title: LINE-1 hypomethylation status of circulating cell-free DNA in plasma as a biomarker for colorectal cancer.
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.
authors.affiliation: Department of Surgical Oncology, Faculty of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan.|Department of Translational Molecular Medicine, Div. Molecular Oncology, John Wayne Cancer Institute, Saint John's Hospital and Health Center, Santa Monica, CA, USA.
authors.forename: Yuzo
authors.initials: Y
authors.lastname: Nagai
authors.affiliation: Department of Surgical Oncology, Faculty of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan.
authors.forename: Eiji
authors.initials: E
authors.lastname: Sunami
authors.affiliation: Department of Surgical Oncology, Faculty of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Yamamoto
authors.affiliation: Department of Surgical Oncology, Faculty of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Hata
authors.affiliation: Department of Surgical Oncology, Faculty of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Okada
authors.affiliation: Department of Surgical Oncology, Faculty of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Murono
authors.affiliation: Department of Surgical Oncology, Faculty of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Yasuda
authors.affiliation: Department of Surgical Oncology, Faculty of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan.
authors.forename: Kensuke
authors.initials: K
authors.lastname: Otani
authors.affiliation: Department of Surgical Oncology, Faculty of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Nishikawa
authors.affiliation: Department of Surgical Oncology, Faculty of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan.
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Tanaka
authors.affiliation: Department of Surgical Oncology, Faculty of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan.
authors.forename: Tomomichi
authors.initials: T
authors.lastname: Kiyomatsu
authors.affiliation: Department of Surgical Oncology, Faculty of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan.
authors.forename: Kazushige
authors.initials: K
authors.lastname: Kawai
authors.affiliation: Department of Surgical Oncology, Faculty of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Nozawa
authors.affiliation: Department of Surgical Oncology, Faculty of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan.
authors.forename: Soichiro
authors.initials: S
authors.lastname: Ishihara
authors.affiliation: Department of Translational Molecular Medicine, Div. Molecular Oncology, John Wayne Cancer Institute, Saint John's Hospital and Health Center, Santa Monica, CA, USA.
authors.forename: Dave S B
authors.initials: DS
authors.lastname: Hoon
authors.affiliation: Department of Surgical Oncology, Faculty of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan.
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Watanabe
mesh_terms: D000328:Adult; D014408:Biomarkers, Tumor / Q000097:blood / Q000235:genetics; D015179:Colorectal Neoplasms / Q000097:blood / Q000235:genetics* / Q000473:pathology; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000097:blood*; D018450:Disease Progression; D005260:Female; D006801:Humans; D020084:Long Interspersed Nucleotide Elements; D008297:Male; D011379:Prognosis
chemical_list: D014408:Biomarkers, Tumor; D004273:DNA, Neoplasm
keywords: LINE-1; cell-free DNA; colorectal cancer; hypomethylation; plasma