Adult; Biomarkers, Tumor; Colorectal Neoplasms; DNA Methylation; DNA, Neoplasm; Disease Progression; Female; Humans; Long Interspersed Nucleotide Elements; Male; Prognosis
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.
Nagai, Yuzo; Sunami, Eiji; Yamamoto, Yoko; Hata, Keisuke; Okada, Satoshi; Murono, Koji; Yasuda, Koji; Otani, Kensuke; Nishikawa, Takeshi; Tanaka, Toshiaki; Kiyomatsu, Tomomichi; Kawai, Kazushige; Nozawa, Hiroaki; Ishihara, Soichiro; Hoon, Dave S B; and Watanabe, Toshiaki, "LINE-1 hypomethylation status of circulating cell-free DNA in plasma as a biomarker for colorectal cancer." (2017). Articles, Abstracts, and Reports. 2361.