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Aberrant DNA methylation of cancer-associated genes in gastric cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC-EURGAST) |
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| Authors: | Balassiano Karen Lima Sheila Jenab Mazda Overvad Kim Tjonneland Anne Boutron-Ruault Marie Christine Clavel-Chapelon Françoise Canzian Federico Kaaks Rudolf Boeing Heiner Meidtner Karina Trichopoulou Antonia Laglou Pagona Vineis Paolo Panico Salvatore Palli Domenico Grioni Sara Tumino Rosario Lund Eiliv Bueno-de-Mesquita H Bas Numans Mattjis E Peeters Petra H M Ramon Quirós J Sánchez María-José Navarro Carmen Ardanaz Eva Dorronsoro Miren Hallmans Göran Stenling Roger Ehrnström Roy Regner Sara Allen Naomi E Travis Ruth C Khaw Kay-Tee Offerhaus G Johan A Sala Nuria Riboli Elio Hainaut Pierre |
| Affiliation: | a International Agency for Research on Cancer (IARC), 150 Cours Albert Thomas, 69008 Lyon, France b Department of Epidemiology, School of Public Health, Aarhus University, Aarhus, Denmark c Danish Cancer Society, Institute of Cancer Epidemiology, Diet Cancer and Health, Copenhagen, Denmark d Centre for Research in Epidemiology and Population Health, Institut Gustave Roussy, Villejuif, France e Paris South University, Villejuif, France f Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg, Germany g Department of Epidemiology, German Institute of Human Nutrition, Potsdam-Rehbrücke, Germany h WHO Collaborating Center for Food and Nutrition Policies, Department of Hygiene, Epidemiology and Medical Statistics, University of Athens Medical School, Athens, Greece i Hellenic Health Foundation, Athens, Greece j University of Turin, Turin, Italy k Department of Clinical and Experimental Medicine, Federico II University, Naples, Italy l Molecular and Nutritional Epidemiology Unit, Cancer Research and Prevention Institute (ISPO), Italy m Department Nutritional Epidemiology Unit, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy n Cancer Registry and Histopathology Unit, “Civile M.P. Arezzo” Hospital, Ragusa, Italy o Department of Community Medicine, University of Tromsø, Norway p National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands q Department of Gastroenterology and Hepatology, University Medical Centre Utrecht (UMCU), Utrecht, The Netherlands r Department of Pathology, University Medical Centre Utrecht, Utrecht, The Netherlands s Public Health and Health Planning Directorate, Asturias, Spain t Andalusian School of Public Health, Granada, Spain u CIBER Epidemiolog?´a y Salud Pública (CIBERESP), Spain v Department of Epidemiology, Murcia Health Council, Murcia, Spain w Navarre Public Health Institute, Pamplona, Spain x Consortium for Biomedical Research in Epidemiology and Public Health (CIBER Epidemiolog?´a y Salud Pública-CIBERESP), Spain y Public Health Division of Gipuzkoa and Ciberesp, Basque Regional Health Department, Spain z Department of Public Health and Clinical Medicine, Nutritional Research, Umeå University, Umeå, Sweden aa Department of Medical Biosciences, Pathology, Umeå University, Umeå, Sweden ab Department of Surgery, Skåne University Hospital Malmö, Lund University, Malmö, Sweden ac Cancer Epidemiology Unit, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom ad Dept. Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom ae Dept. Pathology, University Medical Center, PB 85500, 3508 GA Utrecht, The Netherlands af Unit of Nutrition Environment and Cancer, Catalan Institute of Oncology (ICO-IDIBELL), Barcelona, Spain ag School of Public Health, Imperial College London, St. Mary’s Campus, Imperial College, London, UK ah Edouard Herriot Hospital, Lyon, France |
| Abstract: | Epigenetic events have emerged as key mechanisms in the regulation of critical biological processes and in the development of a wide variety of human malignancies, including gastric cancer (GC), however precise gene targets of aberrant DNA methylation in GC remain largely unknown. Here, we have combined pyrosequencing-based quantitative analysis of DNA methylation in 98 GC cases and 64 controls nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort and in cancer tissue and non-tumorigenic adjacent tissue of an independent series of GC samples. A panel of 10 cancer-associated genes (CHRNA3, DOK1, MGMT, RASSF1A, p14ARF, CDH1, MLH1, ALDH2, GNMT and MTHFR) and LINE-1 repetitive elements were included in the analysis and their association with clinicopathological characteristics (sex, age at diagnosis, anatomical sub-site, histological sub-type) was examined. Three out of the 10 genes analyzed exhibited a marked hypermethylation, whereas two genes (ALDH2 and MTHFR) showed significant hypomethylation, in gastric tumors. Among differentially methylated genes, we identified new genes (CHRNA3 and DOK1) as targets of aberrant hypermethylation in GC, suggesting that epigenetic deregulation of these genes and their corresponding cellular pathways may promote the development and progression of GC. We also found that global demethylation of tumor cell genomes occurs in GC, consistent with the notion that abnormal hypermethylation of specific genes occurs concomitantly with genome-wide hypomethylation. Age and gender had no significant influence on methylation states, but an association was observed between LINE-1 and MLH1 methylation levels with histological sub-type and anatomical sub-site. This study identifies aberrant methylation patters in specific genes in GC thus providing information that could be exploited as novel biomarkers in clinics and molecular epidemiology of GC. |
| Keywords: | DNA methylation Gastric cancer Biomarkers Prospective study |
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