What are oncogenes? |

Discovering Oncogenes

Identifying oncogenes was closely linked to study of the role of certain RNA tumor viruses, retroviruses (Retroviridae), in the etiology of many animal cancers. In 1911, Francis Peyton Rous identified a chicken virus (now called Rous sarcoma virus) that, when injected into healthy chickens, was capable of inducing malignancies called sarcomas. Unexpectedly, these viruses had RNA instead of DNA as their genetic signature. Doctrine had always held that DNA preceded and in effect fathered RNA. The peculiar idea that a virus could spread cancer was largely ignored for some time thereafter; not until more than fifty years later, in 1966, did Rous receive a Nobel Prize for his work.

Because the Rous virus had RNA rather than DNA in its genome (all genes in an organism), researcher Howard Temin predicted that animal retroviruses might propagate “backward” by transcribing their RNA genome into DNA. By the late 1950s Temin’s prediction was validated. RNA tumor viruses indeed work backward, carrying viral oncogenes that, having invaded normal cells, transform them into cancer cells and then withdraw to find other cells to infect, at times adopting a section of the host cell’s genome as they go. In the 1970s both Temin and David Baltimore independently published evidence of a viral enzyme, reverse transcriptase, contained in retroviruses that performs the actual conversion of RNA into DNA. Multiple RNA tumor viruses capable of causing tumors in animals or experimental systems were later discovered, fueling a search for specific viral genes responsible for the cancer-causing properties of these viruses. As well, the search was on for the elusive and initially questioned human retroviruses. Recombinant DNA technology and molecular genetics ultimately revealed that viral oncogenes are actually normal cellular genes incorporated into the genetic material of the RNA tumor virus during infection.

Oncogenes are labeled with such three-letter abbreviations as mas or myc. Viral oncogenes carry the prefix “v-” for virus, while cellular oncogenes are preceded by “c-” for cell or chromosome. More information about the oncogene is conveyed by other alphabetic appendages. The first oncogene discovered was the src gene of the Rous sarcoma virus. Subsequently, a host of different oncogenes was discovered in avian and mammalian RNA tumor viruses. These oncogenes have a cellular counterpart that is the presumed origin of the viral gene; incorporation of the host-cell gene into the virus (called transduction) abridges viral genes, generating a defective virus. The first human retrovirus found, HTLV-1, is almost identical to ones detected in primates and supports a long-ago leap from primate to human.

Properties of Oncogenes

The first dramatic evidence linking oncogenes with cancer was provided by studies of the sis oncogene of simian sarcoma virus, which proved to be an altered form of mammalian platelet-derived growth factor (PDGF). Growth factors are proteins that bind to receptors on target cells and begin an intracellular signaling cascade, inducing growth. This seminal discovery underlies the proto-oncogene model, holding that oncogenes are derived from normal proto-oncogenes. Should proto-oncogene expression be altered somehow, normal cell division may be disrupted and cellular proliferation, a hallmark of malignancy, results.

Subsequent data have corroborated this model. Viral and cellular oncogenes have been identified with functions affecting every step in cellular control. In addition to altered growth factors, researchers have also identified altered growth factor receptors such as the epidermal growth factor receptor (erb-b), elements of the intracellular signal cascade(src and ras), nuclear transcriptional activators (myc), cell-cycle regulators called cyclin-dependent kinases (cdks), and cell-death inhibitors (bc12) in human tumors of diverse tissue origin. Each of these oncogenic gene products displays an altered form of normal cellular genes that participates in cell division.

Infective retroviruses are not the only way to activate proto-oncogenes. Mutations to genes and structural changes among chromosomes can activate proto-oncogenes during normal cell division. A point mutation, or alteration of a single nucleotide base pair, from environmental incidents such as chemical carcinogens, ultraviolet radiation, or X rays, can produce an aberrant protein not subject to normal inhibitions. Certain c-ras proto-oncogenes that normally control growth are converted during cellular division into oncogenes with the growth switch always on. In some cases, single point mutations that exchanged amino acids but encoded the same proteins as those produced normally were considered benign “silent” mutations; it is now known that so-called silent mutations nevertheless can still damage health. The elongated body parts of people with Marfan syndrome result from two silent mutations, and at least fifty other diseases are linked entirely or in part to altered protein production from the aberrant RNA editing of silent mutations. Translocation occurs when a broken-off segment of a chromosome attaches to another chromosome; should the broken segment contain a proto-oncogene, its dysregulation may spawn a profusion of proteins that overwhelms normal cellular processes. The first genetic rearrangement linked to a specific human malignancy involved the “Philadelphia” chromosome in patients with chronic myeloid leukemia (CML)
, where chromosome 22 is shortened from an exchange of genetic material (called reciprocal translocation) between it and chromosome 9. In CML the oncogene abl, originally identified in a mammalian RNA tumor virus, is translocated to chromosome 22. Additional human malignancies involving translocated oncogenes previously identified in RNA tumor viruses have been identified, notably the oncogene myc in patients with Burkitt’s lymphoma
, found primarily in parts of Africa. Amplification, or promiscuous duplication, of copies of a proto-oncogene can also overproduce proteins and forfeit control of cell growth. Gene amplifications may be associated with multiple copies of genetic segments along a chromosome, called homogeneously staining regions (HSRs), or may appear in the form of minichromosomes containing the amplified genes, termed double-minutes (DMs). Late-stage neuroblastomas often contain numerous double-minute chromosomes with amplified copies of the N-myc gene.

