Capping an intensive four-year search, researchers reported today that in studies of the common fruit fly and humans, they have discovered a gene responsible for skin cancer--the most common form of cancer.
The discovery could lead to new ways to treat, and maybe even to prevent, skin tumors, researchers said.
Perhaps even more important, scientists hope the gene can yield new insights into why the most common skin cancers, unlike all other forms of cancer, do not metastasize and spread their deadly tentacles to other sites in the body.
Every year, an estimated 750,000 Americans get skin cancer from exposure to too much sunlight. Now, the two teams say, they know how ultraviolet radiation from the sun does its damage.
That radiation, they found, mutates a gene called “patched” that inhibits cell growth. When both copies of “patched” in a single skin cell are damaged by light, the cell’s reproductive capacities are unleashed and a tumor is born.
The finding, reported today in the journals Science and Cell, “is going to tell us a great deal about cancer and human development,” said Dr. Richard Klausner, director of the National Cancer Institute.
It is also “a wonderful example of how [fruit fly] research can have an impact on human biology,” added Stephen Katz, director of the National Institute of Arthritis and Musculoskeletal and Skin Diseases. “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 gene is not related to the rarer and more deadly form of skin cancer known as malignant melanoma.
Researchers were originally looking for the gene because it also causes a rare, inherited disorder called Gorlin’s syndrome, which affects perhaps one in 57,000 people. Gorlin’s victims develop hundreds or even thousands of basal cell carcinomas over the course of a lifetime and are subject to a wide array of cancers and birth defects.
“Studying this rare hereditary form of basal cell carcinoma allowed us to learn something about [skin cancers] that we would never have learned otherwise,” said Dr. Ervin H. Epstein Jr. of UC San Francisco.
The two teams--one headed by Epstein and Stanford geneticist Matthew P. Scott, the second by Yale University geneticist Dr. Allen E. Bale--zeroed in on the new gene from vastly different directions. Bale’s group has been working with Gorlin’s families and reported four years ago that the suspected gene was located in a large segment of DNA on the end of Chromosome 9, one of the 23 pairs of chromosomes that make up the human genetic blueprint.
Since then, they have been using conventional genetic techniques to pinpoint the gene for Gorlin’s.
The Northern California group, in effect, stumbled on its finding accidentally. Stanford’s Scott discovered “patched” while studying the handful of genes that control how the cells in a fruit fly embryo are converted into the many different organs and body parts of an adult fly.
Scott’s team found that “patched” acts as a brake for another gene called “hedgehog,” which instructs cells on what to do during growth and development. When “patched” is defective or absent in flies, “hedgehog” is unrestrained and produces birth defects and cell proliferation.
Genetically, fruit flies are remarkably similar to humans and for years have provided insight into human biology. Scott’s team began looking for the human version of “patched,” and last summer found it on Chromosome 9 in the same region where Bale had found the Gorlin’s gene.
“At this point, we asked, could a malfunction of the ‘patched’ gene in humans lead to [Gorlin’s] and also to the basal cell carcinomas that many people get in their later years?” said Scott’s colleague, Ronald Johnson.
The Stanford and UC San Francisco groups collaborated on that question and report in Science that they found a defective form of “patched” in DNA from Gorlin’s patients, indicating that the gene causes the disorder. When they also looked at tumor cells from skin cancer patients, they again found defective “patched” genes.
By this time, the Yale group was also closing in on “patched.” They report in Cell that they too found defective forms of the gene in both Gorlin’s patients and skin cancer cells, confirming the Northern California finding.
“In these two papers, scientifically, the content is remarkably similar,” Bale said.
Researchers now believe that, for some still unknown reason, “patched” is particularly susceptible to the mutational effects of sunlight.
Gorlin’s patients are especially prone to skin cancer because they already have inherited one defective copy of the gene, along with one healthy copy.
Normal people have two healthy versions of the gene, and both copies in a single cell must be damaged by sunlight before a tumor is triggered. That is why most people don’t develop skin cancer until later in life, when there has been more exposure to sunlight.
Epstein believes that the discovery of the gene will lead to drugs for skin cancer that can block the effects resulting from the “patched” mutation. “This would be cheaper than surgery, would avoid surgical pain and discomfort, and might even reduce subsequent scarring,” he said.
Researchers are also intrigued because skin cancers do not metastasize. Although tumor cells slough off from skin cancers and circulate through the bloodstream, they rarely attach themselves to other organs and begin a second tumor. Basal cell carcinoma is therefore one of the least deadly of all human cancers.
Researchers hope the discovery of “patched” will give them insight into why the skin cancer cells are unable to colonize other organs and thereby provide new ways to prevent metastasis of other tumors.