title: Molecular biomarkers for progression of intraductal papillary mucinous neoplasm of the pancreas.
abstract: OBJECTIVE
  We aimed to identify molecular biomarkers for assessing the progression of intraductal papillary mucinous neoplasm of the pancreas (IPMN).
  
  
  METHODS
  We retrospectively investigated molecular aberrations and their associations with clinicopathological features in 172 IPMNs.
  
  
  RESULTS
  GNAS and KRAS mutations were detected in 48% and 56% of IPMNs, respectively. No mutations of EGFR, PIK3CA GNAO1, GNAQ, or GNAI2 were observed. Significant associations were observed between IPMN morphological types and GNAS mutations, KRAS mutations, the expression of phosphorylated MAPK (pMAPK), AKT, and phosphorylated AKT (pAKT), nuclear accumulation of β-catenin, SMAD4 loss, and TP53 overexpression; histological grades and the expression of EGFR, pMAPK, AKT, and pAKT, the nuclear β-catenin, SMAD4 loss, and TP53 overexpression; invasive phenotypes and KRAS mutations, the nuclear β-catenin, and SMAD4 loss; and prognosis and SMAD4 loss and TP53 overexpression. Multivariate analysis to compare prognostic impacts of multiple molecular features revealed that TP53 overexpression was an independent prognostic factor (P = 0.030; hazard ratio, 5.533).
  
  
  CONCLUSIONS
  These results indicate that mutations in GNAS and KRAS, the expression of EGFR and pMAPK, the nuclear β-catenin, SMAD4 loss, and TP53 overexpression may be relevant for assessing the clinical course of IPMN, including its progression into different morphological types, invasion, and prognosis.
authors.affiliation: From the *Institute for Integrated Medical Sciences, †Department of Gastroenterology, ‡Department of Gastroenterological Surgery, Institute of Gastroenterology, §Department of Pathology, and ∥Department of Surgical Pathology, Tokyo Women's Medical University, Tokyo, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Kuboki
authors.forename: Kyoko
authors.initials: K
authors.lastname: Shimizu
authors.forename: Takashi
authors.initials: T
authors.lastname: Hatori
authors.forename: Masakazu
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Shibata
authors.forename: Keiko
authors.initials: K
authors.lastname: Shiratori
authors.forename: Toru
authors.initials: T
authors.lastname: Furukawa
mesh_terms: D014408:Biomarkers, Tumor / Q000032:analysis* / Q000235:genetics*; D016009:Chi-Square Distribution; D002864:Chromogranins; D004252:DNA Mutational Analysis; D018450:Disease Progression; D066246:ErbB Receptors / Q000032:analysis / Q000235:genetics; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D020928:Mitogen-Activated Protein Kinases / Q000032:analysis; D015999:Multivariate Analysis; D009154:Mutation; D009364:Neoplasm Recurrence, Local; D018297:Neoplasms, Cystic, Mucinous, and Serous / Q000737:chemistry* / Q000235:genetics* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D010190:Pancreatic Neoplasms / Q000737:chemistry* / Q000235:genetics* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D010766:Phosphorylation; D011237:Predictive Value of Tests; D016016:Proportional Hazards Models; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D012189:Retrospective Studies; D012307:Risk Factors; D051901:Smad4 Protein / Q000032:analysis; D013997:Time Factors; D016896:Treatment Outcome; D016159:Tumor Suppressor Protein p53 / Q000032:analysis; D018631:ras Proteins / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; D002864:Chromogranins; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; C497796:SMAD4 protein, human; D051901:Smad4 Protein; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C512478:EGFR protein, human; D066246:ErbB Receptors; D020928:Mitogen-Activated Protein Kinases; C406732:GNAS protein, human; D019205:GTP-Binding Protein alpha Subunits, Gs; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins