Background: Cancer cells exhibit two types of DNA methylation alterations: global DNA hypomethylation and site-specific CpG island promoter hypermethylation. Selected gene promoter hypermethylation in normal esophageal mucosae has attracted attention as a surrogate marker for the epigenetic field defect induced by smoking and/or drinking in esophageal squamous cell carcinoma (ESCC). However, the significance of global DNA hypomethylation for field cancerization remains unclear.
Methods: By using histologically normal esophageal mucosa samples from 109 ESCC cases and 20 autopsy cases without ESCCs, we measured long interspersed nucleotide element 1 (LINE-1) methylation levels by pyrosequencing, which correlates with global DNA methylation level.
Results: LINE-1 methylation levels in normal esophageal mucosae of ESCC patients were significantly lower than those of autopsy individuals (P = 0.017). LINE-1 methylation of noncancerous mucosae ranged 68.3-93.0 on a 0-100 scale (mean 81.7, median 82.2, standard deviation 5.9). LINE-1 hypomethylation was significantly associated with smoking history (P = 0.014 for smoking duration; P = 0.0017 for number of cigarettes per day; P = 0.0002 for tobacco pack-year). LINE-1 methylation was not associated with alcohol drinking or age at diagnosis.
Conclusions: A history of tobacco use was significantly associated with LINE-1 hypomethylation in noncancerous esophageal mucosae of ESCC patients. These results support the potential of LINE-1 methylation level as an indicator of epigenetic field for ESCC cancerization, particularly when caused by tobacco smoking.