Differential Expression of DNA Mutations in k-ras and GNAS in Pancreatic Cystic Neoplasms

Abstract

Purpose: Mutations in k-ras are known to play an important role in the pathogenesis of pancreatic cancer. Recently GNAS mutations have been discovered in intraductal papillary mucinous neoplasms (IPMN) as well as cancer arising from IPMN. Aim: Identify k-ras and GNAS mutations in benign and premalignant pancreatic cystic neoplasms and malignant pancreatic lesions using formalin-fixed, paraffin-embedded (FFPE) pathology specimens. Methods: Sixty-nine FFPE specimens from patients who had undergone surgical resection of pancreatic lesions were analyzed: a) benign [20 serous cystadenoma (SCA)], b) pre-malignant [10 mucinous cystic neoplasm (MCN) with low grade dysplasia (LGD), 10 branch-duct intraductal papillary mucinous neoplasm (BD-IPMN) with LGD, 10 main-duct IPMN (MD-IPMN) with moderate dysplasia], c) malignant [19 pancreatic ductal adenocarcinoma (PDAC)]. Total nucleic acid extraction was performed using protocols developed at Asuragen. The mutational status of k-ras codon 12/13 and GNAS codon 201 was interrogated via targeted resequencing on the Ion Torrent's Personal Genome Machine (PGM). Statistical analysis performed with Fisher's exact test. Results: Mean age of all 69 patients was 61.4 ± 12.8 with 64% female. K-ras mutations were found in all categories of lesions while GNAS mutations were discovered only in SCA, BD-IPMN, and MD-IPMN. As seen in the Table, in SCA, 4/20 patients (20%) had 4 mutations. In MCN, 1/10 patients (10%) had 1 mutation. In BD-IPMN, 8/10 patients (80%) had 12 mutations. In MD-IPMN, 6/10 patients (60%) had 9 mutations. In PDAC, 18/19 patients (95%) had 18 mutations. Thirty-five percent (7/20) of BD-IPMN and MD-IPMN contained both k-ras and GNAS mutations. GNAS mutations were more commonly observed in IPMN lesions when compared to all non-IPMN lesions (10/20 versus 2/49, p=0.00002). There was no difference in k-ras expression when IPMN lesions were compared to non-IPMN lesions (11/20 versus 21/49, p=0.429). K-ras mutations were more common in PDAC compared to SCA, MCN, BD-IPMN, and MD-IPMN (18/19 versus 14/50, p<0.0001).Table: No Caption available.Conclusion: K-ras mutations were observed in both IPMN and non-IPMN pancreas lesions and were strongly associated with pancreatic cancer. GNAS mutations may be a biomarker to differentiate between IPMN and non-IPMN pancreatic cystic neoplasms. Disclosure: Dr. Lee - none. Dr Szafranska-Schwarzbach - Employee: Asuragen. Dr. Wylie - Employee: Asuragen. Dr. Doyle - none. Dr. Bellizzi - none. Dr. Kadiyala - none. Ms. Suleiman - none. Mr. Kemppainen - Employee: Asuragen. Mr. Kincaid - Employee: Asuragen. Mr. Houghton - Employee: Asuragen. Ms. McGee - Employee: Asuragen. Ms. Sah - Employee: Asuragen. Dr. Banks - none. Dr. Andruss - Employee: Asuragen Dr. Conwell - none.