MC1R Germline Variants Confer Risk for BRAF-Mutant Melanoma
Landi, M.T., Bauer, J., Pfeiffer, R.M., Elder, D.E. et al. Science, 313, 521-522 (July 28, 2006).
An international team has investigated the relationship between variants of the melanocortin-1 receptor gene (MC1R), the BRAF oncogene, and the development of melanoma in two distinct patient populations. (BRAF is a serine/threonine kinase that is considered an oncogene due to mutations that occur in its exon 15 and because of its normal function in carrying mitogenic signals from the cell membrane to the nucleus. BRAF mutations are commonly associated with primary melanoma tumors that lack evidence of chronic sun-induced damage.) Sequence analyses of MC1R and the BRAF exon 15 were performed on 197 melanomas and 171 control tissue samples. Pathologists sorted the tumors into two groups, those related via solar elastosis to chronic sun-induced damage (CSD) and those that lacked evidence of CSD.
The results show that in non-CSD melanomas, BRAF mutations occur 6 to 13 times more frequently when at least one MC1R variant allele is present, versus tumors having wild-type MC1R alleles. Moreover, the risk of developing a melanoma increased with the number of variant MC1R alleles, but that risk was limited to individuals with BRAF mutations. The tumors occurred more often on anatomic sites only intermittently exposed to the sun, such as the trunk, rather than on areas regularly exposed to sunlight, including the face.
CSD tumors, typically found in older patients, had lower BRAF mutation frequencies, suggesting that there is no a simple link between these genetic errors, sun exposure, and oncogenesis. Indeed, BRAF mutations were not associated with such phenotypic traits as hair, skin, or eye color that are related MC1R variants and to sun sensitivity. Note that MC1R variation had no effect on the frequency of BRAF mutations in CSD-related tumors.
The study indicates that susceptibility of developing non-CSD melanoma varies directly with the frequency of MC1R variations and that sunlight plays an indirect role in promoting BRAF mutations. However, MC1R may not be the only factor determining susceptibility for this type of cancer, nor is it likely that melanoma is the only cancer in which genetic variations will be found to influence the development of a neoplasm in response to an environmental stimulus.
Message posted by: Keith Markey
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