Basal cell carcinoma skin cancer

As a fruit fly embryo matures, the activity of a gene called patched helps guide its development. Two research groups now report that the human counterpart of patched is the crucial gene that goes awry in basal cell carcinoma, the most common of all human cancers.

This skin cancer strikes an estimated 750,000 people a year in the United States. Unlike most other cancers, it rarely kills because it seldom invades other parts of the body. Still, if not caught early and removed surgically, basal cell carcinoma can cause severe disfigurement.

Investigators suggest that the newly discovered gene is the cancer's "gatekeeper," the initial gene that must be mutated for disease to occur. As a result of the discovery, "there will be a topical cream that cures basal cell carcinoma" in 5 to 10 years, predicts Allen E. Bale of the Yale University School of Medicine. Bale heads an international team of researchers that reports the finding in the June 14 Cell.

In addition to skin cancer, mutations in the human version of patched result in basal cell nevus syndrome, a rare condition in which affected individuals suffer various cancers, including, often, hundreds of basal cell carcinomas, and developmental defects such as fused ribs, extra digits, spina bifida, and oversized heads. Among the deadliest outcomes of the syndrome-also called Gorlin syndrome-is medulloblastoma, a brain cancer in children. Discovery of the new gene is "incredibly significant in terms of understanding the pathogenesis of basal cell nevus syndrome and basal cell carcinomas in general," comments Bert Vogelstein of the Johns Hopkins Medical Institutions in Baltimore.

A second group has isolated the same cancer gene. Headed by Matthew P. Scott of the Howard Hughes Medical Institute at Stanford University and Ervin H. Epstein Jr. of the University of California, San Francisco, this team describes its work in the June 14 Science.

Scott has been studying patched in fruit flies for more than a decade. Using patched's DNA sequence, his group recently identified a similar human gene. They found it on an area of chromosome 9 long thought to hold the gene responsible for basal cell nevus syndrome. Scott's team then joined forces with Epstein's group, which was looking for the gene behind the syndrome.

"We're working on the most common human cancer at one end of the bay, and 30 miles away someone is working on [fruit flies]-and it turns out we're working on exactly the same gene," marvels Epstein. Working independently, Bale's group had also found patched's human counterpart while examining genes from the same region of chromosome 9. To determine whether the new gene causes the syndrome, both sets of researchers studied the DNA of afflicted families and found that affected members have mutations in the gene, whereas unaffected members do not. Both groups also identified several mutations in the gene when they examined tumor cells from basal cell carcinoma patients not afflicted with basal cell nevus syndrome. One mutation is an alteration often generated by ultraviolet light, supporting the charge that exposure to the sun can trigger skin cancer, says Epstein.

Investigators believe that to trigger basal cell carcinomas and other cancers, flaws must occur in each of a cell's two copies of the newly discovered gene. Basal cell nevus syndrome, however, seems to result when only one copy of the gene is defective. Developmental abnormalities would occur because cells in the embryo make only half the normal amount of the gene's protein. Moreover, having one faulty copy of the gene would predispose people with the syndrome to cancer: A mutation in the one normal copy would be all that's needed to trigger tumor formation.

Though its exact role remains unclear, patched's protein sits in the outer membrane of a cell and may help turn genes off by transferring signals from outside the cell into the nucleus, where genes reside. In embryonic fruit flies, patched counteracts the growth-promoting activity of a gene called hedgehog.

The linking of patched to basal cell carcinoma is one of several instances recently in which a gene involved in fruit fly development has been tied to human cancer. "This is one of the most exciting aspects of the work. We're seeing a merging of the people studying development and the people studying tumorigenesis," says Michael Dean of the Frederick (Md.) Cancer Research and Development Center and a coauthor of the Cell report.