The objective of this project is the identification of recurrent genetic alterations that are relevant to the neoplastic development and provide markers for an early detection and prognostic assessment of cancer, particularly in solid tumors. Localization of genes is essential for molecular analysis of chromosomal alterations in cancer cells and for the identification of specific disease loci. In July 1996 a new Molecular Cytogenetics Section was established in LEC. The research program of this Section focused primarily on human and induced hepatic cancer in mice. Certain genomic regions exhibit an increase fragility and tendency to recombination due to structural chromatin organization and DNA replication A fragile site of the short arm of chromosome 3 (FRA3B) is frequently associated with deletions, translocations and virus integration in several forms of cancer. FRA3B encompasses the locus of the fragile histidine triad (FHIT) gene, a multiple tumor suppressor gene which is abnormally expressed in a variety of common forms of cancer. By FISH, using cosmids covering specific regions of the FHIT gene, it was found that most of the aphidicolin-induced gaps at FRA3B fall within the FHIT gene. These results demonstrate that the cancer-specific deletions, which frequently involve introns 4 and 5 of the FHIT gene, originated through breaks in FRA3B. Also, sequences that are prone to damage and recombination at a critical site in human cancer were identified at the intragenic level. Keratinocyte growth factor (KGF) is a member of the fibroblast growth factor family. Portions of the gene encoding KGF were amplified during primate evolution and are present in multiple non-processed copies in the human genome. KGF sequences were identified and mapped in human and great apes providing insights in the dating of amplification and dispersion events that began in gibbon. Most importantly, evidence for a closer evolutionary relationship of human and chimpanzee and a possible selective pressure for such dispersion during the evolution of higher primates were provided. The localization of several newly isolated cancer-related genes for frizzled-related protein, ninjurin, mouse cyclin G1 and dipeptidyl I peptidase genes, and three glial-derived neurotrophic factor genes is of special importance as it will facilitate the identification of loci in genetic diseases of unknown etiology mapping at the same chromosomal regions.
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