title: Clinicopathological effects of protein phosphatase 2, regulatory subunit A, alpha mutations in gastrointestinal stromal tumors.
abstract: Recently, several studies have reported that dysfunctions in protein phosphatase 2A (PP2A) caused by alterations in protein phosphatase 2 regulatory subunit A, alpha (PPP2R1A) are responsible for tumorigenesis and tumor progression in several types of cancers. The impact of PPP2R1A mutations remains unknown in gastrointestinal stromal tumors (GISTs), although mutations in KIT and PDGFRA, which result in constitutive activation of the receptor tyrosine kinase pathway, are important in GIST tumorigenesis. In this study, we performed mutation analysis of PPP2R1A to examine the frequency of PPP2R1A mutations and their clinicopathological correlation in 94 GIST cases. In addition, we performed an in vitro analysis to investigate the effects of PPP2R1A mutations on cell proliferation and kinase phosphorylation in GIST cells. Seventeen GIST cases (18%) harbored mutations in PPP2R1A. All but one of these 17 cases harbored a KIT, PDGFRA, HRAS, NRAS, or KRAS mutation as the oncogenic driver mutation, and the remaining case was immunohistochemically negative for succinate dehydrogenase B (SDHB). Multivariate analysis showed that larger tumor size, higher mitotic rate, and PPP2R1A mutation are independent prognostic factors for overall survival; however, PPP2R1A mutation was not an independent prognostic factor for disease-free survival. The transduction of GIST cells with mutant PPP2R1A induced an accelerated growth rate via increased phosphorylation of Akt1/2, ERK1/2, and WNK1, a kinase associated with angiogenesis. In addition, the transduction of GIST cells with mutant PPP2R1A caused increased c-kit phosphorylation, suggesting that c-kit is also a target of PP2A, reinforcing the tumorigenic capabilities of c-kit. Furthermore, the transducing GIST cells with wild-type PP2A dephosphorylated mutant c-kit. This study provides a new insight into the biology of GISTs and their phosphatase activity, and activated PP2A could be a therapeutic target in GISTs.
authors.affiliation: Department of Human Pathology, Juntendo University School of Medicine, Tokyo, Japan.|Department of Orthopaedic Surgery, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: Midori
authors.initials: M
authors.lastname: Toda-Ishii
authors.affiliation: Department of Human Pathology, Juntendo University School of Medicine, Tokyo, Japan.|Department of Orthopaedic Surgery, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Akaike
authors.affiliation: Department of Orthopaedic Surgery, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Suehara
authors.affiliation: Department of Human Pathology, Juntendo University School of Medicine, Tokyo, Japan.|Department of Orthopaedic Surgery, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: Kenta
authors.initials: K
authors.lastname: Mukaihara
authors.affiliation: Department of Orthopaedic Surgery, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Kubota
authors.affiliation: Department of Medical Genomics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Kohsaka
authors.affiliation: Department of Orthopaedic Surgery, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: Taketo
authors.initials: T
authors.lastname: Okubo
authors.affiliation: Department of Human Pathology, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Mitani
authors.affiliation: Center for Genomic and Regenerative Medicine, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: Kaoru
authors.initials: K
authors.lastname: Mogushi
authors.affiliation: Department of Orthopaedic Surgery, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Takagi
authors.affiliation: Department of Orthopaedic Surgery, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Kaneko
authors.affiliation: Department of Human Pathology, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Yao
authors.affiliation: Department of Human Pathology, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Saito
mesh_terms: D000368:Aged; D004252:DNA Mutational Analysis; D018572:Disease-Free Survival; D005260:Female; D046152:Gastrointestinal Stromal Tumors / Q000235:genetics* / Q000401:mortality; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011379:Prognosis; D054648:Protein Phosphatase 2 / Q000235:genetics*
chemical_list: C517191:PPP2R1A protein, human; D054648:Protein Phosphatase 2