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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.

SUBMITTER: Furukawa T

PROVIDER: S-EPMC3240977 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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Whole-exome sequencing uncovers frequent GNAS mutations in intraductal papillary mucinous neoplasms of the pancreas.

Furukawa Toru T Kuboki Yuko Y Tanji Etsuko E Yoshida Shoko S Hatori Takashi T Yamamoto Masakazu M Shibata Noriyuki N Shimizu Kyoko K Kamatani Naoyuki N Shiratori Keiko K

Scientific reports 20111118

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 a ...[more]

PMID: 22355676

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Project description:Intraductal Papillary Mucinous Neoplasms (IPMNs) of the pancreas are cyst-like precursor lesions that give rise to 25% of pancreatic ductal adenocarcinomas (PDAC). While ~90% of cases are diagnosed before cancer forms, metrics and markers by which to determine if an IPMN will progress are currently lacking. Overall, 96% of IPMNs harbor KRAS (~80%) and/or GNAS (~66%) driver mutations and IPMN may be classified as either gastric, intestinal, or pancreatobiliary type. Recently, we identified a shared program of pyloric type metaplasia between pancreatic and gastric injury. Here, we combined immunostaining, RNA-sequencing, molecular biology, and analysis of patient samples to identify major drivers of this program in IPMN. Methods Single cell RNA-sequencing datasets of human IPMN were assayed for markers of pyloric-type metaplasia. 37 IPMN patient samples were immunostained using MxIHC for MUC5AC, CD44v9, and AQP5. KrasG12D and GnasR201C expression was modified in IPMN cell lines to identify transcriptomic programs driven by each oncogene, and in combination. Gene sets were compared to murine and human gastric cell types. Transcriptomic drivers were identified and manipulated in vitro. Candidate driver expression was evaluated by immunostaining of patient IPMN and graded. Results Analysis of published bulk and scRNA-seq IPMN datasets revealed expression of previously described markers of pyloric type metaplasia. Marker expression was confirmed in patient samples. Manipulation of KrasG12D and GnasR201C expression in IPMN cell lines identified the relative contributions of each oncogene to this gastric phenotype. Regulon analysis suggests that transcription factors SPDEF, CREB3L1, and CREB3L4 amplify this program in response to GnasR201C expression. All transcription factors were expressed in patient IPMN samples. Conclusions In response to oncogenic mutation(s), IPMN form in the pancreas and express markers of pyloric type metaplasia. KrasG12D and GnasR201C expression drive this program through independent and synergistic mechanisms that result in amplified expression of mucins and gastrokines, consistent with the phenotype identified in vivo.

Dataset Information

Whole-exome sequencing uncovers frequent GNAS mutations in intraductal papillary mucinous neoplasms of the pancreas.

Publications

Whole-exome sequencing uncovers frequent GNAS mutations in intraductal papillary mucinous neoplasms of the pancreas.

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