Blonde, freckled, fair-skinned people who live in sunny climates, andlove the outdoors, are reputedly at highest risk of contracting malignantmelanoma _ from solar ultraviolet radiation. But even moresusceptible to this deadly cancer are members of another group, thosewhose melanoma runs in the family."People with familial melanoma could sit in a darkened room theirwhole lives," said molecular geneticist Nicholas Dracopoli, "andthey're still going to get melanoma." Why? "Simply because a randomerror of cell replication will eventually lead to a cell that loses its onlycopy of the p16 gene, and then that cell will become malignant."Dracopoli is a visiting scientist at the Laboratory of Genetic DiseaseResearch in the National Institute of Health's National Center forHuman Genome Research. He is lead author of a paper titled"Germline p16 mutations in familial melanoma," in the Septemberissue of Nature Genetics, out today.Up to 10 of every 100 cases of melanoma are hereditary in origin; therest are labeled "sporadic." An estimated one in 14 men, and one in 17women, said a "News & Views" commentary in the same NatureGenetics, can expect to incur melanoma by age 74. Its incidence in theU.S. is rising faster than that of any other cancer.A tumor suppresser gene, p16 was discovered last year by scientists atMyriad Genetics Inc. in Salt Lake City. (See BioWorld Today, May 4,1994, p. 1.) Although associated with many cancers, p16's mutationshave a decided preference for melanoma.The intact gene presumably suppresses tumors by preventing cells fromcompleting their division cycle. Mutated p16 loses this function,allowing malignant cells _ which in melanoma are melanocytes _ tomultiply out of control.Once discovered, p16 was mapped to the short arm of chromosome 9,into a region known to be deleted and rearranged in melanomas.Dracopoli and his collaborators had been collecting kindreds withmelanoma for a decade. "Our goal," he told BioWorld Today, "was tofind out what are the genes that are mutated in the course ofdevelopment of melanoma in these families."Screening that genomic hot spot of chromosome 9, he and his co-authors turned up eight different inherited p16 mutations among 13 of18 melanoma-prone families. Six of these mutants were actuallyimplicated in the disease."These people who inherit the susceptibility," Dracopoli observed,"already have in every cell in their body only one functional p16 allele,so as soon as it gets mutated, they get melanoma."Similar Means, Similar FindingsMyriad's vice-president of scientific research, Mark Skolnick, who ison the University of Utah faculty, reached similar conclusion bysimilar means, which they report in the same September issue ofNature Genetics. Their paper identified a familial susceptibility locuson a sharply defined region of chromosome 9's short arm.They pinpointed two p16 mutations to this site in two extendedfamilies from Utah and Texas. Both alterations matched two ofDracopoli's six."The next question to be resolved," he said, is: What is the role of p16in the non-familial melanomas, "which make up the sporadicmajority?"The two cancers are clinically very similar. They may start with a mole(a "nevus") on the skin. This soon becomes malignant, andmetastasizes to visceral organs of the body.In melanoma's familial minority, this onset is usually marked bymultiple primary skin lesions. "If one is excised," Dracopoli said,"they're still at risk of getting another one." Unlike the presumablysun-exposed sporadics, the familials often get these warning cutaneousgrowths on covered parts of their bodies, such as scalp or buttocks.Sporadic cases typically arise fairly late in life, the 40s or 50s. Familialmelanoma appears much earlier, in the 20s and 30s. "It's the same infamilial breast cancer," Dracopoli observed. "Somebody in the familywill get it at a much younger age than someone who doesn't have thesusceptibility gene."He sees one potential clinical pay-off of the currently reportedresearch: "If these results are confirmed, you'll be able to screen peoplein families with hereditary melanoma, and ask: Do they have p16mutations? To those who do, you could counsel presymptomaticmonitoring."Dracopoli poses another pressing question: Why do p16 mutations leadspecifically to melanoma? "These susceptible family members don'tget kidney cancer," he said. "They don't get brain cancer. They don'tget lung cancer. They get melanoma."He added, "We don't have an answer to that yet."His next step is to "show that the p16 mutations really do inactivate theproteins they encode." One approach he is pursuing is to clone the wildtype and mutated gene together into an expression vector, use them totransfect tumor cells, then see if the cells stay malignant.Another assay will compare the binding of wild type and mutant p16 tocyclin-dependant kinase (CDK4), a key factor in cell division. "If youcan consistently show that the disease-related mutations prevent p16binding to CDK4," Dracopoli pointed out, "that's very strong evidencethat that's how the mutation causes the disease." n
-- David N. Leff Science Editor
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