LINE-1 Hypomethylation, DNA Copy Number Alterations, and CDK6 Amplification in Esophageal Squamous Cell Carcinoma

作者：Baba Yoshifumi; Watanabe Masayuki; Murata Asuka; Shigaki Hironobu; Miyake Keisuke; Ishimoto Takatsugu; Iwatsuki Masaaki; Iwagami Shiro; Yoshida Naoya; Oki Eiji; Sakamaki Kentaro; Nakao Mitsuyoshi; Baba Hideo^*

来源：Clinical Cancer Research, 2014, 20(5): 1114-1124.

DOI：10.1158/1078-0432.CCR-13-1645

Purpose: Global DNA hypomethylation plays a crucial role in genomic instability and carcinogenesis. DNA methylation of the long interspersed nucleotide element-1, L1 (LINE-1) repetitive element is a good indicator of the global DNA methylation level, and is attracting interest as a useful marker for predicting cancer prognosis. Our previous study using more than 200 esophageal squamous cell carcinoma (ESCC) specimens demonstrated the significant relationship between LINE-1 hypomethylation and poor prognosis. However, the mechanism by which LINE-1 hypomethylation affects aggressive tumor behavior has yet to be revealed. %26lt;br%26gt;Experimental Design: To examine the relationship between LINE-1 hypomethylation and DNA copy number variations, we investigated LINE-1-hypomethylated and LINE-1-hypermethylated ESCC tumors by comparative genomic hybridization array. %26lt;br%26gt;Results: LINE-1-hypomethylated tumors showed highly frequent genomic gains at various loci containing candidate oncogenes such as CDK6. LINE-1 methylation levels were significantly associated with CDK6 mRNA and CDK6 protein expression levels in ESCC specimens. In our cohort of 129 patients with ESCC, cases with CDK6-positive expression experienced worse clinical outcome compared with those with CDK6-negative expression, supporting the oncogenic role of CDK6 in ESCC. In addition, we found that the prognostic impact of LINE-1 hypomethylation might be attenuated by CDK6 expression. %26lt;br%26gt;Conclusion: LINE-1 hypomethylation (i.e., global DNA hypomethylation) in ESCC might contribute to the acquisition of aggressive tumor behavior through genomic gains of oncogenes such as CDK6.

• 出版日期2014-3-1