e21048 Background: Pancreatic cysts pose a challenge in patient management primarily due to difficulties distinguishing non-mucinous cysts from potentially pre-malignant mucinous ones, and in determining the malignant potential of mucinous cysts. Mutations to the GNAS gene have been identified as a marker for intraductal papillary mucinous neoplasm (IPMN). [1,2] We evaluated the significance of GNAS mutation in diagnosis of pancreatic cysts. Methods: We retrieved archival DNA from 237 cyst fluids. 200 specimens were chosen with 100 KRAS mutant and 100 KRAS wild type in a range of CEA values. 37 specimens were chosen with a molecular diagnosis of aggressive biological behavior, to enrich for malignant IPMNs. We sequenced each fluid’s DNA from for codon 201 of GNAS. Molecular criteria for mucinous cysts included KRAS mutation, elevated DNA, or ≥2 high clonality LOH mutations. Results: Of the 237 specimens, 25 were not amplifiable due to degraded DNA, 52 (25%) had a GNAS mutation, and 160 had no GNAS mutation. Of the 52 GNAS mutated specimens, 5 were diagnosed as biologically aggressive based on significant associated mutations, 28 as statistically indolent based on associated molecular changes, and 19 as benign (no accompanying mutations). The proportion of GNAS mutations decreased with increasing molecular changes linked to malignancy. Data from [1] shows no statistical difference in frequency of GNAS mutation in side branch vs. main vs. mixed IPMNs (p= 0.46). Similarly, in our cohort, 6 cases had clear imaging features of a side branch IPMN, and of these 2 (33%) had a mutation in GNAS. Using molecular criteria for identification of mucinous cysts, 166 were mucinous and 71 non-mucinous. Incorporation of GNAS into the molecular determination of mucinous etiology identified 13 additional cases (7%). Conclusions: Use of GNAS increases sensitivity for detection of mucinous lesions. GNAS does not appear to correlate with molecular measures of biological aggressiveness. These findings confirm those in [1], that GNAS should be used in conjunction with a panel of molecular markers for evaluating the malignant potential of pancreatic cystic lesions. References 1. Sci Transl Med. 2011 Jul 20; 3:92ra66. 2. PNAS 2011 Dec 27; 108:21188-93.
Case report: An infantile lethal form of Albright hereditary osteodystrophy due to a GNAS
mutation
