March 1, 1997
When a Tulane biochemist set out to study an abnormal chromosomal rearrangement linked to a relatively rare cancer, she never expected to find nearly half of the healthy individuals in her study to have this abnormality. Melanie Ehrlich, professor of biochemistry and member of the Human Genetics Program and the Tulane Cancer Center, and Xian-Yang Zhang, assistant research professor of biochemistry, developed an ultrasensitive assay to examine the presence of a specific chromosomal rearrangement found in 90 percent of follicular lymphomas, a cancer of white blood cells that develops in lymph nodes.
Although the incidence of this cancer is relatively rare--35,000-50,000 new cases in the United States each year compared to more than 300,000 new cases of prostate cancer--half of the healthy individuals she studied had this rearrangement, the BCL-2/JH translocation, in their blood.
"It has been proven in the last decade that there are many translocations which help in the development of cancer," Ehrlich says. "This translocation is not sufficient to cause any kind of cancer, but when other combinations of certain changes occur in the DNA after this chromosomal rearrangement, then you can get a full-blown cancer."
A translocation is the swap of parts between two different chromosomes. In the BCL-2/JH translocation, this exchange alters the BCL-2 gene, which codes for a protein that normally blocks cell suicide, a natural process known as apoptosis. With this alteration, the gene codes for the protein at inappropriate times. This prevents the body's natural tendency to eliminate most lymphocytes, a kind of white blood cell, to allow their replenishment with new cells.
"One of the reasons why this chromosome translocation contributes to carcinogenesis is that it greatly prolongs the lifetime of lymphocytes," Ehrlich says. "The body wants to keep turning over most of its stock of lymphocytes through this programmed cell death, and this translocation prevents it."
Another biological consequence of this translocation is that it results in a long-lived lymphocyte with lasting damage to its DNA. "We're always having damage to our DNA. Much of that is spontaneous damage that you can't avoid," Ehrlich says. "Sometimes a cell with unrepaired damage to its DNA will undergo apoptosis. A lymphocyte that has the BCL-2/JH translocation doesn't use this pathway. So it's more likely to survive with a kind of DNA damage that helps give rise to cancer."
Using a technique called polymerase chain reaction (PCR), which makes millions of copies of a tiny piece of DNA, Ehrlich developed an assay to detect even one DNA molecule containing this chromosomal rearrangement. In her study of 132 individuals, most of whom were healthy, she found that 43 percent of the participants had the translocation in their blood. She also found that the incidence of the translocation increased with age. Since the incidence of follicular lymphoma is rare--less than 1 percent of the U.S. population develops this cancer--and usually found in individuals older than 50, Ehrlich says she was particularly surprised at how many of the healthy, younger participants showed evidence of the translocation.
"Three people in our study were under age 40 and had fairly high levels of this translocation," she says. "These people were off the curve and may be at increased risk of developing follicular lymphoma." They may also be more prone to develop other cancers, she adds. "Because there are other types of cancer that involve translocations that contribute to cancer formation, maybe these people are more prone to rearrange their chromosomes abnormally and accumulate cells with these chromosomal rearrangements," she says.
Although Ehrlich says her research attempts to reveal more about the nature of the disease rather than give rise to practical applications, she says there are now some clinical uses of the assay she developed. One such use concerns tracking "minimal residual disease" in cancer patients. After chemotherapy or other types of cancer treatments, a cancer patient may show no evidence of a tumor but may still have a small number of cancerous cells in the body that clinicians must monitor.
"The PCR technique, in which you can detect a single cell with this translocation, is excellent for tracking minimal residual disease," Ehrlich says. "It's possible that by following the level of translocations in the blood, you could make predictions about the prognosis, and this could possibly lead to more aggressive therapeutic treatment."
She cautions, however, that clinicians should not confuse background levels of the translocation in the lymphocytes of healthy people with the abnormally high levels of this translocation in cancers cells of follicular lymphoma patients. Ehrlich is also using a different PCR assay on a project with Alan Miller, associate professor of medicine and director of the Tulane Cancer Center's bone marrow transplant program. This assay detects a translocation specific to chronic myeloid leukemia, and the researchers are using it to monitor the effectiveness of chemotherapy treatment.
Ehrlich's research on follicular lymphomas may eventually shed light on an individual's susceptibility to a particular cancer and offer clues for developing preventive techniques. "In terms of cancer predisposition, the important question is the frequency of cells that have the translocation," she says. "The more cells you have that contain this early pre-cancerous chromosomal mistake, the more likely you are to have subsequent damage to your DNA in at least one cell that can go on to develop into a cancer."
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