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Press Releases for 1996
|NATIONAL INSTITUTES OF HEALTH|
| FOR IMMEDIATE RELEASE
Thursday, June 13, 1996
Contact: Bob Kuska,
NCI Press Office
Researchers Clone New Skin Cancer Gene
An international team of researchers reported today in the journal Cell that after a four-year search it has cloned the gene for nevoid basal cell carcinoma syndrome (NBCCS), a rare disorder that causes numerous birth defects and cancers, particularly an inherited form of the skin cancer basal cell carcinoma.
Although NBCCS is rare, its gene also appears to play a role in sporadic (noninherited) basal cell carcinoma, the most common cancer in the United States. Indeed, the researchers also report finding that the cloned gene, called patched (PTC), was mutated in two sporadic basal cell carcinoma tumors.
This finding, coupled with previous studies implicating the gene in sporadic basal cell carcinoma, opens a promising, new avenue to explore the precise causes of basal cell carcinoma. "PTC is an extremely interesting cancer gene because it appears to be involved in regulating the cell cycle, and it also plays a fundamental role in embryonic development, as we can tell by the multitude of birth defects in people with the syndrome," said Richard Klausner, M.D., director of the National Cancer Institute (NCI). "It's going to tell us a great deal about cancer and human development."
According to Michael Dean, Ph.D., an NCI scientist and one of the authors of the Cell paper, today's finding also could lay the groundwork for more novel approaches to treating basal cell carcinoma. "Now that we know PTC is involved in basal cell carcinoma, it's reasonable to conceive of new approaches, using molecular biology, to develop ointments that, when applied to the skin, control the growth of the cancer," said Dean, whose laboratory collaborated with scientists in the U.S., Australia, and Sweden to isolate the gene.
A related study on the role of the PTC gene in basal cell carcinoma, supported in part by the National Institute of Arthritis and Musculoskelatal and Skin Diseases, part of the National Institutes of Health, appears in the June 14, 1996 issue of the journal Science.
NBCCS affects between 1 in 57,000 to 1 in 164,000 people, with about 60 percent of the cases arising in individuals with no family history of the syndrome. The syndrome involves a wide array of cancers and birth defects, including basal cell carcinoma, jaw cysts, ovarian fibromas, and numerous skeletal and craniofacial abnormalities.
However, the syndrome is best known for basal cell carcinoma. About 70 percent of those with NBCCS develop dense clusters of basal cell carcinomas throughout their body. These cancerous moles appear between puberty and age 35 and often number into the hundreds or thousands over a person's lifetime.
Unlike sporadic basal cell carcinoma, which is associated with exposure to sunlight, fair complexions, and an inability to tan, carcinomas linked to NBCCS arise independently of these risk factors and are associated with genetic alterations.
In today's paper, the researchers also propose a genetic description of the syndrome and the expression of its many symptoms. They state that children born with one altered copy of PTC will have many of the birth defects typical of the syndrome without the associated cancers. But, in those with two inactivated copies of the gene, basal cell carcinoma and the other NBCCS-linked cancers are likely to arise.
Because both copies of PTC must be knocked out to trigger basal cell carcinoma, the researchers state that, in support of previous data, PTC fits the classic description of a tumor suppressor gene. Tumor suppressor genes have a negative influence on cell division in healthy cells and, when deleted as in NBCCS, can lead to cancer.
With the cloning of PTC, researchers can now begin to better explore the molecular peculiarities of basal cell carcinoma. The cancer originates in skin cells called keratinocytes, that replicate without control forming clusters of dark moles on the skin that can be very disfiguring.
Although basal cell carcinoma is an extremely slow-growing tumor, recent reports indicate that cancerous cells slough off from the skin tumor and circulate through the bloodstream. But these migrating cells rarely are able to attach themselves to other organs and spread throughout the body, making basal cell carcinoma one of the least deadly of all human cancers.
By studying PTC and other genes known to be mutated in basal cell carcinoma, the scientists said they might be able to gain insights into the biology of other cancers. For instance, by identifying the factors that inhibit basal cell carcinoma from colonizing other organs, researchers might be able to tease out valuable clues to prevent the metastasis of other, more.
serious epithelial cancers, such as breast and colon cancer. Today's announcement also marks the culmination of a four-year search to find the NBCCS gene. In 1992, the gene hunt began in earnest when Alan Bale, M.D., a scientist at Yale.
University and one of the authors of today's paper, reported finding signs on chromosome 9 of a mutated cancer gene in both sporadic and NBCCS-linked basal cell carcinoma. Within the year, other groups confirmed the linkage testing DNA samples from families with a history of NBCCS.
Although the location of the gene had been greatly narrowed down, the search was far from over. The researchers still had to sort through about 10 million bases of DNA containing several genes known to be linked to other forms of cancer.
Using a variety of gene mapping techniques, Bale, Dean, and colleagues in Australia and Sweden were able to narrow down their search to a few candidate genes in a narrower region of the chromosome. The researchers soon recognized that one of their candidate genes was the human counterpart to a well-characterized gene in the fruit fly, known as patched. The fruit fly gene was particularly interesting because it was known to help relay chemical signals from the cell membrane into the cell and was involved in embryonic development. Moreover, the patched gene was clearly important to the well-being of the cell, otherwise it would have been lost between species during evolution.
The researchers searched for mutations in PTC in six unrelated patients with NBCCS. They found that the gene was mutated in all six DNA samples, confirming that they had finally found the gene responsible for NBCCS. Next, the scientists tested the DNA of two sporadic basal cell carcinomas. Both had mutations in the PTC gene.
Knowing the function of the fruit fly gene, Dean said he and his colleagues now have a head start on nailing down the function of the human PTC gene. In fact, in a recently published paper, they found that the PTC gene is transcribed in five different forms, leading potentially to the expression of different PTC proteins in a variety of tissues. "We can never underestimate the value of model organisms, such as the fruit fly and the mouse, in furthering the study of human biology," said Dean.
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