Blood-Based Protein Biomarker Panel for the Detection of Colorectal Cancer

BackgroundThe majority of colorectal cancer (CRC) cases are preventable by early detection and removal of precancerous polyps. Even though CRC is the second most common internal cancer in Australia, only 30 per cent of the population considered to have risk factors participate in stool-based test screening programs. Evidence indicates a robust, blood-based, diagnostic assay would increase screening compliance. A number of potential diagnostic blood-based protein biomarkers for CRC have been reported, but all lack sensitivity or specificity for use as a stand-alone diagnostic. The aim of this study was to identify and validate a panel of protein-based biomarkers in independent cohorts that could be translated to a reliable, non-invasive blood-based screening test.Principal FindingsIn two independent cohorts (n = 145 and n = 197), we evaluated seven single biomarkers in serum of CRC patients and age/gender matched controls that showed a significant difference between controls and CRC, but individually lack the sensitivity for diagnostic application. Using logistic regression strategies, we identified a panel of three biomarkers that discriminated between controls and CRC with 73% sensitivity at 95% specificity, when applied to either of the two cohorts. This panel comprised of Insulin like growth factor binding protein 2 (IGFBP2), Dickkopf-3 (DKK3), and Pyruvate kinase M2(PKM2).ConclusionsDue to the heterogeneous nature of CRC, a single biomarker is unlikely to have sufficient sensitivity or specificity for use as a stand-alone diagnostic screening test and a panel of markers may be more effective. We have identified a 3 biomarker panel that has higher sensitivity and specificity for early stage (Stage I and -II) disease than the faecal occult blood test, raising the possibility for its use as a non-invasive blood diagnostic or screening test.

研究背景：绝大多数结直肠癌（colorectal cancer, CRC）病例可通过早期检出并切除癌前息肉实现预防。尽管结直肠癌是澳大利亚第二大高发内脏恶性肿瘤，但仅有30%的存在患病风险因素的人群参与了粪便检测筛查项目。研究证据表明，性能可靠的血液诊断检测方法可显著提升筛查依从性。目前已有多项研究报道了结直肠癌潜在的血液蛋白诊断生物标志物，但所有单一标志物均缺乏足够的灵敏度与特异性，无法单独作为诊断工具使用。本研究旨在独立队列中筛选并验证一组蛋白生物标志物，以期将其转化为可靠的非侵入性血液筛查检测方法。主要研究结果：在两个独立队列（样本量分别为n=145与n=197）中，我们对结直肠癌患者及年龄、性别匹配的对照组人群的血清中的7种单一生物标志物进行了评估。这些标志物在对照组与结直肠癌患者间存在显著差异，但单独使用时均无法满足诊断应用的灵敏度要求。通过logistic回归分析策略，我们筛选出一组由3种生物标志物组成的组合，在两个队列中均实现了95%特异性下73%的灵敏度，可有效区分对照组与结直肠癌患者。该标志物组合包含胰岛素样生长因子结合蛋白2（Insulin-like growth factor binding protein 2, IGFBP2）、Dickkopf-3（DKK3）以及丙酮酸激酶M2（Pyruvate kinase M2, PKM2）。研究结论：鉴于结直肠癌的异质性，单一生物标志物很难具备足够的灵敏度与特异性以单独作为诊断筛查工具，而多标志物组合或许能实现更优的检测效果。本研究筛选出的3种生物标志物组合，针对早期（I期与II期）结直肠癌的灵敏度与特异性均优于粪便隐血试验，为其作为非侵入性血液诊断或筛查检测方法提供了应用可能。