Number of Nevi and Early-Life Ambient UV Exposure Are Associated with BRAF-Mutant Melanoma

Abstract

Malignant melanomas often contain BRAF or NRAS mutations, but the relationship of these mutations to ambient UV exposure in combination with phenotypic characteristics is unknown. In a population-based case series from North Carolina, 214 first primary invasive melanoma patients in the year 2000 were interviewed regarding their risk factors. Ambient solar UV exposures were estimated using residential histories and a satellite-based model. Cases were grouped on the basis of BRAF and NRAS somatic mutations, determined using single-strand conformation polymorphism analysis and radiolabeled DNA sequencing, and the risk profiles of these groups were compared. Mutually exclusive BRAF-mutant and NRAS-mutant cases occurred at frequencies of 43.0% and 13.6% with mean ages at diagnosis of 47.3 and 62.1 years, respectively. Tumors from patients with >14 back nevi were more likely to harbor either a BRAF mutation [age-adjusted odds ratio (OR), 3.2; 95% confidence interval (95% CI), 1.4-7.0] or an NRAS mutation (age-adjusted OR, 1.7; 95% CI, 0.6-4.8) compared with patients with 0 to 4 back nevi. However, BRAF-mutant and NRAS-mutant tumors were distinctive in that BRAF-mutant tumors were characteristic of patients with high early-life ambient UV exposure (adjusted OR, 2.6; 95% CI, 1.2-5.3). When ambient UV irradiance was analyzed by decadal age, high exposure at ages 0 to 20 years was associated with BRAF-mutant cases, whereas high exposure at ages 50 and 60 years was characteristic of NRAS-mutant cases. 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. The association of BRAF mutations with early-life UV exposure provides evidence in support of childhood sun protection for melanoma prevention.

Melanoma Epidemiology and Prevention

“…Age-specific incidence patterns display early-and late-onset peak frequencies for trunk and face/ear melanomas, respectively [130,131], consistent with hypotheses that melanoma arises from more than one causal pathway and contain distinct melanoma genotypes [241]. NRAS and BRAF mutations, mutually exclusive of each other, are found, respectively, in 10-30 and 25-60 % of primary melanomas [60,63,64,93,228]. Less frequently, melanomas contain KIT mutations, particularly mucosal melanoma or melanomas arising on acral or on sun-damaged sites [53].…”

“…These findings are plausible as approximately 70 % of nevi contain BRAF mutations [194]. BRAF mutations were associated with the ability to tan but not with freckling or hair or eye color [93,228]. TERT promoter mutations in melanoma were not associated with hair, skin, or eye color or number of nevi [101].…”

“…BRAF-mutant melanomas are associated with young age at diagnosis, intermittently sun-exposed sites such as the trunk, superficial spreading subtype, absence of solar elastosis, and presence of mitoses [17,60,63,64,93,144,155,228]. NRAS-mutant melanomas are associated with older age at diagnosis, but less associated with specific anatomic location, are more likely to be nodular subtype, and show increased Breslow thickness and presence of mitoses [60,63,64,86,139,228,231,234].…”

“…BRAF-mutant melanomas were found to be more common in patients with increased numbers of nevi [93,228] and with the presence of nevi adjacent to the melanomas [63,195]. These findings are plausible as approximately 70 % of nevi contain BRAF mutations [194].…”

Immunohistochemistry is highly sensitive and specific for the detection of NRASQ61R mutation in melanoma

“…The presence of both NRAS and BRAFV600E mutations in the same lesions is contrary to the current consensus that such mutations are almost always mutually exclusive in melanomas and other tumor types. [17][18][19] However, Pollock et al 20 observed concomitant NRAS and BRAFV600E mutations in 9% of nevi and suggested this might be because of different clonal nests of cells within these tumors carrying distinct mutations. In our case carrying both NRASQ61R and V600E mutations, immunohistochemistry with VE1 and N-Ras (Q61R) antibodies allowed direct visual confirmation of the BRAFV600E-and NRAS-mutated positive status in the same tumor cell population.…”