Locus-specific HERV expression identifies an aggressive, NK-depleted, checkpoint-refractory acral melanoma phenotype.
A three-locus human endogenous retroviruses signature independently predicts worse survival in acral melanoma.
Locus-specific HERV expression identifies an aggressive, NK-depleted, checkpoint-refractory acral melanoma phenotype.
Acral melanoma (acral melanoma) is a non-ultraviolet (non-UV)-derived subtype of cutaneous melanoma that is associated with worse survival outcomes compared to UV-driven melanomas.
We quantified locus-specific transposable elements expression from RNA sequencing (RNA-seq) of 36 acral melanoma samples from 33 patients and integrated the results with clinical outcomes, a pathologist-reviewed purity covariate, and immune cell deconvolution.
Each 1-SD higher risk score nearly doubled death risk, independent of tumor factors.
A three-locus human endogenous retroviruses signature, composed of ERV316A3_6p25.1d, HERVH_6q21a , and ERVLE_9q21.32c , stratified acral melanoma tumors by overall survival with a leave-one-patient-out C-index of 0.778 (bootstrap 95% confidence interval [CI]: 0.614-0.914, permutation p = 0.015) and a Kaplan-Meier log-rank of p = 0.003 across risk tertiles.
High-risk tumors were natural killer (natural killer)-cell-depleted (Spearman ρ = -0.58, false discovery rate [FDR] p = 0.004) and showed coordinated elevation of LIN28A and HMGA2 (ρ = +0.55 and +0.45), consistent with reactivation of the LIN28A/let-7/HMGA2 oncofetal axis rather than a full pluripotency program.
Our findings reframe acral melanoma as a transcriptomically stratifiable disease, define a locus-specific human endogenous retroviruses signature of aggressive, checkpoint-refractory acral melanoma, and nominate a structurally intact, pan-HLA-presentable human endogenous retroviruses-K antigen candidate for further evaluation.