title: Deep sequencing of cancer-related genes revealed GNAS mutations to be associated with intraductal papillary mucinous neoplasms and its main pancreatic duct dilation.
abstract: BACKGROUND
  To 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.
  
  
  METHODS
  Pure 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.
  
  
  RESULTS
  Among 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.
  
  
  CONCLUSIONS
  The 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.
authors.affiliation: First Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, Chuo, Yamanashi, Japan.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Takano
authors.affiliation: First Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, Chuo, Yamanashi, Japan.
authors.forename: Mitsuharu
authors.initials: M
authors.lastname: Fukasawa
authors.affiliation: First Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, Chuo, Yamanashi, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Maekawa
authors.affiliation: First Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, Chuo, Yamanashi, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Kadokura
authors.affiliation: First Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, Chuo, Yamanashi, Japan.
authors.forename: Mika
authors.initials: M
authors.lastname: Miura
authors.affiliation: First Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, Chuo, Yamanashi, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Shindo
authors.affiliation: First Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, Chuo, Yamanashi, Japan.
authors.forename: Ei
authors.initials: E
authors.lastname: Takahashi
authors.affiliation: First Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, Chuo, Yamanashi, Japan.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Sato
authors.affiliation: First Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, Chuo, Yamanashi, Japan.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Enomoto
mesh_terms: D002288:Adenocarcinoma, Mucinous / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D021441:Carcinoma, Pancreatic Ductal / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D002291:Carcinoma, Papillary / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D049448:Cholangiopancreatography, Magnetic Resonance; D002864:Chromogranins; D004252:DNA Mutational Analysis; D005260:Female; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics*; D056726:Genetic Association Studies; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D018810:Magnetic Resonance Angiography; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009154:Mutation; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D010183:Pancreatic Ducts / Q000473:pathology; D047368:Tumor Burden
chemical_list: D002864:Chromogranins; C406732:GNAS protein, human; D019205:GTP-Binding Protein alpha Subunits, Gs