Genetic Alterations in Primary Acral Melanoma and Acral Melanocytic Nevus in Korea: Common Mutated Genes Show Distinct Cytomorphological Features

Abstract

Acral melanoma occurring on the palms, soles, and nails is the most common subtype of cutaneous melanoma in Asians. Genetic alterations in acral melanoma and acral melanocytic nevus are not well known. We performed next-generation sequencing and evaluated the correlations between genetic information and the clinicopathologic characteristics from 85 Korean patients with acral melanocytic neoplasms. Of the 64 patients with acral melanoma, most had lesions at the T2 stage or higher, and the heel was the most common anatomical site of melanoma (n = 34 [53.1%]). The five most common mutations were BRAF (22 [34.4%]), NRAS (14, [21.9%]), NF1 (11, [17.2%]), GNAQ (12, [17.2%]), and KIT (7, [10.9%]). In the 21 acral melanocytic nevi, those five gene mutations were also common. Copy number variations were also frequently detected in 75% of acral melanomas and 47.6% of acral melanocytic nevi, and amplification was more common than deletion in both lesions. BRAF mutation was associated with round epithelioid cells and NRAS and NF1 mutations with bizarre cells. NF1 and GNAQ mutations showed elongated and spindle cells with prominent dendrites in acral melanomas. KIT mutations were common in amelanotic acral melanoma. This study suggests that common mutated genes are associated with distinct cytomorphological features in acral melanocytic lesions.

Whole genome sequencing of melanomas in adolescent and young adults reveals distinct mutation landscapes and the potential role of germline variants in disease susceptibility

“…Likewise, our study identified two NRAS mutant cases that arose within congenital nevi, consistent with the results of a previous study by Lu and collegues . Interestingly, our study identified two NF1 mutant AYA melanomas, genotypes not previously described in AYA melanoma and which are rarely found in nevi . Both cases arose on high UVR exposed sites, with the wide excision specimen of one case displaying an extraordinarily high degree of solar elastosis for such a young patient.…”

“…11 Interestingly, our study identified two NF1 mutant AYA melanomas, genotypes not previously described in AYA melanoma and which are rarely found in nevi. 32,33 Both cases arose on high UVR exposed sites, with the wide excision specimen of one case displaying an extraordinarily high degree of solar elastosis for such a young patient. Therefore, the unusual presence of the somatic NF1 mutation, typically seen in much older sundamaged adults, 34 could have arisen in these AYA through increased sensitivity to UVR induced DNA damage.…”

Melanoma subtypes: genomic profiles, prognostic molecular markers and therapeutic possibilities

“…By undertaking unsupervised hierarchical clustering of gene expression profiles, Jönsson and collaborators were able to categorise melanomas into four biologically relevant subgroups; MITFlow/proliferative, high-immune response, MITF-high/ pigmentation and normal-like [19]. Importantly, the MITF-low/proliferative subtype, characterised by an absence of the expression of immune-response genes, had only BRAF/NRAS-mutated samples and more ∼5-10% [3,4] rarely seen [13,43] ∼3-36% [44,46,47,52] ∼11% [53] ∼7-25% [3,51,54] GNAQ ∼1.5-2.1% [3,55] rarely seen [13,43] ∼0-17% [3,47] ∼43-57% [48,49]…”

Immunohistochemical BRAF V600E Expression and Intratumor BRAF V600E Heterogeneity in Acral Melanoma: Implication in Melanoma-Specific Survival

“…Acral melanoma is rare in Caucasian populations, while it is the most common subtype of melanoma in Asian, African, and Latin American populations [2]. Although several genomic profiling studies of melanoma have been conducted, the numbers of acral melanoma cases in these were limited [11][12][13][14][15]. Furthermore, the genetic heterogeneity of acral melanoma has not been fully investigated.…”