Prognostic significance of LINE-1 methylation level in esophageal squamous cell carcinoma.
Prognostic significance of LINE-1 methylation level in esophageal squamous cell carcinoma.
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DOI：
10.1200/jco.2012.30.4_suppl.26
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发表时间：
2012-02
期刊：
影响因子：
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通讯作者：
Y. Baba;S. Iwagami;Masayuki Watanabe;H. Shigaki;S. Ida;Y. Nagai;T. Ishimoto;M. Iwatsuki;Y. Sakamoto;Y. Miyamoto;H. Baba
中科院分区：
文献类型：
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作者：
Y. Baba;S. Iwagami;Masayuki Watanabe;H. Shigaki;S. Ida;Y. Nagai;T. Ishimoto;M. Iwatsuki;Y. Sakamoto;Y. Miyamoto;H. Baba
26背景：全基因组DNA低甲基化在基因组不稳定性和癌发生中起作用。长散布核苷酸元件L1（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。LINE-1甲基化是预测癌症预后和监测辅助治疗疗效的有用标志物。食管鳞状细胞癌是东亚国家食管癌的主要组织学类型，是最具侵袭性的恶性肿瘤之一。尽管如此，LINE-1低甲基化在食管癌中的预后意义仍不确定。方法采用亚硫酸氢盐-PCR-焦磷酸测序法对217例食管鳞癌患者的LINE-1基因甲基化进行定量分析。采用考克斯比例风险模型计算死亡率风险比（HR），校正临床、流行病学和病理学变量。结果：食管癌患者的LINE-1甲基化水平显著低于正常食管粘膜（p<0.0001; N=50）。肿瘤LINE-1甲基化范围为0-100量表的24.8 - 91.8（N=217;平均值64.5;中位数65.0;标准差12.8）。LINE-1低甲基化与无病生存率[对数秩p=0.0008;单变量HR= 2.31，95%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]和总生存率（对数秩p=0.0013;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]。结论：LINE-1低甲基化与食管癌患者生存期缩短相关，提示其作为预后生物标志物的作用。鉴于表观遗传变化，包括DNA甲基化改变，是可逆的，因此可以作为治疗或化学预防的目标，我们的发现可能具有相当大的临床意义。
26 Background: Genome-wide DNA hypomethylation plays a role in genomic instability and carcinogenesis. DNA methylation in the long interspersed nucleotide element-1, L1 (LINE-1) repetitive element is a good indicator of global DNA methylation level. LINE-1 methylation is a useful marker for predicting cancer prognosis and monitoring efficacy of adjuvant therapy. Esophageal squamous cell carcinoma, the major histological type of esophageal cancer in East Asian countries, is one of the most aggressive malignant tumors. Nonetheless, prognostic significance of LINE-1 hypomethylaiton in esophageal cancer remains uncertain. METHODS Using 217 curatively resected esophageal squamous cell carcinomas, we quantified LINE-1 methylation using bisulfite-PCR-pyrosequencing assay. Cox proportional hazards model was used to calculate mortality hazard ratio (HR), adjusted for clinical, epidemiologic, and pathological variables. RESULTS Esophageal cancers showed significantly lower LINE-1 methylation level compared to matched normal esophageal mucosa (p<0.0001; N=50). Tumoral LINE-1 methylation ranged from 24.8 to 91.8 of 0-100 scale (N=217; mean 64.5; median 65.0; standard deviation 12.8). LINE-1 hypomethylation was significantly associated with disease-free survival [log-rank p=0.0008; univariate HR= 2.31, 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 overall survival (log-rank p=0.0013; 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]. CONCLUSIONS LINE-1 hypomethylation in esophageal cancer is associated with shorter survival, suggesting its role as a prognostic biomarker. Given that epigenetic changes, including DNA methylation alterations, are reversible and can thus be targets for therapy or chemoprevention, our findings may have considerable clinical implications.