Validation of four candidate pancreatic cancer serological biomarkers that improve the performance of CA19.9

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.

Identification of a Three-Biomarker Panel in Urine for Early Detection of Pancreatic Adenocarcinoma

“…REG1A and REG1B proteins are almost 90% identical (29), and are difficult to distinguish. REG1A levels have previously been observed in the plasma of mice with PanIN (Pancreatic intraepithelial neoplasia) lesions compared to control mice (30), and REG1B has recently been reported as one of the four candidate serological biomarkers that can improve the performance of CA19.9 in PDAC (31). Both proteins were able to significantly differentiate healthy from PDAC urine samples, demonstrating thus for the first time their high discriminatory power in urine specimens.…”

Oncogenic KRAS Targets MUC16/CA125 in Pancreatic Ductal Adenocarcinoma

“…It reflects the tumor burden and activity, and has predictive role for postoperative outcomes (7)(8)(9). CA125 was firstly detected in ovarian cancer and had been reported to be positive in 80% of ovarian epithelial tumor patients (10).…”

Validation of Biomarkers That Complement CA19.9 in Detecting Early Pancreatic Cancer

“…Our multiple approaches enabled us to identify numerous biomarker candidates including anterior gradient homolog 2 (AGR2), regenerating islet-derived 1 beta (REG1B), syncollin (SYCN), laminin gamma C (LAMC2) and cancer antigen 125 (CA125), all of which were subsequently validated in over 400 samples (11, 12, 14). (Notably, CA125 was re-discovered as “CUZD1 protein” (15)).…”