基于蛋白质组学分析的区分胰头癌和远端胆管癌的新型生物标志物。
Novel biomarkers distinguishing pancreatic head Cancer from distal cholangiocarcinoma based on proteomic analysis.
机构信息
Department of Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8574, Japan.
Department of Pathology and Histotechnology, Tohoku University Graduate School of Medicine, Sendai, Japan.
出版信息
BMC Cancer. 2019 Apr 5;19(1):318. doi: 10.1186/s12885-019-5548-x.
BACKGROUND
The differentiation between pancreatic head cancer (PHC) and distal cholangiocarcinoma (DCC) can be challenging because of their anatomical and histopathological similarity. This is an important problem, because the distinction has important implications for the treatment of these malignancies. However, there are no biomarkers for the differential diagnosis of PHC and DCC. The present study aimed to identify novel diagnostic immunohistochemical biomarkers to distinguish PHC from DCC.
METHODS
Liquid chromatography tandem mass spectrometry (LC-MS/MS) was employed to detect candidate proteins. Ten PHC and 8 DCC specimens were analyzed by LC-MS/MS. Selected proteins were evaluated, using immunohistochemical analysis, to determine whether they would be appropriate biomarkers. Finally, we generated biomarker panels to improve diagnostic accuracy. We applied these panels to clinically difficult cases (cases in which different diagnoses were made before and after operation).
RESULTS
Consequently, 1820 proteins were detected using LC-MS/MS. Fifteen differentially expressed proteins were selected as candidates based on semi-quantitative comparison. We first performed immunohistochemical staining on samples from the small cohort group (12 PHCs and 12 DCCs) using 15 candidates. KRT17, ANXA10, TMEM109, PTMS, and ATP1B1 showed favorable performances and were tested in the next large cohort group (72 PHCs and 74 DCCs). Based on immunohistochemical analysis, KRT17 performed best for the diagnosis of PHC as a single marker; additionally, PTMS exhibited good performance for the diagnosis of DCCs. Moreover, we indicated the KRT17+/ANXA10+/PTMS- staining pattern as a biomarker panel for the correct diagnosis of PHC and KRT17-/ANXA10-/PTMS+ for the diagnosis of DCC. After immunohistochemical staining for examining samples from the clinically difficult cases, these panels showed satisfactory diagnostic performance with 85.7% (6/7) accuracy.
CONCLUSIONS
We conclude that 5 proteins and 2 biomarker panels are promising for distinguishing PHC from DCC, and patients with an equivocal diagnosis would benefit from the application of these biomarkers. Confirmatory studies are needed to generalize these findings to other populations.
背景
由于解剖学和组织病理学上的相似性，胰头癌（PHC）和远端胆管癌（DCC）之间的区分具有挑战性。这是一个重要的问题，因为这种区别对这些恶性肿瘤的治疗有重要影响。然而，目前还没有用于鉴别诊断 PHC 和 DCC 的生物标志物。本研究旨在寻找新的诊断免疫组织化学生物标志物，以区分 PHC 和 DCC。
方法
采用液相色谱-串联质谱（LC-MS/MS）检测候选蛋白。分析了 10 例 PHC 和 8 例 DCC 标本。通过免疫组织化学分析评估选定的蛋白，以确定它们是否适合作为生物标志物。最后，我们生成了生物标志物组合，以提高诊断准确性。我们将这些组合应用于临床困难病例（手术前后做出不同诊断的病例）。
结果
因此，通过 LC-MS/MS 检测到 1820 种蛋白质。基于半定量比较，选择了 15 种差异表达蛋白作为候选蛋白。我们首先使用 15 种候选蛋白对小队列组（12 例 PHC 和 12 例 DCC）的样本进行免疫组织化学染色。KRT17、ANXA10、TMEM109、PTMS 和 ATP1B1 表现出良好的性能，并在接下来的大队列组（72 例 PHC 和 74 例 DCC）中进行了测试。基于免疫组织化学分析，KRT17 作为单一标志物对 PHC 的诊断性能最佳；此外，PTMS 对 DCC 的诊断也表现出良好的性能。此外，我们指出 KRT17+/ANXA10+/PTMS-染色模式是 PHC 正确诊断的生物标志物组合，KRT17-/ANXA10-/PTMS+是 DCC 的诊断生物标志物组合。对临床困难病例的样本进行免疫组织化学染色后，这些组合的诊断性能令人满意，准确率为 85.7%（6/7）。
结论
我们得出结论，5 种蛋白和 2 种生物标志物组合有望用于区分 PHC 和 DCC，对于诊断不明确的患者，应用这些标志物将有所裨益。需要进一步的研究来推广这些发现到其他人群。
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