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.

Figure 1. Processing of data obtained by whole-exome sequencing using a massively parallel deep sequencer.

Figure 2. Expression of the G-protein α subunit (B, E) and phosphorylated substrates of protein kinase A (C, F) in intraductal papillary mucinous neoplasm (A–C) and ductal adenocarcinoma of the pancreas (D–F). Diaminobenzidine was used as the chromogen to visualize the immunoreaction in immunohistochemistry (B, C, E, F). Panels (A) and (D) show images of hematoxylin-eosin staining.

Original magnification, ×200.

Figure 3. Kaplan–Meier survival analyses of patients with intraductal papillary mucinous neoplasms according to molecular alterations and expression profiles.