Systematic review and meta‐analysis of genomic alterations in acral melanoma

Abstract

Acral melanoma (AM) occurs on glabrous skin, the non-hair-bearing skin of the volar surfaces of the extremities, including palms, soles, fingers, toes, and nailbeds (subungual). The genomic aberrations in AM differ from the other subtypes of cutaneous melanoma (CM; nodular, lentigo maligna, and superficial spreading), notably in number and signatures of mutations, and the frequency of chromosomal rearrangements, such as copy-number alterations (CNAs) and structural variants (SV) (Hayward et al., 2017).

Basic Concepts in Nail Pathology

“…83 In addition, new mutations in KRAS, CTNNB1, TP53, ERBB2, and SMAD4 have been reported in subungual melanoma. 83 This contrasts greatly with acral melanoma, in which BRAF is the most frequently mutated gene, 84 followed by NRAS, PTEN, TYRP1, TP53, NF1, NOTCH2, and TYRP1 85,86 while mutations in the TERT promoter, KIT, and ARID1A genes are less frequent. 84…”

“…In addition, whole-genome duplication, aneuploidy, and complex rearrangements were common in affected cases. Recurrent complex rearrangements were found to be associated with amplification of TERT, CDK4, MDM2, CCND1, PAK1, and GAB2 genes Broit et al 85 The commonly mutated genes include BRAF, NRAS, PTEN, TYRP1, and KIT. In addition, frequent copy-number aberrations have been identified in key cancer-related genes, such as CDKN2A, KIT, MDM2, CCND1, CDK4, and PAK1…”

Nail Apparatus Melanoma: Current Management and Future Perspectives

“…For unresectable BRAF wild-type melanoma, immune checkpoint inhibitors, including anti-PD-1 monotherapy (nivolumab or pembrolizumab) or combination therapy (nivolumab/ipilimumab or nivolumab/relatlimab) are recommended as first-line treatments [ 64 ]. Since most NAM cases have wild-type BRAF , unresectable cases are principally treated with immune checkpoint inhibitors [ 52 , 92 , 93 , 94 ]. Cutaneous melanomas are rich in tumor mutations [ 45 ], which is a biomarker for the sensitivity to immune checkpoint inhibitors [ 95 ].…”

“…The latest NCCN guidelines recommend BRAF/MEK inhibitor combination therapy (dabrafenib/trametinib, encorafenib/binimetinib, and vemurafenib/cobimetinib) as one of the first-line treatments for BRAF -mutated cutaneous melanoma [ 64 ]. As already mentioned, BRAF mutations are uncommon in acral melanoma (about 20%) and NAM (about 10%), and BRAF/MEK inhibitor therapy is suitable for only a subset of patients [ 23 , 52 , 92 , 93 , 94 , 114 ]. Evidence on the efficacy of BRAF/MEK inhibitors for acral melanoma, especially NAM, is accordingly limited.…”

Comparative Genomics Provides Etiologic and Biological Insight into Melanoma Subtypes

“… 28, 29 ). Recent reviews of AM ( 30 ) and MM ( 31 ) genomics present comprehensive summaries of driver gene mutations and copy-number aberrations in these melanoma subtypes based on published WGS, WES, and targeted sequencing studies. Curtin and colleagues ( 32 ) performed the first genomic comparison of melanoma subtypes, looking at copy-number alterations (CNA) and BRAF and NRAS hotspot mutations in 126 tumors.…”