Most people have a scattering of tiny dark blemishes strewn overtheir skin _ and think nothing of it. These pinhead-sized moles ornevi are clusters of melanocytes, skin cells that make the pigmentmelanin.
Now and then _ increasingly in recent decades _ a nevus willdarken, get bigger, start to itch or bleed. These warning signs oftensignal the onset of melanoma, fastest-growing, quickest-killing of allsolid tumors.
Unless a surgeon promptly excises the upstart mole, its malignantcells will strike down into the bloodstream, and spread throughvisceral organs. At that point, death can come in a matter of months,or a few years at best.
Genetic epidemiologist Alisa Goldstein of the National CancerInstitute (NCI) said that men and women should keep an eye on theirskin to catch a dysplastic nevus early. "Just as breast self-exams help,hopefully, to diagnose early breast cancer," she told BioWorldToday, "finding changes in skin nevi will help identify melanoma orpremalignant lesions."
But these moles, usually hereditary, are only the tip of melanoma'sepidemiological iceberg. Ninety percent of the hyper-aggressivemalignancies are not inherited, but arise mainly from skin cancerscaused by excess solar exposure. Fair-haired, freckled beach-baskersand outdoor machos are particularly prone; skin cancer, with 843,000new cases diagnosed in 1995, is the commonest type of malignancyin the U.S.
Most skin cancers are readily cured, but one type in particular,melanoma, if not treated in time, is deadly, Goldstein said. Last year,34,100 cases of melanoma, both the familial and sporadic types,occurred in the U.S., and 7,000 deaths.
About one-tenth of these sinister statistics refer to the inheriteddisease, which by its nature lends itself to studying melanoma'scause. As in familial breast cancer, researchers have implicated twomutated genes, so far, in the etiology of familial melanoma.
One is p16, a tumor suppressor gene gone wrong. Family memberswho inherit an altered, oncogenic, p16 gene stand an 80 percentlifetime chance of getting melanoma, compared with a 1 percent riskin the general population.
In 1993, molecular geneticist Mark Skolnick, founder and researchdirector of Myriad Genetics Inc., of Salt Lake City, identified thetumor suppressor p16 gene on human chromosome 9's short arm.(See BioWorld Today, Sept. 1, 1994, p. 1.) He did as much in 1994to identify BRCA1, the first familial breast cancer oncogene.
Wild-type _ unmutated _ p16 genes play a vital role in curbing anytendency a cell might have to start dividing out of control, NCI'sGoldstein explained.
However, p16 isn't the whole story of cancer-causing genes infamilial melanoma. The fact that it shows up in the genomes of onlyone-third to one-half of all patients with inherited melanoma ledresearchers to predict that at least one more bad oncogene lurked inthe picture.
Sequana Therapeutics Inc., of La Jolla, Calif., with support fromNCI, has just discovered this second perpetrator, a mutant genecalled CDK4, residing on the long arm of human chromosome 12.
NCI's Goldstein is a co-author of the paper reporting this discovery,in the January 1996 issue of Nature Genetics, out today. Its title:"Germline mutations in the p16INK4a binding domain of CDK4 infamilial melanoma." Its principal author is Nicholas Dracopoli,Sequana's vice president of molecular genetics, and a NationalInstitutes of Health alumnus.
"This discovery," Dracopoli said, "is an important step in the processof identifying all of the genes that give rise to melanoma." He hascompared that cancer's inherited version with the melanomaattributed to solar ultraviolet radiation. "People with familialmelanoma," Dracopoli has observed, "could sit in a darkened roomtheir whole lives, and they're still going to get melanoma," from aninherited mutant or missing gene.
In a healthy cell, the newly identified CDK4 gene binds hand-in-glove with the protective p16. To find it, and its mutations,Dracopoli's team examined the genomes of 31 hereditary-melanomafamilies, 10 from the NCI, and 21 from the Queensland Institute ofMedical Research in Australia.
Analysis of DNA samples from 28 members of two NCI families,showed an identical point mutation in the CDK4 gene, changing thenormal arginine-coding sequence to an aberrant cysteine. Each of the11 melanoma patients in both families carried this variant, as did twoof 17 unaffected family members.
However, those two may yet develop the disease, the papersuggested, because both are much younger than the average age ofonset in these families, 38 years.
Identification of this mutation in two apparently unrelated kindreds,the co-authors pointed out, "provides strong evidence that CDK4 is asecond familial melanoma gene." But because it occurred in only twoof the 31 families analyzed, "it is likely that other genes . . . will playa role in the development of familial melanoma."
From Gene To Screen: Drug Discovery Pathway
By understanding how p16, CDK4 and other genes work, Goldsteinobserved, "we can get a better handle on how melanoma is formed,and then, hopefully, how to prevent it from occurring."
But she added, "There's a definite difference of opinion in thescientific community as to whether identifying a gene like p16 orCDK4 will have implications for early diagnosis or treatment."
In announcing Sequana's discovery, the company's president andCEO, Kevin Kinsella, predicted that "identification of disease geneswill . . . facilitate the development of highly specific diagnostic andtherapeutic products."
He told BioWorld Today that "What we intend to do is look up anddown the genetically validated pathway to find a pharmacologicaltarget, then put that into screens, against which we would screensmall molecules for drug discovery.
"We are already taking steps in general terms," Kinsella concluded,"to go from gene to screen." n
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.