Shen Lei, Wu Xiaoguang, Tan Jinjing, Gu Meng, Teng Yu, Wang Zitong, Yue Wentao
Department of Cellular and Molecular Biology, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute.
Department of Ward 2, Beijing Chest Hospital, Capital Medical University, Beijing.
Onco Targets Ther. 2017 Jul 18;10:3545-3556. doi: 10.2147/OTT.S134162. eCollection 2017.
This study aims to identify the clinical significance of serum autoantibodies against dickkopf-1 (DKK1) and evaluate their feasibility in the immunodiagnosis and prognosis of non-small cell lung cancer (NSCLC).
Epitope mapping by peptide microarray-based serum screening of NSCLC patients (n=72) and healthy controls (n=16) was performed. Indirect ELISA with peptides was used to measure the serum levels of autoantibodies in 206 NSCLC patients and 99 healthy controls. A 3-year follow-up was monitored to evaluate the correlation between serological levels of autoantibodies and overall survival (OS) and progression-free survival (PFS).
Four highly reactive epitopes were identified, which included peptides 67-84 (Pep A), 37-54 (Pep B), 145-156 (Pep C) and 247-261 (Pep D). The autoantibodies levels were considerably higher in sera of NSCLC patients compared with controls (<0.001), and a highly significant correlation with distant metastases was observed (Pep A: =0.09, Pep B: <0.01, Pep C: <0.01 and Pep D: <0.01). High levels of antibody subtype to Pep B were remarkably associated with better OS (=0.004) and PFS (=0.006). Subsequent Cox regression analysis disclosed that antibody to Pep B was an independent prognostic factor for NSCLC (OS: =0.008, HR =0.435, 95% CI 0.236-0.802; PFS: =0.032, HR =0.533, 95% CI 0.322-0.950).
Identified linear epitopes of antigens by peptide microarray are easily available, and subtype classification of DKK1 autoantibodies as novel biomarkers for the diagnosis and prognosis of NSCLC. Our results also highlight the antibody subtype to Pep B as the most valuable biomarker for favorable prognosis of NSCLC.
本研究旨在确定抗Dickkopf-1（DKK1）血清自身抗体的临床意义，并评估其在非小细胞肺癌（NSCLC）免疫诊断和预后评估中的可行性。
通过基于肽微阵列的血清筛选对72例NSCLC患者和16例健康对照进行表位作图。使用肽间接ELISA法检测206例NSCLC患者和99例健康对照血清中自身抗体水平。进行为期3年的随访，以评估自身抗体血清学水平与总生存期（OS）和无进展生存期（PFS）之间的相关性。
鉴定出四个高反应性表位，包括肽段67 - 84（肽段A）、37 - 54（肽段B）、145 - 156（肽段C）和247 - 261（肽段D）。NSCLC患者血清中自身抗体水平显著高于对照组（<0.001），且与远处转移存在高度显著相关性（肽段A：=0.09，肽段B：<0.01，肽段C：<0.01，肽段D：<0.01）。肽段B抗体亚型水平高与更好的OS（=0.004）和PFS（=0.006）显著相关。随后的Cox回归分析表明，肽段B抗体是NSCLC的独立预后因素（OS：=0.008，HR =0.435，95%CI 0.236 - 0.802；PFS：=0.032，HR =0.533，95%CI 0.322 - 0.950）。
通过肽微阵列鉴定的抗原线性表位易于获得，DKK1自身抗体亚型分类可作为NSCLC诊断和预后的新型生物标志物。我们的结果还突出了肽段B抗体亚型是NSCLC良好预后最有价值的生物标志物。
