Most melanocytic nevi develop on sun-exposed skin during childhood and adolescence and commonly harbor BRAF mutations or, less frequently, NRAS mutations.
Our results suggest that although nevus propensity is important for the occurrence of both BRAF and NRAS-mutant melanomas, ambient UV irradiance influences risk differently based on the age of exposure.
Both Spitz naevi and spitzoid melanoma had a lower combined BRAF and NRAS mutation frequency compared with common acquired naevi (P = 0.0001) and common forms of melanoma (P = 0.0072), respectively.
The polyclonality of BRAF mutations in acquired melanocytic nevi suggests that mutation of BRAF may not be an initial event in melanocyte transformation.
Oncogenic BRAF mutation had been considered to be a founder event in the formation of melanocytic tumours; however, we recently argued against this notion by showing marked polyclonality of BRAF mutations in acquired melanocytic nevi (Lin et al, J Natl Cancer Inst., 2009; 101:1423-7).
BRAF(V600E) mutations are also present in benign melanocytic naevi, highlighting the importance of additional genetic alterations in the genesis of malignant tumours.
Mutations of the BRAF gene are correlated with younger age, a higher number of melanocytic naevi and a tumour location in intermittently UV-exposed skin.
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.
In contrast, only 21% of the primary melanomas unassociated with naevi were BRAF(V600E) mutant (p = 0.009).Our results suggest that melanomas with associated naevi have a higher frequency of BRAF(V600E) mutations than melanomas unassociated with naevi.
Biopsy findings from 1 unchanged and 1 involuted nevus showed BRAF wild type in the unchanged nevus, BRAFV600E mutation in the involuting nevus, and no malignant histopathologic characteristics in either one.