understand the interplay between etiological factors, cellular molecular characteristics, and disease evolution, the field of 'molecular pathological epidemiology (MPE)' has emerged as an interdisciplinary integration of 'molecular pathology' and 'epidemiology'. In contrast to traditional epidemiological research including genome-wide association studies (GWAS), MPE is founded on the unique disease principle, that is, each disease process results from unique profiles of exposomes, epigenomes, transcriptomes, proteomes, metabolomes, microbiomes, and interactomes in relation to the macroenvironment and tissue microenvironment. MPE may represent a logical evolution of GWAS, termed 'GWAS-MPE approach'. Although epigenome-wide association study attracts increasing attention, currently, it has a fundamental problem in that each cell within one individual has a unique, time-varying epigenome. Having a similar conceptual framework to systems biology, the holistic MPE approach enables us to link potential etiological factors to specific molecular pathology, and gain novel pathogenic insights on causality. The widespread application of epigenome (eg, methylome) analyses will enhance our understanding of disease heterogeneity, epigenotypes (CpG island methylator phenotype, LINE-1 (long interspersed nucleotide element-1; also called long interspersed nuclear element-1; long interspersed element-1; L1) hypomethylation, etc), and host-disease interactions. In this article, we illustrate increasing contribution of modern pathology to broader public health sciences, which attests pivotal roles of pathologists in the new integrated MPE science towards our ultimate goal of personalized medicine and prevention.
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Affiliation(s)
- Shuji Ogino
- Department of Pathology, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA 02215, USA.
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Pancione M, Remo A, Sabatino L, Zanella C, Votino C, Fucci A, Di Blasi A, Lepore G, Daniele B, Fenizia F, Molinari E, Normanno N, Manfrin E, Vendraminelli R, Colantuoni V. Right-sided rhabdoid colorectal tumors might be related to the serrated pathway. Diagn Pathol 2013; 8:31. [PMID: 23425390 PMCID: PMC3640919 DOI: 10.1186/1746-1596-8-31] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2012] [Accepted: 10/24/2012] [Indexed: 01/16/2023] Open
Abstract
BACKGROUND Rhabdoid colorectal tumor (RCT) is a rare, highly aggressive neoplasm recurrent in elderly patients, commonly at the caecum. The molecular mechanisms underlying RCT pathogenesis remain poorly elucidated. The differential diagnosis is with the malignant rhabdoid tumors of infancy characterized by genetic inactivation of SMARCB1 (INI1) or deletions of chromosome 22q12 locus. MATERIALS AND METHODS To shed light on RCT pathogenesis, we investigated genetic and epigenetic alterations in two cases of pure and composite RCT and compared them with the profiles of matched adenomas and normal mucosa. Immunohistochemical analysis, FISH, methylation specific PCR and DNA sequencing analysis were performed on paraffin-embedded tissues. RESULTS Loss of epithelial markers, (CK20, CDX2 and E-cadherin) and intense vimentin expression was observed in RCTs but neither in the normal mucosa or adenomas. INI1 expression was detected in normal mucosa, adenomas and retained in pure RCT, while it was undetected in composite RCT. Rearrangement of the 22q12 locus was found only in pure RCT. The APC/β-catenin pathway was not altered, while MLH1 immunostaining was negative in RCTs and positive in adenomas and normal mucosa. These expression profiles were associated with V600E BRAF mutation, a progressive accumulation of promoter methylation at specific CIMP loci and additional genes from the normal mucosa to tubular adenoma and RCT. CONCLUSIONS Right-sided RCT could be characterized by epigenetic events and molecular features likely similar to those occurring in the serrated pathway and associated with epithelial-mesenchymal transition. These extremely rare tumors may benefit from the use of new biological molecules specific for colorectal carcinoma. VIRTUAL SLIDES The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1641385210804556.
