National Institute of Arthritis and Musculoskeletal and Skin Diseases

June 14, 1996

Contact: Elia Ben-Ari 
Office of Scientific and 
Health Communications 
(301) 496-8188

Scientists have discovered that mutations in the human version of a gene that controls fruit fly growth and development are the likely cause of both the basal cell nevus syndrome (BCNS), a rare inherited disorder, and sporadic basal cell carcinoma of the skin, the most common human cancer. People with BCNS have developmental abnormalities as well as multiple types of benign and cancerous tumors, especially basal cell carcinomas. The work identifies a new gene that is important in human development as well as tumor suppression, and may lead to novel, non- surgical treatments for basal cell carcinoma.

The research was funded in part by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), part of the National Institutes of Health (NIH). The results are reported in the June 14, 1996 issue of Science. A related study, supported in part by the NIH's National Cancer Institute (NCI), appears in the June 14, 1996 issue of Cell.

"This is a wonderful convergence of research on human disease and basic research on Drosophila [fruit fly] development," says Dr. Stephen I. Katz, NIAMS Director and chief of the Dermatology Branch at the NCI. "It identifies a gene that is likely to play a key role in basal cell carcinomas, which account for the vast majority of all skin cancers in the United States."

The scientists found that the human version of the patched gene (PTC) is mutated in people with BCNS and in tumor tissue from a person with sporadic (not hereditary) basal cell carcinoma who does not have BCNS. People with BCNS suffer from a variety of developmental abnormalities, most often of the ribs and skull bones. The patched gene was first identified as the cause, when mutated, of developmental abnormalities in fruit flies. These abnormalities were first described as part of research that led to the 1995 Nobel Prize in medicine or physiology.

About 750,000 new cases of sporadic basal cell carcinoma occur each year in the United States. Ultraviolet (UV) radiation from the sun is the main trigger of these cancers, and people with fair skin are especially at risk. Most sporadic basal cell carcinomas arise singly or in small numbers on sun-exposed skin of people over age 50, although many younger people are also affected. By comparison, "One of the prime features of BCNS is development of multiple basal cell carcinomas at an early age often in the teen years," says Dr. Ervin H. Epstein, Jr., a dermatology researcher at the University of California, San Francisco (UCSF). Epstein and Dr. Matthew P. Scott, a developmental biologist in the Howard Hughes Medical Institute at Stanford University in Stanford, Calif., led the collaborative study by researchers at UCSF and Stanford.

"Although BCNS is very rare, it has manifestations that are extraordinarily common, namely basal cell carcinomas," says Epstein. "Studying this rare hereditary form of basal cell carcinoma allowed us to learn something about the much more common sporadic form that we would never have learned otherwise." Epstein's research group has been working for several years to identify the gene responsible for BCNS because he believed the gene for this hereditary disorder might also be involved in sporadic basal cell carcinomas.

At about the same time, Scott's lab was studying the role of the patched gene in development first in fruit flies, and then in higher animals. Scott, Dr. Ronald L. Johnson, and their colleagues isolated the human version of the patched gene, and they wondered whether the gene was involved in human disease. They determined that the PTC gene was located on human chromosome 9, in a region that had previously been implicated in BCNS. Scott then contacted Epstein and asked whether it was possible that the PTC gene underlies this disease. "We started to look at the PTC gene in DNA that we had accumulated from patients and families with BCNS," says Epstein. "We picked up abnormalities-heritable mutations-in this gene in DNA from white blood cells of patients with BCNS."

In the Science article, the researchers describe two different mutations of the PTC gene that they found in two people with BCNS. They found the same mutations in relatives of these patients who also had BCNS, but not in unaffected family members.

The researchers also found a mutation in the PTC gene in tumor DNA from one of 12 sporadic basal cell carcinomas, but not in blood cell DNA from that patient. This indicates that the mutation in this case is not hereditary, but rather arose spontaneously, most likely as the result of damage from UV radiation from the sun. In fact, says Epstein, "The mutation in this patient had the characteristic signature of a UV light-induced mutation."

Although basal cell carcinomas grow slowly and very rarely spread to other parts of the body, they can invade and destroy neighboring tissues. Therefore, it is important that these skin cancers are found and treated early. Treatment most commonly involves some type of surgery, although radiation therapy or chemotherapy are sometimes used alone or with surgery. Of course, prevention of these cancers is still the best approach. "The best prevention," says Epstein, "is a hat, a roof, and sunscreen."

The researchers believe this finding eventually could lead to an innovative treatment for basal cell carcinomas, such as a protein or other small molecule that could be applied to the skin in a cream, and that would block the effects resulting from mutation of the PTC gene. "This would be cheaper than surgery, would avoid surgical pain and discomfort, and might even reduce subsequent scarring," Epstein says. The researchers say developing such therapies is possible because, unlike other cancer genes that have been found, there already is a lot of information about what the PTC gene does from studies in the fruit fly. In fact, says Scott, "We know not only about this single gene, but a whole network of genes to which the patched gene belongs. There is real potential both to understand the molecular basis of the cancer and someday possibly to prevent or treat it." Further down the road, Epstein says, some type of gene therapy might also be possible.

In fruit flies, the patched gene codes for a protein that controls embryonic development by sending a signal that turns off, in specific cells, production of factors involved in coordinating cell behavior during development. If the patched gene is mutated in the embryo, developmental abnormalities result. The results of the current study indicate that mutations of this gene in the developing human embryo cause the developmental abnormalities of BCNS.

The results also indicate that in humans, after birth, the PTC gene acts to prevent excessive cell growth. Mutation of the PTC gene apparently results in excessively rapid, uncontrolled growth of some cells, which is the hallmark of cancer. The findings suggest that the PTC gene can be added to the list of so-called tumor suppressor genes.

Epstein still marvels at the circumstances that enabled them to identify this gene as the probable cause of BCNS and sporadic basal cell carcinoma. "Here's a guy [Matthew Scott] who's 30 miles away from me who is working on fruit flies, and it turns out that it's the same gene I've been looking for."

The National Institute of Arthritis and Musculoskeletal and Skin Diseases, a component of the National Institutes of Health, leads the Federal biomedical research effort on the skin and skin diseases by conducting and supporting research projects, research training, clinical trials, and epidemiologic studies, and through dissemination of health information and research results.

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Reference : Ronald L. Johnson, Alana L. Rothman, Jingwu Xie, Lisa V. Goodrich, John W. Bare, Jeannettte M. Bonifas, Anthony G. Quinn, Richard M. Myers, David R. Cox, Ervin H. Epstein Jr., Matthew P. Scott. Human homolog of patched, a candidate gene for the basal cell nevus syndrome. Science 272: 1668-1671, June 14, 1996.

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