M1965 Integrative Transcriptomic and Genomic Analysis Reveals Pathways and Networks Underlying Clinicopathological Characteristics of Pancreatic Ductal Adenocarcinoma

Abstract

Background The dismal outcome associated with pancreatic ductal adenocarcinoma (PDAC) despite surgery and adjuvant therapy, demands the identification of accurate diagnostic as well as prognostic biomarkers. MicroRNAs (miRNAs) constitute a class of small (21-23 nucleotides) noncoding RNAs that function as post-transcriptional gene regulators with alteration in expression correlating with cancer pathogenesis. The aim of the current study was to investigate the miRNA expression profile associated with PDAC and to correlate this with patient outcome. Methods We used 723 feature miRNA arrays (Agilent) to investigate miRNA expression in normal pancreas, PDAC tissues as well as PDAC-derived cell lines. Total RNA from tumour tissue from 42 PDAC patients undergoing pancreatico-duodenectomywith curative intent was profiled. The expression status of selected miRNAs was then investigated by real-time RT-PCR. Results MiRNA Microarray analysis identified unique profiles, which discriminate PDAC from non-cancerous pancreatic tissues included significant over expression of miR-155, miR-221, miR-21 and miR-143 (p < 0.001) as well under-expression of miR-29c, miR-216, miR-217, and miR-148a (p < 0.001). Molecular signatures that differ according to histopathological features and the presence of lymph node metastasis were also identified. Using a Cox proportional hazard regression model, expression of a number of miRNAs was found to correlate with outcome including miR-29c, miR-30d, miR-33a and miR-224 (p < 0.05), independent of tumour stage. Integration of the miRNA data with expression levels of proteins associated with cell cycle control and apoptosis (BCL-2, Ki67, p53, cyclin D1) as well as bioinformatic analysis of the predicted gene targets of the miRNAs of interest was also performed with the intent of identifying novel targets relevant to PDAC biology. Conclusions Our data provides novel insights into the miRNA-driven pathophysiological mechanisms involved in PDAC development and offers new candidate targets to be exploited both for diagnostic and therapeutic strategies. Furthermore, following resection with curative intent, the miRNAmolecular signature of PDAC correlates with patient survival.