LINE-1 hypomethylation, DNA copy number alterations, and CDK6 amplification in esophageal squamous cell carcinoma

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

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47 Citations (Scopus)

Abstract

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. 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. 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. 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 asCDK6.

Original languageEnglish
Pages (from-to)1114-1124
Number of pages11
JournalClinical Cancer Research
Volume20
Issue number5
DOIs
Publication statusPublished - 2014

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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