Low Gene Repair Ability Raises Risk of Melanoma Skin Cancer

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People who have a lower DNA repair capacity are at increased risk for melanoma skin cancer, according to a new study by scientists at The University of Texas M. D. Anderson Cancer Center.

The study, which appears in the February 19, 2003, issue of the Journal of the National Cancer Institute, demonstrates for the first time a direct link between reduced capacity to repair damage to DNA genetic material and development of melanoma.

"It is well known that sunlight exposure is a risk factor for developing skin cancer, and this study confirms that, but we wanted to know the molecular mechanisms underlying this known risk factor," says Qingyi Wei, M.D., Ph.D., associate professor in the Department of Epidemiology and lead investigator of the study. Why do some people get melanoma while others with the same sun exposure do not? What we have shown is that people who get melanoma have less capacity to repair the damage that sunlight does to the skin."

Melanoma is the most serious form of skin cancer, and its incidence has been increasing 4 percent per year since 1973. According to the American Cancer Society, in 2003, 54,200 new cases of melanoma are expected to be diagnosed and 7,600 people will die of the disease.

Previous studies have shown that certain people are at higher risk for developing melanoma. Individuals with fair skin, blue eyes and who freckle easily after sun exposure are particularly at risk. In addition, people who have more than one severe sunburn with blisters during their childhood are at higher risk.

"Melanoma is a deadly disease compared to non-melanoma skin cancer," said Wei. "We are looking for the underlying etiology or cause for melanoma so that we can better advise people how to reduce their risk of developing the disease."

While the exact causes of melanoma remain unclear, scientists know that exposure to the sun's ultraviolet (UV) light causes damage to DNA in the skin. UV light can break apart the chemical bonds that hold DNA together and cause abnormal bonding. Such abnormal DNA bonds, if they occur in genes that normally control growth, can lead to uncontrolled growth and eventually cancer. The body is equipped with a sophisticated system to detect and repair these chemical breaks or abnormal bonds before they cause mutations and develop into cancer. However, each person's DNA repair capacity varies.

People with xeroderma pigmentosum, an extreme sensitivity to sun exposure, have an inherited defect in DNA repair and a high incidence of melanoma. However, no such link between DNA repair capacity and sunlight-induced melanoma had been proven in the general population.

To test his idea that having a lower DNA repair capacity might increase the risk of melanoma, Wei and his colleagues recruited 312 melanoma patients receiving treatment at M. D. Anderson and 324 people who were cancer-free. Each study subject completed a questionnaire about their lifetime sun exposure, tanning ability, sunburns, and other variables that might increase risk of skin cancer, and blood was drawn for genetic testing.

The scientists found that melanoma patients had a 19 percent lower ability to repair DNA damage than control subjects. In addition, they found that anyone who had a lower than average ability to repair DNA is at increased risk for melanoma. Those with lower DNA repair capacity tended also to be those with fair skin, light hair, and eye color. The data suggests that low DNA repair may be a significant risk factor for developing melanoma in the general population, independent of any other risk factor.

"These findings are consistent with our previous findings on non-melanoma skin cancers, which are rarely lethal but more common than melanoma. Our new findings reinforce the general recommendations that people who have fair skin, blue eyes, and who burn and freckle easily, should take extra precautions to avoid exposure to the sun's ultraviolet radiation," says Wei. "These people should avoid sun exposure, especially during mid-day when UV light is the strongest, and should in general wear sunscreen and protective clothing such as hats and sunglasses."

The scientists are continuing their work by searching for gene or genetic abnormalities that cause variations in the DNA repair machinery that could account for differences in repair capacity among people. Such differences, while not abnormal clinically, could increase risk among the populations for not only melanoma, but other cancers as well, says Wei. If further study confirms these findings, Wei says that it may be possible to develop a way to screen people for their DNA repair capacity. Such a test, he says, could be used to help identify which people need to take extra precautions to avoid sun exposure, particularly early in life.

Other contributors to the study included Sara Strom, Ph.D., Li-E Wang, M.D., Zhaozheng Guo, Yawei Qiao, M.D., Christopher Amos, Ph.D., and Margaret Spitz, M.D., from the Department of Epidemiology; Jeffrey Lee, M.D., Jeffrey Gershenwald, M.D., Merrick Ross, M.D., and Paul Mansfield, M.D., from the Department of Surgical Oncology; and Madeleine Duvic, M.D., from the Department of Dermatology; all of M. D. Anderson Cancer Center. The study was funded by grants from the National Cancer Institute and the National Institutes of Health.