Capello Michela, Cappello Paola, Linty Federica Caterina, Chiarle Roberto, Sperduti Isabella, Novarino Anna, Salacone Paola, Mandili Giorgia, Naccarati Alessio, Sacerdote Carlotta, Beghelli Stefania, Bersani Samantha, Barbi Stefano, Bassi Claudio, Scarpa Aldo, Nisticò Paola, Giovarelli Mirella, Vineis Paolo, Milella Michele, Novelli Francesco
Center for Experimental Research and Medical Studies (CeRMS), Azienda Ospedaliera Città della Salute e della Scienza di Torino, Turin, Italy.
J Hematol Oncol. 2013 Sep 6;6:67. doi: 10.1186/1756-8722-6-67.
Pancreatic Ductal Adenocarcinoma (PDAC) is a highly aggressive malignancy with only a 5% 5-year survival rate. Reliable biomarkers for early detection are still lacking. The goals of this study were (a) to identify early humoral responses in genetically engineered mice (GEM) spontaneously developing PDAC; and (b) to test their diagnostic/predictive value in newly diagnosed PDAC patients and in prediagnostic sera.
The serum reactivity of GEM from inception to invasive cancer, and in resectable or advanced human PDAC was tested by two-dimensional electrophoresis Western blot against proteins from murine and human PDAC cell lines, respectively. A common mouse-to-human autoantibody signature, directed against six antigens identified by MALDI-TOF mass spectrometry, was determined. Of the six antigens, Ezrin displayed the highest frequency of autoantibodies in GEM with early disease and in PDAC patients with resectable disease. The diagnostic value of Ezrin-autoantibodies to discriminate PDAC from controls was further shown by ELISA and ROC analyses (P < 0.0001). This observation was confirmed in prediagnostic sera from the EPIC prospective study in patients who eventually developed PDAC (with a mean time lag of 61.2 months between blood drawing and PDAC diagnosis). A combination of Ezrin-autoantibodies with CA19.9 serum levels and phosphorylated α-Enolase autoantibodies showed an overall diagnostic accuracy of 0.96 ± 0.02.
Autoantibodies against Ezrin are induced early in PDAC and their combination with other serological markers may provide a predictive and diagnostic signature.
胰腺导管腺癌（PDAC）是一种侵袭性很强的恶性肿瘤，5年生存率仅为5%。目前仍缺乏可靠的早期检测生物标志物。本研究的目的是：（a）在自发发生PDAC的基因工程小鼠（GEM）中识别早期体液反应；（b）在新诊断的PDAC患者和诊断前血清中测试其诊断/预测价值。
分别通过二维电泳免疫印迹法检测从起始到侵袭性癌阶段的GEM血清反应性，以及可切除或晚期人类PDAC血清与鼠源和人源PDAC细胞系蛋白的反应性。确定了一种针对通过基质辅助激光解吸电离飞行时间质谱鉴定的六种抗原的常见小鼠-人类自身抗体特征。在患有早期疾病的GEM和患有可切除疾病的PDAC患者中，六种抗原中的埃兹蛋白（Ezrin）显示出最高频率的自身抗体。酶联免疫吸附测定（ELISA）和受试者工作特征（ROC）分析进一步显示了埃兹蛋白自身抗体区分PDAC与对照的诊断价值（P < 0.0001）。在最终发生PDAC的患者的欧洲癌症前瞻性调查（EPIC）前瞻性研究的诊断前血清中证实了这一观察结果（采血与PDAC诊断之间的平均时间间隔为61.2个月）。埃兹蛋白自身抗体与糖类抗原19-9（CA19.9）血清水平和磷酸化α-烯醇化酶自身抗体的组合显示总体诊断准确性为0.96±0.02。
针对埃兹蛋白的自身抗体在PDAC早期被诱导产生，其与其他血清学标志物的组合可能提供一种预测和诊断特征。
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