Shedding Light on the Role of UV Exposure in Melanoma
The irregularly pigmented skin lesion in a sun-exposed area demonstrates the ABCD characteristic features of malignant melanoma: Assymetry, irregular Borders, multiple Colors, and Diameter >6mm. This lesion has a UV-type PTEN mutation.
Melanoma develops from skin cells that produce the brown pigment melanin, which normally protects the deep layers of skin from sunlight. There is a well-documented relationship between nonmelanoma skin cancer and exposure to UV radiation, but the role of sunlight in the development of melanoma has proven to be more complex and is currently not well understood.
When a cell is exposed to UV radiation, the chemical makeup of its DNA is changed in a specific manner, resulting in a recognizable modification that can be measured by scientists. These changes are normally detected and fixed by cellular mechanisms for DNA repair. However, if the damage is extensive or if a cell has defective DNA repair machinery, permanent mutations can be produced with harmful consequences for the cell. If the mutation occurs within the gene for a protein that regulates cellular growth, the development of cancer is possible.
Yun Wang, M.D., Ph.D., is a visiting postdoctoral fellow in the DNA Repair Section of CCR, headed by Ken Kraemer, M.D., which focuses on how defects in DNA repair lead to cancer-prone genetic diseases. Individuals with a genetic condition called xeroderma pigmetosum (XP) have defects in their DNA repair mechanisms and, as a result, have a 1,000-fold increase in melanoma risk compared with the general population. Since the effects of UV radiation on DNA can be measured, Dr. Wang and his associates were able to use melanomas from XP patients to investigate the role of UV exposure in the development of melanomas. They have published their study results in a recent Proceedings of the National Academy of Sciences paper.
In patients with XP, the mechanism of UV-induced damage is the same as that in people without the condition. However, the effects are amplified because individuals with XP are not able to repair the damage. Many XP patients develop multiple melanomas, making it possible to study lesions that developed in the same environment and genetic background. Fifty-nine melanomas from eight patients were examined for evidence of damage from UV radiation.
In order to analyze the results of UV exposure, mutations in the tumor suppressor gene PTEN – one of the most frequently mutated genes in human cancer – were measured. When functioning properly, PTEN suppresses cell growth and proliferation by preventing activation of a protein called Akt. Of the melanomas examined for this study, 56% contained at least one mutation in the PTEN gene, and 89% of these mutations were of the type caused by UV radiation. A sampling of the mutated proteins was analyzed to determine if the changes altered PTEN activity. Of the six PTEN mutants tested, three were unable to prevent activation of Akt, indicating that these mutations interfere with the tumor suppressor function of PTEN.
This study provides strong evidence that exposure to UV radiation leads to mutations that contribute to the formation of melanomas in XP patients. The authors also point out similarities between melanomas in XP patients and those in the general public, suggesting a comparable role for UV induction of mutations in both groups. These results provide a sound rationale for the practice of limiting exposure to sunlight for the prevention of melanoma.Summary Posted: Wed, 04/01/2009
PNAS. 2009 Mar. 27. Epub 2009 Mar.10