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: firstname.lastname@example.org.
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.
Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.annalsofsurgery.com).