Defining the nature and temporal sequence of events propelling a cell towards neoplastic transformation is pivotal to the understanding of the malignant process. What role oncogenes and proto-oncogenes have in this process is still obscure. Melanoma provides a valuable model system to study this problem. Our objectives are to define the role of oncogenes and proto- oncogenes in the pathogenesis of malignant melanoma, one of the few cancers whose incidence is on the rise. Our long term goals are (1) to determine the status of oncogene and proto-oncogene activation and expression during specific clinically-defined stages of melanoma, (2) to determine the types of specific oncogene and proto-oncogene related events which disrupt the normal functioning of the melanocyte, and (3) to decipher the relationship of neoplastic transformation to differentiation programs in this disease. Specifically, we propose (i) to expand our studies showning that ras oncogenes induce in normal human melanocytes a complex series of alterations known to occur in melanomas, (ii) to determine if oncogene encoded proteins with intracellular locations and functions different from ras can transform melanocytes singly or in combination with other oncogenes, (iii) to delineate specific and progressive chromosomal perturbations in transformed melanocytes and to determine their correlation with known phenotypic characteristics of melanomas, (iv) to expand our studies designed to detect consistent oncogene or proto- oncogene perturbations in non-cultured melanomas and in precursor lesions, and (v) to isolate novel transforming genes and differentially regulated genes from the DNAs of melanomas and melanocytes. Our research to date suggests a definite, but complex, role for oncogenes in the development of melanoma and points to a probable interrelatedness of melanocyte-melanoma cellular differentiation programs and the process of malignant transformation. Further, this work has generated information suggesting the presence of as yet undefined genetic elements possibly necessary for the fully neoplastic features of melanoma. Our proposed research will pursue these themes in order to acquire a precise knowledge of the contribution of oncogenes in this disease.
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