Clonal BRAF Mutations in Melanocytic Nevi and Initiating Role of BRAF in Melanocytic Neoplasia

Department of Neuropathology, University Hospital Heidelberg, and CCU Neuropathology, DKFZ, Heidelberg, Germany (AvD).
Journal of the National Cancer Institute (Impact Factor: 12.58). 05/2013; 105(12). DOI: 10.1093/jnci/djt119
Source: PubMed


BRAF(V600E) mutations are frequent in melanomas originating from intermittently sun-exposed skin and also in common acquired melanocytic nevi, suggesting that BRAF mutation is an early event in melanocytic neoplasia. All neoplastic melanocytes within such a nevus would be expected to carry the BRAF mutation, and thus we evaluated the frequency of cells with BRAF(V600E) mutations within acquired nevi by droplet digital polymerase chain reaction. In BRAF-mutant nevi the number of BRAF mutant alleles equaled the number of wild-type (WT) alleles in the neoplastic cell population, consistent with a fully clonal heterozygous BRAF mutation. The allelic ratio of BRAF(V600E) to BRAF(WT) in the eight VE1-positive nevi, adjusted for degree of stromal contamination, ranged from 0.84 to 1.12 with an average ratio of 1.01. This was confirmed by immunohistochemistry with an antibody specific for BRAF(V600E), which uniformly labeled the neoplastic cells without any evidence of heterogeneity. We found BRAF(V600E) mutations in the melanocytic nevi to be fully clonal, strongly suggesting that BRAF-activating mutations typically are early initiating events in melanocytic neoplasia.

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    • "Mutations in B-RAF or N-RAS are found in the majority of melanomas, and are often identified in benign nevi as well [5,6]. Activating mutations in B-RAF and N-RAS occur in 40-60% and 15-25% of melanomas, respectively. "
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    • "The latter may be controlled for through the use of an additional antibody capable of detecting total BRAF protein expression. With regard to the intra-tumor heterogeneity of BRAF V600E, only few cases with non-homogenous expression have been observed following immunohistochemical detection (67, 69). These results are in direct contrast to previous reports describing significant variability of BRAF mutational status among individual cells within a tumor and warrant further investigation (70, 71). "
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