title: Chromosomal instability associated with global DNA hypomethylation is associated with the initiation and progression of esophageal squamous cell carcinoma.
abstract: 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.
authors.affiliation: Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kawano
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Saeki
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kitao
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Tsuda
authors.forename: Hajime
authors.initials: H
authors.lastname: Otsu
authors.forename: Koji
authors.initials: K
authors.lastname: Ando
authors.forename: Shuhei
authors.initials: S
authors.lastname: Ito
authors.forename: Akinori
authors.initials: A
authors.lastname: Egashira
authors.forename: Eiji
authors.initials: E
authors.lastname: Oki
authors.forename: Masaru
authors.initials: M
authors.lastname: Morita
authors.forename: Yoshinao
authors.initials: Y
authors.lastname: Oda
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Maehara
mesh_terms: D000368:Aged; D000428:Alcohol Drinking / Q000235:genetics; D001808:Blood Vessels / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000556:secondary / Q000601:surgery; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D043171:Chromosomal Instability; D019175:DNA Methylation; D018450:Disease Progression; D004938:Esophageal Neoplasms / Q000235:genetics* / Q000473:pathology* / Q000601:surgery; D004947:Esophagus; D005091:Exons; D005260:Female; D006801:Humans; D020084:Long Interspersed Nucleotide Elements / Q000235:genetics; D019656:Loss of Heterozygosity; D008207:Lymphatic Metastasis; D042601:Lymphatic Vessels / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009092:Mucous Membrane; D059645:Mutation Rate; D012907:Smoking / Q000235:genetics; D015996:Survival Rate; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: D016159:Tumor Suppressor Protein p53