Research Papers:

LINE-1 hypomethylation status of circulating cell-free DNA in plasma as a biomarker for colorectal cancer

Yuzo Nagai, Eiji Sunami, Yoko Yamamoto, Keisuke Hata, Satoshi Okada, Koji Murono, Koji Yasuda, Kensuke Otani, Takeshi Nishikawa, Toshiaki Tanaka, Tomomichi Kiyomatsu, Kazushige Kawai, Hiroaki Nozawa, Soichiro Ishihara, Dave S.B. Hoon and Toshiaki Watanabe _

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Oncotarget. 2017; 8:11906-11916. https://doi.org/10.18632/oncotarget.14439

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Yuzo Nagai1,2, Eiji Sunami1, Yoko Yamamoto1, Keisuke Hata1, Satoshi Okada1, Koji Murono1, Koji Yasuda1, Kensuke Otani1, Takeshi Nishikawa1, Toshiaki Tanaka1, Tomomichi Kiyomatsu1, Kazushige Kawai1, Hiroaki Nozawa1, Soichiro Ishihara1, Dave S.B. Hoon2, Toshiaki Watanabe1

1Department of Surgical Oncology, Faculty of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan

2Department 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: [email protected]

Keywords: colorectal cancer, cell-free DNA, LINE-1, hypomethylation, plasma

Received: October 12, 2016    Accepted: December 20, 2016    Published: January 02, 2017


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.

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