Activated oncogenes in human tumors

The search for the genetic targets responsible for tumorigenesis has led to the identification of a number of cancer genes or cellular oncogenes (c-oncogenes). The oncogenes are activated forms of the proto-oncogenes, which are normal cellular genes and are scattered throughout the cellular genome. The number of known cellular proto-oncogenes and associated oncogenes now exceeds 30. There are different proto-oncogene families and their products have different functions and cellular localisation. They may function in normal cells in the process of proliferation, regulation of cellular metabolism through signal transfer, or cell differentiation. Activation of proto-oncogenes in man is now assumed to be due to: 1) point mutation; 2) overexpression or 3) gene rearrangement. The observation that in some tumors multiple oncogenes are altered could be interpreted in terms of a multigene hypothesis. However, in some cases, a single properly-activated oncogene may be able to trigger the whole process of malignant conversion. It is difficult to correlate, without ambiguity, tumor induction to specific types of DNA lesions in human tumors. Xeroderma pigmentosum (XP), a rare recessive autosomal skin disorder characterized biochemically as a DNA repair-deficient disease, is the first example in which unrepaired UV-induced DNA lesions are directly responsible for tumorigenesis. In two independent XP skin tumors, isolated from the same patient, we have detected several (N-ras, c-myc, Ha-ras) altered oncogenes in the same tumor. We postulate that the modifications we have found in these tumors are primarily due to the presence of unrepaired UV-adducts. Long term treatment of human tumoral cell lines bearing an activated ras oncogene, with Interferon-alpha (IFN), showed that IFN can affect the phenotype of the tumor cells without altering the expression of the activated ras gene. IFN may have the capacity to affect diverse cellular pathways. Consequently, the nature of the biological response of a given type of tumor cell to IFN may depend on its inherent properties.