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: 6108984
• 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/6108984
• 关键词: carcinogenesis; cervix neoplasms; chromosome aberrations; colorectal neoplasms; comparative genomic hybridization; confocal scanning microscopy; cytogenetics; digital imaging; fluorescent in situ hybridization; gene expression; gene mutation; genetic mapping; genetically modified animals; genotype; human tissue; image processing; laboratory mouse; loss of heterozygosity; neoplasm /cancer invasiveness; neoplastic process; nucleic acid hybridization; nucleic acid probes; 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 colorectal tumors and 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 this aberrations can now be tested directly in cytological preparation used in routine diagnostic settings by means of interphase cytogenetics and automated spot counting. Tumor metaphase chromosome analysis was greatly facilitated by the development of spectral karyotyping. SKY allows to display all human chromosomes in different colors after FISH with chromosome specific painting probes. In order to dissect the effects of specific gene mutations on genetic stability and genomic integrity we have developed molecular cytogenetic techniques (spectral karyotyping 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.

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