The Molecular Landscape of Primary Acral Melanoma: A Multicenter Study of the Italian Melanoma Intergroup (IMI)

Abstract

Acral melanoma (AM) is a rare and aggressive subtype of melanoma affecting the palms, soles, and nail apparatus with similar incidence among different ethnicities. AM is unrelated to ultraviolet radiation and has a low mutation burden but frequent chromosomal rearrangements and gene amplifications. Next generation sequencing of 33 genes and somatic copy number variation (CNV) analysis with genome-wide single nucleotide polymorphism arrays were performed in order to molecularly characterize 48 primary AMs of Italian patients in association with clinicopathological and prognostic features. <i>BRAF</i> was the most commonly mutated gene, followed by <i>NRAS</i> and <i>TP53</i>, whereas <i>TERT</i> promoter, <i>KIT</i>, and <i>ARID1A</i> were less frequently mutated. Gains and losses were recurrently found in the 1q, 6p, 7, 8q, 20 and 22 chromosomes involving <i>PREX2</i>, <i>RAC1</i>, <i>KMT2C</i>, <i>BRAF</i>, <i>CCND1</i>, <i>TERT</i>, and <i>AKT3</i> genes, and in the 6q, 9, 10, 11q and 16q chromosomes including <i>CDKN2A</i>, <i>PTEN</i>, and <i>ADAMTS18</i> genes, respectively. This study confirmed the variety of gene mutations and the high load of CNV in primary AM. Some genomic alterations were associated with histologic prognostic features. <i>BRAF</i> mutations, found with a higher rate than previously reported, correlated with a low Breslow thickness, low mitotic count, low CNV of the AMs, and with early-stage of disease.