ONCOGENE

genetic material that carries the ability to induce cancer. An oncogene is a sequence of deoxyribonucleic acid (DNA) that has been altered or mutated from its original form, the proto-oncogene. Operating as a positive growth regulator, the proto-oncogene is involved in promoting the differentiation and proliferation of normal cells. A variety of proto-oncogenes are involved in different crucial steps of cell growth, and a change in the proto-oncogene's sequence or in the amount of protein it produces can interfere with its normal role in cellular regulation. Uncontrolled cell growth, or neoplastic transformation, can ensue, ultimately resulting in the formation of a cancerous tumour. Oncogenes first were discovered in certain retroviruses (viruses composed of RNA instead of DNA and that contain reverse transcriptase) and were identified as cancer-causing agents in many animals. In the mid-1970s, the American microbiologists John Michael Bishop and Harold Varmus tested the theory that healthy body cells contain dormant viral oncogenes that, when triggered, cause cancer. They showed that oncogenes are actually derived from normal genes (proto-oncogenes) present in the body cells of their host. With DNA sequences similar, but not identical, to their viral equivalents, proto-oncogenes occur naturally within the genomes of a wide variety of vertebrate species, including humans, but do not cause cellular transformation. Although a useful function of the proto-oncogene was not initially apparent, and it was believed to be silent or not expressed until being switched on to cause uncontrolled growth, its importance in cell regulation was soon identified. The similarity between viral and cellular oncogenes can be explained by the life strategy of the retrovirus. The virus inserts itself into the genome of the host cell in order to replicate and then removes itself to infect other cells, sometimes capturing a portion of the host cell's genome along with its own. If a proto-oncogene has been integrated into a virus' own genetic material, its proper regulation may not be possible given the limited genetic repertoire of the retrovirus and it is transformed into an oncogene. The term proto-oncogene was coined to distinguish the normal gene from its altered form. The resulting nomenclature is somewhat misleading. Onco-, from the Greek onkos, meaning bulk, or mass, refers to the tumour-causing ability of the oncogene, which is apt, but the term proto-oncogene stresses the potential the gene has to become a malignant force, rather than its integral role as a regulator of cell activity. Oncogenes are designated by three-letter abbreviations, such as myc, ras, and mas. The origin or location of the gene is indicated by the prefix of v- for virus or c- for cell or chromosome; additional prefixes, suffixes, and superscripts provide further delineation. About 60 human oncogenes have been identified. Breast cancer has been linked to the c-neu oncogene and lung cancer to the c-L-myc gene. Oncogenes arising in members of the ras gene family are found in 20 percent of all human cancers, including lung, colon, and pancreatic. In humans, proto-oncogenes can be transformed into oncogenes in three ways, all of which result in a loss of or reduction in cell regulation. An alteration of a single nucleotide base pair, called a point mutation, can arise spontaneously or as a result of environmental influences such as chemical carcinogens or ultraviolet radiation. This seemingly minor event can lead to the production of an altered protein that cannot be properly regulated. Point mutations are responsible for converting certain c-ras proto-oncogenes to oncogenes. A second method of oncogenesis occurs by the process of translocation, in which a segment of the chromosome breaks off and attaches to another chromosome. If the dislocated chromosome contains a proto-oncogene, it may be removed from its regulatory controls and be continuously produced. Too many protein molecules can swamp the cellular process normally under their control, disrupting the delicate balance of the mechanisms of cell growth. Many leukemias and lymphomas are caused by translocations of proto-oncogenes. The third method of transformation involves an amplification in the number of copies of the proto-oncogene, which also can result in overproduction of the protein and its concomitant effects. Amplified proto-oncogenes have been found in tumours from patients with breast cancer and neuroblastoma.