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// Yuzo Nagai 1, 2 , Eiji Sunami 1 , Yoko Yamamoto 1 , Keisuke Hata 1 , Satoshi Okada 1 , Koji Murono 1 , Koji Yasuda 1 , Kensuke Otani 1 , Takeshi Nishikawa 1 , Toshiaki Tanaka 1 , Tomomichi Kiyomatsu 1 , Kazushige Kawai 1 , Hiroaki Nozawa 1 , Soichiro Ishihara 1 , Dave S.B. Hoon 2 , Toshiaki Watanabe 1 1 Department of Surgical Oncology, Faculty of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan 2 Department of Translational Molecular Medicine, Div. Molecular Oncology, John Wayne Cancer Institute, Saint John’s Hospital and Health Center, Santa Monica, CA, USA Correspondence to: Toshiaki Watanabe, email: toshwatanabe@yahoo.co.jp Keywords: colorectal cancer, cell-free DNA, LINE-1, hypomethylation, plasma Received: October 12, 2016 Accepted: December 20, 2016 Published: January 02, 2017 ABSTRACT Colorectal cancer (CRC) is a serious public health problem and non-invasive biomarkers improving diagnosis or therapy are strongly required. Circulating cell-free DNA (cfDNA) has been a promising target for this purpose. In this study, we evaluated the potential of long interspersed nuclear element-1 (LINE-1) hypomethylation as a blood biomarker for CRC. LINE-1 hypomethylation level in plasma cfDNA in 114 CRC patients was retrospectively examined by absolute quantitative analysis of methylated alleles real-time PCR, and was expressed using LINE-1 hypomethylation index (LHI) [unmethylated copy number/ (methylated copy number + unmethylated copy number)]. Greater LHI values indicated enhanced hypomethylation. In our clinicopathological analysis, CRC patients with large tumors (≥6.0 cm), advanced N stage (≥2), and distant metastasis (M1) had statistically significantly higher cfDNA LHI than other CRC patients, suggesting cfDNA LHI as a disease progression biomarker for CRC. Furthermore, early stage I/II (n = 57) as well as advanced stage III/IV (n =57) CRC patients had significantly higher cfDNA LHI than healthy donors (n=53) [stage I/II: median 0.369 (95% confidence interval, 0.360–0.380) vs. 0.332 (0.325–0.339), P < 0.0001; stage III/IV: 0.372 (0.365–0.388) vs. 0.332 (0.325–0.339), P < 0.0001]. The receiver operating characteristic analysis showed that cfDNA LHI had the detection capacity of CRC with area under the curve(AUC) of 0.79 and 0.83 in stage I/II and stage III/IV CRC patients, respectively. The present study demonstrated for the first time the potential of plasma cfDNA LHI as a novel biomarker for CRC, particularly for early stage detection. |
