Peng Hong, Chen Ru, Brentnall Teresa A, Eng Jimmy K, Picozzi Vincent J, Pan Sheng
1Institute of Molecular Medicine, the University of Texas Health Science Center at Houston, Houston, TX 77030 USA.
2Division of Gastroenterology, Department of Medicine, Baylor College of Medicine, Houston, TX 77030 USA.
Clin Proteomics. 2019 Jul 17;16:31. doi: 10.1186/s12014-019-9251-3. eCollection 2019.
Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer that is characterized by its poor prognosis, rapid progression and development of drug resistance. Chemotherapy is a vital treatment option for most of PDAC patients. Stratification of PDAC patients, who would have a higher likelihood of responding to chemotherapy, could facilitate treatment selection and patient management.
A quantitative proteomic study was performed to characterize the protein profiles in the plasma of PDAC patients undergoing chemotherapy to determine if specific biomarkers could be used to predict likelihood of therapeutic response.
By comparing the plasma proteome of the PDAC patients with positive therapeutic response and longer overall survival (Good-responders) to those who did not respond as well with shorter survival time (Limited-responders), we identified differential proteins and protein variants that could effectively segregate Good-responders from Limited-responders. Functional clustering and pathway analysis further suggested that many of these differential proteins were involved in pancreatic tumorigenesis. Four proteins, including vitamin-K dependent protein Z (PZ), sex hormone-binding globulin (SHBG), von Willebrand factor (VWF) and zinc-alpha-2-glycoprotein (AZGP1), were further evaluated as single or composite predictive biomarker with/without inclusion of CA 19-9. A composite biomarker panel that consists of PZ, SHBG, VWF and CA 19-9 demonstrated the best performance in distinguishing Good-responders from Limited-responders.
Based on the cohort investigated, our data suggested that systemic proteome alterations involved in pathways associated with inflammation, immunoresponse, coagulation and complement cascades may be reporters of chemo-treatment outcome in PDAC patients. For the majority of the patients involved, the panel consisting of PZ, SHBG, VWF and CA 19-9 was able to segregate Good-responders from Limited-responders effectively. Our data also showed that dramatic fluctuations of biomarker concentration in the circulating system of a PDAC patient, which might result from biological heterogeneity or confounding complications, could diminish the performance of a biomarker. Categorization of PDAC patients in terms of their tumor stages and histological types could potentially facilitate patient stratification for treatment.
胰腺导管腺癌（PDAC）是一种致命性癌症，其特点是预后差、进展迅速且易产生耐药性。化疗是大多数PDAC患者的重要治疗选择。对更有可能对化疗产生反应的PDAC患者进行分层，有助于治疗选择和患者管理。
进行了一项定量蛋白质组学研究，以表征接受化疗的PDAC患者血浆中的蛋白质谱，确定是否可以使用特定生物标志物来预测治疗反应的可能性。
通过比较治疗反应良好且总生存期较长的PDAC患者（良好反应者）与反应不佳且生存时间较短的患者（有限反应者）的血浆蛋白质组，我们鉴定出了能够有效区分良好反应者和有限反应者的差异蛋白质和蛋白质变体。功能聚类和通路分析进一步表明，许多这些差异蛋白质参与了胰腺肿瘤的发生。对包括维生素K依赖性蛋白Z（PZ）、性激素结合球蛋白（SHBG）、血管性血友病因子（VWF）和锌α2糖蛋白（AZGP1）在内的四种蛋白质，在纳入或不纳入CA 19-9的情况下，作为单一或复合预测生物标志物进行了进一步评估。由PZ、SHBG、VWF和CA 19-9组成的复合生物标志物面板在区分良好反应者和有限反应者方面表现最佳。
基于所研究的队列，我们的数据表明，参与炎症、免疫反应、凝血和补体级联相关通路的全身蛋白质组改变可能是PDAC患者化疗治疗结果的指标。对于大多数所涉及的患者，由PZ、SHBG、VWF和CA 19-9组成的面板能够有效区分良好反应者和有限反应者。我们的数据还表明，PDAC患者循环系统中生物标志物浓度的剧烈波动，可能是由于生物异质性或混杂并发症导致的，这可能会降低生物标志物的性能。根据肿瘤分期和组织学类型对PDAC患者进行分类可能有助于治疗的患者分层。
