Risk Factors for Melanoma: Intermittent Sun Exposures and Sunburns

EMBARGOED UNTIL APRIL 28, 1999

WHY INTERMITTENT SUN EXPOSURES AND SUNBURNS ARE RISK FACTORS FOR MELANOMA: THE SOS RESPONSE IN HUMAN SKIN

NEW YORK (April 28, 1999) - While sun exposure has long been linked to skin cancer, new research appears to explain why a specific pattern of sun exposure leads to melanoma - the deadliest form of skin cancer - and suggests that a genetic response to ultraviolet (UV) radiation-induced DNA damage may permit development of a novel photoprotective agent to decrease cancer risk.

Speaking today at the American Academy of Dermatology's annual Melanoma/Skin Cancer Detection and Prevention Month press conference, dermatologist Barbara A. Gilchrest, MD, Professor and Chairman, Department of Dermatology, Boston University, discussed the implications of her Mechanisms of Disease review published in the April 29, 1999 issue of the New England Journal of Medicine.

There are three different types of skin cancers - basal-cell and squamous-cell carcinomas and melanoma. For each type of skin cancer, there are specific patterns of sun exposure that are linked to their development.

"Previous research has shown that basal-cell and squamous-cell carcinomas most often occur on regularly sun-exposed areas of the body, such as the face, back of the hands and forearms, and are associated with a person's total cumulative exposure to UV radiation," explained Dr. Gilchrest. "Individuals who are good candidates for non-melanoma skin cancers are those who have practically daily UV exposure, work outdoors, or otherwise have large cumulative lifetime sun exposure."

"On the other hand, melanoma typically occurs on areas of the body not exposed to the sun on a regular basis, such as the lower legs or the back," added Dr. Gilchrest. "Most people who develop melanoma work indoors and have intense, but limited, exposure to the sun on weekends or vacations. Excessive sun exposure in the first 15 years of life, especially sunburns, also increases a person's chances of developing melanoma."

The new insights involve a genetic mechanism, recognized in bacteria more than 20 years ago, in which DNA damaged by UV radiation induces safeguards against future damage. This process, known as the SOS response, also was found by Dr. Gilchrest's research group to exist in human skin cells.

"The SOS response is actually nature's way of enhancing repair of frequently encountered DNA damage," explained Dr. Gilchrest. "What happens in bacteria is that single stranded DNA fragments generated by UV damage or its repair combine with a specific protein. This DNA-protein complex adjusts the transcription of more than 20 genes whose protein products enhance cell survival after subsequent UV irradiation."

"We have found that human cells similarly increase their production of DNA repair proteins within two or three days of damaging sun exposure or after treatment with DNA fragments, commercially manufactured and supplied from the outside, which the cell appears to interpret as damage to its own DNA," added Gilchrest. "Tanning, which is the increased production of melanin pigment that darkens our skin color after sun exposure, is part of this SOS response. Thus, nature has perpetuated the same environmental defense system throughout evolution, from bacteria to man."

A tan is a result of injury to the skin. Research on tanning has shown that the ability of UV light to tan skin exactly parallels its ability to damage DNA. Dr. Gilchrest's group therefore asked whether thymidine dinucleotides (pTpT), commonly present in DNA damaged by UV exposure and cut out of the chromosomes during the repair process, might stimulate tanning in the absence of UV exposure. Experiments were performed using guinea pigs. After two weeks, guinea pig skin treated topically with pTpT appeared much darker than the control areas. Biopsies confirmed that the skin treated with pTpT had much more melanin distributed throughout the epidermis, identical to tanned human skin. Further testing determined that the pTpT-induced tan in the guinea pig was also photoprotective, equivalent to an SPF of 6 or higher. In other experiments, topical treatment of guinea pig skin with pTpT also increased the rate of removal of DNA damage in cells after UV exposure.

Dr. Gilchrest's research suggests that the combined effect of UV-induced tanning and enhanced DNA repair capacity makes the skin more resistant to subsequent UV injury, including skin cancer. These SOS-like responses appear to be mimicked even without any DNA damage by pTpT and other single-stranded DNA fragments.

