Oncogene research

Research into the structure and function of oncogenes has been a major endeavor for many years. The first chromosome rearrangement (Ph') involving a proto-oncogene to be directly associated with cancer induction was identified in 1960. Since then, over 50 proto-oncogenes have been mapped in the human genome, and many cancer-related mutations have been detected. Once the role of oncogenes and protooncogenes in cancer was understood, the task of elucidating the exact mutations, specific breakpoints for translocations, and how protein products are altered in the disease process was undertaken.

Karyotype analysis has been used for many years to identify chromosome abnormalities that are specifically associated with particular types of leukemia and lymphoma aiding in diagnosis and the understanding of prognosis. Now that many of the genes involved in the chromosome rearrangements have been cloned, newer, more effective detection techniques, have been discovered. FISH , fluorescence in situ hybridization , uses molecular probes to detect chromosome rearrangements. Probes are developed to detect deletions or to flank the breakpoints of a translocation. or example, using a dual color system for chronic myelogenous leukemia (CML), a green probe hybridizes just distal to the c-abl locus on chromosome 9 and a red probe hybridizes just proximal to the locus on chromosome 22. In the absence of a rearrangement, independent colored signals (two green and two red) are observed. When the rearrangement occurs, two of the fluorescent probes are moved adjacent to one another on one chromosome and their signals merge producing a new color (yellow) that can be easily detected (net result: one green, one red, and one yellow signal).

Other molecular techniques such as Southern blotting and PCR are also used for cancer detection and can identify point mutations as well as translocations. These systems are set up such that one series of DNA fragments indicate no mutation, and a different size fragment or series of fragments will be seen if a mutation is present. All of the newer techniques are more sensitive than cytogenetic analysis and can pick up abnormal cell lines occurring at very low frequencies. Clinically, it may be useful to detect the disease in an early stage when there are fewer cancer cells present so that treatment may begin before severe symptoms are experienced. In addition, these techniques aid in detection of minimal residual disease (the presence of low levels of disease after treatment) and may give warning that the disease is returning.

A major breakthrough has come in treatment of diseases caused by oncogenes. The current standard of care for cancer patients has been chemotherapy and radiation therapy. This is successful in limiting or eradicating the disease, but, because the whole body is affected by these treatments, there are usually multiple side effects such as hair loss, nausea, fatigue, etc. New drugs are designed to counteract the particular mutation associated with the patient's disease and thus are target specific. This is only possible if the mutation causing the disease is known and a treatment can be developed that inactivates the negative affect of that mutation. Because only one cellular component is affected, negative physical side effects may be reduced.

The most successful of these drugs to date is STI-571, or Gleevec, and was developed for use in patients with chronic myelogenous leukemia (CML). In CML, the proto-oncogene translocation results in overproduction of the enzyme tyrosine kinase. Gleevec is an inhibitor of tyrosine kinase and works at the cellular level to block excess enzyme activity. Although there are several different types of tyrosine kinase in humans, STI-571 is specific to the form produced by the CML mutation and does not affect other members of this enzyme family. The drug is therefore so specific, other cells and tissues in the body are not impacted, and there are few negative side effects resulting in a therapy that is much more tolerable to the patient. Early clinical trials showed such a high degree of success that the trails were terminated early and the drug was FDA approved and released for general use. There is now new evidence to suggest that this drug also may be effective for other diseases, including some types of solid tumors. This is clearly the way drug treatments will be designed in the future. By targeting only the defect and correcting that, a disease can be managed without impairing other aspects of a patient's health or quality of life.

Other types of ongoing research include further elucidation of normal proto-oncogene function and how the oncogenic mutations change cellular regulation. In particular, issues involving oncogene impact on apoptosis, programmed cell death, have become an important avenue of investigation. It has been shown that normal cells have a fixed life span but that cancer cells lose this characteristic and exhibit uncontrolled cell growth with aspects of immortality. A better understanding of the role oncogenes play in this process may give insight into additional ways to treat cancer.

See also Fluorescence in situ hybridization (FISH); Immunogenetics; Immunologic therapies; Mutations and mutagenesis