Abstract
BackgroundThe identification of new serum biomarkers with high sensitivity and specificity is an important priority in pancreatic cancer research. Through an extensive proteomics analysis of pancreatic cancer cell lines and pancreatic juice, we previously generated a list of candidate pancreatic cancer biomarkers. The present study details further validation of four of our previously identified candidates: regenerating islet-derived 1 beta (REG1B), syncollin (SYCN), anterior gradient homolog 2 protein (AGR2), and lysyl oxidase-like 2 (LOXL2).MethodsThe candidate biomarkers were validated using enzyme-linked immunosorbent assays in two sample sets of serum/plasma comprising a total of 432 samples (Sample Set A: pancreatic ductal adenocarcinoma (PDAC, n = 100), healthy (n = 92); Sample Set B: PDAC (n = 82), benign (n = 41), disease-free (n = 47), other cancers (n = 70)). Biomarker performance in distinguishing PDAC from each control group was assessed individually in the two sample sets. Subsequently, multiparametric modeling was applied to assess the ability of all possible two and three marker panels in distinguishing PDAC from disease-free controls. The models were generated using sample set B, and then validated in Sample Set A.ResultsIndividually, all markers were significantly elevated in PDAC compared to healthy controls in at least one sample set (p ≤ 0.01). SYCN, REG1B and AGR2 were also significantly elevated in PDAC compared to benign controls (p ≤ 0.01), and AGR2 was significantly elevated in PDAC compared to other cancers (p < 0.01). CA19.9 was also assessed. Individually, CA19.9 showed the greatest area under the curve (AUC) in receiver operating characteristic (ROC) analysis when compared to the tested candidates; however when analyzed in combination, three panels (CA19.9 + REG1B (AUC of 0.88), CA19.9 + SYCN + REG1B (AUC of 0.87) and CA19.9 + AGR2 + REG1B (AUC of 0.87)) showed an AUC that was significantly greater (p < 0.05) than that of CA19.9 alone (AUC of 0.82). In a comparison of early-stage (Stage I-II) PDAC to disease free controls, the combination of SYCN + REG1B + CA19.9 showed the greatest AUC in both sample sets, (AUC of 0.87 and 0.92 in Sets A and B, respectively).ConclusionsAdditional serum biomarkers, particularly SYCN and REG1B, when combined with CA19.9, show promise as improved diagnostic indicators of pancreatic cancer, which therefore warrants further validation.
Highlights
The identification of new serum biomarkers with high sensitivity and specificity is an important priority in pancreatic cancer research
Very good inter-assay reproducibility was shown for SYCN, anterior gradient homolog 2 protein (AGR2), regenerating islet-derived 1 beta (REG1B) and lysyl oxidase-like 2 (LOXL2) assays with % Coefficients of variation (CV)
Performance of SYCN, REG1B, AGR2, LOXL2 and CA19.9 analyzed individually in pancreatic cancer and control groups All samples (n = 432) from the two sample sets described in the Methods section were subjected to Enzymelinked immunosorbent assays (ELISA) analysis in parallel and on the same day for each candidate
Summary
The identification of new serum biomarkers with high sensitivity and specificity is an important priority in pancreatic cancer research. The major drawback of all of these methods for the optimal management of pancreatic cancer patients is that they are primarily utilized after the onset of symptoms (i.e. predominantly after the onset of latestage disease). They are associated with relatively high operating costs, and can be somewhat time consuming and/or invasive in nature. In this regard, implementation of highly sensitive and specific biomarkers or marker panels for pancreatic cancer can further enhance detection strategies by offsetting many of the limitations described above [5,6]
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