It is now well established that nonrandom chromosomal rearrangements are characteristic of human malignant diseases, particularly the leukemias and lymphomas. Experimental evidence obtained during the past few years suggests that the genes located at the breakpoints in specific rearrangements play an intergral role in tumorigenesis. Another factor that has added to the interest in cancer specific abnormalities is the recent recognition of the remarkable concordance between the breakpoints noted in the nonrandom abnormalities in human tumors, and the recognized chromosomal fragile sites. The subsequent identification of individuals with malignant diseases characterized by specific abnormalities who were also carriers of a rare fragile site at that chromosomal breakpoint suggests that fragile sites may act as a predisposing factor for chromosomal rearrangements in human neoplasia. At present, there are 21 recognized fragile sites; 17 of the 21 are the rare, heritable fragile sites. The objective is to address some of the quesitons that currently exist regarding fragile sites and their potential role as predisposing factors to malignancy. The studies are designed to determine whether patients with various forms of cancer are carriers of freagile sites and whether the frequency differs from that in the general population. These studies will correlate fragile sites noted in patients with the breakpoints noted in the chromosomal abnormalities in their malignant cells, thereby providing data necessary to determine if individual fragile sites predispose to a specific type of cancer, characterized by a nonrandom abnormality. Analysis of family members of cancer patients who are carriers of chromosomal fragile sites will enable us to determine if these sites are familial, and hence, whether the cancer predisposition associated with fragile sites is likely to be familial. We propose to identify the genes located at some of the recognized fragile sites, and to study the relationship of fragile sites and chromosomal breakpoints in cancer cells at the molecular level, by using DNA probes isolated from selected breakpoints. These studies will provide data regarding the frequency of fragile sites in cancer patients, the relationship of specific sites to the chromosomal breakpoints noted in the malignant cells of individual patients, the role of fragile sites as predisposing factors to neoplastic diseases, and the relationship of fragile sites to chromosomal breakpoints at the DNA level.
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