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There is increasing epidemiological and molecular evidence that cutaneous melanomas
arise through multiple causal pathways. The purpose of this study was to explore the
relationship between germline and somatic mutations in a population-based series of
melanoma patients to reshape and refine the divergent pathway model for melanoma.
Melanomas collected from 123 Australian patients were analyzed for melanocortin-1
receptor (MC1R) variants and mutations in the BRAF and NRAS genes. Detailed phenotypic
and sun exposure data were systematically collected from all patients. We found that
BRAF-mutant melanomas were significantly more likely from younger patients and those
with high nevus counts, and were more likely in melanomas with adjacent neval remnants.
Conversely, BRAF-mutant melanomas were significantly less likely in people with high
levels of lifetime sun exposure. We observed no association between germline MC1R
status and somatic BRAF mutations in melanomas from this population. BRAF-mutant melanomas
have different origins from other cutaneous melanomas. These data support the divergent
pathways hypothesis for melanoma, which may require a reappraisal of targeted cancer