High gene mutation rate may contribute to hereditary skin cancers

Sun exposure and genetic predisposition are two known risk factors for cutaneous malignant melanoma. However, the genetic changes that occur during the development of melanoma have not been definitively determined. Inherited mutations in the CDKN2A tumor suppressor gene have been implicated in the development of melanoma, as have non-inherited (acquired) mutations in the UV-inducible proto-oncogene NRAS. How these events are related is unclear.

Malihe Eskandarpour, M.Sc., Johan Hansson, M.D., Ph.D., and their colleagues at the Karolinska Hospital and Karolinska Institute in Stockholm, Sweden, examined the frequency of NRAS mutations in 39 biopsy samples of primary melanomas, metastatic melanomas, and dysplastic nevi (atypical moles, which can progress to cancer) taken from 25 patients in six Swedish families who carry germline CDKN2A mutations. They also examined the frequency of NRAS mutations in biopsy samples taken from 10 patients with sporadic (non-hereditary) melanomas.

The researchers found NRAS mutations in 95% (20/21) of primary hereditary melanomas but in only 10% (1/10) of sporadic melanomas. Of the primary hereditary melanomas containing NRAS mutations, 19 were found in occasionally or continually sun-exposed parts of the body (such as leg, trunk, neck, and hand), suggesting an association between UV light exposure and the activation of NRAS mutations.

An examination of NRAS mutations in dysplastic nevi revealed that 5 out of 7 biopsy samples contained NRAS mutations, suggesting that NRAS mutations may occur in the early stages of hereditary melanoma development. The researchers did not find any NRAS mutations in normal moles and normal skin tissue.

These findings also suggest that NRAS mutations could be a target for specific anticancer therapy in patients with melanoma. Because these mutations appear to occur early in tumor development, targeting NRAS mutations for the development of specific interventions could be a new approach to melanoma prevention, the authors speculate.

However, the authors acknowledge that their study examined mainly individuals with a specific inherited CDKN2A germline mutation. They suggest that future studies extend NRAS mutation analyses to melanomas arising in individuals belonging to families with other CDKN2A mutations and in those with normal CDKN2A genes.

In an accompanying editorial, Kenneth H. Kraemer, M.D., of the National Cancer Institute, says that the link between UV light exposure and NRAS mutations must be viewed as tentative. He points out that other agents may also produce these mutations. "Other yet-to-be-identified abnormalities in DNA repair may be present in cells from patients with familial melanoma that contribute to the observed in vitro and in vivo hypermutability," he writes.

Contact: Ulla Bredberg-R�d�n, Karolinska Institute, 46-8-524-86389; fax: 46-8-33-56-25, [email protected].

Editorial: NCI Press Office, 301-496-6641; fax: 301-496-0846, [email protected].

Eskandarpour M, Hashemi J, Kanter L, Ringborg U, Platz A, Hansson J. Frequency of UV-inducible NRAS mutations in melanomas of patients with germline CDKN2A mutations. J Natl Cancer Inst 2003;95:790�8.

Editorial: Kraemer KH. NRAS hypermutability in familial melanoma with CDKN2A mutations--cause and effect? J Natl Cancer Inst 2003;95:768�9.

Note: The Journal of the National Cancer Institute is published by Oxford University Press and is not affiliated with the National Cancer Institute. Attribution to the Journal of the National Cancer Institute is requested in all news coverage.