title: Clinicopathological correlates of activating GNAS mutations in intraductal papillary mucinous neoplasm (IPMN) of the pancreas.
abstract: BACKGROUND
  Intraductal papillary mucinous neoplasms (IPMNs) are the most common cystic precursor lesions of invasive pancreatic cancer. The recent identification of activating GNAS mutations at codon 201 in IPMNs is a promising target for early detection and therapy. The purpose of this study was to explore clinicopathological correlates of GNAS mutational status in resected IPMNs.
  
  
  METHODS
  Clinical and pathologic characteristics were retrieved on 54 patients in whom GNAS codon 201 mutational status was previously reported ("historical group", Wu et al. Sci Transl Med 3:92ra66, 2011). In addition, a separate cohort of 32 patients (validation group) was included. After microdissection and DNA extraction, GNAS status was determined in the validation group by pyrosequencing.
  
  
  RESULTS
  GNAS activating mutations were found in 64% of the 32 IPMNs included in the validation group, compared with a previously reported prevalence of 57% in the historical group. Overall, 52 of 86 (61%) of IPMNs demonstrated GNAS mutations in the two studies combined. Analysis of both groups confirmed that demographic characteristics, tumor location, ductal system involvement, focality, size, grade of dysplasia, presence of an associated cancer, and overall survival were not correlated with GNAS mutational status. Stratified by histological subtype, 100% of intestinal type IPMNs demonstrated GNAS mutations compared to 51% of gastric IPMN, 71% of pancreatobiliary IPMNs, and 0% of oncocytic IPMNs.
  
  
  CONCLUSIONS
  GNAS activating mutations can be reliably detected in IPMNs by pyrosequencing. In terms of clinicopathological parameters, only histological subtype was correlated with mutational frequency, with the intestinal phenotype always associated with GNAS mutations.
authors.affiliation: Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD.|Unit of General Surgery B, Pancreas Institute, Department of Surgery, "G.B. Rossi" Hospital, University of Verona Hospital Trust, Verona, Italy.
authors.forename: Marco Dal
authors.initials: MD
authors.lastname: Molin
authors.affiliation: Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD.|Department of General, Visceral, Thoracic and Vascular Surgery, University of Bonn, Bonn, Germany.
authors.forename: Hanno
authors.initials: H
authors.lastname: Matthaei
authors.affiliation: Ludwig Center for Cancer Genetics, Johns Hopkins University School of Medicine, Baltimore, MD.|Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Jian
authors.initials: J
authors.lastname: Wu
authors.affiliation: Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Amanda
authors.initials: A
authors.lastname: Blackford
authors.affiliation: Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Marija
authors.initials: M
authors.lastname: Debeljak
authors.affiliation: Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Neda
authors.initials: N
authors.lastname: Rezaee
authors.affiliation: Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD.|Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Wolfgang
authors.affiliation: Unit of General Surgery B, Pancreas Institute, Department of Surgery, "G.B. Rossi" Hospital, University of Verona Hospital Trust, Verona, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Butturini
authors.affiliation: Unit of General Surgery B, Pancreas Institute, Department of Surgery, "G.B. Rossi" Hospital, University of Verona Hospital Trust, Verona, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Salvia
authors.affiliation: Unit of General Surgery B, Pancreas Institute, Department of Surgery, "G.B. Rossi" Hospital, University of Verona Hospital Trust, Verona, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Bassi
authors.affiliation: Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD.|Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Goggins
authors.affiliation: Ludwig Center for Cancer Genetics, Johns Hopkins University School of Medicine, Baltimore, MD.|Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Kenneth W
authors.initials: KW
authors.lastname: Kinzler
authors.affiliation: Ludwig Center for Cancer Genetics, Johns Hopkins University School of Medicine, Baltimore, MD.|Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Bert
authors.initials: B
authors.lastname: Vogelstein
authors.affiliation: Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD.|Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: James R
authors.initials: JR
authors.lastname: Eshleman
authors.affiliation: Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD.|Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD.|Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Ralph H
authors.initials: RH
authors.lastname: Hruban
authors.affiliation: Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD.|Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Anirban
authors.initials: A
authors.lastname: Maitra
mesh_terms: D002288:Adenocarcinoma, Mucinous / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D002291:Carcinoma, Papillary / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D002864:Chromogranins; D005260:Female; D005500:Follow-Up Studies; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009367:Neoplasm Staging; D010179:Pancreas / Q000378:metabolism / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D011379:Prognosis; D011446:Prospective Studies; D015996:Survival Rate
chemical_list: D002864:Chromogranins; C406732:GNAS protein, human; D019205:GTP-Binding Protein alpha Subunits, Gs