It is interesting to note that most tumors thus far analyzed display multiple oncogenes and tumor-suppressor genes
, which, when functioning correctly, suppress tumors. Once a tumor-suppressor gene is impaired, however, that preventive factor is gone. This is not as probable in a tumor-suppressor gene, as according to the two-hit hypothesis, both alleles(genes occupying the same locus on a chromosome) must be defective before it malfunctions. Oncogenes, on the other hand, can mutate with damage to a single allele. To borrow an analogy, if oncogenes are the accelerator in a cancer cell, tumor-suppressor genes are the brakes. In malignancies, the accelerator is floored while the brakes are malfunctioning. Studies of developing human colorectal carcinomas show steady increases in number and types of oncogenes. From these studies, a model of oncogenesis emerges as a multistage disorder characterized by successive mutations in specific oncogenes and tumor-suppressor genes, with consequent explosive growth.

Impact and Applications

Biomarkers, the overexpressed molecular abnormalities peculiar to cancer, are the fingerprints of disease. Molecular imaging through positron emission tomography (PET) and single photon emission computed tomography (SPECT) identifies biomarkers not otherwise detectable. Such techniques can detect abnormalities at low frequencies and so assist in identifying early-stage disease, as well as detect evidence post-treatment of residual disease. In diagnosis, karyotype analysis (staining during certain growth phases) has detected the chromosomal aberrations of lymphoma and certain leukemias. Now that many genes have been cloned, more effective diagnostics are available. Fluorescence in situ hybridization (FISH) locates chromosome abnormalities with molecular probes, which can identify deletions or mark the boundaries of a dislocation. Point mutations and translocations can also be found with such techniques as Southern blotting, which transfers and fixes
DNA sequences, and polymerase chain reaction (PCR), which amplifies DNA in vitro. Exploring our molecular terrain also enables accurate pretreatment testing to predict response.

Researchers are devising specific molecular interventions that target only diseased cells and dramatically decrease side effects compared to conventional chemotherapy. Researchers are designing inhibitors of specific oncogenes and of malignant oncogenic effects such as cellular proliferation and angiogenesis (blood vessel formation), both crucial to tumor establishment. Known structural abnormalities in oncogene products inform development of monoclonal antibodies directed at those proteins. Toxins may be linked to antibodies to generate immunotoxins that seek malignant cells. In CML, a drug now inhibits the enzyme tyrosine kinase that is overproduced from a proto-oncogene translocation. Although tyrosine kinase is active in humans in numerous ways, the drug interferes only with the form specific to the CML mutation. Helping the immune system recognize and combat tumor growth through immunology may one day enable cancer vaccination. Another promising approach arises from the observation that, despite the numerous genetic abnormalities of cancer cells, their continued existence can require a single oncogene; this is called “oncogene addiction.” Debilitating pivotal oncogenes provides impetus for increasingly targeted molecular therapy.

Key terms



proto-oncogenes

:

cellular genes that carry out specific steps in the process of cellular proliferation; as a consequence of mutation or deregulation, they may be converted into cancer-causing genes





retrovirus


:

a virus that converts its RNA genome into a DNA copy that integrates into the host chromosome





Bibliography

Angier, Natalie. Natural Obsessions: Striving to Unlock the Deepest Secrets of the Cancer Cell. Boston: Mariner/Houghton, 1999. Print.

Chamary, J. V., and Laurence D. Hurst. “The Price of Silent Mutations.” Scientific American 300.6 (2009): 46–53. Print.

Cooper, Geoffrey M. Oncogenes. 2d ed. Boston: Jones, 1995. Print.

Ehrlich, Melanie, ed. DNA Alterations in Cancer: Genetic and Epigenetic Changes. Natick: Eaton, 2000. Print.

Gallo, Robert C. “History of the Discoveries of the First Human Retroviruses: HTLV-1 and HTLV-2.” Oncogene 24 (2005): 5926–930. Print.

Hartwell, Leland, et al. “Cell Cycle Control and Cancer.” Science 266 (1994). Print.

Kavsan, V. M. "Structure and Function of Oncogene-Transfected Immortal Cells." Biopolymers & Cell 30.1 (2014): 25–28. Print.

La Thangue, Nicholas B., and Lasantha R. Bandara, eds. Targets for Cancer Chemotherapy: Transcription Factors and Other Nuclear Proteins. Totowa: Humana, 2002. Print.

Mulvihill, John J. Catalog of Human Cancer Genes: McKusick’s Mendelian Inheritance in Man for Clinical and Research Oncologists. Baltimore: Johns Hopkins UP, 1999. Print.

Oikonomou, Eftychia, and Alexander Pintzas. "The Trail of Oncogenes to Apoptosis." Biofactors 39.4 (2013): 343–54. Print.

Varmus, Harold. “The Molecular Genetics of Cellular Oncogenes.” Annual Review of Genetics 18 (1994). Print.

Weinstein, Bernard, and Andrew Joe. “Oncogene Addiction.” Cancer Research 68 (2008): 3077. Print.

Willis, Rudolph E. "Human Gene Control by Vital Oncogenes: Revisiting a Theoretical Model and Its Implications for Targeted Cancer Therapy." Intl. Journ. of Molecular Sciences 13.1 (2012): 316–35. Print.