胶质瘤基因组不稳定性的机理研究

Gliomas are the most common primary tumor in adult brain. Morphological observation-based WHO classification standard for gliomas assigns adult gliomas into astrocytoma, oligodendroglioma, or mixed oligoastrocyoma, which are further divided into grades II to IV according to the severities of cellular atypia, cell proliferation, angiogenesis and necrosis, with grade II as the low grade and III-IV as the high grades. The grade IV gliomas, or glioblastoma multiforme (GBM) account for more than 50% of all adult gliomas.. Gliomas represent the worst challenges in many types of cancers, were therefore chosen as the first research target by the TCGA consortium. Despite maximal surgical resection and chemoradiotherapy, the median survival of GBM patients is only 14-16 months. All low-grade gliomas typically progress into GBM within 5-10 years of diagnosis, followed by rapid fatal outcome.. The lack of therapy is caused by the following main obstacles: 1) morphological diagnosis has brought artificial complexities, as morphologically defined glioma subtypes are not distinct biological entities, but rather heterogeneous regarding their pathogenic mechanisms and response to treatment. 2) The mechanisms of glioma initiation and progression are inadequately understood. 3) Gliomas are insensitive to the radiotherapy and DNA-damaging chemotherapy.. Genomic instability is a key contributing factor to intratumor heterogeneity and resistance to therapy in GBM, as well as to the progression of low-grade gliomas. FGFR-TACC fusion genes are reported in 3% of the GBMs, which cause chromosome instability in normal astrocytes and promote tumorgenesis in adult mouse brain. Further, 16% gliomas harbor mutations and/or copy number alterations in members of the cohesion complex. However, the mechanisms of genomic instability in the bulk of gliomas, and a means to identify gliomas harbouring genomic instability are to date not identified.. Unlike previous reports seeking the role of individual genes, we are applying a network approach to identify the root of genomic instability in gliomas and other cancers. We hypothesize that abnormal activities of the gene network controlling cell proliferating and genomic stability may drive genomic instability in gliomas. We recently described a hypothesis-based bioinformatics strategy to screen for gene networks that are converged between glioma genesis and neural development. This approach allowed us to establish an EM/PM classification assigning all adult diffuse gliomas into three subtypes with distinct genomic, transcriptomic and clinical characteristics.. We have screened gene co-expression networks around key regulators of cell cycle check points in glioma transcriptome data bases. Our preliminary data show that gene co-expression module around CDC20, a master regulator of the anaphase-promoting complex, comprises genes regulating cell proliferation and various functions in maintaining genome stability, including DNA damage response, and controllers of chromosome segregation. High CDC20-M expression marks cell proliferation in human brain development and hematopoiesis, as well as in model systems of C. elegans and drosophlia. In gliomas and multiple types of cancers, high CDC20-M expression marks extensive copy number alterations and point mutations. In addition, multi-variate Cox-regression analysis suggests that high CDC20-M is an independent marker of poor prognosis. Integrating bioinformatics analysis, validation in glioma samples and gene transfer into the normal astrocytes, we aim to identify the hub genes of the CDC20-M and characterize their role in inducing genomic instability. Finally, we will test whether inhibition of CDC20-M induces killing of glioma cells harbouring genomic instability, but leaving normal cells without genomic instability unaffected. We believe that our project will shed light on the pathogenic mechanisms and new therapeutic targets for gliomas and other cancers.

胶质瘤是成人最常见颅内原发恶性肿瘤，目前未有有效的治疗方案。基因组不稳定性（GIN）是驱动胶质瘤发生、亚克隆进化及治疗耐受的重要因素之一; 能代表胶质瘤GIN并解释其产生机理的标志物的发现将促进GIN的机理研究和临床应用。在前期基因组大数据分析和EM/PM分子分型的研究基础上，本课题组提出，胶质瘤GIN起源于调控细胞增殖和基因组稳定性基因网路的异常。我们在来自不同国家的1500余例胶质瘤转录组中筛选与调控基因组稳定性核心基因共表达的基因模块，发现CDC20高表达模块(CDC20-M，143个基因)富集调控细胞增殖和基因组稳定性的基因。CDC20-M高表达提示胶质瘤样本的高度增殖、高频率拷贝数变异及点突变、以及病人的高风险预后。整合组学大数据分析、样本中验证及正常细胞中逆转录病毒介导的基因转移研究，我们拟鉴定驱动CDC20-M的枢纽基因，探究抑制CDC20-M活性能否特异杀伤胶质瘤细胞。

胶质瘤是成人最常见颅内原发恶性肿瘤，目前尚未有有效治疗方案。基因组不稳定性（GIN）是驱动胶质瘤发生、亚克隆进化及治疗耐受的重要因素之一。本项目的核心目的是发现能代表胶质瘤GIN的标志物，解释其产生机理，探索其在胶质瘤起源或演进中的作用和作为新型治疗靶点的可能性。在前期工作原创发现EM/PM分子分型的基础上(PNAS 111:3538-3543, 2014)，本项目提出如下科学假设: 胶质瘤GIN起源于调控细胞增殖和基因组稳定性基因网路的异常。我们在来自不同国家的1500余例胶质瘤转录组中筛选与调控基因组稳定性核心基因共表达的基因模块，发现CDC20高表达模块(CDC20-M，143个基因)富集调控细胞增殖和基因组稳定性的基因。CDC20-M高表达提示胶质瘤样本的高度增殖、高频率拷贝数变异及点突变。CDC20-M高表达的胶质瘤细胞株呈现高度的染色体不稳定表型，表现为染色体分离异常、胞浆DNA、异常细胞核和各单细胞间不同的染色体数目。在来自中国、美国和欧洲的数据库中，CDC20-M的高表达均为独立的风险因素，无论何种形态学亚型，高表达CDC20-M提示胶质瘤病人的快速进展。.应用病人来源的原代细胞株培养和免疫缺陷小鼠移植实验，我们发现，抑制CDC20-M的核心基因AURKA能显著抑制胶质瘤细胞的体外、体内生长。因此，本项目发现和鉴定了CDC20-M可以作为胶质瘤GIN的标志物，并初步阐明了其在胶质瘤演进和治疗中的作用。成果发表于:PNAS 116:6975-6984, 2019; 并获得国家发明专利一项 (专利号: ZL 201910171388.4)。..以上述成果为基础，本团队目前在进一步阐明CDC20-M如何促进胶质瘤演进的机制未明。现阶段工作的科学假说为:基因组不稳定性导致先天免疫反应cGAS-STING信号通道的激活，cGAS-STING信号通道的激活导致恶性胶质瘤细胞大量合成感染类细胞因子，感染类细胞因子的释放导致血液循环中的巨噬细胞和其它免疫细胞被招募到胶质瘤微环境中。而巨噬细胞又大量合成促进胶质瘤细胞和血管上皮细胞增殖的生长因子。因此，基因组不稳定与胶质瘤微环境并行演进，二者共同促进胶质瘤的演进。 ..本项目成果也将为阐明其他肿瘤的演进机制提供参考。

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