Clinical Significance of Serum COL6A3 in Pancreatic Ductal Adenocarcinoma

Abstract

Introduction: Type VI collagen (COL6) forms a microfibrillar network associated with type I collagen fibrils and constitutes a major component of the prominent desmoplastic reaction in pancreatic ductal adenocarcinoma (PDA). We have demonstrated recently that a subunit of COL6, COL6A3, is expressed in high levels in PDA tissue and that the COL6A3 gene undergoes tumor-specific alternative splicing. the aim of this study is to investigate the diagnostic value and clinical significance of circulating COL6A3 in PDA. Methods: Serum samples were obtained from patients that underwent pancreatic resection at Thomas Jefferson University Hospital between 2006 and 2009. COL6A3 levels in the sera from patients with pathologically confirmed PDA (n=44), intraductal papillary mucinous neoplasms (IPMN) (n=22), cystadenomas (n=15), chronic pancreatitis (n=10) and neuroendocrine tumors (NET) (n=7) were analyzed by ELISA. Serum CA19-9 values were obtained from the electronic medical records. the prediction levels for malignancy were determined by the area under the receiver operating characteristic curve (AUC). Immunohistochemical staining for COL6A3 was performed on 12 tissue samples where both serum and paraffinized tissue samples from the same patients were available. Results: Circulating COL6A3 levels were significantly (p=0.0035) elevated in PDA patients when compared to all benign lesions. Compared to IPMN alone, COL6A3 levels were significantly higher in PDA (p=0.014). There were no significant differences between the levels in PDA and NET (p= 0.59). Interestingly, high COL6A3 serum levels correlated with lymph node invasion (p=0.006) and with tumor size (p=0.045). We assessed the level of association of log(col6a3) and log(ca19-9) with cancer status using a logistic regression model. With each increasing unit of log COL6A3, a patient is 12.9 times more likely to have cancer, with 95% CI (1.9, 86.8), p=0.009. the odds for each increasing unit of log CA19-9 are 2.4 times, with 95% CI (1.6, 3.7), p<0.001. the overall area under the receiver-operator curve (ROC) is 0.90. Immunohistochemical analysis revealed a strong COL6A3 staining in PDA and NET and its localization to the perineoplastic stroma and the malignant cells. Conclusions: Our data show for the first time the potential clinical significance of circulating COL6A3 levels in the diagnosis of pancreatic malignancy. Correlation of the high COL6A3 levels with tumor size and lymph node invasion suggests a role for COL6A3 in PDA progression and metastatic potential.