Clinicopathological Correlates of Activating GNAS Mutations in Intraductal Papillary Mucinous Neoplasm (IPMN) of the Pancreas

• Published in: Annals of surgical oncology Vol. 20; no. 12; pp. 3802 - 3808
• Main Authors: Dal Molin, Marco, Matthaei, Hanno, Wu, Jian, Blackford, Amanda, Debeljak, Marija, Rezaee, Neda, Wolfgang, Christopher L., Butturini, Giovanni, Salvia, Roberto, Bassi, Claudio, Goggins, Michael G., Kinzler, Kenneth W., Vogelstein, Bert, Eshleman, James R., Hruban, Ralph H., Maitra, Anirban
• Format: Journal Article
• Language: English
• Published: Boston Springer US 01.11.2013; Springer Nature B.V
• Subjects: Adenocarcinoma, Mucinous - genetics; Adenocarcinoma, Mucinous - mortality; Adenocarcinoma, Mucinous - pathology; Adult; Aged; Aged, 80 and over; Carcinoma, Pancreatic Ductal - genetics; Carcinoma, Pancreatic Ductal - mortality; Carcinoma, Pancreatic Ductal - pathology; Carcinoma, Papillary - genetics; Carcinoma, Papillary - mortality; Carcinoma, Papillary - pathology; Chromogranins; Female; Follow-Up Studies; GTP-Binding Protein alpha Subunits, Gs - genetics; Humans; Male; Medicine; Medicine & Public Health; Middle Aged; Mutation - genetics; Neoplasm Staging; Oncology; Pancreas - metabolism; Pancreas - pathology; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - mortality; Pancreatic Neoplasms - pathology; Pancreatic Tumors; Prognosis; Prospective Studies; Surgery; Surgical Oncology; Survival Rate; Validation Group; Villous Adenoma; Pancreatic Cystic Neoplasm; Intraductal Papillary Mucinous Neoplasm; Historical Group
• ISSN: 1068-9265; 1534-4681
• DOI: 10.1245/s10434-013-3096-1

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.