Chromosomal Instability Associated with Global DNA Hypomethylation is Associated with the Initiation and Progression of Esophageal Squamous Cell Carcinoma

• Published in: Annals of surgical oncology Vol. 21; no. Suppl 4; pp. 696 - 702
• Main Authors: Kawano, Hiroyuki, Saeki, Hiroshi, Kitao, Hiroyuki, Tsuda, Yasuo, Otsu, Hajime, Ando, Koji, Ito, Shuhei, Egashira, Akinori, Oki, Eiji, Morita, Masaru, Oda, Yoshinao, Maehara, Yoshihiko
• Format: Journal Article
• Language: English
• Published: Boston Springer US 01.12.2014; Springer Nature B.V
• Subjects: Aged; Alcohol Drinking - genetics; Blood Vessels - pathology; Carcinoma, Squamous Cell - genetics; Carcinoma, Squamous Cell - secondary; Carcinoma, Squamous Cell - surgery; Cell Transformation, Neoplastic - genetics; Chromosomal Instability; Disease Progression; DNA Methylation; Esophageal Neoplasms - genetics; Esophageal Neoplasms - pathology; Esophageal Neoplasms - surgery; Esophagus; Exons; Female; Humans; Long Interspersed Nucleotide Elements - genetics; Loss of Heterozygosity; Lymphatic Metastasis; Lymphatic Vessels - pathology; Male; Medicine; Medicine & Public Health; Middle Aged; Mucous Membrane; Mutation Rate; Oncology; Smoking - genetics; Surgery; Surgical Oncology; Survival Rate; Translational Research and Biomarkers; Tumor Suppressor Protein p53 - genetics; Noncancerous Tissue; Single Nucleotide Polymorphism Array; Chromosomal Instability; Methylation Level; Esophageal Squamous Cell Carcinoma
• ISSN: 1068-9265; 1534-4681; 1534-4681
• DOI: 10.1245/s10434-014-3818-z

Background Global DNA hypomethylation is associated with increased chromosomal instability and plays an important role in tumorigenesis. The methylation status of the long interspersed nuclear element-1 (LINE-1) element is a useful surrogate marker for global DNA methylation. Although LINE-1 hypomethylation is recognized as a poor prognostic marker, the correlation of LINE-1 methylation level with tumor suppressor gene mutation, chromosomal instability, and clinical significance in esophageal squamous cell carcinoma (ESCC) remains unclear. Methods Using resected tumor tissues and the corresponding normal esophageal mucosa from 105 patients with ESCC, bisulfite pyrosequencing analysis was performed to quantify the LINE-1 methylation levels. p53 mutations in exons two to ten were detected by polymerase chain reaction direct sequencing. Chromosomal instability was assessed by single nucleotide polymorphism array comparative genomic hybridization analysis. Results The LINE-1 methylation level of ESCC was significantly lower than matched normal mucosa. LINE-1 methylation levels of normal mucosa from the esophagus had a significant inverse correlation with both cigarette smoking and alcohol consumption of the study subjects. LINE-1 hypomethylation of ESCC was significantly associated with lymph node metastasis, lymphovascular invasion, the frequency of p53 mutation and poor survivability. The LINE-1 methylation levels in ESCC had a significant inverse association with the percentage of copy number alterations in the whole genome, mirroring chromosomal instability. Conclusions Our results suggested that whole genome hypomethylation caused by chronic inflammation could initiate carcinogenesis of esophageal squamous cells through chromosomal instability. In addition, chromosomal instability associated with the global hypomethylation might correlate highly with the progression of ESCC.