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Affiliation(s)
- Massimo Pancione
- Department of Biological, Geological and Environmental Sciences, University of Sannio, Benevento, Italy
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Karpinski P, Walter M, Szmida E, Ramsey D, Misiak B, Kozlowska J, Bebenek M, Grzebieniak Z, Blin N, Laczmanski L, Sasiadek MM. Intermediate- and low-methylation epigenotypes do not correspond to CpG island methylator phenotype (low and -zero) in colorectal cancer. Cancer Epidemiol Biomarkers Prev 2012; 22:201-8. [PMID: 23175427 DOI: 10.1158/1055-9965.epi-12-0157] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND Most recent genome-wide studies on the CpG island methylation in colorectal cancer (CRC) have led to the discovery of at least 3 distinct methylation clusters. However, there remains an uncertainty whether the CRC clusters identified in these studies represent compatible phenotypes. METHODS We carried out comprehensive genome-scale DNA methylation profiling by Illumina Infinium HumanMethylation27 of 21 DNA pools that represent 84 CRC samples divided according to their high-, intermediate-, and low-methylation epigenotypes (HME, IME, and LME, respectively) and 70 normal-adjacent colonic tissues. We have also examined the relationship among 3 epigenotypes and chromosomal gains and deletions (assessed by Comparative Genomic Hybridization) in a group of 100 CRC samples. RESULTS The HME subgroup showed features associated with CpG island methylator phenotype - high (CIMP-high) including methylation of specific CpG sites (CpGs) as well as significantly lower mean number of chromosomal imbalances when compared with other epigenotypes. The IME subgroup displayed the lowest number of methylated CpGs (717 vs. 2,399 and 2,679 in HME and LME, respectively) and highest mean number of chromosomal imbalances when compared with HME (P, 0.001) and LME (P, 0.004). A comparison between the methylation profiles of 3 epigenotypes revealed more similarities between the HME and LME (1,669 methylated CpGs overlapped) than HME and IME (673 methylated CpGs overlapped). CONCLUSION Our results provide evidence that IME and LME CRCs show opposite features to those that have been previously attributed to CIMP-low and CIMP-0 CRCs. IMPACT These discrepancies should be considered when interpreting the data from a particular epigenotyping method.
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Affiliation(s)
- Pawel Karpinski
- Department of Genetics, Wroclaw Medical University, Poland, Poland.
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Abstract
A high-quality body of evidence supports the use of aspirin in reducing sporadic and hereditary adenomatous polyps, and numerous observational studies point to a reduction in colorectal cancer (CRC) risk. However, using aspirin as an adjuvant therapy in established CRC was until recently inconceivable. Now, evidence from both observational and clinical trials of aspirin for other indications suggests that aspirin initiation after (or before) the diagnosis of CRC improves CRC-specific mortality. These exciting findings need to be confirmed in prospective randomized trials that are underway. The recent failure of adjuvant irinotecan, bevacizumab, and cetuximab clinical trials compels us to reconsider our assumptions and paradigms for treating CRC. In this Review, we summarize clinical and preclinical evidence supporting aspirin use in established CRC and outline a framework for better understanding aspirin activity in the pathogenesis of CRC. We describe the data supporting adjuvant aspirin in resected CRC, including the issues of dose, duration and toxicity, and discuss potential biomarkers that may help better select patients for aspirin therapy.
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30
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Identification of constitutional MLH1 epimutations and promoter variants in colorectal cancer patients from the Colon Cancer Family Registry. Genet Med 2012; 15:25-35. [PMID: 22878509 PMCID: PMC3908650 DOI: 10.1038/gim.2012.91] [Citation(s) in RCA: 74] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
PURPOSE Constitutional MLH1 epimutations manifest as promoter methylation and silencing of the affected allele in normal tissues, predisposing to Lynch syndrome-associated cancers. This study investigated their frequency and inheritance. METHODS A total of 416 individuals with a colorectal cancer showing loss of MLH1 expression and without deleterious germline mutations in MLH1 were ascertained from the Colon Cancer Family Registry (C-CFR). Constitutive DNA samples were screened for MLH1 methylation in all 416 subjects and for promoter sequence changes in 357 individuals. RESULTS Constitutional MLH1 epimutations were identified in 16 subjects. Of these, seven (1.7%) had mono- or hemi-allelic methylation and eight had low-level methylation (2%). In one subject the epimutation was linked to the c.-27C>A promoter variant. Testing of 37 relatives from nine probands revealed paternal transmission of low-level methylation segregating with a c.+27G>A variant in one case. Five additional probands had a promoter variant without an MLH1 epimutation, with three showing diminished promoter activity in functional assays. CONCLUSION Although rare, sequence changes in the regulatory region of MLH1 and aberrant methylation may alone or together predispose to the development of cancer. Screening for these changes is warranted in individuals who have a negative germline sequence screen of MLH1 and loss of MLH1 expression in their tumor.Genet Med 2013:15(1):25-35.
