PHILADELPHIA -- Using customized DNA arrays to assess the activity of 4,500 different genes in a leukemic form of lymphoma known as Sezary syndrome, researchers at The Wistar Institute have identified 385 genes that may play a role in the disease. The genes were either overactive or underactive in blood samples taken from the 45 cancer patients, as compared to 20 normal controls. Looking at the activity of a panel of only eight of the 385 genes permitted the scientists to accurately diagnose the condition in patients with tumor burdens as low as five percent of their circulating blood cells. A panel of ten genes was sufficient to identify a class of patients who will succumb to their disease within six months regardless of their tumor burden. And one gene was seen to occur in about 70 percent of the cancer patients but never in the controls, making it a highly specific marker for the malignant cells.
The findings, reported in the June 2 issue of the Journal of Experimental Medicine, confirm the power of DNA arrays, still an emerging technology, to identify genetic markers that will more accurately diagnose and predict the course of different types of cancer, vital information that may help guide clinicians weighing treatment options for their patients. In addition, each of the genes identified may be a potential target for drug development, greatly expanding the field of possibility for future treatments.
"Our goal in this study was to develop the ability to diagnose cancer at the molecular level using the new technology of DNA arrays," says Louise C. Showe, Ph.D., a professor at The Wistar Institute and senior author on the report. "These results demonstrate that we can do that. It's also becoming clear to us and to others working in this area that being able to look at many genes simultaneously to catch all the shades of the disease is going to be important for improving cancer diagnosis and treatment. We need to be looking at a bigger picture, and with this technology we are going to be able to do that."
Sezary syndrome is a leukemic variant of a cancer called cutaneous T-cell lymphoma, or CTCL. The skin-associated variant of CTCL, mycosis fungoides, is the more common form of the disease. It is relatively easy to treat if diagnosed early in its course, but because its appearance is similar to that of many benign skin diseases, it is often misdiagnosed. Once CTCL progresses from the skin to the peripheral blood, it becomes a more serious health threat. Patients with the skin-associated form of the disease can expect to live 10 to 15 years or longer, according to Showe, while the mean survival for Sezary syndrome patients is about three years. Between 1,500 and 2,000 new cases of CTCL are diagnosed each year in the United States.
"Cutaneous T-cell lymphoma is very treatable in its earlier stages, but very resistant to treatment later on," Showe says. "One of our hopes is to be able to take what we've learned about Sezary syndrome, the leukemic variant of the disease, and use it to develop an earlier-stage, more accurate diagnosis of the skin-associated form of this disease, which can be treated so much more effectively."
DNA arrays, also called microarrays, are patterns of DNA that are spotted onto a glass slide or nylon filter. The DNA on the arrays can represent thousands, even tens of thousands of genes. Corresponding genetic material called RNA taken from study cells – in this case, the cancer cells – can be screened against a DNA array to judge which genes represented by the array are active, or expressed, in those particular cells and to what degree. Expressed genes define the structure and function of a cell. By comparing cancerous cells to normal ones, the precise genetic profile for particular cancers at specific stages of their transformation can be determined. DNA arrays are allowing researchers to put to work information from the Human Genome Project about the estimated 35,000 human genes.
In 1999, Showe became one of the first group of 10 investigators nationwide to receive five-year backing from the National Cancer Institute to help develop DNA array technology to be able to provide molecular classifications of tumors. The current study represents a major step toward fulfilling that aim.
Laszlo Kari was the lead author on the Journal of Experimental Medicine study. The other Wistar-based coauthors were Andrey Loboda, Michael Nebozhyn, Calen Nichols, Dezso Virok, Celia Chang, Wen-Hwai Horng, James Johnston, and Michael K. Showe. Coauthors at other institutions included Alain H. Rook and Maria Wysocka at the University of Pennsylvania and Eric C. Vonderheid at The Johns Hopkins University.
###Funding for the research was provided by the National Cancer Institute, with additional support from the Commonwealth of Pennsylvania's share of the Master Settlement Agreement with the tobacco industry.
The Wistar Institute is an independent nonprofit biomedical research institution dedicated to discovering the causes and cures for major diseases, including cancer, cardiovascular disease, autoimmune disorders, and infectious diseases. Founded in 1892 as the first institution of its kind in the nation, The Wistar Institute today is a National Cancer Institute-designated Cancer Center – one of only eight focused on basic research. Discoveries at Wistar have led to the development of vaccines for such diseases as rabies and rubella, the identification of genes associated with breast, lung, and prostate cancer, and the development of monoclonal antibodies and other significant research technologies and tools.
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