Distinct genomic features in a retrospective cohort of mucosal, acral, and vulvovaginal melanomas

Abstract

Background: Compared with sun-exposed melanomas, less is known regarding the pathogenesis of sun-protected melanomas. Sun-protected melanomas share many epidemiologic factors, but their genetic heterogeneity is not well studied.

Objective: We investigated the genomic profile of acral, mucosal, and vulvovaginal melanomas. We hypothesize that mucosal melanomas, recognized for their uniquely aggressive clinical behavior, have distinct genomic features.

Methods: We performed whole transcriptome messenger RNA and DNA (1711 genes) sequencing, messenger RNA expression profiling, tumor mutational burden, ultraviolet signature, and copy number variants analysis on 29 volar/digital acral, 7 mucosal, and 6 vulvovaginal melanomas.

Results: There was significant genetic heterogeneity, particularly in acral melanomas, with 36% having BRAF alterations, whereas other melanomas had none (P = .0159). Nonzero ultraviolet signatures were more frequent in acral melanomas, suggesting greater ultraviolet involvement. Mucosal melanomas formed a distinct group with increased expression of cell cycle and proliferation genes. Various targetable aberrations were identified, such as AURKA and ERBB2, in mucosal and acral melanomas, respectively.

Limitations: The sample size was a small.

Conclusion: There is significant genetic heterogeneity among sun-protected melanomas. Mucosal melanomas have upregulation in cell cycle and proliferation genes, which may explain their aggressive behavior. Ultraviolet radiation plays some role in a subset of acral but not other melanomas.

Keywords: AURKA; BRAF; CDKN2A; CNV; DNA; ERBB2; HER2/Neu; KIT; NF1; NRAS; TERT; TMB; acral; cell cycle and proliferation; expression; genomic; head and neck; mRNA; melanoma; mucosal; sequencing; sun-exposed; sun-protected; ultraviolet; vaginal; vulvar; vulvovaginal.