In melanocytic lesions the fraction of BRAFV600Ealleles is associated with sun exposure but unrelated to ERK phosphorylation

BRAFV600Emutation has been frequently reported in different types of melanocytic lesions, but its role in melanomagenesis is poorly understood, having been associated with either the proliferative-induced MAPK pathway activation or the acquisition of oncogene-driven senescence. The presence of BRAF alterations has been related to sun exposure, although the molecular mechanisms underlying this event are only partly known. To elucidate the relationships among BRAF/NRAS alterations, MAPK pathway activation, and sun exposure, we examined 22 acquired nevi and 18 cutaneus melanomas from 38 patients. Microdissected tissues from each lesion were subjected to BRAF/NRAS mutation analysis by sequencing, allele-specific PCR and pyrosequencing assay. The same lesions were also examined for the expression of phosphorylated ERK1/2. Phototype and an accurate history of sun exposure were evaluated for each patient. BRAFV600Emutation was detected in 50% of the acquired nevi and in 70% of the cutaneus melanomas in the absence of NRAS alterations. The fraction of alleles carrying BRAFV600Esubstitution was variable but strongly associated with sun exposure. In contrast, no relationship was evidenced between the presence of this mutation and patients' phototype, phosphorylated ERK1/2 expression, or Clark's level. Our findings indicate that in melanocytic lesions, BRAFV600Emutation can affect a subset of the cells and is associated with the type and quantity of sun exposure. This mutation is independent of the nevo-melanoma progression and unrelated to ERK phosphorylation, suggesting that alternative mechanisms to the MAPK activation are also involved in this type of transformation.Modern Pathology (2008) 21, 716–726; doi:10.1038/modpathol.2008.41; published online 11 April 2008