Research Papers:

Prognostic value of LINE-1 methylation level in 321 patients with primary liver cancer including hepatocellular carcinoma and intrahepatic cholangiocarcinoma

Tatsunori Miyata, Yo-Ichi Yamashita, Yoshifumi Baba, Kazuto Harada, Takanobu Yamao, Naoki Umezaki, Masayo Tsukamoto, Yuki Kitano, Kensuke Yamamura, Kota Arima, Shigeki Nakagawa, Hirohisa Okabe, Katsunori Imai, Daisuke Hashimoto, Akira Chikamoto, Mototsugu Shimokawa and Hideo Baba _

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Oncotarget. 2018; 9:20795-20806. https://doi.org/10.18632/oncotarget.25124

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Tatsunori Miyata1, Yo-Ichi Yamashita1, Yoshifumi Baba1, Kazuto Harada1, Takanobu Yamao1, Naoki Umezaki1, Masayo Tsukamoto1, Yuki Kitano1, Kensuke Yamamura1, Kota Arima1, Shigeki Nakagawa1, Hirohisa Okabe1, Katsunori Imai1, Daisuke Hashimoto1, Akira Chikamoto1, Mototsugu Shimokawa2 and Hideo Baba1

1Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan

2Clinical Research Institute, National Kyushu Cancer Center, Fukuoka, Japan

Correspondence to:

Hideo Baba, email: [email protected]

Keywords: LINE-1; methylation; epigenetics; primary liver cancer; prognosis

Received: October 18, 2017     Accepted: March 22, 2018     Published: April 17, 2018


Background: The methylation level of long interspersed nucleotide element-1 (LINE-1) is a good surrogate marker of the global DNA methylation level. The relationship between LINE-1 methylation level and prognosis in primary liver cancer (PLC) patients remains unclear.

Results: LINE-1 methylation levels were significantly lower in HCC and cHCC-CC tissues, but not in ICC tissues, than those in noncancerous liver parenchyma (HCC: p < 0.0001; cHCC-CC: p < 0.001; and ICC: p = 0.053). HCC cases with hypomethylated LINE-1 had significantly shorter relapse-free survival (RFS) (log-rank, p = 0.008); however, this was not observed for the cHCC-CC or ICC cases. Multivariate Cox regression analysis revealed a significantly higher HCC recurrence rate in the group with hypomethylated LINE-1 (hazard ratio, 1.62; 95% confidence interval, 1.06–2.58; p = 0.025).

Conclusions: The genome-wide DNA hypomethylation status estimated via LINE-1 methylation levels might be indicative of poor RFS in patients with HCC but not ICC or cHCC-CC.

Methods: We evaluated the level of LINE-1 methylation in 321 cases of curatively resected PLC {231 hepatocellular carcinoma (HCC), 19 combined hepatocellular and cholangiocarcinoma (cHCC-CC) and 71 intrahepatic cholangiocarcinoma (ICC)} via pyrosequencing of formalin-fixed paraffin-embedded (FFPE) tissues and examined its prognostic value.

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