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Cytogenetics: Major Insights from Microscopic Detailsby Beth Notzon Down a long, quiet hallway, far removed from the daily hubbub of a busy cancer center, is a room full of cytogenetic technologists peering intently through microscopes and studying highly magnified images of chromosomes on computer monitors. They are looking at the body’s earliest signposts of cancer, searching for microscopic missteps in the DNA that will offer more insight about the type and course of a particular person’s cancer. With the realization that cancers stem from some kind of genetic defect, many are now being identified by these characteristic defects, explained Stanley R. Hamilton, M.D., a professor and the head of the Division of Pathology and Laboratory Medicine at The University of Texas M. D. Anderson Cancer Center. “Cytogenetics is the science of studying chromosomes themselves as a means of providing a more specific diagnosis and prognosis,” he said. “A number of cancers have characteristic cytogenetic abnormalities that tell us exactly what kind of cancer we’re dealing with.” One example of a genetic abnormality that is seen in virtually every patient with chronic myeloid leukemia is called the Philadelphia chromosome. It results from a translocation between chromosomes 9 and 22. In fact, it is virtually the hallmark of this cancer. Such information can be the key to a successful outcome because it not only identifies exactly the type of cancer a patient has but also tells clinicians more precisely what the best treatment for a patient should be, how well patients are responding to treatment, and when the disease is recurring—often before it is evident by any other means. Kimberly Hayes, manager of the cytogenetics laboratory, explained, “When a morphologist looks at cells, the appearance can vary and the findings can be difficult to interpret. In fact, the morphology—the phenotype—can look normal, but the cytogenetics, which looks at the genotype, can be very abnormal, which can help identify relapse in the early stages.” And this, of course, means the treatment of recurrent disease can be instituted earlier, with a better chance of success. Currently, it is mainly patients with hematologic malignancies—the leukemias and lymphomas—plus patients with sarcoma and certain childhood cancers who benefit the most from cytogenetics. The reasons are simple. One is that the material is easy to get and often plentiful in hematologic diseases. The second is that it is not difficult to grow these cancer cells in cultures. The third is that the genetic abnormalities seen in these cancers are not particularly complex.
The story is different for solid tumors. As Dr. Hamilton explained, “The four big cancers—lung, colorectal, breast, and prostate—are more difficult to work with. First, it’s hard to get them to grow in culture. The solid tumors also consist of a mixture of stromal and epithelial cells, so it’s difficult to get a pure cancer cell population, and finally, the genetic abnormalities are incredibly complex in most tumors.” Other means are being used, and sought, to get to the root genetic causes of these cancers. To appreciate why cytogenetics is so valuable, it helps to understand the process cytogeneticists follow. First, the material is obtained; for most patients with cancer, that is usually peripheral blood and bone marrow. After this, the technologists count the cells in a specified volume to determine the sample size needed for cell culture. Next is the critical event that all of cytogenetics hinges on—the cells are cultured in a growth medium for 24 hours or more and then treated with colcemid, which stops cell division and allows the metaphases to be studied more closely. Then, Giemsa staining of the cells highlights the chromosome bands in a process called GTG (Giemsa Trypsin G) banding. Each normal chromosome shows a characteristic banding pattern, and any departure from this banding pattern indicates a genetic abnormality—a deletion, inversion, or translocation. There can also be a loss or gain of entire chromosomes. Finally, the chromosomes are assembled into a karyotype, which is the grouping of the pairs of chromosomes. Another technique cytogeneticists use to determine genetic abnormalities is fluorescent in situ hybridization, or FISH. DNA in chromosomes is labeled with a fluorescent probe, and then the cells are viewed under a fluorescent microscope. Though different from cytogenetic analysis, the information FISH yields enhances the karyotype information. In particular, while the karyotype gives overall information about the number and physical appearance of chromosomes, FISH can show whether a gene or mutation specific to a particular cancer is present.
With the increasing demand for cytogenetic information, M. D. Anderson currently has two shifts of cytogenetic technologists, and there’s talk of adding a third. And because it has been a challenge to find people with the right set of skills and training to be cancer cytogenetic technologists, M. D. Anderson has started its own school to train them. Although cytogenetics and molecular diagnostics have become an increasingly important part of the field of pathology and laboratory medicine, the traditional tools of the specialty will remain an important part of diagnosis and treatment. As Dr. Hamilton explained, “The traditional cytology, pathology, and histopathology will remain a mainstay of diagnosis for decades. The morphology of what we see under the microscope is the end result of all of the genetic and epigenetic abnormalities that occur in cancer cells. These are very cost-effective techniques, and they give us a huge amount of information.” Lynne V. Abruzzo, M.D., Ph.D., an associate professor in the Department of Hematopathology and the chief of the cytogenetics laboratory at M. D. Anderson, pointed out that cytogenetics is such an important tool in the diagnosis and follow-up of patients at the cancer center that the clinicians also “speak the language” of cytogenetics. “It’s part of their thinking, and they know how to apply it,” said Dr. Abruzzo. Another benefit of cytogenetics at M. D. Anderson is the effective communication between the different team members—the clinician, the cytogeneticist, the pathologist, the radiologist—who are involved in treating the patient. The information is shared. At weekly leukemia conferences, as Dr. Abruzzo explained, members of the team come together to “look at the flow cytometry results, the cytogenetics results, radiology, pathology, and other findings” and create a complete picture of a patient’s cancer that gives them a comprehensive roadmap for treatment.
For more information on this topic or for questions about M. D. Anderson’s treatments, programs, or services, call askMDAnderson at (877) MDA-6789. Other articles in OncoLog, October 2005 issue:
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