LINE-1 hypomethylation status of circulating cell-free DNA in plasma as a biomarker for colorectal cancer
LINE-1 hypomethylation status of circulating cell-free DNA in plasma as a biomarker for colorectal cancer
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DOI：
10.18632/oncotarget.14439
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发表时间：
2017-02-14
期刊：
影响因子：
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通讯作者：
Watanabe, Toshiaki
中科院分区：
文献类型：
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作者：
Nagai, Yuzo;Sunami, Eiji;Watanabe, Toshiaki
结直肠癌（CRC）是一个严重的公共卫生问题，迫切需要非侵入性生物标志物来改善诊断或治疗。循环无细胞DNA（cfDNA）已成为用于此目的的有希望的靶标。在这项研究中，我们评估了长散布核元件-1（LINE-1）低甲基化作为CRC血液生物标志物的潜力。通过甲基化等位基因实时PCR的绝对定量分析回顾性地检查了114名CRC患者中血浆cfDNA中的LINE-1低甲基化水平，并使用LINE-1低甲基化指数（LHI）[未甲基化拷贝数/（甲基化拷贝数+未甲基化拷贝数）]表示。较大的LHI值表明增强的低甲基化。在我们的临床病理学分析中，具有大肿瘤（>= 6.0 cm）、晚期N分期（>= 2）和远处转移（M1）的CRC患者具有统计学显著高于其他CRC患者的cfDNA LHI，表明cfDNA LHI是CRC的疾病进展生物标志物。此外，早期I/II期（n = 57）以及晚期III/IV期（n = 57）CRC患者具有比健康供体（n=53）显著更高的cfDNA LHI [I/II期：中值0.369（95%置信区间，0.360-0.380）vs. 0.332（0.325-0.339），P < 0.0001; III/IV期：0.372（0.365-0.388）vs. 0.332（0.325-0.339），P < 0.0001]。受试者操作特征分析显示cfDNA LHI具有CRC的检测能力，在I/II期和III/IV期CRC患者中的曲线下面积（AUC）分别为0.79和0.83。本研究首次证明了血浆cfDNA LHI作为CRC的新型生物标志物的潜力，特别是用于早期检测。
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.