Recent work from two independent lines of investigation has merged to suggest that neoplasia results, at least in part, from the abnormal activation of a relatively small number of cellular genes. These genes, termed proto-oncogenes, can be activated by genetic alterations which range from point mutations to gross DNA rearrangements such as translocation or amplification. Induction of tumors in rodents by genotoxic carcinogens results in activation of specific oncogenes with high frequency. We have investigated oncogene activation in chemical-induced and spontaneous rodent tumors as well as some types of human tumors. For example, we have shown K-rat activation as a common event in both human and rodent pulmonary adenocarcinomas. In addition, several non-rat genes have been detected in human lung tumors. A high percentage (70%) of human lung tumors from smokers were found to contain activated oncogenes and the majority of the detected oncogenes (70%) were detected only by a method seldom used to screen human tumors (nude mouse tumorigenicity assay). Therefore, the actual percentage of human tumors which contain activated oncogenes may be much higher than previously estimated (i.e., approximately 20%). In another study' activated rat-oncogenes were detected in a high percentage of several tumor types induced in rats by benzidine-derived dyes. Human bladder tumors associated with exposure to benzidine are being examined for the presence of activated rat genes. Oncogene activation is being assessed in spontaneous liver tumors from several mouse strains which are used in carcinogenic studies. Characterization of oncogene activation in human and rodent tumors suggests that activation of a proto- oncogene is a common pathway for tumor induction for some carcinogens. These approaches may enable us to more accurately estimate risk of cancer in humans exposed to specific classes of carcinogens.
