Public Release: 

UT Southwestern researchers identify important bone cancer gene

UT Southwestern Medical Center

DALLAS -- September 2, 1996 -- The discovery of a gene associated with a rare bone disorder, hereditary multiple exostoses, presents researchers with a host of questions about the gene and its possible role as a tumor suppressor.

In the September issue of Nature Genetics, researchers from UT Southwestern Medical Center at Dallas, led by Drs. Glen Evans and Michael Lovett, report the identification of the second gene associated with the disease C EXT2, residing on chromosome 11. Evans is professor of internal medicine, director of UT Southwestern's Eugene McDermott Center for Human Growth and Development and holder of the Eugene McDermott Distinguished Chair for the Study of Human Growth and Development. Lovett is an associate professor in the center.

The primary feature of hereditary multiple exostoses is the proliferation of benign tumors that block bone growth. Consequently, people with severe cases are noticeably short. These tumors, or exostoses, develop on the ends of the bone as the bone grows out. Some of the tumors, usually located on cartilage, become cancerous. The disease occurs in about one in 50,000 people. Because the severity of the cases varies widely, many people may have the disease and not know it.

The first hereditary multiple exostoses gene, EXT1, was identified on chromosome 8 last year by researchers at the UT Health Science Center at Houston. The Houston researchers collaborated with Evans and Lovett in the EXT2 discovery. Researchers at several institutions, including UT Southwestern, are examining candidate genes on chromosome 19 and may eventually identify a third multiple exostoses gene.

"Our research proves EXT2 is responsible for the disease," Evans said. The two genes do not complement each other. In other words, it is not necessary for persons to carry mutated forms of both genes to be at risk for developing the disease.

"Because this gene is so similar to EXT1 and other genes, we are able to define a whole family of genes," said Dominique Stickens, a research fellow on the project.

One of the next challenges for the researchers is to understand the function of the genes and the proteins they express. For example, Evans said if the gene is involved in bone formation, then it may be present only in organisms capable of making bone. The gene isn't found in yeast. Current work in mouse models will help them understand how the multiple exostoses genes work.

Lovett said an analysis of the protein may tell researchers how the gene is involved in the formation of bone tumors.

"We also know EXT1 and EXT2 are present in many other areas of the body, but we don't know why they don't cause tumors there," said Gregory Clines, a graduate student also working on the research. "Why do they cause bone tumors but not others?"

Evans said this project gives additional support to the notion that a variety of tumor suppressor genes important for lung, breast, bone and endocrine

Evans also said this project is one of the first examples of a gene being cloned directly as a result of the Human Genome Project, an international effort to locate and analyze the approximately 100,000 human genes. "The Genome Project is in its final stage: sequencing all human DNA. This gene was discovered because of that effort."

Researchers from the two schools studied genetic material from families with a history of multiple exostoses. Then they compared their information with a public database C a product of the genome project C which allowed them to identify a number of possible EXT2 gene clones. Further study of the candidate genes pointed them to a single gene whose structure matched EXT1. This approach, developed by Lovett's group, allowed the researchers to short-circuit the traditional approach of positional gene cloning. Evans said it also validated the usefulness of the gene database in helping researchers identify and analyze human disease genes more quickly.

"This is a lesson in what is to come in genetics research," Lovett added.

Research assistant professor Dr. David Burbee, research scientist Purita Ramos and research associate Sylvia Thomas, from UT Southwestern, also have been involved in the work.

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