This study aimed to establish the number of expression-based molecular subclasses in cutaneous melanoma, identify their dominant biological pathways and evaluate their clinical relevance. To this end, consensus clustering was performed separately on two independent datasets (n = 405 and n = 473) composed of publicly available cutaneous melanoma expression profiles from previous studies. Four expression-based molecular subclasses were identified and labelled 'Oxidative phosphorylation', 'Oestrogen response/p53-pathway', 'Immune' and 'Cell cycle', based on their dominantly expressed biological pathways determined by gene set enrichment analysis. Multivariate survival analysis revealed shorter overall survival in the 'Oxidative phosphorylation' subclass compared to the other subclasses. This was validated in a third independent dataset (n = 214). Finally, in a pooled cohort of 76 patients treated with anti-PD-1 therapy a trend towards a difference in response rates between subclasses was observed ('Immune' subclass: 65% responders, 'Oxidative Phosphorylation' subclass: 60% responders, other subclasses: <50% responders). These findings support the stratification of cutaneous melanoma in four expression-based molecular subclasses.
Keywords: Cutaneous melanoma; anti-PD-1 therapy; consensus clustering; gene expression; molecular classification; pooled analysis.