title: Recurrent GNAS mutations define an unexpected pathway for pancreatic cyst development.
abstract: More than 2% of the adult U.S. population harbors a pancreatic cyst. These often pose a difficult management problem because conventional criteria cannot always distinguish cysts with malignant potential from those that are innocuous. One of the most common cystic neoplasms of the pancreas, and a bona fide precursor to invasive adenocarcinoma, is called intraductal papillary mucinous neoplasm (IPMN). To help reveal the pathogenesis of these lesions, we purified the DNA from IPMN cyst fluids from 19 patients and searched for mutations in 169 genes commonly altered in human cancers. In addition to the expected KRAS mutations, we identified recurrent mutations at codon 201 of GNAS. A larger number (113) of additional IPMNs were then analyzed to determine the prevalence of KRAS and GNAS mutations. In total, we found that GNAS mutations were present in 66% of IPMNs and that either KRAS or GNAS mutations could be identified in 96%. In eight cases, we could investigate invasive adenocarcinomas that developed in association with IPMNs containing GNAS mutations. In seven of these eight cases, the GNAS mutations present in the IPMNs were also found in the invasive lesion. GNAS mutations were not found in other types of cystic neoplasms of the pancreas or in invasive adenocarcinomas not associated with IPMNs. In addition to defining a new pathway for pancreatic neoplasia, these data suggest that GNAS mutations can inform the diagnosis and management of patients with cystic pancreatic lesions.
authors.affiliation: Ludwig Center for Cancer Genetics and Howard Hughes Medical Institutions, Johns Hopkins Kimmel Cancer Center, Baltimore, MD 21231, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Wu
authors.forename: Hanno
authors.initials: H
authors.lastname: Matthaei
authors.forename: Anirban
authors.initials: A
authors.lastname: Maitra
authors.forename: Marco
authors.initials: M
authors.lastname: Dal Molin
authors.forename: Laura D
authors.initials: LD
authors.lastname: Wood
authors.forename: James R
authors.initials: JR
authors.lastname: Eshleman
authors.forename: Michael
authors.initials: M
authors.lastname: Goggins
authors.forename: Marcia I
authors.initials: MI
authors.lastname: Canto
authors.forename: Richard D
authors.initials: RD
authors.lastname: Schulick
authors.forename: Barish H
authors.initials: BH
authors.lastname: Edil
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Wolfgang
authors.forename: Alison P
authors.initials: AP
authors.lastname: Klein
authors.forename: Luis A
authors.initials: LA
authors.lastname: Diaz
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Allen
authors.forename: C Max
authors.initials: CM
authors.lastname: Schmidt
authors.forename: Kenneth W
authors.initials: KW
authors.lastname: Kinzler
authors.forename: Nickolas
authors.initials: N
authors.lastname: Papadopoulos
authors.forename: Ralph H
authors.initials: RH
authors.lastname: Hruban
authors.forename: Bert
authors.initials: B
authors.lastname: Vogelstein
mesh_terms: D002288:Adenocarcinoma, Mucinous / Q000235:genetics / Q000473:pathology; D000328:Adult; D000368:Aged; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics / Q000473:pathology; D002864:Chromogranins; D002999:Clone Cells; D020420:Cyst Fluid / Q000378:metabolism; D004247:DNA / Q000235:genetics; D005260:Female; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009361:Neoplasm Invasiveness; D010181:Pancreatic Cyst / Q000235:genetics* / Q000473:pathology*; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins / Q000235:genetics
chemical_list: D002864:Chromogranins; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D004247:DNA; C406732:GNAS protein, human; D019205:GTP-Binding Protein alpha Subunits, Gs; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins