Clinicopathological effects of protein phosphatase 2, regulatory subunit A, alpha mutations in gastrointestinal stromal tumors
Clinicopathological effects of protein phosphatase 2, regulatory subunit A, alpha mutations in gastrointestinal stromal tumors
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DOI：
10.1038/modpathol.2016.138
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发表时间：
2016-07
期刊：
影响因子：
7.5
通讯作者：
Midori Toda-Ishii;K. Akaike;Y. Suehara;Kenta Mukaihara;Daisuke Kubota;S. Kohsaka;T. Okubo;K. Mitani;K. Mogushi;T. Takagi;Kazuo Kaneko;T. Yao;Tsuyoshi Saito
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文献类型：
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作者：
Midori Toda-Ishii;K. Akaike;Y. Suehara;Kenta Mukaihara;Daisuke Kubota;S. Kohsaka;T. Okubo;K. Mitani;K. Mogushi;T. Takagi;Kazuo Kaneko;T. Yao;Tsuyoshi Saito
最近，一些研究报道了由蛋白磷酸酶2调节亚基A，α（PPP 2 R1 A）的改变引起的蛋白磷酸酶2A（PP 2A）的功能障碍负责几种类型的癌症中的肿瘤发生和肿瘤进展。PPP 2 R1 A突变对胃肠道间质瘤（GIST）的影响尚不清楚，尽管KIT和PDGFRA突变导致受体酪氨酸激酶途径的组成性激活，在GIST肿瘤发生中很重要。在本研究中，我们进行了PPP 2 R1 A的突变分析，以检查PPP 2 R1 A突变的频率和它们的临床病理相关性在94例GIST。此外，我们进行了体外分析，以研究PPP 2 R1 A突变对GIST细胞中细胞增殖和激酶磷酸化的影响。17例GIST病例（18%）携带PPP 2 R1 A突变。这17例病例中，除1例外，所有病例均携带KIT、PDGFRA、HRAS、NRAS或KRAS突变作为致癌驱动突变，其余病例的琥珀酸脱氢酶B（SDHB）化学染色阴性。多因素分析显示，较大的肿瘤大小、较高的有丝分裂率和PPP 2 R1 A突变是总生存期的独立预后因素;然而，PPP 2 R1 A突变不是无病生存期的独立预后因素。PPP 2 R1 A突变体转导GIST细胞后，
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. Additionally, 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