Frequent LOH at Chromosome 12q22‐23 and Apaf‐1 Inactivation in Glioblastoma
Frequent LOH at Chromosome 12q22‐23 and Apaf‐1 Inactivation in Glioblastoma
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DOI：
10.1111/j.1750-3639.2003.tb00474.x
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发表时间：
2003-10
期刊：
影响因子：
6.4
通讯作者：
Takuya Watanabe;Y. Hirota;Y. Arakawa;H. Fujisawa;O. Tachibana;M. Hasegawa;J. Yamashita;Y. Hayashi-Y.-H
中科院分区：
文献类型：
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作者：
Takuya Watanabe;Y. Hirota;Y. Arakawa;H. Fujisawa;O. Tachibana;M. Hasegawa;J. Yamashita;Y. Hayashi-Y.-H
胶质母细胞瘤（GB）通常在1p、10p、10q、11p、17p、19q、22q等染色体上存在杂合性缺失。在12q染色体的例子中；然而，LOH是否会发生还有待观察。Apaf‐1，凋亡蛋白酶激活因子‐1，位于染色体12q22‐23，是p53介导的细胞凋亡通路的主要影响因子，染色体12q22‐23 LOH和高甲基化导致的Apaf‐1失活可能参与了一些恶性肿瘤的发生。然而，关于12q22‐23 LOH的频率或Apaf‐1在GB中的状态知之甚少。为了阐明它们在GB中的作用，我们分别使用微卫星分析、逆转录（RT）‐PCR分析和免疫组化（IHC）分析了33 GB染色体12q22‐23 LOH、Apaf‐1 mRNA表达和Apaf‐1蛋白表达。我们还评估了12q22‐23 LOH是否以及如何与p53基因突变和EGFR基因扩增相关。在33例病例中，有14例（42%）检测到12q22‐23染色体LOH。在12q22‐23的LOH病例中，13例中有9例（69%）检测到Apaf‐1 mRNA的低表达，14例中有12例（86%）检测到Apaf‐1蛋白的低表达。12q22‐23 LOH与mRNA和蛋白的低表达显著相关（p<0.05, p<0.001）。p53基因突变13例（39%），EGFR基因扩增8例（24%），两者呈负相关。然而，12q22‐23 LOH与p53基因突变或EGFR基因扩增无关。没有p53基因突变和EGFR基因扩增的9 gb患者中有6例（67%）检测出12q22‐23 LOH阳性。这些GB可能属于另一个独立于GB中2个常见遗传亚群（一个是p53基因突变，没有EGFR基因扩增，另一个是EGFR基因扩增，没有p53基因突变）的亚群。具有12q22‐23 LOH的33 gb中有23 gb（70%）也检测出Apaf‐1失活或p53基因突变阳性。凋亡相关因子的高频率改变促使我们推测，Apaf - 1和p53介导的凋亡途径的缺失可能在GB的肿瘤发生中发挥重要作用。
Glioblastoma (GB) often has loss of heterozygosity on the chromosomes, 1p, 10p, 10q, 11p, 17p, 19q, 22q, and several others. In the case of chromosome 12q; however, it remains to be seen whether LOH occurs. Apaf‐1, the apoptotic protease activating factor‐1, located at chromosome 12q22‐23, is a major effecter of the p53 mediated apoptosis pathway, and Apaf‐1 inactivation due to chromosome 12q22‐23 LOH and hypermethylation may be involved in some of the neoplasms in malignancy. However, little is known about the frequency of the 12q22‐23 LOH or the state of Apaf‐1 in GB. To elucidate their involvement in GB, we analyzed a series of 33 GBs for chromosome 12q22‐23 LOH, Apaf‐1 mRNA expression, and Apaf‐1 protein expression, using microsatellite analysis, reverse transcription (RT) ‐PCR analysis, and immunohistochemical (IHC) analysis, respectively. We also evaluated if and how the 12q22‐23 LOH correlated with the p53 gene mutation and EGFR gene amplification. Chromosome 12q22‐23 LOH was detected in 14 (42%) of 33 cases. Among the examined cases with LOH at 12q22‐23, a low expression of Apaf‐1 mRNA was detected in 9 (69%) of 13 cases, and a low expression of Apaf‐1 protein was detected in 12 (86%) of 14 cases. The 12q22‐23 LOH was significantly correlated with low expression of mRNA and protein (p<0.05, p<0.001 respectively). The p53 gene mutation and EGFR gene amplification were found in 13 cases (39%) and 8 cases (24%), respectively, and these gene alterations were inversely correlated. However, 12q22‐23 LOH had no correlations with the p53 gene mutation or EGFR gene amplification. Six of 9 GBs (67%) with neither p53 gene mutation nor EGFR gene amplification tested positive for 12q22‐23 LOH. These GBs are likely to belong to another subset independent from the 2 common genetic subsets in GB (one with p53 gene mutation and without EGFR gene amplification, and the other with EGFR gene amplification and without p53 gene mutation). Twenty‐three (70%) out of the 33 GBs with the 12q22‐23 LOH also tested positive for Apaf‐1 inactivation or p53 gene mutation. This high frequency of alterations in the apoptosis‐associated factors prompts a speculation that abrogation of the Apaf‐1 and p53 mediated apoptosis pathway may play an important role in the tumorigenesis of GB.