中国科学院昆明动物研究所机构知识库

非整倍体是恶性肿瘤细胞的重要细胞遗传特征，存在于大约90%的实体瘤和75%的造血系统肿瘤。非整倍体是癌症发生的驱动者而不是结果，并且非整倍体对细胞健康的影响取决于具体核型和环境条件，因此非整倍体对肿瘤产生的效应是一个复杂的情况。有趣的是，正常细胞出现非整倍体对肿瘤的发生率产生明显的影响，最为明显的是21三体综合征患者的实体瘤发生率降低和白血病高发。21三体综合征为非整倍体对肿瘤的影响提供了研究模型。本研究将以21三体综合征为研究对象，探索实体瘤低发和白血病高发的分子机制，以及它们是通过什么方式发挥作用的？ 肿瘤细胞具有特定的染色体核型，例如实体瘤中频繁增加的是染色体7、12和20，非实体瘤中频繁获得染色体6、8、10、18、19和21，其中21号染色体在实体瘤优先缺失但是在非实体瘤中优先获得。这与21三体综合征患者的肿瘤易感性的流行病学调查相符，表现为患者的实体瘤发生率显著性低于正常人群，但是白血病的发生率显著性高于正常人群，提示正常细胞额外增加一条21号染色体对肿瘤的发生产生了影响，并且不同的肿瘤类型存在差异性。大规模流行病学调查研究发现，21三体综合征患者的实体瘤发生率显著性的低于正常人群，最为显著的是乳腺癌、皮肤癌和肺癌。针对患者临床表型的出现，提出了不同的假说进行解释，如基因剂量不平衡假说和重要区域假说，我们推测这两种假说可能都是通过剂量敏感基因发挥作用的。究其根源，是由于患者体内额外增加了一条21号染色体，导致的直接影响是体内的平衡被打破，基因的表达量随之受到影响，我们将以21号染色体上的剂量敏感基因切入点研究实体瘤低发的分子机制。收集了21三体综合征患者和对应的正常人群的9种组织或细胞系的300份表达谱数据，筛选在3种或3种以上组织或细胞系均符合基因剂量效应的基因，获得150个剂量敏感基因。同时，差异表达分析TCGA数据库中的14中实体瘤的转录组数据，筛选在7种及7种以上的实体瘤中表达量显著性降低的基因为候选基因。整合21三体综合征和肿瘤的表达谱数据，获得14个候选基因，其中5个基因同时在乳腺癌、皮肤癌、肺癌和pan-cancer中显著性低表达。通过查阅文献和相关性分析， 3个候选基因在21三体综合征临床表型和实体瘤中同时发挥重要作用。针对没有被研究的2个基因，我们在三种肿瘤细胞系中通过体内和体外实验对其功能进行验证。同时，对5个候选基因在乳腺癌中进行共表达分析，共表达基因功能聚类主要集中在血管发育，提示它们是通过抑制血管生成来降低实体瘤的发生。综上，21三体综合征通过基因剂量效应假说和重要区域假说抑制实体瘤的发生，是通过剂量敏感基因来实现的。与21三体综合征患者实体瘤发生率完全不同的是，21三体综合征患者的白血病的患病风险是正常人群的10-20倍。我们收集和分析了21三体综合征患者淋巴细胞和骨髓组织的6组表达谱数据，筛选在2组和2组以上的表达谱数据均符合剂量效应的基因，共有24个剂量敏感基因。针对白血病高发，我们重点关注白血病中显著性高表达的潜在癌基因。整合以上的表达谱数据，我们共获得19个候选基因。通过候选基因与白血病各种临床数据的相关性分析，共有9个基因在绝大多数的相关性分析中存在显著性，其中的5个基因存在相似的靶基因，主要集中在21q22.3区域，提示存在21三体综合征白血病高发的重要区域。综上，本研究对21三体综合征患者低发实体瘤和高发白血病分子机制进行了研究，通过基因剂量效应筛选候选基因，以剂量敏感基因为研究对象对其进行深入探究，进而解释其分子机制。本研究可能为实体瘤和白血病发病的分子机制提供一种新的研究途径，为肿瘤的预防和治疗提供理论依据，同时，为探讨非整倍体对肿瘤发生的研究提供一种新的视角。

Aueuploidy has been recognized as a common feature of human malignancies. Approximately 90% of solid tumors and 75% of haematological cancers exhibit some degree of aneuploidy. Researchs shows that aueuploidy drives the development of cancer, and effect of aneuploidy on cellular fitness depends on both the specific karyotype and the environmental condition, so aneuploidy is a complex process for cancer. Intristingly, normal cells with aneuploidy have s significant effect on the incidence of tumor, most notably is trisomy 21 with a significantly decreased incidence of solid tumor and increase risk of leukemia. Trisomy individual provides a model for researching the effect of aueuploidy on tumor. This study will discuss the way and the molecular mechanism of this phenomenon which is based on the Trisomy 21.Cancer cells have a specific karyotype, for example solid tumors frequently gains chromosomes 7,12 and 20, and gains of chromosomes 6, 8, 10, 18, 19 and 21were often observed in non-solid tumors. According with epidemiological investigation of tumor susceptibility in Trisomy 21, patients are preferentially absent in solid tumors but preferentially obtained in non-solid tumors. Trisomy 21 displays a unique spectrum of malignancies, suggesting that an extra chromosome 21 affects the occurrence of tumors and has tumor heterogeneity.A large epidemiological study