Oesophageal squamous cell carcinoma may develop within a background of accumulating DNA methylation in normal and dysplastic mucosa

• Published in: Gut Vol. 56; no. 1; pp. 13 - 19
• Main Authors: Ishii, T, Murakami, J, Notohara, K, Cullings, H M, Sasamoto, H, Kambara, T, Shirakawa, Y, Naomoto, Y, Ouchida, M, Shimizu, K, Tanaka, N, Jass, J R, Matsubara, N
• Format: Journal Article
• Language: English
• Published: London BMJ Publishing Group Ltd and British Society of Gastroenterology 01-01-2007; BMJ; BMJ Publishing Group LTD; BMJ Group
• Subjects: Adult; Age; Biological and medical sciences; Cancer; Carcinoma in Situ - genetics; Carcinoma in Situ - metabolism; Carcinoma in Situ - pathology; Carcinoma, Squamous Cell - genetics; Carcinoma, Squamous Cell - metabolism; Carcinoma, Squamous Cell - pathology; COBRA; combined bisulphite restriction analysis; CpG Islands - genetics; Deoxyribonucleic acid; Disease Progression; DNA; DNA Methylation; DNA, Neoplasm - genetics; DNA, Neoplasm - metabolism; Epigenetics; Epithelium - metabolism; Esophageal Neoplasms - genetics; Esophageal Neoplasms - metabolism; Esophageal Neoplasms - pathology; Esophagus; Female; Gastroenterology. Liver. Pancreas. Abdomen; Genes; H&E; haematoxylin and eosin; Humans; IEN; intraepithelial neoplasia; Male; Medical sciences; Mucous Membrane - metabolism; Mutation; oesophageal squamous cell carcinoma; Oesophagus; OSCC; PAS; PCR; periodic acid schiff; polymerase chain reaction; Promoter Regions, Genetic - genetics; Tumor Suppressor Protein p53 - genetics; Tumorigenesis; Tumors; Japan; California; Prognosis; Mucosa; p53 Protein; Volunteer; Esophageal disease; Esophagus squamous cell carcinoma; Carcinogenesis; Promoter; Evolution; Sequencing; Human; Dysplasia; Premalignant lesion; Multiple; Nucleotide sequence; Malignant tumor; Epithelium; Polymerase chain reaction; DNA; Digestive diseases; Mutation; Molecular biology; Methylation; Intraepithelial neoplasia; Cancer
• ISSN: 0017-5749; 1468-3288
• DOI: 10.1136/gut.2005.089813

Background: Oesophageal squamous cell carcinoma (OSCC) often arises from preceding dysplastic lesions in the oesophageal epithelium. However, the molecular changes occurring in premalignant lesions are not well understood. An epigenetic change is an example of OSCC that may occur within the epithelium. Aim: To investigate the methylation status of multiple promoters in cancer-derived DNA, as well as in the background epithelium of OSCC, including dysplastic lesions and non-neoplastic mucosa. The normal epithelium from patients without cancer was also examined. The findings were correlated with the mutational status of p53. Patients and methods: 56 patients with advanced OSCC, 21 patients with intraepithelial neoplasia (IEN), 56 patients with a background of non-neoplastic epithelium, adjacent to the OSCC, and 42 normal control epithelia from healthy volunteers were studied. The promoter methylation status of SFRP1, SFRP2, DCC, APC, p16INK4a, p14ARF, MINT1, MINT2, MINT31, CACNA1G, COX2, DAPK, hMLH1 and MGMT was examined by methylation-specific single polymerase chain reaction or combined bisulphite restriction analysis. The mutation of p53 by direct sequencing was assessed. Results: DNA methylation was observed in OSCC and in its background epithelium. The frequency of CpG island methylation increased from a baseline level in the background non-neoplastic epithelium, through IEN, to advanced OSCC. However, mutations in p53 were almost exclusively observed in IEN and OSCC. More extensive DNA methylation was seen in the neoplastic lesions (OSCC or IEN) having a p53 mutation than in those with wild-type p53. Conclusion: DNA methylation is present at low levels in the non-neoplastic oesophageal epithelium and appears to contribute to the progression of the dysplasia–carcinoma sequence in OSCC carcinogenesis.