Abstract
BackgroundTo clarify the genetic mutations associated with intraductal papillary mucinous neoplasms (IPMN) and IPMN-related pancreatic tumours, we conducted cancer-related gene profiling analyses using pure pancreatic juice and resected pancreatic tissues.MethodsPure pancreatic juice was collected from 152 patients [nine with a normal pancreas, 22 with chronic pancreatitis (CP), 39 with pancreatic ductal adenocarcinoma (PDAC), and 82 with IPMN], and resected tissues from the pancreas were collected from 48 patients (six IPMNs and 42 PDACs). The extracted DNA was amplified by multiplexed polymerase chain reaction (PCR) targeting 46 cancer-related genes containing 739 mutational hotspots. The mutations were analysed using a semiconductor-based DNA sequencer.ResultsAmong the 46 cancer-related genes, KRAS and GNAS mutations were most frequently detected in both PDAC and IPMN cases. In pure pancreatic juice, GNAS mutations were detected in 7.7% of PDAC cases and 41.5% of IPMN cases (p<0.001 vs. others). All PDAC cases with GNAS mutations (n = 3) were accompanied by IPMN. Multivariate analysis revealed that GNAS mutations in IPMN cases were associated with dilated main pancreatic ducts (MPD, p = 0.016), while no statistically independent associations with clinical variables were observed for KRAS mutations. In the resected pancreatic tissues, GNAS mutations were detected in 50% of PDAC cases concomitant with IPMN, 33.3% of PDAC cases derived from IPMN, and 66.7% of IPMN cases, while no GNAS mutations were detected in cases of PDAC without IPMN.ConclusionsThe GNAS mutation was specifically found in the cases with IPMN and it was speculated that some PDACs might be influenced by the concomitant but separately-located IPMN in their pathogenic mechanism. Furthermore, the GNAS mutation was significantly associated with MPD dilatation in IPMN cases, suggesting its role in mucus hypersecretion.
Highlights
Intraductal papillary mucinous neoplasm (IPMN) is a pancreatic exocrine tumour characterised by cystic dilatation of the main and/or branch pancreatic ducts; these ducts are lined with a mucin-producing atypical epithelium that often proliferates in a papillary fashion [1,2,3]
A GNAS mutation was detected in one case with chronic pancreatitis (CP) that was accompanied by a small cyst (5 mm); this may have been representative of an early intraductal papillary mucinous neoplasms (IPMN) lesion (Fig. 1B and Fig. 3A)
GNAS mutations were detected in 7.7% of pancreatic ductal adenocarcinoma (PDAC) cases and 41.5% of IPMN cases (p, 0.001 vs. others)
Summary
Intraductal papillary mucinous neoplasm (IPMN) is a pancreatic exocrine tumour characterised by cystic dilatation of the main and/or branch pancreatic ducts; these ducts are lined with a mucin-producing atypical epithelium that often proliferates in a papillary fashion [1,2,3]. IPMN is associated with a spectrum of diseases ranging from adenoma to invasive pancreatic ductal adenocarcinoma (PDAC). PDAC may be derived from IPMN or may concomitantly develop in other regions of a pancreas in which IPMN has developed. The two IPMN-related forms of PDAC are considered to be different disease entities due to their different proximities to the IPMN in the pancreas. The prognosis of these IPMN-related forms of PDAC is often better than that of ordinary PDAC if early diagnosis is made [4,5]. The genetic characteristics of these two IPMN-related forms of PDAC and the reasons for their differing prognoses are not fully understood. To clarify the genetic mutations associated with intraductal papillary mucinous neoplasms (IPMN) and IPMNrelated pancreatic tumours, we conducted cancer-related gene profiling analyses using pure pancreatic juice and resected pancreatic tissues
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