Studies In Patients With Surgically Resected Pancreatic Neuroendocrine Tumours - MicroRNA Expression And Clinical Correlation

Abstract

INTRODUCTION Pancreatic Neuroendocrine Tumours (PNETS) have increased in incidence over the past three decades. Treatment options currently include surgery, locoregional and systemic therapies, however the prognosis remains poor and biomarkers that accurately predict the clinical behavior of these tumours are lacking. Dysregulation of microRNAs (miRNAs) has recently been shown to play a role in the development of many cancers through post-transcriptional gene regulation, however, few studies have investigated the role of miRNAs as diagnostic or prognostic markers in PNETs. METHODS Patients undergoing resection of PNETs at our institutions between 1992 and 2014 were retrospectively included in this study. RNA was extracted from formalin-fixed, paraffin embedded PNET samples and microarray analysis performed and correlated with clinicopathological data. MicroRNAs with statistically significant differential expression between patients with locoregional disease only, versus those who developed metastases were subject to in-silico analysis using three target gene prediction databases. RESULTS 37 patients were included in the study. Patient subgroup DM had poorer overall survival (OS) as compared to subgroup L (p = 0.046). 506 miRNAs with differential expression between the ‘Distant metastasis’ group and ‘Locoregional’ group were identified. Of these, 265 miRNAs were downregulated, whilst 241 were upregulated. Four of these miRNAs were differentially expressed to statistical significance. These included miR-3653 which was upregulated and miR-4417, miR-574-3p and miR-664b-3p which were all downregulated. Only miRNA-3653 was identified by all three databases as having a potential PNET-related target; ATRX. CONCLUSION Higher expression of tumour miR-3653 was seen in the group of patients with metastatic disease compared to those with only locoregional disease. Several bioinformatic tools predicted transcriptional regulator ATRX as a possible target for miR-3653. Thus, it is possible that miR-3653 could be a biomarker for metastatic potential and consequently poorer prognosis in patients with PNETs. However, these conclusions cannot be made with certainty given the limitations of this study and further work beginning with validation is required.