shows that trisomy 21 has a significalt low risk of solid tumors, especially breast tumor, skin tumor and lung tumor. There are many hypotheses to explain clinical phenotypes, such as gene dosage imbalance hypothesis and critical region(s) hypothesis, which may be mediated by dosage sensitive genes. To its source, patients with three copies of chromosome 21 lead to an increase in genes expression. So we use dosage sensitive genes on chromosome 21 to research its molecular mechanism. We collected trisomy 21 espression profiles, including 300 samples of 9 tissues or cell lines, and screened 150 dosage sensitive genes that accordance with the gene dose effect in more than 3 tissues or cell lines. At the same time, we analyzed the transcriptome data of 14 solid tumors in TCGA database, and selected candidate genes down-regulated in more than half of 14 kinds of solid tumors. Integrating the above transcriptome data, 14 candidate genes were obtained, of which 5 genes were down-regulated in breast cancer, skin cancer, lung cancer and pan-cancer. 3 candidate genes play an important role in the trisomy 21 clinical phenotype and solid tumors. We confirmed the function of 2 novel genes by in vivo and in vitro expreiments. Meanwhile, we analyzed the co-expression of 5 candidate genes in breast cancer, and the related genes function clustering were mainly concentrated on the development of blood vessels, suggesting that they were to reduce the occurrence of solid tumors by inhibiting angiogenesis. In conclsion, trisomy 21 patient inhibite the risk of solid tumors by gene dosage effect, and chromosome 21 has key genes and regions for this phenomone.Unlike the risk of solid tumors in trisomy 21, patients have a high occurrence of leukemia. We collected and analyzed 6 groups of expression profiles of Lymphocyte and bone marrow tissue in Trisomy 21, and obtained 24 dosage sensitive genes in more than two data. In view of the high incidence of leukemia, we focus on the potential oncogenes with significant high expression in leukemia. Based on the above expression data, we obtained 19 candidate genes. Through the correlation analysis of candidate genes and various clinical data of leukemia, a total of 9 genes were significant in most of the correlation analysis. 5 of them had similar target genes and mainly concentrated in the 21q22.3 region, suggesting the existence of an important region with high incidence of 21 trisomy syndrome.To sum up, our results indicated that the molecular mechanism of trisomy 21 with a unique pattern of through gene dosage effect. We selected key genes which play critical roles in this phenomone using dosage sensitive genes, and provid the the rationale for the prevention and treatment of the tumor. This study may provide a new approach to the molecular mechanisms of tumor and leukemia, and to provide a new perspective for the study of aneuploidy on the occurrence of tumor.