COX-2 (PTGS2) gene methylation in epithelial,subepithelial lymphocyte and stromal tissue compartments in a spectrum of esophageal squamous neoplasia |
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| Institution: | 1. Cancer Genetics Branch, Center for Cancer Research, National Cancer Institute, Rockville, MD 20892, USA;2. Nutritional Epidemiology Branch, Division of Cancer Epidemiology and Genetics (DCEG), National Cancer Institute, 6120 Executive Boulevard, Suite 320, MSC 7232, Rockville, MD 20892-7232, USA;3. Genetics Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD 20892, USA;4. Department of Pathology, Shanxi Cancer Hospital and Institute, Taiyuan, Shanxi, China;1. NeuroRepair Department, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland;2. First Department of Obstetrics and Gynecology, Medical University of Warsaw, Warsaw, Poland;3. Cryo-Save Labs NV (The Cell Factory), Niel, Belgium;1. Department of Neurobiology, Neuroscience Research Institute, Peking University Health Science Center, Beijing 100191, China;2. Biomedical Research Institute, Shenzhen-PKU-HKUST Medical Center, Guangdong Province, Shenzhen 518036, China;3. Department of Molecular and Cellular Pharmacology, State Key Laboratory of Natural and Biomimetic Drugs, Peking University School of Pharmaceutical Sciences, Beijing 100191, China;1. Oncology Unit, Oncology Department, ASST Bergamo Ovest, Treviglio (BG), Italy;2. OncologyDepartment, ASST Ospedale di Cremona, Cremona, Italy;3. Surgical Oncology Unit, Surgery Department, ASST Bergamo Ovest, Treviglio (BG), Italy;4. Nuclear Medicine Unit, Radiology Department, ASST Bergamo Ovest, Treviglio (BG), Italy;1. Laboratory of Vaccines and Immunotherapeutics, Institute of Bioscience, Universiti Putra Malaysia, Selangor, Malaysia;2. Department of Cell and Molecular Biology, Faculty of Biotechnology and Biomolecular Sciences, Universiti Putra Malaysia, Selangor, Malaysia;3. Department of Veterinary Clinical Studies, Faculty of Veterinary Medicine, Universiti Putra Malaysia, Selangor, Malaysia;4. Department of Veterinary Pathology and Microbiology, Faculty of Veterinary Medicine, Universiti Putra Malaysia, Selangor, Malaysia;5. Viral Oncogenesis Group, The Pirbright Institute, Pirbright, Woking, UK;6. The Jenner Institute, The Centre for Cellular and Molecular Physiology, Roosevelt Drive, Oxford, United Kingdom;1. Systems Biology and Personalised Medicine Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia;2. Department of Medical Oncology, Royal Melbourne Hospital, Parkville, Victoria 3050, Australia;3. Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria 3000, Australia;4. Department of Pathology, Royal Melbourne Hospital, Parkville, Victoria 3050, Australia;5. Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, Victoria 3010, Australia;6. Inflammation Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia;7. Department of Medical Biology, University of Melbourne, Parkville, Victoria 3010, Australia |
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| Abstract: | Background: Previous studies have shown important effects of stromal elements in carcinogenesis. To explore the tumor–stromal relationship in esophageal neoplasia, we examined methylation of COX-2 (PTGS2), a gene etiologically associated with the development of gastrointestinal cancers, in adjacent foci of epithelium, subepithelial lymphocytes and non-lymphocytic stromal cells found in sections of normal squamous epithelium, squamous dysplasia and invasive esophageal squamous cell carcinoma. Methods: Adjacent foci of epithelium, subepithelial lymphocytic aggregates and non-lymphocytic stromal tissues were laser microdissected from six fully embedded, ethanol fixed, esophagectomy samples from Shanxi, China, a high-risk region for esophageal cancer. Promoter CpG site-specific hypermethylation status of COX-2 was determined using real-time methylation-specific PCR (qMS-PCR) based on Taqman Chemistry. The methylation status of a subset of samples was confirmed by pyrosequencing. Results: Forty-nine microdissected foci were analyzed. COX-2 gene methylation was significantly more common in subepithelial lymphocytes (12/16 (75% of all foci)) than in epithelial foci (3/16 (19%)) or foci of non-lymphocytic stromal tissues (3/17 (18%)) (Fisher's exact p = 0.05). Two of three epithelial samples and all three stromal samples that showed COX-2 methylation were adjacent to foci of methylated subepithelial lymphocytes. Pyrosequencing confirmed the methylation status in a subset of samples. Conclusions: In these esopohageal cancer patients, COX-2 gene methylation was more common in subepithelial lymphocytes than in adjacent epithelial or stromal cells in both grades of dysplasia and in foci of invasive cancer. These findings raise the possibility that methylation of subepithelial lymphocytes may be important for tumorigenesis. Future studies of gene methylation should consider separate evaluation of epithelial and non-epithelial cell populations. |
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