title: Whole-exome sequencing uncovers frequent GNAS mutations in intraductal papillary mucinous neoplasms of the pancreas.
abstract: Intraductal papillary mucinous neoplasm (IPMN) is a common pancreatic cystic neoplasm that is often invasive and metastatic, resulting in a poor prognosis. Few molecular alterations unique to IPMN are known. We performed whole-exome sequencing for a primary IPMN tissue, which uncovered somatic mutations in KCNF1, DYNC1H1, PGCP, STAB1, PTPRM, PRPF8, RNASE3, SPHKAP, MLXIPL, VPS13C, PRCC, GNAS, KRAS, RBM10, RNF43, DOCK2, and CENPF. We further analyzed GNAS mutations in archival cases of 118 IPMNs and 32 pancreatic ductal adenocarcinomas (PDAs), which revealed that 48 (40.7%) of the 118 IPMNs but none of the 32 PDAs harbored GNAS mutations. G-protein alpha-subunit encoded by GNAS and its downstream targets, phosphorylated substrates of protein kinase A, were evidently expressed in IPMN; the latter was associated with neoplastic grade. These results indicate that GNAS mutations are common and specific for IPMN, and activation of G-protein signaling appears to play a pivotal role in IPMN.
authors.affiliation: Institute for Integrated Medical Sciences, Institute of Gastroenterology, Deparment of Surgical Pathology, Tokyo Women's Medical University, Tokyo, Japan. furukawa.toru@twmu.ac.jp
authors.forename: Toru
authors.initials: T
authors.lastname: Furukawa
authors.forename: Yuko
authors.initials: Y
authors.lastname: Kuboki
authors.forename: Etsuko
authors.initials: E
authors.lastname: Tanji
authors.forename: Shoko
authors.initials: S
authors.lastname: Yoshida
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: Kyoko
authors.initials: K
authors.lastname: Shimizu
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Kamatani
authors.forename: Keiko
authors.initials: K
authors.lastname: Shiratori
mesh_terms: D000368:Aged; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics / Q000473:pathology; D002864:Chromogranins; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000235:genetics; D005260:Female; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D018297:Neoplasms, Cystic, Mucinous, and Serous / Q000235:genetics* / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000473:pathology; D015398:Signal Transduction / Q000235:genetics
chemical_list: D002864:Chromogranins; D004273:DNA, Neoplasm; C406732:GNAS protein, human; D019205:GTP-Binding Protein alpha Subunits, Gs