The objective of project is to identify 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. A number of growth regulatory genes have been found to be associated with cancer-specific translocations or deletions. Recurrent genomic alterations having potentially predictive or diagnostic value were identified in several malignancies using molecular cytogenetic procedures of fluorescence in situ hybridization (FISH). In Kaposi's sarcoma (KS) deletions and translocations non-randomly involving the region of fragility 3p14, and related loss of heterozygosity of loci on 3p, including the loci of a newly isolated FHIT gene, were identified in two tumorigenic cell lines. This represents a first step toward the generation of molecular probes for detecting neoplastic cells early in the development of KS. FISH with centromeric chromosome 3 probe and a YAC probe spanning the 3p14 region are currently used in cytological preparations to detect neoplastic cells in KS lesions. In the past years nonrandom alterations of chromosomes 1, 3, 8, 11 and 17 were identified in cervical carcinoma. These alterations were confirmed and new changes, undetectable by chromosome banding, were identified by fluorescence in situ hybridization (FISH), and spectral karyotype, a new method for simultaneous multiprobe hybridization and global visualization of structural rearrangements in cancer cells. FISH with these chromosomes are now used for diagnosis on PAP smears in ambiguous cases. In human melanoma cell lines, etoposide resistance was found to be associated with the acquisition of multiple copies of a mutant topoisomerase II alpha gene allele due to a series of numerical and structural alterations of chromosome 17. In contrast, camptothecin resistance of human leukemic cell is associated with topoisomerase I mutation in the absence of alterations of chromosome 20. Several newly isolated gene have been mapped in human chromosomes. Human vascular endothelial growth factor gene, NAB-2 gene a corepressor of the nerve growth factor-induced gene, and two Ras exchange factor genes have been mapped to chromosomes 6p12, 12q13-14, 15q24 and 2p21-22, respectively.Two rat multidrug resistance genes were mapped on rat chromosome 4q14, and the first oncogene isolated in Syrian hamster was localized on X chromosome. Structural alterations involving the loci of these genes can now be examined.
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