title: 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.
abstract: BACKGROUND
  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.
  
  
  RESULTS
  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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center, Tampa, FL, United States of America.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Permuth-Wey
authors.affiliation: Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center, Tampa, FL, United States of America.
authors.forename: Y Ann
authors.initials: YA
authors.lastname: Chen
authors.affiliation: Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center, Tampa, FL, United States of America.
authors.forename: Kate
authors.initials: K
authors.lastname: Fisher
authors.affiliation: Department of Clinical Testing Development, H. Lee Moffitt Cancer Center, Tampa, FL, United States of America.
authors.forename: Susan
authors.initials: S
authors.lastname: McCarthy
authors.affiliation: Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center, Tampa, FL, United States of America.
authors.forename: Xiaotao
authors.initials: X
authors.lastname: Qu
authors.affiliation: Department of Analytic Microscopy, H. Lee Moffitt Cancer Center, Tampa, FL, United States of America.
authors.forename: Mark C
authors.initials: MC
authors.lastname: Lloyd
authors.affiliation: Department of Analytic Microscopy, H. Lee Moffitt Cancer Center, Tampa, FL, United States of America.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Kasprzak
authors.affiliation: Department of Tissue Core Administration, H. Lee Moffitt Cancer Center, Tampa, FL, United States of America.
authors.forename: Michelle
authors.initials: M
authors.lastname: Fournier
authors.affiliation: Department of Information Shared Services, H. Lee Moffitt Cancer Center, Tampa, FL, United States of America.
authors.forename: Vonetta L
authors.initials: VL
authors.lastname: Williams
authors.affiliation: Department of Information Shared Services, H. Lee Moffitt Cancer Center, Tampa, FL, United States of America.
authors.forename: Kavita M
authors.initials: KM
authors.lastname: Ghia
authors.affiliation: Department of Molecular Genomics, H. Lee Moffitt Cancer Center, Tampa, FL, United States of America.
authors.forename: Sean J
authors.initials: SJ
authors.lastname: Yoder
authors.affiliation: Department of Molecular Genomics, H. Lee Moffitt Cancer Center, Tampa, FL, United States of America.
authors.forename: Laura
authors.initials: L
authors.lastname: Hall
authors.affiliation: Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center, Tampa, FL, United States of America.
authors.forename: Christina
authors.initials: C
authors.lastname: Georgeades
authors.affiliation: Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center, Tampa, FL, United States of America.
authors.forename: Funmilayo
authors.initials: F
authors.lastname: Olaoye
authors.affiliation: Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center, Tampa, FL, United States of America.
authors.forename: Kazim
authors.initials: K
authors.lastname: Husain
authors.affiliation: Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center, Tampa, FL, United States of America.
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Springett
authors.affiliation: Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center, Tampa, FL, United States of America.
authors.forename: Dung-Tsa
authors.initials: DT
authors.lastname: Chen
authors.affiliation: Department of Surgery, Gibbs Cancer Center and Research Institute, Spartanburg, SC, United States of America.
authors.forename: Timothy
authors.initials: T
authors.lastname: Yeatman
authors.affiliation: Department of Anatomic Pathology, H. Lee Moffitt Cancer Center, Tampa, FL, United States of America.
authors.forename: Barbara Ann
authors.initials: BA
authors.lastname: Centeno
authors.affiliation: Department of Gastroenterology, H. Lee Moffitt Cancer Center, Tampa, FL, United States of America.
authors.forename: Jason
authors.initials: J
authors.lastname: Klapman
authors.affiliation: Department of Anatomic Pathology, H. Lee Moffitt Cancer Center, Tampa, FL, United States of America.
authors.forename: Domenico
authors.initials: D
authors.lastname: Coppola
authors.affiliation: Department of Gastrointestinal Surgical Oncology, H. Lee Moffitt Cancer Center, Tampa, FL, United States of America.
authors.forename: Mokenge
authors.initials: M
authors.lastname: Malafa
mesh_terms: D002288:Adenocarcinoma, Mucinous / Q000235:genetics / Q000473:pathology*; D000231:Adenocarcinoma, Papillary / Q000235:genetics / Q000473:pathology*; D000368:Aged; D000369:Aged, 80 and over; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics / Q000473:pathology*; D003937:Diagnosis, Differential; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000473:pathology*; D010865:Pilot Projects; D012709:Serum Albumin / Q000378:metabolism
chemical_list: D035683:MicroRNAs; D012709:Serum Albumin