The recognition of recurring sites of chromosome change in several malignant disorders of animals and man has pinpointed the location in the genome of important growth regulatory sequences (e.g., cellular oncogenes). Subsequent molecular analysis of these regions has directly implicated chromosome abnormalities in the aberrant expression of these genes. For this reason, identification of sites of recurring chromosome change has become increasingly important to our understanding of cancer biology. The continuing direction of this application involves first the identification and subsequently the molecular characterization of chromosomal abnormalities in solid tumors. We are beginning to exploit several somatic cell and molecular strategies to assess cancer associated deletions and translocations including: the establishment of hybrid mapping panels, pulsed field gel electrophoresis, and chromosome jumping libraries. These approaches are being systematically applied in order to physically map specific chromosomal regions which cytologically we predict will harbor genes important in the etiology or progression of cancer. The specific goals of this renewal are twofold. First, the investigation of two specific chromosomal alterations involving chromosome 6q in human malignant melanoma. We intend to define at the molecular level the loss of heterozygosity involving 6q21-23, a band region which appears cytologically to be deleted in many malignant melanomas. Also, we intend to molecularly analyze the translocation t(1;6) (q11-q12;q11-q13) which we recently identified as a recurring change in melanoma. Second, we will examine selected regions of chromosomes 1, 6, 7 and 11 for loss of heterozygosity, rearrangement and altered gene expression in melanoma, breast, and ovarian cancers. The ultimate goal of this research is to identify genes residing at the sites of chromosome rearrangements which may be germinally involved in human malignant disorders.
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