ROLE OF FRAGILE SITES IN CHROMOSOME BREAKAGE AND CANCER

脆弱部位在染色体断裂和癌症中的作用

• 批准号: 3185310
• 负责人: THOMAS W GLOVER
• 金额: $ 7.46万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 1986
• 资助国家: 美国
• 起止时间: 1986-07-01 至 1989-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3185310
• 关键词: carcinogenesis; cell transformation; chromosome disorders; cytogenetics; developmental genetics; gene expression; genetic disorder diagnosis; genetic mapping; genetic markers; genetic models; human population genetics; hybrid cells; leukemia; lymphoblast; lymphoma; neoplasm /cancer genetics; tissue /cell culture

Cytogenetic data collected for over two decades has revealed that most subgroups of the leukemias and many solid tumors have consistent and characteristic chromosome defects. These specific defects are usually rearrangements or deletions of chromosomes with breakage at specific sites in the genome. Research in another area of cytogenetics has led to the recent discovery of chromosome fragile sites. Fragile sites are points on chromosomes that are especially prone to forming gaps and breaks as seen in metaphase spreads when cells are cultured under special conditions. Some fragile sites are rare while others are common in the population. It has recently been observed that there is a very high correlation between the location of fragile sites and the chromosome breakpoints recognized as characteristic of the leukemias, lymphomas and other forms of cancer. Suggestions have been made that fragile sites predispose to chromosome breakage and rearrangement and thus to cancer. This study proposes to begin to address this question by going beyond the development of correlation and coincidence of sites and studying the biological significance of fragile sites. The overall aim of this proposal is to test the hypothesis that chromosome fragile sites are "hot spots" that predispose to chromosome deletions, rearrangements or recombination in somatic cells and that individual variation occurs in such predisposition. Human lymphocytes and lymphoblasts treat for fragile site expression in vitro will be cytogenetically characterized for chromosome rearrangements and other changes. In some experiments, these cells will be concurrently treated with known clastogens. In addition, the location of sister chromatid exchange breakpoints will be determined following fragile site induction to determine if fragile site expression may increase somatic recombination. In another approach, novel somatic cell hybrid systems will be created and characterized to serve as model systems for the study of chromosome breakage at both rare and common fragile sites. These hybrids will have the advantage that chromosome breakage and deletion at fragile sites will confer no selective disadvantage to the cells. Finally, given the hypothesis that fragile sites predispose to chromosome breakage at sites important in cancer, it will be determined if individual variation occurs in the expression of common fragile sites and if such variation has a heritable component in individual chromosomes that may place certain individuals at increased risk for cancer.

二十多年来收集的细胞遗传学数据表明，大多数 白血病亚组和许多实体瘤具有一致和 特征性染色体缺陷。 这些具体的缺陷通常是 染色体重排或缺失，并在特定位点断裂 在基因组中。 细胞遗传学另一个领域的研究最近发现了 染色体脆弱位点。 脆弱位点是染色体上的点 特别容易形成间隙和断裂，如中期扩散所示 当细胞在特殊条件下培养时。 一些脆弱的网站是 罕见，而其他则在人群中常见。 最近发现，两者之间存在很高的相关性。 脆弱位点的位置和染色体断点被认为是 白血病、淋巴瘤和其他形式的癌症的特征。 有人建议脆弱位点易受染色体影响 断裂和重排从而导致癌症。 本研究提出 开始通过超越发展来解决这个问题 位点的相关性和重合性并研究生物学 脆弱场地的重要性。 该提案的总体目标是检验染色体的假设 脆弱位点是容易发生染色体缺失的“热点”， 体细胞中的重排或重组以及个体 这种倾向会发生变异。 人类淋巴细胞和 淋巴母细胞在体外治疗脆弱位点表达将是 细胞遗传学特征的染色体重排和其他 变化。 在一些实验中，这些细胞将被同时处理 与已知的断裂剂。 另外，姐妹染色单体的位置 交换断点将在脆弱站点感应后确定 确定脆弱位点表达是否可以增加体细胞重组。 在另一种方法中，将创建新型体细胞混合系统并 作为染色体研究的模型系统 罕见和常见脆弱部位的破损。 这些混合动力车将具有 脆弱位点染色体断裂和缺失的优点 不会给细胞带来选择性劣势。 最后，假设脆弱位点易受染色体影响 癌症重要部位的断裂，将确定个人是否 常见脆弱位点的表达发生变化，如果这样的话 变异在个体染色体中具有可遗传的成分，可能 使某些人患癌症的风险增加。