GNAS but Not Extended RAS Mutations Spectrum are Associated with a Better Prognosis in Intraductal Pancreatic Mucinous Neoplasms

BackgroundThe management of intraductal papillary mucinous neoplasms (IPMNs) is mainly based on imaging features and clinical symptoms, and remains challenging.ObjectiveThe aim of this study was to assess GNAS, RAS family (KRAS, NRAS and HRAS), BRAF, and PIK3CA mutation status in resected IPMNs and correlate it with clinicopathological characteristics and patient survival.MethodsOverall, 149 consecutive unselected patients who underwent pancreatectomy for IPMNs were included. After dissection from formalin-fixed and paraffin-embedded tumors, GNAS mutational screening was assessed by allelic discrimination using Taqman((R)) probes and confirmed by SNaPshot analysis. RAS family, BRAF, and PIK3CA mutational screening was assessed by high resolution melt and Sanger sequencing.ResultsGastric- and intestinal-type IPMNs were the most frequent lesions (52% and 41%, respectively). Intestinal-type IPMNs were more frequently associated high-grade dysplasia (49%) and were the only IPMNs associated with colloid-type carcinoma. All pancreatobiliary IPMNs were invasive lesions, located in the main pancreatic duct. GNAS-activating mutations were strongly associated with the intestinal phenotype (p<10(-4)), while RAS pathway mutations were not associated with any particular phenotype. Mutations within other members of the epidermal growth factor receptor (EGFR) pathway were very rare (2%). GNAS-mutated IPMNs were rarely invasive (11%) and almost exclusively (83%) of the colloid type. For invasive lesions, multivariate analyses determined that only node negativity was associated with improved cancer-specific survival, but, in univariate analysis, GNAS mutation was associated with prolonged survival.ConclusionIn patients selected for surgery, GNAS mutation analysis and tumor phenotype can help to better predict patient prognosis. In the near future, a more precise mutational analysis of IPMNs might help to better tailor their management.