A Comprehensive Assessment of the Role of miRNAs as Biomarkers in Gastroenteropancreatic Neuroendocrine Tumors.

ABSTRACT

BACKGROUND/AIMS: A key issue in neuroendocrine neoplasia management is the identification of blood signatures that specifically define the activity of a cancer or local tumor microenvironment. MicroRNAs (miRNAs) may represent such a candidate. To evaluate their clinical utility as biomarkers in gastroenteropancreatic neuroendocrine tumors (GEP-NETs), we assessed their expression in tissue and blood. METHODS: A systematic review of PubMed was undertaken to identify studies investigating miRNAs in GEP-NETs and their utility as blood or tissue biomarkers. RESULTS: Twenty-two studies using a range of methodologies with different normalization protocols were identified tumor - gastric NET type 1 (n = 1 study MiR-222, regulates p27KIP1), pancreatic (n = 6 MiR-21 [inflammatory marker, oncogene] and MiR-144 [PI3K/AKT signaling], both up- and downregulated depending on the method), small intestinal (n = 7 no consistent signature), and colorectal (n = 3 no consistent signature); blood - gastric NET type 1 (n = 1 MiR-222), pancreatic (n = 3 MiR-21), and small intestinal (n = 3 no consistent signature). The studies all included heterogeneous cohorts, were insufficiently powered, and utilized different methodologies, and age- and gender-matched controls were not used. Different miRNA isolation methods and detection protocols resulted in inconsistent expression comparing tumor and blood. A scientific discrepancy was the downregulated expression of some circulating candidates compared to tissue levels, suggesting methodological issues or physiological responses to the tumor. Both are of concern in defining the biometrics of a marker. CONCLUSIONS: A potential biomarker for GEP-NETs included MiR-21 (small bowel and pancreas), but this epithelial tumor marker requires prospective validation. Overall, significant scientific investigation remains to identify and demonstrate neuroendocrine specificity and to validate candidate miRNA biomarkers.