Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada;
Mol Cell Proteomics. 2013 Oct;12(10):2820-32. doi: 10.1074/mcp.M112.023507. Epub 2013 Jun 24.
In pancreatic cancer, the incidence and mortality curves coincide. One major reason for this high mortality rate in pancreatic ductal adenocarcinoma (PDAC) patients is the dearth of effective diagnostic, prognostic, and disease-monitoring biomarkers. Unfortunately, existing tumor markers, as well as current imaging modalities, are not sufficiently sensitive and/or specific for early-stage diagnosis. There is, therefore, an urgent need for improved serum markers of the disease. Herein, we performed Orbitrap® mass spectrometry proteomic analysis of four PDAC tissues and their adjacent benign tissues and identified a total of 2190 nonredundant proteins. Sixteen promising candidates were selected for further scrutiny using a systematic scoring algorithm. Our preliminary serum verification of the top four candidates (DSP, LAMC2, GP73, and DSG2) in 20 patients diagnosed with pancreatic cancer and 20 with benign pancreatic cysts, showed a significant (p < 0.05) elevation of LAMC2 in pancreatic cancer serum. Extensive validation of LAMC2 in healthy, benign, and PDAC sera from geographically diverse cohorts (n = 425) (Japan, Europe, and USA) demonstrated a significant increase in levels in early-stage PDAC compared with benign diseases. The sensitivity of LAMC2 was comparable to CA19.9 in all data sets, with an AUC value greater than 0.85 in discriminating healthy patients from early-stage PDAC patients. LAMC2 exhibited diagnostic complementarity with CA19.9 by showing significant (p < 0.001 in two out of three cohorts) elevation in PDAC patients with clinically low CA19.9 levels.
在胰腺癌中，发病率和死亡率曲线相吻合。导致胰腺导管腺癌 (PDAC) 患者死亡率如此之高的一个主要原因是缺乏有效的诊断、预后和疾病监测生物标志物。不幸的是，现有的肿瘤标志物以及当前的成像方式在灵敏度和/或特异性方面都不足以用于早期诊断。因此，迫切需要改善疾病的血清标志物。在此，我们对 4 个 PDAC 组织及其相邻良性组织进行了 Orbitrap®质谱蛋白质组学分析，共鉴定出 2190 个非冗余蛋白。使用系统评分算法对 16 个有前途的候选蛋白进行了进一步分析。我们对 20 名经诊断患有胰腺癌和 20 名患有良性胰腺囊肿的患者的前 4 名候选蛋白（DSP、LAMC2、GP73 和 DSG2）进行了初步的血清验证，结果显示 LAMC2 在胰腺癌血清中显著升高（p < 0.05）。在来自不同地理区域（日本、欧洲和美国）的健康、良性和 PDAC 血清的广泛验证中（n = 425），与良性疾病相比，早期 PDAC 患者的 LAMC2 水平显著升高。LAMC2 在所有数据集的灵敏度与 CA19.9 相当，在区分健康患者和早期 PDAC 患者时，AUC 值大于 0.85。LAMC2 与 CA19.9 具有诊断互补性，在三个队列中的两个队列中（p < 0.001），CA19.9 水平较低的 PDAC 患者 LAMC2 显著升高。
