Abstract
10523 Background: Genome-wide DNA hypomethylation plays a role in genomic instability and carcinogenesis. DNA methylation in long interspersed nucleotide element-1 (LINE-1) is a good indicator of global DNA methylation level. Although LINE-1 methylation level is attracting interest as a useful marker for predicting cancer prognosis, the prognostic significance of LINE-1 hypomethylaiton in the upper gastrointestinal cancer [i.e., esophageal squamous cell carcinoma (ESCC) and gastric cancer (GC)] remains unclear. Methods: Using 217 ESCC and 207 GC specimens, we quantified the LINE-1 methylation using bisulfite-pyrosequencing technology. During the follow-up, there were a total of 63 ESCC recurrences, 51 ESCC deaths and 56 GC deaths. The median follow-up time for censored patients was 2.8 years. A Cox proportional hazards model was used to calculate the hazard ratio (HR), adjusted for the clinical, epidemiological, and pathological variables. The term “prognostic marker” is used throughout this study according to the REMARK Guidelines. Results: ESCCs and GCs showed significantly lower LINE-1 methylation levels compared to matched normal mucosa (p<0.0001). In ESCC, LINE-1 hypomethylation was significantly associated with disease-free survival [log-rank p=0.0008; univariate 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]. We found a significant modifying effect of the tumor stage on the relationship between LINE-1 methylation and the recurrence rate (P for interaction = 0.031). In GC, LINE-1 hypomethylation was significantly associated with cancer-specific survival (log-rank p=0.029; univariate HR=2.01, 95% CI 1.09-3.99). Conclusions: LINE-1 hypomethylation is associated with shorter survival in both ESCC and GC, suggesting that it has potential for use as a prognostic biomarker.
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