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Zeroing In On Two Melanoma Genes
By Kate Dalke

The two most important risk factors for developing melanoma—the deadliest form of skin cancer—are genes and exposure to sunlight. A new study of people with inherited and noninherited forms of the disease has found a link between two genes—and, possibly, between those genes and UV rays.

In the study, melanoma patients with an inherited gene defect acquired many more mutations in a second gene than did patients who had no family history of the disease.

The researchers hypothesize that the mutations in the second gene were due to sunlight.

“We found that an inborn genetic defect may cause sensitivity to UV radiation, and the combination of the two is important to the development of melanoma,” says Johan Hansson, who led the study at the Karolinska Cancer Center in Stockholm, Sweden.

The study included 25 patients from six Swedish families with hereditary melanoma who had a rare defect in a gene called CDKN2A, which normally suppresses the development of tumors. Also in the study were melanoma patients with no family history of the disease.

The scientists collected tumor cells from skin lesions and moles, and sequenced the DNA to identify mutations in the NRAS gene, which have been linked to UV exposure.

They found NRAS mutations in 95 percent of tumors from patients with hereditary melanoma; only 10 percent of tumors from nonfamilial melanomas had mutations in NRAS.

Although studies in mice have shown that UV exposure can trigger NRAS mutations, Hansson acknowledges that the findings do not demonstrate that sun exposure caused these mutations.

“It’s likely that sunlight is playing a role, but these mutations could also be caused by other carcinogens,” says Kenneth H. Kraemer of the National Cancer Institute of Bethesda, Maryland. Kraemer wrote a commentary accompanying the study in the Journal of the National Cancer Institute.

See related GNN article
»Melanoma Linked to Problems with Repairing DNA

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Eskandarpour, M. et al. Frequency of UV-inducible NRAS mutations in melanomas of patients with germline CDKN2A mutations. J Natl Cancer Inst 95, 790-797 (June 4, 2003).

Kraemer, Kenneth H. NRAS hypermutability in familial melanoma with CDKN2A mutations—cause and effect? J Natl Cancer Inst 95, 798-799 (June 4, 2003).

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