ROLE OF FRAGILE SITES IN CHROMOSOME BREAKAGE AND CANCER

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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.