Bioinformatic analysis identifies epidermal development genes that contribute to melanoma progression

Several diagnostic and prognostic markers for melanoma have been identified in last few years. However, their actual contribution to melanoma progression have not been investigated in detail. This study was aimed to identify genes, biological processes, and signaling pathways implicated in melanoma progression by applying bioinformatics analysis. We identified nine differentially expressed genes (DEGs) (IL36RN, KRT6A, KRT6B, KRT16, S100A7, SPRR1A, SPRR1B, SPRR2B, and KLK7) that were upregulated in primary melanoma compared with metastatic melanoma in all five datasets analyzed. All these genes except IL36RN, both form a protein-protein interaction network and have cellular functions associated with constitutive processes of keratinocytes. Thus, they were generically termed Epidermal Development and Cornification (EDC) genes. The differential expression of these genes in primary and metastatic melanoma was confirmed in the TCGA-SKCM cohort. High expression of the EDC genes correlated with reduced tumor thickness in primary melanoma and shorter survival in metastatic melanoma. Analysis of DEGs from primary melanoma patients displaying high or low expression of all eight EDC revealed that the upregulated genes are enriched in biological process related to cell migration, extracellular matrix organization, invasion, and Epithelial-Mesenchymal Transition. Further analysis of enriched curated oncogenic genesets together with RPPA data of phosphorylated proteins revealed the activation of MEK, ATF2, and EGFR pathways in tumors displaying high expression of EDC genes. Thus, EDC genes may contribute to melanoma progression by promoting the activation of MEK, ATF2, and EGFR pathways together with biological processes associated with tumor aggressiveness.