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.
Highlights
Colorectal cancer (CRC) is a serious public health problem third leading cause of cancer-related deaths worldwide, owing to its high incidence and cancerrelated mortality [1]
The long interspersed nuclear element-1 (LINE-1) hypomethylation levels were evaluated by a modified absolute quantitative analysis of methylated alleles (AQAMA) real-time PCR assay, which were validated in our previous studies [12, 13, 16, 20], and was expressed as LINE-1 hypomethylation index (LHI); greater LHI indicated enhanced hypomethylation
We examined 114 plasma samples of CRC patients, and quantified LINE-1 hypomethylation status in plasma cell-free DNA (cfDNA) by AQAMA PCR method
Summary
Colorectal cancer (CRC) is a serious public health problem third leading cause of cancer-related deaths worldwide, owing to its high incidence and cancerrelated mortality [1]. Tumor-related circulating cell-free DNA (cfDNA) in plasma and serum has been a promising target for cancer biomarker studies. Aberrant DNA hypomethylation is one of the major DNA methylation abnormalities in cancer It generally occurs in repetitive transposable DNA elements such as long interspersed nuclear element-1 (LINE-1) as well as short interspersed nucleotide elements (SINE or ALU), and is associated with genomic instability [6]. Previous studies have reported a correlation between the presence of LINE-1 hypomethylation in CRC tissue with tumor progression [12] and poor prognosis [8, 9, 11, 18, 19]
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