title: GNAS and KRAS Mutations Define Separate Progression Pathways in Intraductal Papillary Mucinous Neoplasm-Associated Carcinoma.
abstract: BACKGROUND
  Intraductal papillary mucinous neoplasms (IPMN) are being increasingly recognized as important precursors to pancreatic adenocarcinoma. Elucidation of the genetic changes underlying IPMN carcinogenesis may improve the diagnosis and management of IPMN. We sought to determine whether different histologic subtypes of IPMN would exhibit different frequencies of specific genetic mutations.
  
  
  METHODS
  Patients with resected IPMN-associated invasive carcinoma (IPMN-INV) between 1997 and 2012 were reviewed. Areas of carcinoma, high-grade dysplasia, and low-grade dysplasia were micro-dissected from each pathologic specimen. Targeted, massively parallel sequencing was then performed on a panel of 275 genes (including KRAS, GNAS, and RNF43).
  
  
  RESULTS
  Thirty-eight patients with resected IPMN-INV and sufficient tissue for micro-dissection were identified. Median follow-up was 2.6 years. Mutations in GNAS were more prevalent in colloid-type IPMN-INV than tubular-type IPMN-INV (89% vs 32% respectively; p = 0.0003). Conversely, KRAS mutations were more prevalent in tubular-type than colloid-type IPMN-INV (89% vs 52%, respectively; p = 0.01). For noninvasive IPMN subtypes, GNAS mutations were more prevalent in intestinal (74%) compared with pancreatobiliary (31%) and gastric (50%) subtypes (p = 0.02). The presence of these mutations did not vary according to the degree of dysplasia (GNAS: invasive 61%, high-grade 59%, low-grade 53%; KRAS: invasive 71%, high-grade 62%, low-grade 74%), suggesting that mutations in these genes occur early in IPMN carcinogenesis.
  
  
  CONCLUSIONS
  Colloid carcinoma associated with IPMN and its intestinal-type preinvasive precursor are associated with high frequencies of GNAS mutations. The mutation profile of tubular carcinoma resembles that of conventional pancreatic adenocarcinoma. Preoperative determination of mutational status may assist with clinical treatment decisions.
authors.affiliation: Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY.
authors.forename: Marcus C
authors.initials: MC
authors.lastname: Tan
authors.affiliation: Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY.
authors.forename: Olca
authors.initials: O
authors.lastname: Basturk
authors.affiliation: Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY.
authors.forename: A Rose
authors.initials: AR
authors.lastname: Brannon
authors.affiliation: Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY.
authors.forename: Umesh
authors.initials: U
authors.lastname: Bhanot
authors.affiliation: Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY.
authors.forename: Sasinya N
authors.initials: SN
authors.lastname: Scott
authors.affiliation: Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY.
authors.forename: Nancy
authors.initials: N
authors.lastname: Bouvier
authors.affiliation: Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY.
authors.forename: Jennifer
authors.initials: J
authors.lastname: LaFemina
authors.affiliation: Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY.
authors.forename: William R
authors.initials: WR
authors.lastname: Jarnagin
authors.affiliation: Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Berger
authors.affiliation: Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY.
authors.forename: David
authors.initials: D
authors.lastname: Klimstra
authors.affiliation: Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Allen
mesh_terms: D002288:Adenocarcinoma, Mucinous / Q000235:genetics* / Q000401:mortality / Q000473:pathology / Q000601:surgery; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics*; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics* / Q000401:mortality / Q000473:pathology / Q000601:surgery; D002291:Carcinoma, Papillary / Q000235:genetics* / Q000401:mortality / Q000473:pathology / Q000601:surgery; D002864:Chromogranins; D004268:DNA-Binding Proteins / Q000235:genetics; D018450:Disease Progression; D005260:Female; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009154:Mutation; D015513:Oncogene Proteins / Q000235:genetics; D010180:Pancreatectomy; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology / Q000601:surgery; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D012189:Retrospective Studies; D044767:Ubiquitin-Protein Ligases; D018631:ras Proteins / Q000235:genetics*
chemical_list: D014408:Biomarkers, Tumor; D002864:Chromogranins; D004268:DNA-Binding Proteins; C117307:KRAS protein, human; D015513:Oncogene Proteins; D011518:Proto-Oncogene Proteins; C496945:RNF43 protein, human; D044767:Ubiquitin-Protein Ligases; C406732:GNAS protein, human; D019205:GTP-Binding Protein alpha Subunits, Gs; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins
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