Nonrandom chromosomal rearrangements are characteristic of human malignant diseases. Experimental evidence obtained recently indicate that the genes located at the breakpoints of the specific rearrangements play an integral 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 several individuals with malignant diseases characterized by specific abnormalities who were also carriers of a rare fragile site at that chromosomal breakpoint, the observation that expression of fragile sites can mediate chromosomal rearrangements, and the observation that cancer patients express common fragile sites at an elevated level suggest that fragile sites may act as predisposing factors for chromosomal rearrangements in human neoplasia. At present, there are 143 recognized fragile sites (124 of these are the common fragile sites) and 134 cancer- specific breakpoints. An objective of this proposal is to address some of the questions that currently exist regarding the potential role of fragile sites as predisposing factors to malignancy by examining the intraindividual expression of common fragile sites in cancer patients, and by determining whether elevated expression of these sites is a general phenomenon in cancer patients that is induced by a variety of chemical agents. 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, and the role of fragile sites as predisposing factors to neoplasms. Analysis of family members of patients will enable us to examine some of the genetic factors affecting the expression of common fragile sites. Another objective of this proposal is to use several molecular approaches to isolate the DNA sequences located at several fragile sites. Using the cloned sequences, we will examine the relationship of fragile sites and chromosomal breakpoints in cancer cells and begin to study, at the molecular level, the biological behavior of fragile sites, including their propensity for involvement in chromosome rearrangements.
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