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

// Tatsunori Miyata 1 , Yo-Ichi Yamashita 1 , Yoshifumi Baba 1 , Kazuto Harada 1 , Takanobu Yamao 1 , Naoki Umezaki 1 , Masayo Tsukamoto 1 , Yuki Kitano 1 , Kensuke Yamamura 1 , Kota Arima 1 , Shigeki Nakagawa 1 , Hirohisa Okabe 1 , Katsunori Imai 1 , Daisuke Hashimoto 1 , Akira Chikamoto 1 , Mototsugu Shimokawa 2 and Hideo Baba 1 1 Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan 2 Clinical Research Institute, National Kyushu Cancer Center, Fukuoka, Japan Correspondence to: Hideo Baba, email: hdobaba@kumamoto-u.ac.jp Keywords: LINE-1; methylation; epigenetics; primary liver cancer; prognosis Received: October 18, 2017 Accepted: March 22, 2018 Published: April 17, 2018 ABSTRACT 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.