Identification of two molecularly and prognostically distinct subtypes in acral melanoma using network prediction method

Abstract Background Acral melanoma, characterized by its aggressiveness and poor prognosis compared to other melanoma subtypes, poses significant challenges in clinical management. However, the molecular underpinnings driving the biological and clinical features of this disease remain poorly understood. Objectives In this study, our aim was to elucidate the molecular landscape and the correlation between subtypes and clinical features of acral melanoma. Methods We conducted comprehensive analyses to dissect the molecular characteristics of acral melanoma, employing a combination of multi‐omics data analysis and network‐based disease gene prediction algorithms. Single‐cell RNA‐Seq data were utilized to investigate the contribution of immunocytes to the molecular classification of acral melanoma. Additionally, we used clinical samples to validate the correlation between new subtypes and the prognosis of acral melanoma and the expression of subtype markers and verified the interaction between macrophages and acral melanoma cells at cellular level. Results Our study reveals the existence of two distinct subtypes of acral melanoma exhibiting marked differences in clinical behaviour, cellular and molecular mechanisms. We identified a robust biomarker panel (EREG, VSIG4, FCGR3A and RAB20) that accurately distinguishes these two subtypes with an impressive AUC of 0.946, validated using clinical samples. Subtype I, characterized by thinner Breslow thickness, demonstrates a favourable prognosis, whereas Subtype II represents a high‐risk subtype with a propensity for dermal invasion. Notably, the signature gene EREG of Subtype I is enriched in FCN1 + macrophages, known for promoting inflammatory and immune responses. Conversely, signature genes VSIG4 and FCGR3A of Subtype II are enriched in SPP1 + macrophages, which exhibit significant crosstalk with tumour cells. Conclusions Our findings significantly enhance the understanding of the molecular landscape of acral melanoma and offer novel insights into its clinical management by identifying distinct subtypes and potential therapeutic targets. The findings have to be confirmed in different cohorts in the future for full validation.