Clinical Correlates of NRAS and BRAF Mutations in Primary Human Melanoma

Abstract

Purpose: NRAS and BRAF mutations are common in cutaneous melanomas, although rarely detected mutually in the same tumor. Distinct clinical correlates of these mutations have not been described, despite in vitro data suggesting enhanced oncogenic effects. This study was designed to test the hypothesis that primary human cutaneous melanomas harboring mutations in NRAS or BRAF display a more aggressive clinical phenotype than tumors wild type at both loci.Experimental Design: Microdissection of 223 primary melanomas was carried out, followed by determination of the NRAS and BRAF mutational status. Genotypic findings were correlated with features known to influence tumor behavior including age, gender, Breslow depth, Clark level, mitotic rate, the presence of ulceration, and American Joint Committee on Cancer (AJCC) staging.Results: Breslow depth and Clark level varied significantly among the genotypes, with NRAS mutants showing the deepest levels and wild-type tumors the least depth. Ulceration also differed significantly among the genotypes, with BRAF mutants demonstrating the highest rate. In addition, tumors with mutated NRAS were more likely to be located on the extremities. Patients whose tumors carried either mutation presented with more advanced AJCC stages compared with patients with wild-type tumors, and specifically, were more likely to have stage III disease at diagnosis. Overall survival did not differ among the 3 groups.Conclusions: Distinct clinical phenotypes exist for melanomas bearing NRAS and BRAF mutations, whether considered together or separately, and are associated with features known to predict aggressive tumor behavior. The impact of these mutations is most evident at earlier stages of disease progression.

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].…”

“…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].…”

Nras in melanoma: Targeting the undruggable target

“…Ulceration was reported to be lower in NRAS-mutated tumors in comparison to BRAF mutated tumors (9.7 versus 22.4%, respectively) [63] but no obvious effect of mutational status on the presence of ulceration was reported by others [68]. Melanomas harboring NRAS mutations have shown greater mitotic rates than BRAF mutant melanomas [63,68].…”

“…The incidence of the NRAS mutation according to tumor site was highest in the extremities (25%), followed by the face or scalp (18%) and trunk (18%) [55,61,63]. NRAS mutations have also been found in conjunctival melanomas (18% frequency) [63], sinonasal melanomas (22%) [65], esophageal melanomas (37.5%), including mutations in exon 1, which is a rare mutation site for cutaneous melanoma [66]. Interestingly, melanoma of unknown primary sites showed NRAS mutations in 32% of cases associated with high somatic mutation rates, high ratios of C>T/G>A transitions, and a 45% of BRAF mutations, collectively indicating a mutation profile consistent with cutaneous sun-exposed melanomas [67].…”

Mutational dichotomy in desmoplastic malignant melanoma corroborated by multigene panel analysis

“…6,7 Targeted therapies (vemurafenib and imatinib) available for patients harbouring BRAF, 8 NRAS, 9 and KIT 10 mutations have added therapeutic relevance to mutational subtyping of malignant melanoma. Increasing evidence demonstrated that mutational characteristics segregate with currently accepted subtyping based on histology and tumor location: [11][12][13][14][15][16] uveal melanomas present the prototypical case of a melanoma entity with a distinct mutation profile as they typically lack BRAF mutations, 17 but instead frequently display GNAQ or GNA11 mutations. 18,19 Spitzoid melanomas demonstrate a reduced BRAF mutation frequency compared to general melanoma, 11 and mucosal melanomas are frequently KIT mutated but BRAF wild type.…”