Compared to 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 mRNA and DNA (1711 genes) sequencing, mRNA expression profiling, TMB, UV signature and CNV 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 while other melanomas had none (p = 0.0159). Nonzero UV signatures were more frequent in acral melanomas, suggesting greater UV 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

There was a small sample size.

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.