中国科学院昆明动物研究所机构知识库

在人类众多的疾病之中，多形性胶质母细胞瘤（glioblastoma multiforme，GBM）属于最常见的一种同时也是恶性程度最高的一种脑部的肿瘤。在分级系统中属于WHO IV 级。多形性胶质母细胞瘤（GBM）占脑实体瘤的50％左右，是最恶性类型的脑癌，具有非常差的预后和非常有限的治疗措施。而从已有的研究成果来看，肿瘤的分型研究对于癌症的研究领域和治疗领域都是非常重要的。在这里，我们提出了一种基于GBM的遗传改变进行分类的最新方法和合理的分类证据，并且构建了相应的动物模型。 CDKN2A全称为细胞周期依赖性激酶抑制基因，主要在细胞周期中发挥作用，这个基因主要编码两种蛋白即p14ARF和p16INK4，本身属于抑癌基因。目前很多的肿瘤中都有CDKN2A基因的变异，而TP53则是最早发现的抑癌基因之一。p53蛋白主要的功能是1，调节细胞周期2，避免细胞癌变，还有保持基因组的稳定性以及避免突变发生的作用。而且CDKN2A和TP53都是GBM中最常见的突变基因，突变率分别为60％和30％。我们经过生存分析发现CDKN2A缺失的患者比那些有突变的TP53的患者生存更差。有趣的是，具有突变的TP53和缺失的CDKN2A的患者的存活率没有比仅具有这些遗传改变中的一个的那些病人更差，但是与仅具有TP53突变的那些病人类似。接下来，我们深入地研究了TP53和CDKN2A样品之间的基因表达谱的差异。具有TP53突变和CDKN2A缺失的样品显示与仅具有TP53突变的那些样品相似的基因表达谱，与生存分析的结果一致。最后，我们发现通过H-RASG12V并且沉默Cdkn2a/b的过表达激活RAS途径，并且与H-RASG12V并且沉默TP53的相似过表达RAS的方式诱导小鼠GBM的形成。总之，我们发现了CDKN2A和TP53的遗传改变可用于对GBM进行分类，我们生成主要亚型的动物模型则可以用来作为以后研究的“标本”。而在分类的机制研究上，我们发现水通道蛋白Aquaporin 4（AQP4）以及其家族的很多基因在我们不同的分类体系中，其表达量有显著的差异，而这也可以进一步解释在临床上观察到的脑胶质瘤病人水肿严重的原因。而其实也有文章报道AQP4基因的表达与病人的生存有非常紧密的关系。除此之外，经过GSEA的分析发现，细胞周期也极有可能是分类的机制基础。而我们利用已有的胶质瘤干细胞表达数据，以及我们的特征基因进行分类时发现，我们的分类方法同样适用于肿瘤干细胞，对肿瘤干细胞的研究也会产生深刻的意义。

Glioblastoma multiforme (GBM) is the most common and most malignant brain tumor in human disease. It is in the classification of WHO IV grade tumors. Polymorphic glioblastoma (GBM) accounts for up to 50% of brain parenchymal tumors. It is the most malignant type of brain cancer, with very poor survival and limited remedy. Cancer subtypes are important for cancer research and treatment. Here, we report the latest classification method based on genetic change GBM.CDKN2A is called a cell cycle-dependent kinase inhibitor, which is a tumor suppressor gene and plays an important role in the cell cycle. Encoding two proteins p14ARF and p16INK4a. At present, many tumors have CDKN2A gene variation, and TP53 is one of the earliest found tumor suppressor gene. main functions of the p53 protein is regulating cell cycle and avoiding cell carcinogenesis, to maintain the stability of the genome and to avoid mutations. And CDKN2A and TP53 are the most common mutant genes, mutation rates were 60% and 30%. We survived the analysis found that CDKN2A deletion of patients than those who have mutations in the survival of patients with TP53 worse. Interestingly, the survival rate of patients with mutated TP53 and deleted CDKN2A was no worse than those with only one of these genetic alterations, but similar to those with only TP53 mutations. Next, we investigated the differences in gene expression profiles between TP53 and CDKN2A samples. Samples consistent with survival data, samples with TP53 mutations and CDKN2A deletions showed similar gene expression profiles to those with only TP53 mutations. Finally, we found that activation of the RAS pathway by H-RASG12V plus Cdkn2a / b silencing overexpression can induce GBM in a manner similar to H-RASG12V plus TP53 silencing overexpression. In conclusion, we show that genetic alterations of CDKN2A and TP53 can be used to classify GBM, and that we produce animal models of major subtypes that can be used as a "specimen" for later research. In the study of the classification mechanism, we found that expression of aquaporin 4 (AQP4) and some genes of its family in different classification was significantly different. And this can also be further explained in clinical observation of brain glioma patients with severe edema. In fact, there are articles reported that the expression of AQP4 gene and the survival of patients have a very close relationship. In addition, after the GSEA analysis, we found that the cell cycle is also very likely to be the basis of classification mechanism. Then we used some expression data of glioma stem cells, with characteristics of the gene classification used before, then we found that this classification method is also applicable to tumor stem cells. The study of cancer stem cells will have a more profound significance.