DELINEATION OF CHROMOSOMAL ABERRATIONS DURING THE PROGRESSION OF SOLID TUMORS

实体瘤进展过程中染色体畸变的描绘

• 批准号: 5203450
• 负责人: Thomas E. Ried
• 金额: --
• 依托单位: NATIONAL HUMAN GENOME RESEARCH INSTITUTE
• 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/5203450
• 关键词: carcinogenesis; cervix neoplasms; chromosome aberrations; confocal scanning microscopy; cytogenetics; gene expression; gene mutation; genetic mapping; genetically modified animals; genotype; human tissue; image processing; in situ hybridization; laboratory mouse; loss of heterozygosity; molecular genetics; neoplasm /cancer invasiveness; neoplastic process; nucleic acid hybridization; nucleic acid probes; oncogenes; phenotype; tumor suppressor genes

This laboratory is interested in the delineation of chromosomal aberration that occur during the genesis of solid tumors. The laboratory uses a variety of molecular cytogenetic and biology techniques with particular focus on fluorescence in situ hybridization, quantitative digital image analysis and confocal laser scanning microscopy. Loss of function of tumor suppressor genes and gain of function of proto-oncogenes in solid tumors is often accompanied by a net loss or gain of genetic material. These changes occur sequentially and are accumulated during the transition from normal epithelium to dysplasia and eventually invasive carcinoma. In order to establish a phenotype/genotype correlation in solid tumor progression we have analyzed tumors of the uterine cervix as a model system. Using comparative genomic hybridization which is a new molecular cytogenetic technique, that allows to screen tumor genomes for genetic imbalances and to determine the chromosomal map position of DNA copy number changes on reference metaphase chromosomes we delineated a consistent chromosomal aberrations that occurs at the transition point of severe dysplasia to invasive carcinoma. Using region specific DNA probes these aberrations can now be tested directly in cytological preparation used in routine diagnostic settings by means of interphase cytogenetics. Other model systems for tumor progression were studied in the lab using a similar analytical approach: the progression from low grade to high grade astrocytic tumors, differences in diploid and aneuploid breast carcinomas, genetic aberrations in the genesis of colorectal carcinomas, and chromosomal aberration that define the differences between low and high grade lymphomas. In order to dissect the effects of specific gene mutations on genetic stability and genomic integrity we have developed molecular cytogenetic techniques (interphase FISH and comparative genomic hybridization) for the study of chromosomal aberration in mice. Transgenic animals for loss of function mutation of tumor suppressor genes (e.g. p53 or BRCA1) and gain of function mutations of oncogenes are analyzed and the status quo of DNA gains and losses studied at specific time points during malignant transformation.

这个实验室对染色体的描绘感兴趣 在实体瘤发生过程中发生的畸变。实验室 使用多种分子细胞遗传学和生物学技术， 特别注重荧光原位杂交，定量 数字图像分析和共聚焦激光扫描显微镜。 肿瘤抑制基因功能的丧失和肿瘤抑制基因功能的获得 实体瘤中的原癌基因通常伴随着净丢失或 获得遗传物质。这些变化依次发生， 在从正常上皮向发育不良的转变过程中积累， 最终是浸润性癌。为了建立表型/基因型 我们已经分析了实体瘤进展中的肿瘤， 子宫颈作为模型系统。利用比较基因组杂交 这是一种新的分子细胞遗传学技术， 肿瘤基因组的遗传不平衡，并确定染色体图谱 参考中期染色体上DNA拷贝数变化的位置 我们描绘了一个一致的染色体畸变发生在 严重异型增生向浸润性癌的转变点。使用区域 特异性DNA探针，这些畸变现在可以直接测试， 通过常规诊断装置使用的细胞学制剂 间期细胞遗传学肿瘤进展的其他模型系统包括 在实验室中使用类似的分析方法进行研究： 从低级别到高级别的星形细胞肿瘤，二倍体细胞的差异 和非整倍体乳腺癌，遗传畸变的发生， 结直肠癌和染色体畸变， 低级别和高级别淋巴瘤之间的差异。 为了剖析特定基因突变对遗传的影响， 稳定性和基因组完整性，我们已经开发了分子细胞遗传学 技术（间期FISH和比较基因组杂交）， 对老鼠染色体畸变的研究。转基因动物的损失 肿瘤抑制基因（如p53或BRCA 1）的功能突变， 分析了癌基因功能突变的研究进展， 在恶性肿瘤发生的特定时间点研究DNA的获得和丢失 转型