Kato H, Kato S, Kumabe T, Sonoda Y, Yoshimoto T, Kato S, Han S Y, Suzuki T, Shibata H, Kanamaru R, Ishioka C
Department of Clinical Oncology, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan.
Clin Cancer Res. 2000 Oct;6(10):3937-43.
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.
我们分别使用基于酵母的功能分析和基于cDNA的直接测序方法，对66例人脑肿瘤中的两个主要肿瘤抑制基因p53和PTEN的突变情况进行了筛查。p53突变的频率为28.8%（66例中的19例），在间变性星形细胞瘤中（14例中的9例，64.3%）高于多形性胶质母细胞瘤（GBM；27例中的7例，25.9%），这支持了之前的推测，即至少有两条遗传途径导致GBM，一条是无p53突变的从头途径，另一条是有p53突变的“进展性”途径。在64例肿瘤中的8例（12.5%）检测到PTEN突变，主要是GBM（26例中的7例，26.9%），既有p53突变的，也有无p53突变的。这些结果表明，在胶质瘤进展过程中，PTEN基因的突变比p53基因的突变发生得晚，并且与这两条遗传途径都相关。所有检测到的PTEN错义突变和一个框内小缺失在体外均使PTEN磷酸肌醇磷酸酶活性失活。由于含有PTEN突变的肿瘤在PTEN基因侧翼的染色体10q23区域也显示杂合性缺失，我们的数据清楚地表明，在一部分高级别胶质瘤中发生了两个PTEN等位基因的失活，因此证实了之前的观点，即PTEN作为一个肿瘤抑制基因发挥作用。
