mutations are known to predispose to melanoma with a reported attributable risk of 1.6% and have been found in both melanocytic naevi and melanoma.7,8
However, the mutation is not present in all types of melanoma, and differences in incidence have been attributed to aetiological factors including sun exposure.9
In keeping with this, BRAF
mutations have been documented in 62% of melanomas arising in sun-exposed sites compared with 0% of vulval melanomas, suggesting that distinct molecular pathways may be involved depending on the presence or absence of sun exposure.9
However, the BRAF
V600E mutation was identified in 23% and 43% of AGN and genital naevi without atypia, respectively, in the current study. Ichii-Nakato et al
. also found the presence of the BRAF
V600E mutation in up to 81% of acquired naevi from glabrous skin.10
The higher proportion may be attributable to different methodologies used in mutation analysis (Mutector assay vs. direct sequencing in the current study) and the cohort studied (acquired naevi without atypia vs. congenital naevi and naevi with atypia in the current study). None the less, both studies support the concept that ultraviolet (UV) radiation is not essential for acquisition of the BRAF
mutation. While the clinical relevance of BRAF
mutations in naevomelanocytic proliferations in non-sunexposed skin remains unclear, somatic mutations of BRAF
have previously been identified as the most common early genetic event causally associated with development of papillary thyroid cancer in patients without a history of radiation exposure.11
This implicates other environmental or intrinsic biological factors as potential causative agents for BRAF
AGN pose a significant diagnostic conundrum. Exemplifying this, one of the cases in the current study was that of a ‘moderate to severely atypical compound neoplasm’ in a 14-year-old patient. The report noted that ‘although the lesion exhibited maturation, given the degree of cytological atypia, florid junctional melanocytic proliferation and presence of dyscohesive nests, malignant melanoma, level III could not be excluded’ by five experienced dermatopathologists. No study to date has sought to elucidate the genomic profile of AGN as compared with benign genital naevi without atypia. We found no significant difference in the frequency of oncogenic BRAF in AGN compared with naevi without atypia from the same anatomical location. Thus, the utility of oncogenic BRAF as a diagnostic adjunct appears to be limited. However, a larger study is needed before a definitive conclusion can be reached.
We have previously found that normal melanocytes express detectable, albeit low, levels of IGFBP7.4
evidence indicates that IGFBP7 blocks BRAF-MEK-ERK
signalling to activate the apoptotic pathway, suggesting that it is an inducer of senescence and apoptosis. Consistent with this, we also found IGFBP7 expression to be upregulated in BRAF
WT melanomas and oncogenic BRAF
V600E-positive naevi, but absent in BRAF
V600E-positive melanoma. In the current study, the enhanced expression of IGFBP7 found in 67% of oncogenic BRAF
-positive AGN suggests that these lesions are biologically inert. While the significance of our findings is limited by the small number of cases studied, oncogenic BRAF
-positive AGN cases with loss of IGFBP7 expression may warrant complete excision and close clinical follow-up.
In conclusion, the prevalence of BRAF V600E in AGN suggests that UV exposure is not essential for generating the BRAF V600E mutation. Furthermore, AGN appear not to differ from genital naevi without atypia with respect to BRAF mutational status. Enhanced expression of the tumour suppressor IGFBP7 in oncogenic BRAF-positive AGN suggests that these lesions behave similarly to oncogenic BRAF-positive naevi. Larger studies and long-term follow-up of AGN is required to confirm their putative banal biological behaviour.