LINE-1 Hypomethylation Is Associated With a Poor Prognosis Among Patients With Curatively Resected Esophageal Squamous Cell Carcinoma
LINE-1 Hypomethylation Is Associated With a Poor Prognosis Among Patients With Curatively Resected Esophageal Squamous Cell Carcinoma
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DOI：
10.1097/sla.0b013e31826d8602
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发表时间：
2013-03-01
影响因子：
9
通讯作者：
Baba, Hideo
中科院分区：
文献类型：
--
作者：
Iwagami, Shiro;Baba, Yoshifumi;Baba, Hideo
目标：目的：探讨食管鳞癌（esophageal squamous cell carcinoma，ESCC）中长散布核苷酸元件-1（long interspersed nucleotide element-1，L1/LINE-1）甲基化水平与患者无病生存期和癌症特异性生存期的关系。整体DNA低甲基化在基因组不稳定性和癌发生中起作用。LINE-1重复元件中的DNA甲基化是整体DNA甲基化水平的良好指标。虽然LINE-1甲基化水平作为预测癌症预后的有用标记物引起了人们的兴趣，但LINE-1低甲基化在ESCC中的预后意义尚不清楚。结果：食管鳞癌中LINE-1基因甲基化水平显著低于正常食管黏膜（P < 0.0001; N = 50）。LINE-1低甲基化与无病生存率显著相关[对数秩P = 0.0008;单变量风险比（HR）：2.32，95%置信区间（CI）：1.38-3.84，P = 0.0017;多变量HR：1.81，95% CI：1.06-3.05，P = 0.031]和癌症特异性生存期（对数秩P = 0.0020;单变量HR：2.21，95% CI：1.33-3.60，P = 0.0026;多变量HR：1.87，95% CI：1.12-3.08，P = 0.018]。MGMT和MLH 1高甲基化与患者预后无关。结论：LINE-1低甲基化在ESCC中与较短的生存期相关，因此表明它具有作为预后生物标志物的潜力。
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.