ROLE OF FRAGILE SITES IN CHROMOSOME BREAKAGE AND CANCER

二十多年来收集的细胞遗传学数据显示， 白血病和许多实体瘤的亚组具有一致的 典型的染色体缺陷 这些特定缺陷通常是 染色体重排或缺失，在特定位点断裂 在基因组中。 在细胞遗传学的另一个领域的研究导致了最近的发现， 染色体脆性部位 脆性位点是染色体上的点， 特别容易形成间隙和断裂，如中期扩散中所见 当细胞在特殊条件下培养时。 一些脆弱的网站是 罕见的，而另一些则在人群中很常见。 最近观察到， 脆性位点和染色体断裂点的位置被认为是 白血病、淋巴瘤和其他形式的癌症的特征。 有人认为，脆性位点易使染色体 断裂和重排从而导致癌症。 本研究建议， 开始解决这个问题，超越发展， 地点的相关性和重合性， 脆弱网站的重要性。 这项提议的总体目标是检验染色体 脆性位点是易于染色体缺失的“热点”， 体细胞中的重排或重组， 这种倾向会发生变化。 人淋巴细胞和 在体外处理脆性位点表达的淋巴母细胞将 细胞遗传学特征为染色体重排和其他 变化 在一些实验中，这些细胞将同时被处理， 已知的染色体断裂素 此外，姐妹染色单体的位置 交换断点将在脆性位点诱导后确定， 确定脆性位点表达是否会增加体细胞重组。 在另一种方法中，将创建新的体细胞杂交系统， 其特征在于作为研究染色体的模型系统， 罕见和常见脆弱部位的断裂。 这些混血儿 在脆性位点染色体断裂和缺失将 不会对细胞造成选择性不利。 最后，鉴于脆性位点倾向于染色体的假设， 在癌症中重要部位的断裂，将确定个体 在常见的脆性位点的表达中发生变化，如果这样， 变异在个体染色体中具有可遗传的成分， 使某些人患癌症的风险增加。

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.