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LINE-1 Hypomethylation Is Associated With a Poor Prognosis Among Patients With Curatively Resected Esophageal Squamous Cell Carcinoma

Iwagami, Shiro MD*; Baba, Yoshifumi MD, PhD*; Watanabe, Masayuki MD, PhD, FACS*; Shigaki, Hironobu MD*; Miyake, Keisuke MSc*; Ishimoto, Takatsugu MD, PhD*; Iwatsuki, Masaaki MD, PhD*; Sakamaki, Kentaro MPH; Ohashi, Yasuo PhD; Baba, Hideo MD, PhD, FACS*

doi: 10.1097/SLA.0b013e31826d8602
Original Articles

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.

Genome-wide DNA hypomethylation plays a role in genomic instability and carcinogenesis. The DNA methylation in the long interspersed nucleotide element-1 (LINE-1) repetitive element is a good indicator of the global DNA methylation level. LINE-1 hypomethylation, detected by bisulfite pyrosequencing, in esophageal squamous cell carcinoma is associated with shorter survival, suggesting that it has potential for use as a prognostic biomarker.

*Department of Gastroenterological Surgery, Graduate School of Medical Science, Kumamoto University, Kumamoto, Japan

Department of Biostatistics, School of Public Health, University of Tokyo, Tokyo, Japan.

Reprints: Hideo Baba, MD, PhD, FACS, Department of Gastroenterological Surgery, Graduate School of Medical Science, Kumamoto University, 1-1-1 Honjo, Kumamoto City, Kumamoto 860–8556, Japan. E-mail: hdobaba@kumamoto-u.ac.jp.

S. Iwagami and Y. Baba contributed equally.

Disclosure: This work was supported in part by the Japan Society for the Promotion of Science (JSPS) Grant-in-Aid for Scientific Research, grant number 23689061 and the Kobayashi Foundation for Cancer Research. No conflict of interest exists.

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© 2013 Lippincott Williams & Wilkins, Inc.