title: Different subtypes of intraductal papillary mucinous neoplasm in the pancreas have distinct pathways to pancreatic cancer progression.
abstract: BACKGROUND
  Intraductal papillary mucinous neoplasm (IPMN) is recognized as a precursor lesion to pancreatic cancer, a unique pathological entity. IPMN has subtypes with different clinical characteristics. However, the molecular mechanisms of cancer progression from IPMN remain largely unknown. In this study we examined the differences in genetic alteration(s) among the IPMN subtypes.
  
  
  METHODS
  Surgically resected IPMNs (n = 25) were classified into four subtypes by hematoxylin and eosin (H&E) and mucin immunostaining. Mutations in KRAS, BRAF, and PIK3CA genes and expression of CDKN2A, TP53, SMAD4, phospho-ERK, and phospho-SMAD1/5/8 proteins were examined.
  
  
  RESULTS
  There were 11 gastric, 11 intestinal, one pancreatobiliary, and two oncocytic types in this study. We then compared the two major subtypes, gastric-type and intestinal-type IPMN. Gastric-type IPMN showed a significantly higher incidence of KRAS mutations (9/11, 81.8%) compared with intestinal type (3/11, 27.3%; p < 0.05), although the intestinal type showed a higher grade of dysplasia than gastric type (p < 0.01). All cases with KRAS mutations showed phospho-ERK immunostaining. In contrast, intestinal type (9/11, 81.8%) showed more frequent SMAD1/5/8 phosphorylation compared with gastric-type IPMN (3/11, 27.3%; p < 0.05%).
  
  
  CONCLUSIONS
  There may be distinct mechanisms of pancreatic cancer progression in the different subtypes of IPMN. In particular, KRAS mutation and bone morphogenetic protein-SMAD signaling status may be crucial diverging steps for the two representative pathways to pancreatic cancer in IPMN patients.
authors: Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. dmouri-gi@umin.ac.jp
authors: Dai
authors: D
authors: Mohri
authors: Yoshinari
authors: Y
authors: Asaoka
authors: Hideaki
authors: H
authors: Ijichi
authors: Koji
authors: K
authors: Miyabayashi
authors: Yotaro
authors: Y
authors: Kudo
authors: Motoko
authors: M
authors: Seto
authors: Miki
authors: M
authors: Ohta
authors: Motohisa
authors: M
authors: Tada
authors: Yasuo
authors: Y
authors: Tanaka
authors: Tsuneo
authors: T
authors: Ikenoue
authors: Keisuke
authors: K
authors: Tateishi
authors: Hiroyuki
authors: H
authors: Isayama
authors: Fumihiko
authors: F
authors: Kanai
authors: Noriyoshi
authors: N
authors: Fukushima
authors: Minoru
authors: M
authors: Tada
authors: Takao
authors: T
authors: Kawabe
authors: Masao
authors: M
authors: Omata
authors: Kazuhiko
authors: K
authors: Koike
mesh_terms: D002288:Adenocarcinoma, Mucinous / Q000235:genetics*; D000328:Adult; D000368:Aged; D019485:Bone Morphogenetic Proteins / Q000502:physiology; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics* / Q000473:pathology*; D058534:Class I Phosphatidylinositol 3-Kinases; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D004252:DNA Mutational Analysis; D018450:Disease Progression; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000473:pathology*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D015398:Signal Transduction / Q000235:genetics; D051785:Smad Proteins / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D018631:ras Proteins / Q000235:genetics
chemical_list: D019485:Bone Morphogenetic Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D051785:Smad Proteins; D016159:Tumor Suppressor Protein p53; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; C096335:B59 protein, human; D017027:Protein Tyrosine Phosphatases; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins