Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen N, Denmark.
Int J Cancer. 2011 Apr 15;128(8):1860-71. doi: 10.1002/ijc.25778. Epub 2011 Jan 12.
Cancer-associated autoantibodies hold promise as sensitive biomarkers for early detection of cancer. Aberrant post-translational variants of proteins are likely to induce autoantibodies, and changes in O-linked glycosylation represent one of the most important cancer-associated post-translational modifications (PTMs). Short aberrant O-glycans on proteins may introduce novel glycopeptide epitopes that can elicit autoantibodies because of lack of tolerance. Technical barriers, however, have hampered detection of such glycopeptide-specific autoantibodies. Here, we have constructed an expanded glycopeptide array displaying a comprehensive library of glycopeptides and glycoproteins derived from a panel of human mucins (MUC1, MUC2, MUC4, MUC5AC, MUC6 and MUC7) known to have altered glycosylation and expression in cancer. Seromic profiling of patients with colorectal cancer identified cancer-associated autoantibodies to a set of aberrant glycopeptides derived from MUC1 and MUC4. The cumulative sensitivity of the array analysis was 79% with a specificity of 92%. The most prevalent of the identified autoantibody targets were validated as authentic cancer immunogens by showing expression of the epitopes in cancer using novel monoclonal antibodies. Our study provides evidence for the value of glycopeptides and other PTM-peptide arrays in diagnostic measures.
癌症相关自身抗体有望成为癌症早期检测的敏感生物标志物。蛋白质翻译后变体的异常很可能会诱导自身抗体产生，而 O -linked 糖基化的改变则代表最重要的癌症相关翻译后修饰 (PTM) 之一。蛋白质上短的异常 O-聚糖可能会产生新的糖肽表位，由于缺乏耐受性，这些表位可能会引发自身抗体。然而，技术障碍阻碍了对这些糖肽特异性自身抗体的检测。在这里，我们构建了一个扩展的糖肽阵列，展示了一组源自人类粘蛋白 (MUC1、MUC2、MUC4、MUC5AC、MUC6 和 MUC7) 的糖肽和糖蛋白的综合文库，这些粘蛋白已知在癌症中发生糖基化和表达改变。对结直肠癌患者的血清学分析鉴定了一组源自 MUC1 和 MUC4 的异常糖肽的癌症相关自身抗体。该阵列分析的累积灵敏度为 79%，特异性为 92%。所鉴定的自身抗体靶标中最常见的是通过使用新型单克隆抗体显示在癌症中表达这些表位来验证为真实的癌症免疫原。我们的研究为糖肽和其他 PTM-肽阵列在诊断措施中的价值提供了证据。
