People who take early retirement and move to the sun belt are courting cancer.

In particular, individuals over 50 years old, with fair complexions, are inviting basal cell carcinoma, (BCC), a.k.a. skin cancer. With 750,000 cases diagnosed every year, BCC is the commonest malignancy in the U.S.

Ultraviolet wavelengths of solar radiation attack basal cells in the lower layers of the epidermis, and makes them malignant. Although these flattish tumors, usually on the neck and face, don't metastasize, they do disrupt adjacent skin structures, so must be surgically removed.

Basal cell carcinomas take years of latency to reach such a critical stage _ with one rare exception. That is an inherited skin disorder called nevoid basal cell carcinoma syndrome (NBCCS), or Gorlin's disease. Its hallmark is the eruption of dozens to literally hundreds of BCCs all over the body _ but that's only the beginning.

NBCCS strikes one in 100,000 children above the age of 10, and leaves them with stigmata ranging from large heads, misshapen ribs, spinal curvature, neural tube defects, cysts in the jaws to extra fingers to medulloblastoma childhood brain tumors.

In today's Science and Cell, molecular geneticists at Stanford University and Yale University report separately on the same mutated gene found in tumors of the horrendous NBCCS, and in the relatively benign BCC as well.

Yale cancer geneticist Allen Bale is senior author of the Cell paper, titled: "Mutations of the human homolog of Drosophila patched [gene] in the nevoid basal cell carcinoma syndrome."

Stanford's Matthew Scott is senior author of the coincidentally similar-sounding article in Science: "Human homolog of patched, [ptc for short], a candidate gene for the Basal Cell Nevus Syndrome."

Patched's peculiar moniker harks back to the fact that geneticists found it in the fruit fly long before Scott and Bale independently located its mutant human counterpart in NBCCS tumor cells.

In its normal unmutated mode, ptc acts to hold back another Drosophila gene, hedgehog by name, from overdoing its job of briefing embryonic cells on how to develop and grow. When ptc goes wrong, its mutant protein unleashes hedgehog to foment unbridled cell proliferation _ i.e., cancer. That makes ptc a candidate for membership in the tumor-suppressor club.

Both research teams have mapped human ptc to the long arm of chromosome 9.

Bale's group at Yale found the human version of mutant ptc, skulking throughout all the cells of an NBCCS patient. "We showed that, in fact, patients with this disease have mutations in this gene," he told BioWorld Today. "In six unrelated patients with independent mutations, and two with sporadic, non-hereditary BCC, both copies of the ptc gene are inactivated in that type of tumor."

At Stanford, Scott and his co-authors discovered a single base difference in a BCC tumor from a person who had come by it sporadically, and did not have Gorlin's hereditary syndrome. What's more, the mutation did not occur in this patient's non-tumorous cells.

From Prevention To Conceptual Cure

"A hat, a roof and sunscreen cream are the best prescription for preventing skin cancer." So said research dermatologist Ervin Epstein of San Francisco General Hospital, co-senior author of the Science paper.

Innovative therapeutics may be in the offing, based on Scott's and Bale's elucidation of the genes implicated in both basal carcinoma syndromes. "I don't think gene therapy is the way to go," Bale observed. "Rather, one might conceive of some clever way to add a chemical, acting as a substitute for patched, to inhibit hedgehog in a BCC tumor."

Epstein envisages "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." Such treatment, he observed, "would be cheaper than surgery, and might even reduce subsequent scarring."

Ontogeny Inc., a small biotech firm in Cambridge, Mass., already has begun working on gene-based therapies for basal cell carcinoma. Stanford's Matthew Scott is a member of the company's scientific advisory board, and the university has licensed the patched and hedgehog genes to Ontogeny.

"We already have extensive programs in hedgehog for treating central nervous system, musculoskeletal and male fertility diseases," the firm's CEO, Heidi Wyle, told BioWorld Today. "Cancer applications are not something we have done before, so Ontogeny would certainly be interested in a big company collaborating with us in that area."

She observed, "We now know a little bit more about the gene mechanisms than was published in Science, and we're thinking about small-molecule approaches to therapy, both oral and topical." n

-- David N. Leff Science Editor

(c) 1997 American Health Consultants. All rights reserved.