Oncogenes and the molecular biology of cancer

Gene transfer experiments have made it possible to detect active transforming sequences in the DNA of various human tumor cells. These sequences, the cellular oncogenes, have been found in tumors as diverse as neuroblastomas, leuke-mias, carcinomas, and sarcomas. They appear to represent molecular determinants that participate in transformation mechanisms that are common to a wide variety of tumors. From this perspective, cancer seems to be a single, unitary disease, and not 100 different diseases, each characterized by a different type of tumor. Several of these oncogenes have been isolated by molecular cloning (1-4). The most well studied of these is one from a human bladder carcinoma cell line, referred to as T24/EJ. Use of this oncogene in sequence hybridization has revealed a property common to this and the other cellular oncogenes : these oncogenes derive from closely related antecedent genes residing in the normal cellular genome. It appears that these normal genes, often called "proto-oncogenes," become converted into oncogenes via processes of "somatic mutation ." This last conclusion remains equivocal, if only because there is little direct evidence to date showing comparison of the oncogene of a tumor with the homologous sequences of closely lying normal tissue. A variety of mechanisms might be imagined to be responsible for the conversion of a proto-oncogene into an active oncogene. In the case of the bladder carcinoma oncogene, a remarkably simple mechanism was revealed within the last year. Comparison of the bladder carcinoma oncogene with its normal antecedent showed that a single nucleotide alteration, occurring in the protein-encoding portion of the gene, was responsible for the activation. This point mutation affected the twelfth amino acid of the encoded 21,000-dalton protein causing the replacement of a glycine by a valine (5-9). Since little is known about the functioning of this protein, it is impossible at present to explain how such a subtle alteration can have such profound effects on this protein, and in turn, on cellular physiology. This bladder carcinoma proto-oncogene has homologs in the DNA of all vertebrates. Its evolutionary origins can, however, be traced back much further. Sequence hybridiza-tion has found homologs of this and other proto-oncogenes in the DNA of Drosophila melanogaster (10). This leads to the realization that these genes are of extremely ancient lineage-their precursors were already present in similar form in the primitive metazoans that served as common ancestors to chordates and arthropods. Such conservation indicates that these …