By the time the bridge to the next century stretches ahead 20 yearsfrom now, cases of the commonest cancer in the U.S. will "hit theroof."
That's the prediction of Yale University biophysicist Douglas Brash,who explained that for him biophysics is a bridge between DNA andultraviolet radiation.
In other words, the bridge from sunlight to skin cancer.
"The frequency of squamous cell carcinomas in the U.S.," Brash toldBioWorld Today, "is roughly equal to all other cancers combined _ amillion or more new cases a year." He added: "As near as we know,the frequency of skin cancers has been doubling every decade,presumably because people have been lying out in the sun more andmore in recent decades."
He pointed out that the lag period between sun exposure in childhoodand diagnosis of disease is about 40 years. "So when I say it'sdoubling every 10 years, those are the patients who are already 70 or80 years old. And they weren't lying out on the beach as much as Iwas," Brash went on. "So the expectation is that over the next 20years, a lot of us baby boomers are going to get it."
Brash teaches therapeutic radiology and genetics at Yale. He is seniorauthor of a paper in today's Proceedings of the National Academy ofSciences (PNAS), dated Nov. 26, 1996, titled: "Frequent clones ofp53-mutated keratinocytes in normal human skin."
His major premise is that solar UV radiation damages the DNA ofgenes that normally encode a p53 tumor repressor protein, andinactivates it.
"UV light photons," Brash explained, "like to land on nucleotidepyrimidine bases _ cytosines or thymines. Then an enzyme comesalong and mutates the p53 gene at that point in the DNA sequence."
His paper in PNAS concludes that sunlight, besides wreakingtumorigenic mutagenesis on p53 genes, also favors the clonalexpansion of those p53-mutated precancerous cells. This one-twopunch, initiating, then promoting, malignancy, ends up causing theearly stages of full-blown skin cancer.
This two-stage process, and the natural history of squamous cellcarcinoma, concords with the "multiple genetic hit model of cancer,"which predicts that "normal individuals should have stablepopulations of cancer-prone, but non-cancerous, mutant cellsawaiting further genetic hits."
Brash and his co-authors obtained some 42 fresh skin samplesdiscarded by Yale's plastic-surgery center. These centimeter-squarefragments of epidermal and dermal tissues came from patientsranging in age from nine to 79, and included specimens from areas ofthe body with low, intermittent and chronic exposure to the sun.
By an original "whole-mount" procedure, the researchers peeledepidermis and hair follicles free of dermis, and analyzed these paper-thin epidermal skin surfaces for signs of mutant p53 protein. Theyfound them in scattered patches 60 to 3,000 cells in size.
They averaged more than 40 patches per square centimeter, andinvolved up to 4 percent of total sample surface in sun-exposed skin.These clonal patches were larger and more frequent in sun-exposedthan in sun-shielded areas.
This effect of sunlight, Brash observed, "is what you already knew.But now it's staring you right in the face. You've already got about60,000 of these little polka dots on your face, and maybe one oughtto do something about it."
What one does about it, he recommended, ranges from keeping out ofthe sun between 10 a.m. and 2 p.m., to wearing hats, to spreading onsolar-blocking creams. As for this last option, he added, "I alwayswonder about slathering lots of chemicals all over your body, becauseyou figure this solar energy has to go somewhere."
He and his group are now hunting down in transgenic knockout micethe cascade of genes triggered by UV. They are asking: "What are thegenes involved in the signaling pathways where UV is telling cells tocommit suicide?"
This query leads to another: "Are there pharmacological ways ofintervening with those pathways?"
Pathways To Therapeutic Discovery
Brash noted that "People are trying several things. One is a genetherapy approach, putting in the p53 gene to make more of thenormal, tumor-suppressing protein. So far, it's tissue-culture stuff. Ithink it's the hard way to go about things."
An alternative therapeutic route is "getting short peptides to changethe configuration of even a mutant p53 protein, and make it a wild-type again.
"What we are now doing," Brash continued, "is taking the signaling-pathway approach: UV-radiate transgenic mice, and see if we getapoptosis [cell death] in vivo."
He went on: "We have about a dozen genes on our list now; three thatdon't seem to affect things, and three that look pretty positive. Inanother two months, we should be ready to submit our findings, andtalk about them."
Some of that talking, Brash allowed, will be with Yale's patentattorneys, and some with pharmaceutical companies that haveexpressed "casual interest" in his project.
"If you want to know how well a sun screen works at preventing skincancers, you have to wait 30 years," he pointed out. "But if you wantto know whether it prevents these little precancerous polka dots, youhave to wait a couple of weeks. So you should imagine these being agood endpoint for assays of chemopreventive or chemotherapeuticregimens."
Melanoma, like squamous cell carcinoma, correlates with intensity ofsolar exposure and with sunburn. But unlike skin cancer, which isreadily cured and seldom fatal, melanoma _ if not caught early _remains uncurable and lethal. n
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.