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Genetic and epigenetic events generate multiple pathways in colorectal cancer progression. PATHOLOGY RESEARCH INTERNATIONAL 2012; 2012:509348. [PMID: 22888469 PMCID: PMC3409552 DOI: 10.1155/2012/509348] [Citation(s) in RCA: 109] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/09/2012] [Revised: 05/15/2012] [Accepted: 05/21/2012] [Indexed: 12/13/2022]
Abstract
Colorectal cancer (CRC) is one of the most common causes of death, despite decades of research. Initially considered as a disease due to genetic mutations, it is now viewed as a complex malignancy because of the involvement of epigenetic abnormalities. A functional equivalence between genetic and epigenetic mechanisms has been suggested in CRC initiation and progression. A hallmark of CRC is its pathogenetic heterogeneity attained through at least three distinct pathways: a traditional (adenoma-carcinoma sequence), an alternative, and more recently the so-called serrated pathway. While the alternative pathway is more heterogeneous and less characterized, the traditional and serrated pathways appear to be more homogeneous and clearly distinct. One unsolved question in colon cancer biology concerns the cells of origin and from which crypt compartment the different pathways originate. Based on molecular and pathological evidences, we propose that the traditional and serrated pathways originate from different crypt compartments explaining their genetic/epigenetic and clinicopathological differences. In this paper, we will discuss the current knowledge of CRC pathogenesis and, specifically, summarize the role of genetic/epigenetic changes in the origin and progression of the multiple CRC pathways. Elucidation of the link between the molecular and clinico-pathological aspects of CRC would improve our understanding of its etiology and impact both prevention and treatment.
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Liu J, Hesson LB, Meagher AP, Bourke MJ, Hawkins NJ, Rand KN, Molloy PL, Pimanda JE, Ward RL. Relative distribution of folate species is associated with global DNA methylation in human colorectal mucosa. Cancer Prev Res (Phila) 2012; 5:921-9. [PMID: 22609762 DOI: 10.1158/1940-6207.capr-11-0577] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Folate exists as functionally diverse species within cells. Although folate deficiency may contribute to DNA hypomethylation in colorectal cancer, findings on the association between total folate concentration and global DNA methylation have been inconsistent. This study determined global, LINE-1, and Alu DNA methylation in blood and colon of healthy and colorectal cancer patients and their relationship to folate distribution. Blood and normal mucosa from 112 colorectal cancer patients and 114 healthy people were analyzed for global DNA methylation and folate species distribution using liquid chromatography tandem mass spectrometry. Repeat element methylation was determined using end-specific PCR. Colorectal mucosa had lower global and repeat element DNA methylation compared with peripheral blood (P < 0.0001). After adjusting for age, sex and smoking history, global but not repeat element methylation was marginally higher in normal mucosa from colorectal cancer patients compared with healthy individuals. Colorectal mucosa from colorectal cancer subjects had lower 5-methyltetrahydrofolate and higher tetrahydrofolate and formyltetrahydrofolate levels than blood from the same individual. Blood folate levels should not be used as a surrogate for the levels in colorectal mucosa because there are marked differences in folate species distribution between the two tissues. Similarly, repeat element methylation is not a good surrogate measure of global DNA methylation in both blood and colonic mucosa. There was no evidence that mucosal global DNA methylation or folate distribution was related to the presence of cancer per se, suggesting that if abnormalities exist, they are confined to individual cells rather than the entire colon.
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Affiliation(s)
- Jia Liu
- Lowy Cancer Research Centre and Prince of Wales Clinical School, Australia
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33
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Dallosso AR, Øster B, Greenhough A, Thorsen K, Curry TJ, Owen C, Hancock AL, Szemes M, Paraskeva C, Frank M, Andersen CL, Malik K. Long-range epigenetic silencing of chromosome 5q31 protocadherins is involved in early and late stages of colorectal tumorigenesis through modulation of oncogenic pathways. Oncogene 2012; 31:4409-19. [PMID: 22249255 DOI: 10.1038/onc.2011.609] [Citation(s) in RCA: 63] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Loss of tumour suppressor gene function can occur as a result of epigenetic silencing of large chromosomal regions, referred to as long-range epigenetic silencing (LRES), and genome-wide analyses have revealed that LRES is present in many cancer types. Here we utilize Illumina Beadchip methylation array analysis to identify LRES across 800 kb of chromosome 5q31 in colorectal adenomas and carcinomas (n=34) relative to normal colonic epithelial DNA (n=6). This region encompasses 53 individual protocadherin (PCDH) genes divided among three gene clusters. Hypermethylation within these gene clusters is asynchronous; while most PCDH hypermethylation occurs early, and is apparent in adenomas, PCDHGC3 promoter methylation occurs later in the adenoma-carcinoma transition. PCDHGC3 was hypermethylated in 17/28 carcinomas (60.7%) according to methylation array analysis. Quantitative real-time reverse transcription-polymerase chain reaction showed that PCDHGC3 is the highest expressed PCDH in normal colonic epithelium, and that there was a strong reciprocal relationship between PCDHGC3 methylation and expression in carcinomas (R=-0.84). PCDH LRES patterns are reflected in colorectal tumour cell lines; adenoma cell lines are not methylated at PCDHGC3 and show abundant expression at the mRNA and protein level, while the expression is suppressed in hypermethylated carcinoma cell lines (R=-0.73). Short-interfering RNA-mediated reduction of PCDHGC3 led to a decrease of apoptosis in RG/C2 adenoma cells, and overexpression of PCDHGC3 in HCT116 cells resulted in the reduction of colony formation, consistent with tumour suppressor capabilities for PCDHGC3. Further functional analysis showed that PCDHGC3 can suppress Wnt and mammalian target of rapamycin signalling in colorectal cancer cell lines. Taken together, our data suggest that the PCDH LRES is an important tumour suppressor locus in colorectal cancer, and that PCDHGC3 may be a strong marker and driver for the adenoma-carcinoma transition.
