Consequences of chromosomal aneuploidy on the cancer

染色体非整倍性对癌症的影响

• 批准号: 7292083
• 负责人: Thomas E. Ried
• 金额: --
• 依托单位: DIVISION OF CLINICAL SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7292083
• 关键词: Consequences; chromosomal; aneuploidy; cancer

The review of CGH analyses performed in our laboratory has revealed that the acquisition of whole chromosomes or chromosome arm gains and losses is a frequent event, particularly at early stages of carcinogenesis. The comparison of 25 cell lines established from solid tumors by SKY and CGH has provided compelling evidence that the vast majority of epithelial cancers have either numerical or structural chromosomal aberrations resulting in genomic imbalances. The comparison of diploid, mismatch repair deficient colorectal carcinomas with aneuploid ones indicates that numerical chromosomal aberrations are 60 times more prevalent in the aneuploid tumors. Abnormalities of the centrosome correlated with chromosomal aneuploidy both in human cancer cell lines and in animal cells deficient for cell cycle regulator genes such as p53 and BRCA1. All these results taken together support the notion that chromosomal aneuploidy is a major theme in epithelial cancers. In order to elucidate mechanisms leading to aneuploidy, to establish the functional relevance of chromosomal aneuploidy, and to identify whether aneuploidy is a cause or a consequence of genetic changes in solid tumors, we have focused on the following projects:1. Structural and functional analysis of abnormal centrosomes and their relationship to chromosome segregation fidelity.2. Sequential inhibition of p53 and Rb-function with E6 and E7-genes from human papilloma virus 16 and subsequent analyses of chromosomal instability.3. Microcell mediated chromosome transfer of chromosomes that are frequently gained in colorectal carcinomas into cells derived from normal colorectal epithelium and adenomas followed by cytogenetic analysis and assays for cellular immortalization and transformation. 4. In vitro induction of chromosomal aneuploidy in primary cultures derived from normal murine cells of different organ origin with aneugens followed by cytogenetic analysis and assays for confirmation of cellular immortalization and transformation.5. Comparison of cells carrying chromosomal aneuploidies with their wildtype parental cells using cDNA microarrays and 2D-gel protein electrophoresis.In two model systems, we have also studied what general consequences recurrent chromosomal aneuploidies exert on gene expression levels in liver metastases of colorectal carcinomas. The results suggest that only a few candidate genes are the target for the acquisition and maintenance of genomic imbalances. However, it became also evident that chromosomal aneuploidies influence average gene expression levels of genes on these aneuploidy chromosomes. The role of such global dysregulation of gene expression patterns with respect to tumorigenesis remains to be elucidated.

我们实验室对CGH分析的回顾表明，获得整个染色体或染色体臂的获得和损失是一种常见的事件，特别是在癌变的早期阶段。SKY和CGH对实体瘤建立的25个细胞系的比较提供了令人信服的证据，表明绝大多数上皮性癌症存在数量或结构染色体畸变，导致基因组失衡。对二倍体、错配修复缺陷型结直肠癌与非整倍体结直肠癌的比较表明，在非整倍体肿瘤中，数值染色体畸变的发生率是非整倍体的60倍。在人类癌细胞系和缺乏细胞周期调节基因（如p53和BRCA1）的动物细胞中，中心体的异常与染色体非整倍体相关。所有这些结果加在一起支持染色体非整倍体是上皮性癌症的一个主要主题的概念。为了阐明导致非整倍体的机制，建立染色体非整倍体的功能相关性，并确定非整倍体是实体肿瘤遗传变化的原因还是结果，我们重点开展了以下项目：1。异常中心体的结构和功能分析及其与染色体分离保真度的关系。人乳头瘤病毒16 E6和e7基因对p53和rb功能的序列抑制及随后的染色体不稳定性分析微细胞介导的染色体转移是在结直肠癌中经常获得的染色体转移到来自正常结直肠上皮和腺瘤的细胞中，随后进行细胞遗传学分析和细胞永生化和转化试验。4. 体外诱导不同器官来源的正常小鼠细胞原代培养的染色体非整倍体，然后进行细胞遗传学分析和细胞永生化和转化试验。利用cDNA微阵列和2d凝胶蛋白电泳技术比较携带染色体非整倍体的细胞与其野生型亲本细胞。在两个模型系统中，我们还研究了复发性染色体非整倍体对结直肠癌肝转移基因表达水平的一般影响。结果表明，只有少数候选基因是获得和维持基因组失衡的目标。然而，也很明显，染色体非整倍体影响这些非整倍体染色体上基因的平均基因表达水平。这种基因表达模式的全球失调在肿瘤发生中的作用仍有待阐明。