LINE-1 hypomethylation, increased retrotransposition and tumor-specific insertion in upper gastrointestinal cancer

被引:1
|
作者
Baba, Yoshifumi [1 ,2 ]
Yasuda, Noriko [1 ]
Bundo, Miki [3 ]
Nakachi, Yutaka [3 ]
Ueda, Junko [3 ]
Ishimoto, Takatsugu [1 ]
Iwatsuki, Masaaki [1 ]
Miyamoto, Yuji [1 ]
Yoshida, Naoya [1 ]
Oshiumi, Hiroyuki [4 ]
Iwamoto, Kazuya [3 ]
Baba, Hideo [1 ,5 ]
机构
[1] Kumamoto Univ, Grad Sch Med Sci, Dept Gastroenterol Surg, Kumamoto, Japan
[2] Kumamoto Univ Hosp, Dept Next Generat Surg Therapy Dev, Kumamoto, Japan
[3] Kumamoto Univ, Grad Sch Med Sci, Dept Mol Brain Sci, Kumamoto, Japan
[4] Kumamoto Univ, Grad Sch Med Sci, Fac Life Sci, Dept Immunol, Kumamoto, Japan
[5] Kumamoto Univ, Grad Sch Med Sci, Dept Gastroenterol Surg, 1-1-1 Honjo, Kumamoto, Kumamoto 8608556, Japan
基金
日本学术振兴会;
关键词
esophageal cancer; gastric cancer; LINE-1; methylation; retrotransposition; POOR-PROGNOSIS; SOMATIC RETROTRANSPOSITION; TRANSPOSABLE ELEMENTS; L1; RETROTRANSPOSITION; GENOME; DATABASE; MOBILE;
D O I
10.1111/cas.16007
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
The long interspersed nuclear element-1 (LINE-1) retrotransposons are a major family of mobile genetic elements, comprising approximately 17% of the human genome. The methylation state of LINE-1 is often used as an indicator of global DNA methylation levels and it regulates the retrotransposition and somatic insertion of the genetic element. We have previously reported the significant relationship between LINE-1 hypomethylation and poor prognosis in upper gastrointestinal (GI) cancers. However, the causal relationships between LINE-1 hypomethylation, retrotransposition, and tumor-specific insertion in upper GI cancers remain unknown. We used bisulfite-pyrosequencing and quantitative real-time PCR to verify LINE-1 methylation and copy number in tissue samples of 101 patients with esophageal and 103 patients with gastric cancer. Furthermore, we analyzed the LINE-1 retrotransposition profile with an originally developed L1Hs-seq. In tumor samples, LINE-1 methylation levels were significantly lower than non-tumor controls, while LINE-1 copy numbers were markedly increased. As such, there was a significant inverse correlation between the LINE-1 methylation level and copy number in tumor tissues, with lower LINE-1 methylation levels corresponding to higher LINE-1 copy numbers. Of particular importance is that somatic LINE-1 insertions were more numerous in tumor than normal tissues. Furthermore, we observed that LINE-1 was inserted evenly across all chromosomes, and most often within genomic regions associated with tumor-suppressive genes. LINE-1 hypomethylation in upper GI cancers is related to increased LINE-1 retrotransposition and tumor-specific insertion events, which may collectively contribute to the acquisition of aggressive tumor features through the inactivation of tumor-suppressive genes.
引用
收藏
页码:247 / 256
页数:10
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