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Affiliation(s)
- A R Dallosso
- Cancer Epigenetics Laboratory, School of Cellular and Molecular Medicine, University of Bristol, Bristol, UK
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Mutations and epimutations in the origin of cancer. Exp Cell Res 2011; 318:299-310. [PMID: 22182599 DOI: 10.1016/j.yexcr.2011.12.001] [Citation(s) in RCA: 59] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2011] [Revised: 12/02/2011] [Accepted: 12/03/2011] [Indexed: 12/12/2022]
Abstract
Cancer is traditionally viewed as a disease of abnormal cell proliferation controlled by a series of mutations. Mutations typically affect oncogenes or tumor suppressor genes thereby conferring growth advantage. Genomic instability facilitates mutation accumulation. Recent findings demonstrate that activation of oncogenes and inactivation of tumor suppressor genes, as well as genomic instability, can be achieved by epigenetic mechanisms as well. Unlike genetic mutations, epimutations do not change the base sequence of DNA and are potentially reversible. Similar to genetic mutations, epimutations are associated with specific patterns of gene expression that are heritable through cell divisions. Knudson's hypothesis postulates that inactivation of tumor suppressor genes requires two hits, with the first hit occurring either in somatic cells (sporadic cancer) or in the germline (hereditary cancer) and the second one always being somatic. Studies on hereditary and sporadic forms of colorectal carcinoma have made it evident that, apart from genetic mutations, epimutations may serve as either hit or both. Furthermore, recent next-generation sequencing studies show that epigenetic genes, such as those encoding histone modifying enzymes and subunits for chromatin remodeling systems, are themselves frequent targets of somatic mutations in cancer and can act like tumor suppressor genes or oncogenes. This review discusses genetic vs. epigenetic origin of cancer, including cancer susceptibility, in light of recent discoveries. Situations in which mutations and epimutations occur to serve analogous purposes are highlighted.
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Curtin K, Slattery ML, Samowitz WS. CpG island methylation in colorectal cancer: past, present and future. PATHOLOGY RESEARCH INTERNATIONAL 2011; 2011:902674. [PMID: 21559209 PMCID: PMC3090226 DOI: 10.4061/2011/902674] [Citation(s) in RCA: 95] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/11/2010] [Revised: 01/13/2011] [Accepted: 01/26/2011] [Indexed: 12/13/2022]
Abstract
The concept of a CpG island methylator phenotype, or CIMP, quickly became the focus of several colorectal cancer studies describing its clinical and pathological features after its introduction in 1999 by Toyota and colleagues. Further characterization of CIMP in tumors lead to widespread acceptance of the concept, as expressed by Shen and Issa in their 2005 editorial, "CIMP, at last." Since that time, extensive research efforts have brought great insights into the epidemiology and prognosis of CIMP+ tumors and other epigenetic mechanisms underlying tumorigenesis. With the advances in technology and subsequent cataloging of the human methylome in cancer and normal tissue, new directions in research to understand CIMP and its role in complex biological systems yield hope for future epigenetically based diagnostics and treatments.
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Affiliation(s)
- Karen Curtin
- Department of Internal Medicine, University of Utah Health Sciences Center, Salt Lake City, UT 84112, USA
| | - Martha L. Slattery
- Department of Internal Medicine, University of Utah Health Sciences Center, Salt Lake City, UT 84112, USA
| | - Wade S. Samowitz
- Department of Pathology, University of Utah Health Sciences Center, Salt Lake City, UT 84112, USA
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