摘要
Glioma 是有有限治疗选择的复杂疾病。最近的进展在多达 80% 更低的等级 gliomas (LGG ) 并且在 76% 第二等的 glioblastomas (GBM ) 识别了 isocitrate 脱氢酶(IDH ) 变化。IDH 变化也在尖锐 myeloid 白血病(AML ) 的 10%-20% 被看见。在 AML，包含 epigenetic 规定的 IDH 和另外的基因的变化是早事件，这被决定，出现在 pre 白血病的干细胞(最低有效字符前) 上演，而在宣传 oncogenic 信号的基因的变化是在白血病的迟了的事件。IDH 变化也是在 glioma 的早事件，发生在 TP53 变化前， 1p/19q 删除，等等。尽管有在 glioma 研究的这些进展，进另外的分子的改变的研究更加落后。在这研究，我们分析了当前可得到的数据库。我们除了已知的基因 IDH1/2 在 glioma 识别了 EZH2， KMT2C，和 CHD4 同样重要的基因。我们也证明 PIK3CA， CDKN2A， CDK4， FIP1L1，或 FUBP1 的 genomic 改变与 IDH 变化协作否定地在 LGG 影响病人幸存。在有 TP53 变化或 IDH1/2 变化的 LGG 病人，没有如此的改变， EZH2， KMC2C，和 CHD4 的另外的 genomic 改变个别地或在联合比病人与显著地减少的没有疾病的幸存被联系。在基因水平或蛋白质水平的 EZH2， KMT2C，和 CHD4 的改变能使不安 epigenetic 节目，在 glioma 导致恶意的转变。由在可得到的数据集上在 AML 和 glioma 和表现生物信息学分析上考察当前的文学，我们从 premalignant 干细胞在 tumorigenesis 上开发了一个假想模型到 glioma。
GUoma is a complex disease with limited treatment options. Recent advances have identified isocitrate dehydrogenase （IDH） mutations in up to 80% lower grade gUomas （LGG） and in 76% secondary gUoblastomas （GBM）. IDH mutations are also seen in 10%-20% of acute myeloid leukemia （AML）. In AML, it was determined that mutations of IDH and other genes involving epigenetic regulations are early events, emerging in the pre-leukemic stem cells （pre-LSCs） stage, whereas mutations in genes propa- gating oncogenic signal are late events in leukemia. IDH mutations are also early events in gUoma, occurring before TP53 mutation, 1p/19q deletion, etc. Despite these advances in gUoma research, studies into other molecular alterations have lagged considerably. In this study, we analyzed currently available databases. We identified EZH2, KMT2C, and CHD# as important genes in glioma in addition to the known gene IDH1/2. We also showed that genomic alterations of PIK3CA, CDKN2A, CDK#, FIPIL1, or FUBP1 collaborate with IDH mutations to negatively affect patients＇ survival in LGG. In LGG patients with TP53 mutations or IDH1/2 mutations, additional genomic alterations of EZH2, KMC2C, and CHD4 individually or in combination were associated with a markedly decreased disease-free survival than patients without such alterations. Alterations of EZH2, KMT2C, and CHD4, at gen- etic level or protein level could perturb epigenetic program, leading to malignant transformation in glioma. By reviewing current literature on both AML and gUoma and performing bioinformatics analysis on available datasets, we developed a hypothetical model on the tumorigenesis from premaUgnant stem cells to gUoma.
