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

In particular, individuals over 50 years old, with fair complexions,are inviting basal cell carcinoma, (BCC), a.k.a. skin cancer. With750,000 cases diagnosed every year, BCC is the commonestmalignancy in the U.S.

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

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

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

In today's Science and Cell, molecular geneticists at StanfordUniversity and Yale University report separately on the same mutatedgene found in tumors of the horrendous NBCCS, and in the relativelybenign 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 coincidentallysimilar-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 geneticistsfound it in the fruit fly long before Scott and Bale independentlylocated its mutant human counterpart in NBCCS tumor cells.

In its normal unmutated mode, ptc acts to hold back anotherDrosophila gene, hedgehog by name, from overdoing its job ofbriefing embryonic cells on how to develop and grow. When ptc goeswrong, its mutant protein unleashes hedgehog to foment unbridledcell proliferation _ i.e., cancer. That makes ptc a candidate formembership in the tumor-suppressor club.

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

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

At Stanford, Scott and his co-authors discovered a single basedifference in a BCC tumor from a person who had come by itsporadically, and did not have Gorlin's hereditary syndrome. What'smore, 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 forpreventing skin cancer." So said research dermatologist Ervin Epsteinof San Francisco General Hospital, co-senior author of the Sciencepaper.

Innovative therapeutics may be in the offing, based on Scott's andBale's elucidation of the genes implicated in both basal carcinomasyndromes. "I don't think gene therapy is the way to go," Baleobserved. "Rather, one might conceive of some clever way to add achemical, acting as a substitute for patched, to inhibit hedgehog in aBCC tumor."

Epstein envisages "a protein or other small molecule that could beapplied to the skin in a cream, and that would block the effectsresulting from mutation of the ptc gene." Such treatment, heobserved, "would be cheaper than surgery, and might even reducesubsequent scarring."

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

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

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

-- David N. Leff Science Editor

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