Decreased Serum Thrombospondin-1 Levels in Pancreatic Cancer Patients Up to 24 Months Prior to Clinical Diagnosis: Association with Diabetes Mellitus.
Decreased Serum Thrombospondin-1 Levels in Pancreatic Cancer Patients Up to 24 Months Prior to Clinical Diagnosis: Association with Diabetes Mellitus.
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DOI：
10.1158/1078-0432.ccr-15-0879
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发表时间：
2016-04-01
期刊：
影响因子：
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通讯作者：
Costello E
中科院分区：
文献类型：
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作者：
Jenkinson C;Elliott VL;Evans A;Oldfield L;Jenkins RE;O'Brien DP;Apostolidou S;Gentry-Maharaj A;Fourkala EO;Jacobs IJ;Menon U;Cox T;Campbell F;Pereira SP;Tuveson DA;Park BK;Greenhalf W;Sutton R;Timms JF;Neoptolemos JP;Costello E
识别血清生物标志物能够早期诊断胰腺导管腺癌（PDAC）可以改善预后。研究了临床前疾病患者和诊断时的血清蛋白谱。研究了 PDAC 诊断前 4 年的病例和对照 (UKCTOCS，n=174) 的血清，以及诊断为 PDAC、慢性胰腺炎、良性胆道疾病、2 型糖尿病和健康受试者 (n=298) 的患者的样本。 iTRAQ 能够对测试集 (n=150) 中的混合血清进行比较。使用 MRM 和/或蛋白质印迹法对所有 472 个人类样本和 KPC 小鼠模型样本进行验证。 iTRAQ 发现临床前和诊断样本中血小板反应蛋白-1 (TSP-1) 降低。 MRM 证实诊断前 24 个月内 TSP-1 水平显着降低。 TSP-1 和 CA19-9 组合的 AUC 为 0.86，显着优于单独使用两种标记物（分别为 0.69 和 0.77；P<0.01）。与健康对照（P<0.05）和良性胆道梗阻患者（P<0.01）相比，PDAC 患者的 TSP-1 也降低。低水平的 TSP-1 与临床前 (P<0.05) 和临床诊断时 (P<0.02) 的较差生存率相关。在 PDAC 患者中，在确诊为糖尿病的患者中更常见 TSP-1 水平降低（P<0.01）。与 2 型糖尿病患者相比，糖尿病患者的 PDAC 水平也显着降低（P=0.01）。在诊断 PDAC 之前，循环 TSP-1 水平下降长达 24 个月，并显着提高 CA19-9 的诊断性能。在未来的研究中应考虑糖尿病对生物标志物行为的影响。
Identification of serum biomarkers enabling earlier diagnosis of pancreatic ductal adenocarcinoma (PDAC) could improve outcome. Serum protein profiles in patients with pre-clinical disease and at diagnosis were investigated. Serum from cases up to 4 years prior to PDAC diagnosis and controls (UKCTOCS,n=174) were studied, alongside samples from patients diagnosed with PDAC, chronic pancreatitis, benign biliary disease, type 2 diabetes mellitus and healthy subjects (n=298). iTRAQ enabled comparisons of pooled serum from a test set (n=150). Validation was undertaken using MRM and/or western blotting in all 472 human samples and samples from a KPC mouse model. iTRAQ identified thrombospondin-1 (TSP-1) as reduced preclinically and in diagnosed samples. MRM confirmed significant reduction in levels of TSP-1 up to 24 months prior to diagnosis. A combination of TSP-1 and CA19-9 gave an AUC of 0.86, significantly outperforming both markers alone (0.69 & 0.77 respectively; P<0.01). TSP-1 was also decreased in PDAC patients compared to healthy controls (P<0.05) and patients with benign biliary obstruction (P<0.01). Low levels of TSP-1 correlated with poorer survival, pre-clinically (P<0.05) and at clinical diagnosis (P<0.02). In PDAC patients, reduced TSP-1 levels were more frequently observed in those with confirmed diabetes mellitus (P<0.01). Significantly lower levels were also observed in PDAC patients with diabetes compared to individuals with type 2 DM (P=0.01). Circulating TSP-1 levels decrease up to 24 months prior to diagnosis of PDAC and significantly enhance the diagnostic performance of CA19-9. The influence of diabetes mellitus on biomarker behaviour should be considered in future studies.