Spatial transcriptomic analysis of amelanotic acral melanoma versus pigmented acral melanoma reveals distinct molecular determinants

Abstract Background Amelanotic acral melanoma (AAM) is a rare type of acral melanoma that has a poor prognosis. Objectives To investigate the transcriptomic differences between AAM and pigmented acral melanoma (PAM). Methods Differences in the spatially resolved transcriptomic profiles of 9 patients with AAM with 29 regions of interest (ROIs) and 11 patients with PAM with 46 ROIs were investigated using S100b and CD3 morphology markers. Results In S100b+ tumour cell areas, we detected 11 upregulated differentially expressed genes (DEGs; including chaperone/ubiquitin-­associated DEGs) and 82 downregulated DEGs (including human leucocyte antigen) in AAMs vs. PAMs. Protein–protein interaction network and pathway analyses revealed significant enrichment of dysregulated translational and nonsense-mediated decay pathways but significant decreases in antigen processing and presentation, interferon signalling and melanin biosynthesis pathways in S100b+ ROIs of AAMs compared with PAMs. In tumour-associated immune cell areas, the numbers of CD8 T cells (P = 0.04) and M1 macrophages (P = 0.01) were significantly decreased, whereas those of monocytes (P = 0.04) and endothelial cells (P = 0.04) were increased in AAMs compared with PAMs. Conclusions These findings could widen our understanding of the biological differences between AAMs and PAMs, which might result in a different clinical course.