Using information from the Human Genome Project

Phoenix, AZ. - Nov. 18, 2002 - Using information from the Human Genome Project, genome scientists have reported finding the gene responsible for a rare form of inherited tumors. The paper appeared in the November 18 issue of the prestigious journal Nature Genetics. The work is an example of the type of practical biomedical research that will be carried out at Phoenix's new Translational Genomics Research Institute (TGen), according to Dr. Jeffrey M. Trent, TGen's President and Scientific Director.

"At TGen, our mission will be to show that findings from gene-based research can be translated into therapies and diagnostic tests that will have a real impact on the way doctors identify and treat diseases," says Trent, one of the authors of the paper describing the new research on the tumor gene.

"Discovering this gene we hope could lead to better diagnosis and therapies," says Dr. John D. Carpten, first author of the paper reporting the new finding.

Carpten is a cancer genomics researcher at the National Human Genome Research Institute (NHGRI), one of the famed National Institutes of Health (NIH) in Bethesda, Maryland. NHGRI's intramural (in-house) research program was founded and directed by Trent for nearly a decade, until he was recruited to Phoenix last June to lead TGen. NHGRI also managed the massive publicly funded Human Genome Project, which collected the data on human DNA that made it possible to find the new tumor gene.

The finding being reported today identified a gene that when damaged, is responsible for the hyperparathyroidism-jaw tumor syndrome (HPT-JT). The damaged gene causes tumors of the parathyroid glands, four pea-sized glands in the neck that control the body's supply of calcium, an essential mineral. "We are delighted that through this collaboration, the more than twelve-year search for this gene has finally borne fruit," said Maurine R. Hobbs, Ph.D., assistant professor of internal medicine and human genetics at the University of Utah School of Medicine, and a senior author of the study. "We couldn't have done it without the selfless contributions of the patients and patients' families affected by HPT-JT, and the many doctors who treat them."

Parathyroid tumors, which are usually benign and fairly common, occur in about one out of every thousand people. While HPT-JT is far less common, many HPT-JT patients develop malignant parathyroid cancers and also tumors of the jaw and cysts and tumors in the kidneys, an element of the disease that may shed light on how other cancers arise. "The clinical significance of this finding is that it will help us to identify patients who are at risk of developing parathyroid cancers, thereby enabling us to plan an earlier treatment for them. Furthermore, the identification of such a key gene in cancer development opens the way to finding compounds that may prevent the development of such tumors" says Prof. Rajesh Thakker of the United Kingdom's University of Oxford, one of the paper's authors.

Parathyroid tumors secrete excess parathyroid hormone, a signal to the body that it needs to raise the blood calcium level. In response to this signal, the bones give up calcium that is released into the blood. But the symptoms of parathyroid tumors are nondescript, such as tiredness and depression. People usually learn they have a parathyroid tumor when they break a bone from a light fall or a routine blood test shows their serum calcium levels are too high.

In HPT-JT families, children have a 50-percent chance of inheriting the syndrome from an affected parent. Of those who inherit the syndrome, 85- to 90-percent develops benign tumors, and are at increased risk of developing parathyroid cancer. People with mutations within HPT-JT families can be screened for developing parathyroid tumors by getting their calcium and parathyroid hormone levels checked regularly. "We hope that early detection and surgical removal of benign tumors will reduce the incidence of parathyroid cancer in these families," said Hobbs.

"The syndrome is a cancer syndrome, so tumors develop in various organs, including the parathyroid, bones, and kidneys. It's possible that a mutation in this gene could cause other forms of tumors," says Carpten. "We'd like to find out what is the overall contribution of a mutation in this gene to other parathyroid tumors and, in fact, to cancer in general."

"Based upon the identification of genes in other cancer syndromes, this finding in a rare genetic disorder is likely to provide information about other more common disorders," points out Trent.

The research is also typical of today's genomics studies: a very large project involving several different kinds of scientists in several countries. Scientists in Canada, Sweden, Australia, the United Kingdom, and the Netherlands, in addition to US researchers in a number of states, pooled data on families that suffer from HPT-JT. They unearthed the damaged gene by comparing DNA from the families with reference DNA from human genome databases.

"It takes these kinds of international, multi-disciplinary, multi-institutional initiatives to successfully accomplish identification of these disease genes. A partnership between academic centers all over the world is absolutely required," Trent says. "At TGen, we intend to be multidisciplinary in our reach, so we want to find investigators who will take the lead in bringing together physician-scientists.

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