Pre-existing cellular DNA sequences called proto-oncogenes can be inappropriately altered or activated to oncogenes with new abilities to produce malignant transformation of cells. More than 40 proto-oncogenes have been identified in normal cells and they appear to play key roles in normal cellular processes of growth and differentiation. Under normal circumstances, these processes are regulated by proteins acting as growth factors, growth factor receptors, and regulators of transcription and signal transduction. When inappropriately activated outside the context of these normal pathways, however, cell transformation can result. The control of proto-oncogenes may be upset by viral interference, ionizing radiation or carcinogenic chemicals. Although it is recognized that most spontaneous neoplasms result from a series of somatic mutations, mutations transmitted in the germ line may also contribute to the evolution of a malignancy. Activated oncogenes exert their effects on cells through the expression of their encoded gene products, termed oncoproteins.  

There is a second category of cancer associated genes, called tumor suppressor genes. The tumor suppressor genes, upon inactivation or deletion, allow cells to exhibit behavior that would otherwise be restrained such as the loss of a gene product which is necessary for the control of cellular proliferations. Unlike the oncogene model in which the product of an altered gene acts in a dominant fashion to induce cancer, it is the lack of normal protein products either through deletion or inactivation of tumor suppressor genes that contributes to tumorigenesis.  

Activation of oncogenes may occur by several mechanisms including deregulation of DNA or modification of the transcribed segment of the gene. In deregulation, the gene is overexpressed, whereas modification implies that the protein product of the gene is modified at one or more amino acid positions. Translocation of chromosomes is an important mechanism whereby proto-oncogenes are activated to oncogenes. In translocation, a proto-oncogene is moved from its normal location. In its new position, it may come under the control of a promoter gene or enhancer resulting in overexpression of the oncoprotein. Alternatively, chimeric mRNA and the modified hybrid protein may be formed with transforming activity, such as increased enzymatic activity without the necessity of increased expression.  

An important mechanism of deregulation of proto-oncogenes is gene amplification, which increases the number of copies of the gene. The resultant increased expression of the proto-oncogene results in escape from normal cellular control.  

Gene mutation is the simplest form of gene modification. Single point mutations can lead to single amino acid substitutions in the protein products encoded by DNA; these mutant proteins may have transformation activities.  

Gene deletions may also modify the proper control of gene expression or result in the production of abnormal proteins with enhanced activity.  

Retroviruses pose unique threats to the integrity of cellular genes. Retroviruses are capable of causing mutations by proviral integration, and in dominant mutations, the gene product is altered. Further, the provirus may integrate in the vicinity of a cellular gene involved in normal cell growth or development, and in so doing, subvert the normal expression of that gene by placing in its proximity powerful proviral regulatory elements.  

Other genes influence susceptibility to cancer, the progression of disease within the tumor-bearing host, and even treatment response. For example, the genes controlling expression of the class I and II major histocompatibility antigens influence immunologic responses to tumors. Analogous to the oncogene/antioncogene model of tumor progression, metastasis is probably governed by both metastasis-promoting and suppressing genes; a candidate metastasis suppressor gene, nm23, has been identified in rodent and human neoplasms, and may similarly influence metastasis in canine and feline neoplasms. From a treatment perspective, expression of the multidrug resistance gene (mdr1) confers multidrug resistance on the cell the ability to withstand exposure to lethal doses of many structurally unrelated antineoplastic agents.