Establishment of a Potential Serum Biomarker Panel for the Diagnosis and Prognosis of Cholangiocarcinoma Using Decision Tree Algorithms

Abstract

Potential biomarkers which include S100 calcium binding protein A9 (S100A9), mucin 5AC (MUC5AC), transforming growth factor β1 (TGF-β1), and angiopoietin-2 have previously been shown to be effective for cholangiocarcinoma (CCA) diagnosis. This study attempted to measure the sera levels of these biomarkers compared with carbohydrate antigen 19-9 (CA19-9). A total of 40 serum cases of CCA, gastrointestinal cancers (non-CCA), and healthy subjects were examined by using an enzyme-linked immunosorbent assay. The panel of biomarkers was evaluated for their accuracy in diagnosing CCA and subsequently used as inputs to construct the decision tree (DT) model as a basis for binary classification. The findings showed that serum levels of S100A9, MUC5AC, and TGF-β1 were dramatically enhanced in CCA patients. In addition, 95% sensitivity and 90% specificity for CCA differentiation from healthy cases, and 70% sensitivity and 83% specificity for CCA versus non-CCA cases was obtained by a panel incorporating all five candidate biomarkers. In CCA patients with low CA19-9 levels, S100A9 might well be a complementary marker for improved diagnostic accuracy. The high levels of TGF-β1 and angiopoietin-2 were both associated with severe tumor stages and metastasis, indicating that they could be used as a reliable prognostic biomarkers panel for CCA patients. Furthermore, the outcome of the CCA burden from the Classification and Regression Tree (CART) algorithm using serial CA19-9 and S100A9 showed high diagnostic efficiency. In conclusion, results have shown the efficacy of CCA diagnosis and prognosis of the novel CCA-biomarkers panel examined herein, which may prove be useful in clinical settings.

Development and validation of circulating protein signatures as diagnostic biomarkers for biliary tract cancer

“… 21 Other studies investigating the use of multiprotein signatures as novel biomarkers are limited by a small number of patients with BTC (n <70) and a lack of validation in independent cohorts. [38] , [39] , [40] , [41] , [42] …”

Novel approaches in search for biomarkers of cholangiocarcinoma

“…Moreover, the combination of MMP-7[ 57 ], DKK1[ 60 ], thrombospondin-2 (TSP-2)[ 61 ] and uPAR[ 59 ] assessed together with CA19-9 showed higher values of sensitivity and specificity than the markers measured individually to diagnose CCA patients. Not least, a biomarker panel consisting of five proteins investigated in a decision tree algorithms based study, namely S100A9, MUC5AC, TGF-β1, angiopoietin-2 (Ang-2), and CA19-9, showed to have the greatest diagnostic potential among all mentioned proteins towards CCA vs HC (sensitivity: 95%, specificity: 90%) and towards CCA vs non-CCA (sensitivity: 70%, specificity: 83%) differentiation[ 62 ].…”

“…Subjected to meta-analysis, high levels of tissue PD-L1[ 17 ] and tissue protein S100P[ 69 ] were also proposed as potential prognostic markers of CCA. Out of a protein multimarker panel consisting of serum S100A9, MUC5AC, TGF-β1, Ang-2, and CA19-9, serum levels of TGF-β1 and Ang-2 provided predictive potential for both metastasis and TNM stage prognosis in CCA patients[ 62 ].…”

Angiopoietin-2 and the Vascular Endothelial Growth Factor Promote Migration and Invasion in Hepatocellular Carcinoma- and Intrahepatic Cholangiocarcinoma-Derived Spheroids

“…This correlation is particularly strong in cases of HCC, especially its more aggressive forms [5,12]. Similarly, in CCA, ANG-2 has been identified as a significant biomarker that can aid in diagnosis and predict outcomes [13]. The vascular endothelial growth factor, commonly known as VEGF, is a protein that modifies the activity of ANG-2.…”