The genetic evolution of acral melanoma

Abstract

Acral melanoma is an aggressive type of melanoma with unknown origins, arising on the sole, palm, or nail apparatus. It is the most common type of melanoma in individuals with dark skin and is notoriously challenging to treat. Our study examined exome sequencing data from 139 tissue samples, spanning different progression stages, collected from 37 patients. We found that 78.4% of the melanomas displayed one or more clustered copy number transitions with focal amplifications, recurring predominantly on chromosomes 5, 11, 12, and 22. These genomic "hailstorms" were typically shared across all progression stages within individual patients. Genetic alterations known to activate TERT also arose early. By contrast, mutations in the MAP-kinase pathway appeared later during progression, often leading to different tumor areas harboring non-overlapping driver mutations. We conclude that the evolutionary trajectories of acral melanomas substantially diverge from those of melanomas on sun-exposed skin, where MAP-kinase pathway activation initiates the neoplastic cascade followed by immortalization later. The punctuated formation of hailstorms, paired with early TERT activation, suggests a unique mutational mechanism underlying the origins of acral melanoma. Our findings highlight an essential role for telomerase, likely in re-stabilizing tumor genomes after hailstorms have initiated the tumors. The marked genetic heterogeneity, in particular of MAP-kinase pathway drivers, may partly explain the limited success of targeted and other therapies in treating this melanoma subtype.

Receptor tyrosine kinase inhibition leads to regression of acral melanoma by targeting the tumor microenvironment

“…Comparatively, while CM suffers both the intrinsic effects of decreased cell proliferation and extrinsic effects of decreased vascularization with Lenvatinib, it appears less sensitive to the extrinsic effects and is capable of overcoming the intrinsic barriers to growth (Figure 6F). The amplification of genes in the FGF/FGFR/CRKL/GAB2 signaling axis in AM has previously been described 6,19,65 , and our work presents the first attempt to drug this pathway in preclinical models. The therapeutic efficacy of Lenvatinib across all tested AM models reveals an important observation: amplification of genes in the FGF signaling pathway is not a pre-requisite for Lenvatinib sensitivity.…”

“…These include highly amplified genes (≥8 copy number) at loci previously observed to be impacted by tyfonas/hailstorm events 18,19 in 7/11 (64%) of AM compared to only one CM tumor (17%).…”

“…A literature search performed in December 2023 identified eight studies that contained genomic, exomic, and/or transcriptomic data for AM 4,6,19,[24][25][26][27][28] . Of these articles, four provided sufficient genomic data for the evaluation of changes in copy number, translocations, InDels, gene expression for RTK proteins, and/or structural variants 4,6,19,28 . CNV analysis was performed on WES data from 37 AM tumors available in Wang 2023 19 .…”

“…A meta-analysis of available single nucleotide variation (SNV), copy number variation (CNV), structural variation (SV), and transcriptomic data was performed for AM. Eight volar melanocyte and/or AM studies were identified to contain whole genome sequencing (WGS), whole exome sequencing (WES), and/or RNA-sequencing data (RNA-seq) 4,6,19,[24][25][26][27][28] . Of these, three provided sufficient genomic data for the evaluation of InDels, CNV, and/or structural variants 4,19,28 , and one provided RNA-sequencing data 6 .…”

Pattern Analysis of Benign and Malignant Atypical Melanocytic Skin Lesions of Palms and Soles: Variations of Dermoscopic Features According to Anatomic Site and Personal Experience

“…Among different melanoma subtypes, acral melanoma (AM) is the most frequent in non-white populations, including Asians and Africans, and is responsible for the higher proportion of cases in countries with a lower incidence of melanoma overall [ 3 , 4 , 5 , 6 , 7 ]. AM differs from the other melanoma forms in the biological profile causing specific genetic/immunohistochemical features and related behaviors [ 8 , 9 , 10 , 11 , 12 ]: first, it is a non-UV-related tumor arising from the epithelium-associated melanocytes; second, it shows the early onset of major chromosomal rearrangements with gene copy number changes and multiple high-level amplifications (e.g., driver mutations in GNAQ, NF1, KIT TP53, PTEN, or RB1 genes, versus BRAF and NRAS of superficial spreading and nodular melanoma) [ 13 ]; third, it exhibits specific molecular findings (e.g., CCND1 overexpression , AURKA , and TERT) [ 14 ]; fourth, it is characterized by a rapid evolution and ability to metastasize and, thus, a poor prognosis [ 15 , 16 , 17 ]. This said, AM is also known for having a late diagnosis compared with other forms: the more reported underlying hypothesis emphasize the patients’ (and/or physicians’) reticence in examining this area and the difficulty of the differential diagnosis with acral nevi -with reported rates of misdiagnosis of 20%—despite dermoscopic examination [ 18 , 19 , 20 , 21 ].…”