title: LINE-1 hypomethylation is associated with a poor prognosis among patients with curatively resected esophageal squamous cell carcinoma.
abstract: OBJECTIVE
  To investigate the relationship between the long interspersed nucleotide element-1 (L1/LINE-1) methylation level and the disease-free survival and cancer-specific survival in patients with esophageal squamous cell carcinoma (ESCC).
  
  
  BACKGROUND
  Cancer cells exhibit 2 types of deoxyribonucleic acid (DNA) methylation alterations: global DNA hypomethylation and site-specific CpG island promoter hypermethylation. Global DNA hypomethylation plays a role in genomic instability and carcinogenesis. DNA methylation in the LINE-1 repetitive element is a good indicator of the global DNA methylation level. Although the LINE-1 methylation level is attracting interest as a useful marker for predicting cancer prognosis, the prognostic significance of LINE-1 hypomethylaiton in ESCC remains unclear.
  
  
  METHODS
  Using 217 curatively resected ESCC specimens, we quantified the LINE-1 methylation by utilizing the bisulfite pyrosequencing technology. Promoter methylation levels of MGMT and MLH1 were also evaluated by pyrosequencing.
  
  
  RESULTS
  ESCC showed significantly lower LINE-1 methylation levels in comparison with matched normal esophageal mucosa (P < 0.0001; N = 50). LINE-1 hypomethylation was significantly associated with disease-free survival [log-rank P = 0.0008; univariate hazard ratio (HR): 2.32, 95% confidence interval (CI): 1.38-3.84, P = 0.0017; multivariate HR: 1.81, 95% CI: 1.06-3.05, P = 0.031] and cancer-specific survival (log-rank P = 0.0020; univariate HR: 2.21, 95% CI: 1.33-3.60, P = 0.0026; multivariate HR: 1.87, 95% CI: 1.12-3.08, P = 0.018]. MGMT and MLH1 hypermethylation were not associated with patient prognosis.
  
  
  CONCLUSIONS
  LINE-1 hypomethylation in ESCC is associated with a shorter survival, thus suggesting that it has potential for use as a prognostic biomarker.
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medical Science, Kumamoto University, Kumamoto, Japan.
authors.forename: Shiro
authors.initials: S
authors.lastname: Iwagami
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Baba
authors.forename: Masayuki
authors.initials: M
authors.lastname: Watanabe
authors.forename: Hironobu
authors.initials: H
authors.lastname: Shigaki
authors.forename: Keisuke
authors.initials: K
authors.lastname: Miyake
authors.forename: Takatsugu
authors.initials: T
authors.lastname: Ishimoto
authors.forename: Masaaki
authors.initials: M
authors.lastname: Iwatsuki
authors.forename: Kentaro
authors.initials: K
authors.lastname: Sakamaki
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Ohashi
authors.forename: Hideo
authors.initials: H
authors.lastname: Baba
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000235:genetics*; D018572:Disease-Free Survival; D004938:Esophageal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D000077277:Esophageal Squamous Cell Carcinoma; D005260:Female; D005500:Follow-Up Studies; D042822:Genomic Instability; D006801:Humans; D007564:Japan / Q000453:epidemiology; D020084:Long Interspersed Nucleotide Elements / Q000235:genetics*; D008297:Male; D012189:Retrospective Studies; D017422:Sequence Analysis, DNA; D015996:Survival Rate / Q000639:trends
chemical_list: D014408:Biomarkers, Tumor; D004273:DNA, Neoplasm