Genetic alteration and expression of the phosphoinositol-3-kinase/Akt pathway genes PIK3CA and PIKE in human glioblastomas
Genetic alteration and expression of the phosphoinositol-3-kinase/Akt pathway genes PIK3CA and PIKE in human glioblastomas
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DOI：
10.1111/j.1365-2990.2005.00660.x
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发表时间：
2005-10-01
影响因子：
5
通讯作者：
Reifenberger, G
中科院分区：
文献类型：
--
作者：
Knobbe, CB;Trampe-Kieslich, A;Reifenberger, G
胶质母细胞瘤经常携带遗传改变，导致磷酸肌醇-3激酶(Pi3k)/蛋白激酶B （Akt）信号通路异常激活，包括最显著的磷酸酶和紧张素同源物（PTEN）突变、表皮生长因子受体（EGFR）扩增和重排，以及羧基末端调节蛋白（CTMP）超甲基化[Knobbe等人]。（2004）胶质母细胞瘤中羧基末端调节蛋白基因的高甲基化和转录下调。中华肿瘤杂志，1999,19(4):483-486。在这里，我们进一步研究了两个Pi3k/Akt通路基因，即PIK3CA （3q26.3）和磷脂酰肌醇-3激酶增强子（PIKE） （CENTG1, 12q14）在一系列97例原发性胶质母细胞瘤中的遗传改变和异常表达。PIK3CA单链构象多态性（SSCP）分析在5个肿瘤中发现体细胞突变（5%）。12例胶质母细胞瘤（12%）显示PIKE基因扩增，并伴有邻近CDK4基因不变的共扩增。与非肿瘤脑组织相比，所有具有PIKE扩增的肿瘤以及绝大多数未扩增的胶质母细胞瘤均表现出PIKE- a转录本的表达增加，而PIKE- s /L转录本的表达没有增加。综上所述，我们的数据支持PIK3CA和PIKE基因畸变在原发性胶质母细胞瘤的分子发病机制中的重要作用。
Glioblastomas frequently carry genetic alterations resulting in an aberrant activation of the phosphoinositol-3-kinase (Pi3k)/protein kinase B (Akt) signalling pathway, including most notably phosphatase and tensin homolog (PTEN) mutation, epidermal growth factor receptor (EGFR) amplification and rearrangement, as well as carboxyl-terminal modulator protein (CTMP) hypermethylation [Knobbe et al., (2004) Hypermethylation and transcriptional downregulation of the carboxyl-terminal modulator protein gene in glioblastomas. J Natl Cancer Institute, 96, 483-486]. Here, we investigated two further Pi3k/Akt pathway genes, namely PIK3CA (3q26.3) and phosphatidylinositol-3-kinase enhancer (PIKE) (CENTG1, 12q14), for genetic alteration and aberrant expression in a series of 97 primary glioblastomas. Single strand conformation polymorphism (SSCP) analysis of PIK3CA revealed somatic mutations in five tumours (5%). Twelve glioblastomas (12%) showed amplification of PIKE with invariable co-amplification of the adjacent CDK4 gene. All tumours with PIKE amplification as well as the vast majority of glioblastomas without amplification demonstrated increased expression of PIKE-A but not PIKE-S/L transcripts as compared with non-neoplastic brain tissue. Taken together, our data support an important role of PIK3CA and PIKE gene aberrations in the molecular pathogenesis of primary glioblastomas.