Recent experiments using DNA mediated gene transfer have uncovered activated genes in human tumors capable of transforming indicator cells in vitro. A second line of investigation has discovered a class of DNA sequences common to acute transforming retroviruses which are responsible for their transforming activity. The activated human and viral sequences are recognized as a family of transforming genes known as oncogenes. A popular hypothesis states that oncogenes are integral to the transformation of normal cells to cancer cells in nature. The explosion of molecular genetic technology has provided an avenue to test this hypothesis in the laboratory. The long range object of this proposal is tocombine laboratory molecular genetic approaches to longitudinal clinical studies in order to define the role of oncogenes in common human malignancies. The current project will study patients with bronchogenic carcinomas and melanomas undergoing surgery and followed in longitudinal surgical oncology clinics at our institution. Tumor DNA from consecutive lung tumors will be transfected onto NIH-3T3 cells to determine the incidence and identity of dominate transforming genes in this human neoplasm. Individual tumor deposits from patients with metastatic melanoma will be analyzed to determine whether activation of transforming genes occurs uniformly in this tumor model. Identification of the responsible genes in this metastatic system will also help to define their role in tumor initiation and progression. Examination of ras gene translational products will be done in bronchogenic tumors and in melanomas. Quantitation of p21 by both RIA and immunohistochemistry will be used to compare normal and malignant tissue. Qualitative differences will be studied by comparing electrophoretic mobility of p21 from activated and wild-type ras genes. Finally, these molecular measurements will be correlated to standard clinical descriptors such as site of origin, histology, clinical-pathologic stage, and outcome. This study is designed to test the hypothesis that oncogenes play a critical role in the process of transformation by studying their significance in a clinical setting. This project will complement the molecular approach to transforming genes now underway in many laboratories.
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