Functional evaluation of p53 and PTEN gene mutations in gliomas.
Functional evaluation of p53 and PTEN gene mutations in gliomas.
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发表时间：
2000-10
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通讯作者：
H. Kato;S. Kato;T. Kumabe;Y. Sonoda;T. Yoshimoto;S. Kato;Shuang-yin Han;Takao Suzuki;H. Shibata;Ryunosuke Kanamaru;C. Ishioka
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作者：
H. Kato;S. Kato;T. Kumabe;Y. Sonoda;T. Yoshimoto;S. Kato;Shuang-yin Han;Takao Suzuki;H. Shibata;Ryunosuke Kanamaru;C. Ishioka
我们筛选两个主要的肿瘤抑制基因，p53和PTEN的突变，在66人脑肿瘤，分别使用酵母为基础的功能分析和cDNA为基础的直接测序。p53基因突变率为28.8%，（19/66），在间变性星形细胞瘤中较高（14例中的9例，64.3%），而多形性胶质母细胞瘤（GBM; 27例中的7例，25.9%），支持先前的推测，即至少有两种遗传途径导致GBM，一种是没有p53突变的从头途径，另一种是有p53突变的“进行性”途径。在64例肿瘤中观察到8例（12.5%）PTEN突变，主要是GBM（26例中的7例，26.9%），有或无p53突变。这些结果表明，在胶质瘤的进展中，PTEN基因的突变是一个晚于p53基因的事件，并与两种遗传途径相关。所有检测到的PTEN错义突变和框内小缺失在体外使PTEN磷酸肌醇磷酸酶活性失活。由于含有PTEN突变的肿瘤也显示出在染色体10 q23区域侧翼的PTEN基因的杂合性丢失，我们的数据清楚地表明，失活的两个PTEN等位基因发生在一个子集的高级别胶质瘤，因此证实了以前的想法，即PTEN作为一个肿瘤抑制基因。
We screened mutations of two major tumor suppressor genes, p53 and PTEN, in 66 human brain tumors using a yeast-based functional assay and cDNA-based direct sequencing, respectively. The frequency of p53 mutations was 28.8% (19 of 66) and was higher in anaplastic astrocytoma (9 of 14, 64.3%,) than in glioblastoma multiforme (GBM; 7 of 27, 25.9%,), supporting previous speculation that there are at least two genetic pathways leading to GBM, a de novo pathway without p53 mutation and a "progressive" pathway with p53 mutation. PTEN mutation was observed in 8 of 64 tumors (12.5%), mainly GBMs (7 of 26, 26.9%), both with and without p53 mutation. These results suggest that mutation of the PTEN gene is a later event than that of the p53 gene in glioma progression and is associated with both the genetic pathways. All of the detected PTEN missense mutations and an in-frame small deletion inactivated PTEN phosphoinositide phosphatase activity in vitro. Because the tumors containing PTEN mutations also showed loss of heterozygosity in the chromosome 10q23 region flanking the PTEN gene, our data clearly indicate that inactivation of both PTEN alleles occurs in a subset of high-grade gliomas, therefore confirming the previous idea that PTEN acts as a tumor suppressor gene.