Clinicopathological and functional analyses of protein phosphatase 2, regulatory subunit A, alpha mutations in gastrointestinal stromal tumors

Aim/Background

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors in gastrointestinal tract. Recent studies report that the disorder of the protein phosphatase 2, regulatory subunit A, alpha (PPP2R1A) is responsible for the constitutive phosphorylation of its substrates, and the activation of specific signaling pathways by the increased phosphorylation plays an important role in the tumorgenesis and the progression of ovarian and uterine carcinomas. The aim of this study was to elucidate the frequency of PPP2R1A mutations and their impacts on the clinicopathological factors in GISTs. Furthermore, we clarified the function of the PPP2R1A mutations in GIST cells.

Methods

Ninety-six cases of GISTs (formalin-fixed paraffin-embedded material) with prognostic information were collected. These cases were examined for PPP2R1A mutations (exon 5 and 6) by PCR followed by direct sequences, and the impacts of PPP2R1A mutations on the clinicopathological features were examined. To elucidate the associations between biological behaviors and the PPP2R1A mutations, we transfected the mutant PPP2R1A into GIST T1 cell and performed cell proliferation assays using these transfected cells.

Results

Seventeen cases (17.7%) of GISTs harbored mutations in PPP2R1A, and types of mutations were various. Among 17 cases, 15 cases (88.2%) harbored either KIT or PDGFRA mutations, and one case had point mutations in both KIT and PDGFRA. Among two cases of KIT/PDGFRA mutation-negative GISTs, one cases showed KRAS mutation. GIST cases with PPP2R1A mutations had a tendency for shorter disease free survival (DFS) and overall survival (OS) rate, respectively (p < 0.05; DFS, p < 0.05; OS). The proliferation assays revealed that the PPP2R1A mutated T1 cells showed significantly higher growth rates compared to those in T1-GFP and T1-WT cell (controls). These results indicated the PPP2R1A mutations in GIST significantly contributed to the aggressive phenotype.

Conclusions

PPP2R1A mutations play an important role in the tumor progression of GISTs. The effect of PPP2R1A alterations on the phosphorylation status of various kinases are under evaluation.

Clinical trial identification

None

Disclosure

All authors have declared no conflicts of interest.