A genome-wide investigation of microRNA expression identifies biologically-meaningful microRNAs that distinguish between high-risk and low-risk intraductal papillary mucinous neoplasms of the pancreas

• Published in: PloS one Vol. 10; no. 1; p. e0116869
• Main Authors: Permuth-Wey, Jennifer, Chen, Y Ann, Fisher, Kate, McCarthy, Susan, Qu, Xiaotao, Lloyd, Mark C, Kasprzak, Agnieszka, Fournier, Michelle, Williams, Vonetta L, Ghia, Kavita M, Yoder, Sean J, Hall, Laura, Georgeades, Christina, Olaoye, Funmilayo, Husain, Kazim, Springett, Gregory M, Chen, Dung-Tsa, Yeatman, Timothy, Centeno, Barbara Ann, Klapman, Jason, Coppola, Domenico, Malafa, Mokenge
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 21-01-2015; Public Library of Science (PLoS)
• Subjects: Adenocarcinoma; Adenocarcinoma, Mucinous - genetics; Adenocarcinoma, Mucinous - pathology; Adenocarcinoma, Papillary - genetics; Adenocarcinoma, Papillary - pathology; Aged; Aged, 80 and over; Bioinformatics; Carcinoma, Pancreatic Ductal - genetics; Carcinoma, Pancreatic Ductal - pathology; Cellular biology; Cysts; Data processing; Deoxyribonucleic acid; Diagnosis, Differential; DNA; DNA microarrays; DNMT1 protein; Epidemiology; Female; Gene expression; Gene Expression Profiling - methods; Gene Expression Regulation, Neoplastic; Gene Regulatory Networks; Genomes; Genomics; Humans; Insulin receptor substrate 1; Investigations; Kinases; Lesions; Male; Malignancy; Medical diagnosis; Medical imaging; Medical prognosis; MicroRNA; MicroRNAs; MicroRNAs - genetics; Microscopy; Middle Aged; miRNA; Mortality; Neoplasms; Oligonucleotide Array Sequence Analysis - methods; Oncology; Pancreas; Pancreatic cancer; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - pathology; Pathology; Pilot Projects; Proteins; Regulators; Ribonucleic acid; Risk; RNA; Serum albumin; Serum Albumin - metabolism; Suppressors; Surgery; Tumors
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0116869

Intraductal papillary mucinous neoplasms (IPMNs) are pancreatic ductal adenocarcinoma (PDAC) precursors. Differentiating between high-risk IPMNs that warrant surgical resection and low-risk IPMNs that can be monitored is a significant clinical problem, and we sought to discover a panel of mi(cro)RNAs that accurately classify IPMN risk status.
In a discovery phase, genome-wide miRNA expression profiling was performed on 28 surgically-resected, pathologically-confirmed IPMNs (19 high-risk, 9 low-risk) using Taqman MicroRNA Arrays. A validation phase was performed in 21 independent IPMNs (13 high-risk, 8 low-risk). We also explored associations between miRNA expression level and various clinical and pathological factors and examined genes and pathways regulated by the identified miRNAs by integrating data from bioinformatic analyses and microarray analysis of miRNA gene targets. Six miRNAs (miR-100, miR-99b, miR-99a, miR-342-3p, miR-126, miR-130a) were down-regulated in high-risk versus low-risk IPMNs and distinguished between groups (P<10-3, area underneath the curve (AUC) = 87%). The same trend was observed in the validation phase (AUC = 74%). Low miR-99b expression was associated with main pancreatic duct involvement (P = 0.021), and serum albumin levels were positively correlated with miR-99a (r = 0.52, P = 0.004) and miR-100 expression (r = 0.49, P = 0.008). Literature, validated miRNA:target gene interactions, and pathway enrichment analysis supported the candidate miRNAs as tumor suppressors and regulators of PDAC development. Microarray analysis revealed that oncogenic targets of miR-130a (ATG2B, MEOX2), miR-342-3p (DNMT1), and miR-126 (IRS-1) were up-regulated in high- versus low-risk IPMNs (P<0.10).
This pilot study highlights miRNAs that may aid in preoperative risk stratification of IPMNs and provides novel insights into miRNA-mediated progression to pancreatic malignancy. The miRNAs identified here and in other recent investigations warrant evaluation in biofluids in a well-powered prospective cohort of individuals newly-diagnosed with IPMNs and other pancreatic cysts and those at increased genetic risk for these lesions.