Development and validation of a panel of five proteins as blood biomarkers for early detection of colorectal cancer.
Development and validation of a panel of five proteins as blood biomarkers for early detection of colorectal cancer.
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DOI：
10.2147/clep.s144171
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发表时间：
2017
影响因子：
3.9
通讯作者：
Brenner H
中科院分区：
文献类型：
--
作者：
Chen H;Qian J;Werner S;Cuk K;Knebel P;Brenner H
可靠的无创生物标志物早期检测结直肠癌（CRC）是非常需要的有效的基于人群的筛查和高依从率。我们的目的是发现和验证基于血液的蛋白标志物，用于早期检测结直肠癌。采用两阶段设计，包括发现和验证集。在发现阶段，226名临床招募的结直肠癌患者和118名结肠镜筛查时未发现结直肠肿瘤的对照组，检测了92种蛋白标志物的血浆水平和TP53自身抗体的血清水平。通过Lasso回归推导出一种预测CRC存在的算法，并在一个验证集中进行了验证，该验证集包括所有41名CRC患者和106名晚期腺瘤患者的代表性样本，以及来自大型结肠镜筛查队列的107名无肿瘤的对照组（N=6018）。进行受试者工作特征（ROC）分析，以评估单个生物标志物和生物标志物组合的诊断性能。构建了基于生长分化因子15 （GDF-15）、双调节蛋白（AREG）、Fas抗原配体（FasL）、Fas相关酪氨酸激酶3配体（Flt3L）和TP53自身抗体的算法。在验证集中，该五标记算法检测CRC的曲线下面积为0.82 (95% CI, 0.74-0.90)，检测晚期腺瘤的曲线下面积为0.60 （95% CI, 0.52-0.69）。在具有90%特异性的临界值下，检测结直肠癌和晚期腺瘤的敏感性（95% CI）分别为56.4%（38.4%-71.8%）和22.0%（13.4%-35.4%）。五标记组对早期和晚期结直肠癌的诊断效果相似。已确定的最有希望的生物标志物可能有助于未来开发强大的基于血液的CRC筛查测试。
Reliable noninvasive biomarkers for early detection of colorectal cancer (CRC) are highly desirable for efficient population-based screening with high adherence rates. We aimed to discover and validate blood-based protein markers for the early detection of CRC. A two-stage design with a discovery and a validation set was used. In the discovery phase, plasma levels of 92 protein markers and serum levels of TP53 autoantibody were measured in 226 clinically recruited CRC patients and 118 controls who were free of colorectal neoplasms at screening colonoscopy. An algorithm predicting the presence of CRC was derived by Lasso regression and validated in a validation set consisting of all available 41 patients with CRC and a representative sample of 106 participants with advanced adenomas and 107 controls free of neoplasm from a large screening colonoscopy cohort (N=6018). Receiver operating characteristic (ROC) analyses were conducted to evaluate the diagnostic performance of individual biomarkers and biomarker combinations. An algorithm based on growth differentiation factor 15 (GDF-15), amphiregulin (AREG), Fas antigen ligand (FasL), Fms-related tyrosine kinase 3 ligand (Flt3L) and TP53 autoantibody was constructed. In the validation set, the areas under the curves of this five-marker algorithm were 0.82 (95% CI, 0.74–0.90) for detecting CRC and 0.60 (95% CI, 0.52–0.69) for detecting advanced adenomas. At cutoffs yielding 90% specificity, the sensitivities (95% CI) for detecting CRC and advanced adenomas were 56.4% (38.4%–71.8%) and 22.0% (13.4%–35.4%), respectively. The five-marker panel showed similar diagnostic efficacy for the detection of early- and late-stage CRC. The identified most promising biomarkers could contribute to the development of powerful blood-based tests for CRC screening in the future.