A large pooled analysis refines gene expression-based molecular subclasses in cutaneous melanoma


Thijs T. Wind, Mathilde Jalving, Jacco J. de Haan, Elisabeth G. E. de Vries, Marcel A. T. M. van Vugt, Dirk-Jan Reijngoud, Rozemarijn S. van Rijn, John B. A. G. Haanen, Christian U. Blank, Geke A. P. Hospers & Rudolf S. N. Fehrmann

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.

Figure 1. (a) Consensus clustering for the GEO-dataset showing four clusters of substantial size in the GEO-dataset at k = 4. (b) Consensus clustering for the TCGA-dataset showing four large and one small cluster (n = 5) at k = 5. (c) Enrichment overview of Hallmark gene sets for all paired GEO- and TCGA-dataset consensus clusters. Green arrows indicate enrichment of a Hallmark gene set in upregulated genes, purple arrows indicate enrichment of Hallmark gene sets in downregulated genes. Transparency and arrow width represent the significance level of enrichment.