As presented in the April 29, 1999 issue of the New England Journal of Medicine, Dr. Gilchrest explains why intermittent sun exposure leads to the development of melanoma rather than other forms of skin cancer. "It is important to compare the effect of UV radiation on keratinocytes, which can give rise to basal-cell and squamous-cell carcinomas, to melanocytes, which can give rise to melanoma," said Dr. Gilchrest.

After exposure to UV radiation, the most severely damaged keratinocytes undergo apoptosis or programmed cell death, a means of eliminating cells at risk of cancer development. This leaves the less damaged keratinocytes to invoke the SOS response, improve their DNA-repair capacity, and to undergo nearly perfect repair. The skin will also tan, providing protective melanin to the surviving cells. Frequent exposure to UV radiation within the SOS response period will then perpetuate the increases in repair capacity and melanin content, minimizing but not eliminating cumulative mutational damage. With each subsequent exposure, the most severely damaged keratinocytes will be removed, so that cells with minimal incremental damage gradually accumulate in the tissue.

According to this hypothesis, intermittent high-dose exposure to UV radiation would have no more effect on the development of non-melanoma skin cancers than repeated low-dose exposures that also would cause occasional mutations in the retained cells of the basal compartment and eventually lead to basal-cell or squamous-cell carcinomas.

"The response to sun exposure in melanocytes is quite different. A first high dose of UV radiation will cause substantial damage, but melanocytes are highly resistant to programmed cell death, perhaps nature's way of assuring the continued presence of protective melanin pigment in the skin. This resistance to cell death enables UV-damaged melanocytes to mutate and divide," explained Dr. Gilchrest.

"Intermittent high-dose exposures are expected to give rise to more melanomas than frequent low-dose exposures because the UV injury occurs when the melanocytes' DNA-repair capacity is relatively low, the DNA damage is poorly repaired, and all the damaged cells are retained."

Dr. Gilchrest's research could lead to a topical treatment composed of small DNA fragments that can evoke the SOS response in the skin in the absence of true DNA damage, thus minimizing sun-induced mutations that cause skin cancer.

"This topical treatment could be applied prior to initial UV exposure, allowing a person to get a photoprotective tan and enhancing DNA repair capacity," said Dr. Gilchrest. "The treatment would increase resistance to future UV damage - which in turn could lower a person's risk of developing skin cancer."

The American Academy of Dermatology, founded in 1938, is the largest, most influential, and most representative of all dermatologic associations. With a membership over 12,000 dermatologists worldwide, the Academy is committed to: advancing the science and art of medicine and surgery related to the skin; advocating high standards in clinical practice, education, and research in dermatology; supporting and enhancing patient care; and promoting a lifetime of healthier skin, hair, and nails. For more information, contact the AAD at 1-888-462-DERM or www.aad.org.

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GLOSSARY OF TERMS

apoptosis - programmed cell death; a means of eliminating cells at risk of cancer development.

epidermis - the outer layer of the skin that protects the dermis.

keratinocytes - epidermal cells that synthesize keratin, a fibrous protein that forms the outermost barrier layer of skin, as well as hair and nails.

melanin - the body's brown-black pigment responsible for skin color and tanning after sun exposure.

melanocytes - the body's melanin-forming cells.

photoprotective - capable of shielding the skin from UV damage; sunscreen is a common photoprotective agent.

SOS response - a genetic mechanism first recognized in bacteria that allows DNA damaged by UV radiation to stimulate production of proteins that prevent or protect against future DNA damage; a very similar process was recently recognized in human skin cells.

thymidine dinucleotides (pTpT) - small DNA fragments that can be made commercially and applied to skin to mimic the DNA damage that normally occurs in cells after sun exposure; a trigger for the SOS response that does not damage DNA.

transcription - the process of creating a messenger RNA molecule by using a DNA molecule as a template, resulting in a transfer of genetic information to the messenger RNA that is then used to make a protein.