• Annals of surgery · Mar 2013

    Comparative Study

    LINE-1 hypomethylation is associated with a poor prognosis among patients with curatively resected esophageal squamous cell carcinoma.

    • Shiro Iwagami, Yoshifumi Baba, Masayuki Watanabe, Hironobu Shigaki, Keisuke Miyake, Takatsugu Ishimoto, Masaaki Iwatsuki, Kentaro Sakamaki, Yasuo Ohashi, and Hideo Baba.
    • Department of Gastroenterological Surgery, Graduate School of Medical Science, Kumamoto University, Kumamoto, Japan.
    • Ann. Surg. 2013 Mar 1; 257 (3): 449-55.

    ObjectiveTo 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).BackgroundCancer 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.MethodsUsing 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.ResultsESCC 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.ConclusionsLINE-1 hypomethylation in ESCC is associated with a shorter survival, thus suggesting that it has potential for use as a prognostic biomarker.

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