title: KIT (c-kit oncogene product) pathway is constitutively activated in human testicular germ cell tumors.
abstract: We investigated the expression of KIT (product of c-kit oncogene), gain-of-function mutations, and activation of its downstream signal transduction in human testicular cancers. KIT was expressed in 88% (22/25) of seminomas and in 44.4% (4/9) of non-seminomas compared to adjacent normal testicular tissue. Nine of the KIT-expressing seminomas had mutations (40.9%; 9/22) in the c-kit gene; two cases in exon 11 and 7 cases in exon 17. Two of these mutations in exon 17 were novel, and the other seven mutations were identical to the already known gain-of-function mutations which cause activation of KIT without ligand stem cell factor. All of the mutant KIT and 53.8% (7/13) of wild-type KIT were phosphorylated (activated) and associated with phosphorylated phosphatidylinositol 3-kinase (PI3K). Akt was also phosphorylated in these seminomas, suggesting that the KIT-PI3K-Akt pathway is activated in seminoma. These findings suggest that the KIT-PI3K-Akt pathway is constitutively activated in testicular germ cell tumors, due to overexpression of KIT protein and/or gain-of-function mutations in the c-kit gene.
authors.affiliation: Department of Urology, Osaka University Graduate School of Medicine, Japan.
authors.forename: Yasutomo
authors.initials: Y
authors.lastname: Nakai
authors.forename: Norio
authors.initials: N
authors.lastname: Nonomura
authors.forename: Daizo
authors.initials: D
authors.lastname: Oka
authors.forename: Masayuki
authors.initials: M
authors.lastname: Shiba
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Arai
authors.forename: Masashi
authors.initials: M
authors.lastname: Nakayama
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Inoue
authors.forename: Kazuo
authors.initials: K
authors.lastname: Nishimura
authors.forename: Katsuyuki
authors.initials: K
authors.lastname: Aozasa
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Mizutani
authors.forename: Tsuneharu
authors.initials: T
authors.lastname: Miki
authors.forename: Akihiko
authors.initials: A
authors.lastname: Okuyama
mesh_terms: D000328:Adult; D000368:Aged; D004789:Enzyme Activation; D018237:Germinoma / Q000201:enzymology* / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics* / Q000378:metabolism*; D018239:Seminoma / Q000201:enzymology / Q000235:genetics; D015398:Signal Transduction; D013736:Testicular Neoplasms / Q000201:enzymology* / Q000235:genetics
chemical_list: D019869:Phosphatidylinositol 3-Kinases; D019009:Proto-Oncogene Proteins c-kit