Bulk RNA sequencing of 43 formalin-fixed, paraffin-embedded nail unit melanomas identified two transcriptomic groups associated with clinical stage. The early-stage-enriched group showed higher expression of epidermal adhesion and keratinocyte differentiation genes, whereas the late-stage-enriched group showed higher expression of melanocytic and collagen/extracellular matrix-stromal genes, inflammatory myeloid genes, and chromatin and interferon-γ/MHC antigen presentation genes.
ABSTRACT
Acral melanoma, a rare subtype arising on the palms, soles, and nail unit, responds poorly to immune checkpoint inhibitors. Among acral melanomas, nail unit melanoma is less common than plantar melanoma, and the transcriptomic programs associated with its progression remain poorly understood. We performed bulk RNA sequencing of 43 nail unit melanoma specimens from early- to late-stage disease. Unsupervised clustering identified two transcriptomic groups that were associated with clinical stage, with one group enriched for late-stage tumors and the other for early-stage tumors. The late-stage-enriched group showed higher expression of collagen/extracellular matrix (ECM) genes involved in collagen processing, assembly, and remodeling, whereas the early-stage-enriched group showed higher expression of epidermal and basement membrane-associated genes. In the late-stage-enriched group, deconvolution showed higher macrophage and lower CD8+ T cell estimates, and SPP1 and APOE were more highly expressed; both genes also showed higher expression in late-stage tumors. Across tumors, macrophage and tumor-associated macrophage signature scores correlated positively with a collagen biosynthesis gene-set score, including after adjustment for histological tumor purity. Several stage-associated differences were attenuated after purity adjustment. These tissue-level associations describe collagen/ECM- and macrophage-associated features of nail unit melanoma; their cellular origin and clinical relevance require independent evaluation.
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