Histologic and phenotypic factors and MC1R status associated with BRAF(V600E), BRAF(V600K), and NRAS mutations in a community-based sample of 414 cutaneous melanomas

Cutaneous melanomas arise through causal pathways involving interplay between exposure to UV radiation and host factors, resulting in characteristic patterns of driver mutations in BRAF, NRAS, and other genes. To gain clearer insights into the factors contributing to somatic mutation genotypes in melanoma, we collected clinical and epidemiologic data, performed skin examinations, and collected saliva and tumor samples from a community-based series of 414 patients aged 18 to 79, newly diagnosed with cutaneous melanoma. We assessed constitutional DNA for nine common polymorphisms in melanocortin-1 receptor gene (MC1R). Tumor DNA was assessed for somatic mutations in 25 different genes. We observed mutually exclusive mutations in BRAF (26%), BRAF (8%), BRAF (5%), and NRAS (9%). Compared to patients with BRAF wild-type melanomas, those with BRAF mutants were significantly younger, had more nevi but fewer actinic keratoses, were more likely to report a family history of melanoma, and had tumors that were more likely to harbor neval remnants. BRAF mutations were also associated with high nevus counts. Both BRAF and NRAS mutants were associated with older age but not with high sun exposure. We also found no association between MC1R status and any somatic mutations in this community sample of cutaneous melanomas, contrary to earlier reports

Site-specific determinants of cutaneous melanoma: a case-case comparison of patients with tumors arising on the head or trunk

Cutaneous melanomas have been hypothesized to arise through different pathways according to phenotype, body site, and sun exposure. To further test this hypothesis, we explored associations between phenotype and melanoma at different sites using a case-case comparative approach.Melanoma patients (n = 762) aged 18 to 79 years and diagnosed from 2007 to 2010 were ascertained from pathology laboratories in Brisbane, Australia. Patients reported phenotypic information and a dermatologist counted melanocytic nevi and solar keratoses. We compared data for patients with trunk melanoma (n = 541, the reference group), head/neck melanoma (n = 122), or lentigo maligna melanoma (LMM) of the head/neck (n = 69). ORs and 95% confidence intervals were calculated using classical or polytomous logistic regression models.Compared with trunk melanoma patients, those with head/neck melanoma were significantly less likely to have high nevus counts (≥135: OR = 0.27; Ptrend = 0.0004). Associations between category of nevus count and LMM head/neck were weaker and significantly different (≥135: OR = 1.09; Ptrend = 0.69; Phomogeneity = 0.02). Patients with head/neck melanoma were more likely than those with truncal melanoma to have high solar keratosis counts (≥7: OR = 1.78, Ptrend = 0.04). Again, associations with LMM head/neck were weaker, albeit not significantly different (≥7: OR = 1.61; Ptrend = 0.42; Phomogeneity = 0.86).Trunk melanomas are more strongly associated with nevus counts than head/neck melanomas, but are less strongly associated with number of solar keratoses, a marker of chronic sun exposure.These findings underscore the notion that melanomas on the trunk typically arise through a causal pathway associated with nevus propensity, whereas melanomas on the head/neck arise through a pathway associated with cumulative sun exposure

Solar elastosis and cutaneous melanoma: a site-specific analysis

Cutaneous melanomas are postulated to arise through at least two causal pathways, namely the "chronic sun exposure" and "nevus" pathways. While chronic sun exposure probably causes many head/neck melanomas, its role at other sites is unclear. In a population-based, case-case comparison study conducted in Brisbane, Australia, we determined the prevalence and epidemiologic correlates of chronic solar damage in skin adjacent to invasive, incident melanomas on the trunk (n-=-418) or head/neck (n-=-92) among patients aged 18-79 in 2007-2010. Participants self-reported information about environmental and phenotypic factors, and a dermatologist counted nevi and actinic keratoses. Dermatopathologists assessed solar elastosis adjacent to each melanoma using a four-point scale (nil, mild, moderate, marked), and noted the presence or absence of adjacent neval remnants. We measured associations between various factors and solar elastosis using polytomous logistic regression. Marked or moderate solar elastosis was observed in 10% and 27%, respectively, of trunk melanomas, and 60% and 17%, respectively, of head/neck melanomas. At both sites, marked elastosis was positively associated with age (p

Factors related to nevus-associated cutaneous melanoma: a case-case study

A proportion of cutaneous melanomas display neval remnants on histologic examination. Converging lines of epidemiologic and molecular evidence suggest that melanomas arising from nevus precursors differ from melanomas arising de novo. In a large, population-based study comprising 636 cutaneous melanomas subjected to dermatopathology review, we explored the molecular, host, and environmental factors associated with the presence of neval remnants. We found that nevus-associated melanomas were significantly associated with younger age at presentation, non-brown eye color, trunk site, thickness of less than 0.5 mm, and BRAF mutation. Compared with patients with de novo melanomas, those with nevus-associated tumors were more likely to self-report many moles on their skin as a teenager (odds ratio\ua0= 1.94, 95% confidence interval\ua0= 1.01-3.72) but less likely to report many facial freckles (odds ratio\ua0= 0.49, 95% confidence interval\ua0= 0.25-0.96). They also had high total nevus counts (odds ratio\ua0= 2.18, 95% confidence interval\ua0= 1.26-3.78). On histologic examination, nevus-associated melanomas exhibited less dermal elastosis in adjacent skin compared with de novo melanomas (odds ratio\ua0= 0.55, 95% confidence interval\ua0= 0.30-1.01). These epidemiologic data accord with the emerging molecular paradigm that nevus-associated melanomas arise through a distinct sequence of causal events that differ from those leading to other cutaneous melanomas