Subclinical fields of BRAF V600E-mutant melanocytes populate human skin and are enriched around melanoma and naevi

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BACKGROUND: The origins of cutaneous melanoma are often traced to visible precursor lesions (e.g. melanocytic naevi), but approximately two-thirds of melanomas arise from clinically healthy skin with no detectable precursor lesion. The BRAF V600E mutation drives melanoma and naevus formation, but eruptive naevi syndromes and the disproportionate role early-life ultraviolet exposure plays in melanoma risk suggest the presence of a hidden field of oncogene-mutant melanocytes in clinically healthy skin, which may represent an earlier step in tumorigenesis. OBJECTIVES: To determine whether BRAF V600E-mutant melanocytes were commonly present in nonlesional skin from adults at high risk of melanoma. METHODS: We examined BRAF V600E mutations in 97 histologically and clinically healthy, nonlesional skin samples from an Australian cohort of individuals at high risk of melanoma. The skin selected was adjacent to a naevus or a prior melanoma site; photodamaged skin proximal (approximately 5 cm) from melanoma excision; photoprotected skin distant from lesions; and low-risk neonatal foreskin-derived melanoblasts. We used immunohistochemistry to locate BRAF V600E-mutant cells in histopathology sections; droplet digital polymerase chain reaction to determine the fractional abundance of BRAF V600E in whole skin; and single-cell RNA sequencing to confirm cells as melanocytes and detect their transcriptional programmes. RESULTS: We identified BRAF V600E-mutant melanocytes in skin surrounding naevi and primary melanomas, even years after tumour excision. Fields of BRAF V600E-mutant melanocytes were commonly found in the skin of patients at high risk for melanoma and were up to 20-fold denser and 50% more frequent in tumour-adjacent skin. Field cells exhibited a gene expression profile characteristic of BRAF V600E-induced growth arrest, consistent with dormant yet genetically primed cells. CONCLUSIONS: There is a reservoir of oncogene-harbouring melanocytes in normal skin. Our findings challenge the prevailing notion that melanocyte expression of BRAF V600E is inherently tumorigenic. The presence of such fields suggests that the scope of melanoma detection and prevention efforts might be extended beyond visible lesions, to encompass potentially precancerous fields of driver-mutant cells. An author video to accompany this article is available online.

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