title: Somatic mutations in PIK3CA and activation of AKT in intraductal tubulopapillary neoplasms of the pancreas.
abstract: Intraductal tubulopapillary neoplasm (ITPN) is a recently recognized rare variant of intraductal neoplasms of the pancreas. Molecular aberrations underlying the neoplasm remain unknown. We investigated somatic mutations in PIK3CA, PTEN, AKT1, KRAS, and BRAF. We also investigated aberrant expressions of phosphorylated AKT, phosphatase and tensin homolog (PTEN), tumor protein 53 (TP53), SMAD4, and CTNNB1 in 11 cases of ITPNs and compared these data with those of 50 cases of intraductal papillary mucinous neoplasm (IPMN), another distinct variant of pancreatic intraductal neoplasms. Mutations in PIK3CA were found in 3 of 11 ITPNs but not in IPMNs (P = 0.005; Fisher exact test). In contrast, mutations in KRAS were found in none of the ITPNs but were found in 26 of the 50 IPMNs (P = 0.001; Fisher exact test). PIK3CA mutations were associated with strong expression of phosphorylated AKT (P < 0.001; the Mann-Whitney U test). Moreover, the expression of phosphorylated AKT was apparent in most ITPNs but only in a few IPMNs (P < 0.001; the Mann-Whitney U test). Aberrant expressions of TP53, SMAD4, and CTNNB1 were not statistically different between these neoplasms. Mutations in PIK3CA and the expression of phosphorylated AKT were not associated with age, sex, tissue invasion, and patients' prognosis in ITPNs. These results indicate that activation of the phosphatidylinositol 3-kinase pathway may play a crucial role in ITPNs but not in IPMNs. In contrast, the mutation in KRAS seems to play a major role in IPMNs but not in ITPNs. The activated phosphatidylinositol 3-kinase pathway may be a potential target for molecular diagnosis and therapy of ITPNs.
authors.affiliation: Institute for Integrated Medical Sciences, Tokyo Women's Medical University, Tokyo, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yamaguchi
authors.forename: Yuko
authors.initials: Y
authors.lastname: Kuboki
authors.forename: Takashi
authors.initials: T
authors.lastname: Hatori
authors.forename: Masakazu
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Keiko
authors.initials: K
authors.lastname: Shiratori
authors.forename: Shunji
authors.initials: S
authors.lastname: Kawamura
authors.forename: Makio
authors.initials: M
authors.lastname: Kobayashi
authors.forename: Michio
authors.initials: M
authors.lastname: Shimizu
authors.forename: Shinichi
authors.initials: S
authors.lastname: Ban
authors.forename: Isamu
authors.initials: I
authors.lastname: Koyama
authors.forename: Morihiro
authors.initials: M
authors.lastname: Higashi
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Shin
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Ishida
authors.forename: Takanori
authors.initials: T
authors.lastname: Morikawa
authors.forename: Fuyuhiko
authors.initials: F
authors.lastname: Motoi
authors.forename: Michiaki
authors.initials: M
authors.lastname: Unno
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kanno
authors.forename: Kennichi
authors.initials: K
authors.lastname: Satoh
authors.forename: Tooru
authors.initials: T
authors.lastname: Shimosegawa
authors.forename: Hideki
authors.initials: H
authors.lastname: Orikasa
authors.forename: Tomoo
authors.initials: T
authors.lastname: Watanabe
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Nishimura
authors.forename: Youji
authors.initials: Y
authors.lastname: Harada
authors.forename: Toru
authors.initials: T
authors.lastname: Furukawa
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000032:analysis* / Q000235:genetics; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D058534:Class I Phosphatidylinositol 3-Kinases; D004252:DNA Mutational Analysis; D004789:Enzyme Activation / Q000502:physiology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; D051057:Proto-Oncogene Proteins c-akt; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins