IDENTIFICATION OF TRANSFORMING GENES IN MELANOMA

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In 1990 nearly 30,000 individuals developed malignant melanoma, representing 3% of all new cancer cases in the U.S. and 6000 people died of this malignancy. In the past decade, the incidence of melanoma increased faster than that of any other cancer except lung cancer in women. The lifetime risks of an individual in the U.S. developing malignant melanoma was 1:135 in 1987 and is projected to be 1:90 by the year 2000. The reasons for the increased incidence are not clearly understood but likely relate to increased exposure to sunlight, increased amount of Uv irradiation reaching the surface, and earlier detection of melanomas. Recent efforts in our laboratory have been directed to the construction and implementation of a cDNA expression system that has been successful in the isolation of activated oncogenes expressed in human malignancies. Expression cloning of a human melanoma cDNA library into NIH/3T3 cells has identified a novel transforming gene, termed tim-1, for transforming in melanoma. This gene has no overall sequence homology to any genes in Genebank, however there is a 102 bp region that is approximately 30% homologous to a common site located on the genes dbl, bcr, CDC 24, ect-2, CDC 25, and vav. This region of homology is representive of an expanding family of genes which may be important to growth control. To investigate the role this gene has in the pathogenesis of malignant melanoma, we propose the following specific aims: #1. We will transfect the transforming tim-1 cDNA into immortalized mouse melanocytes and determine its effect on tumorigenicity #2. To investigate the role the tim-1 gene may have clinically, we will screen melanoma specimens, metastases, and cell lines for tim-1 gene expression. The expression of tim-1 will also be examined in normal human tissue and in the developing mouse. #3. The full-length tim-1 cDNA (6.8 kb) will be isolated and its transforming activity, relative to the cloned transforming cDNA (2.4 kb), will be examined. #4. Define the chromosomal localization of the tim-1 gene and characterize the tim-1 protein.