Transcriptional dissection of melanoma identifies a high-risk subtype underlying TP53 family genes and epigenome deregulation

We set out to identify molecular underpinnings of high-risk melanomas, those that are likely to progress rapidly, metastasize, and result in poor outcomes. Gene expression changes unequivocally discriminated benign versus malignant states, and a dual epigenetic and immune signature emerged defining this transition. We discovered previously unrecognized melanoma subtypes. A high-risk primary melanoma subset was discriminated by a 122-epigenetic gene signature (‘epigenetic’ cluster) and TP53 family gene deregulation (TP53, TP63, and TP73). This subtype associated with poor overall survival and showed enrichment of cell cycle genes. Noncoding repetitive element transcripts (LINEs, SINEs, and ERVs) that can result in immunostimulatory signals recapitulating a state of ‘viral mimicry’ were significantly repressed. The high-risk subtype and its poor predictive characteristics were validated in several independent cohorts. Additionally, primary melanomas distinguished by specific immune signatures (‘immune’ clusters) were identified. TP53 family of genes and genes regulating the epigenetic machinery demonstrate strong prognostic and biological relevance during progression of early disease. Gene expression profiling of RNA transcripts may be better predictors for disease course in melanoma. This study outlines the transcriptional interplay of the cancer cell’s epigenome with the immune milieu with potential for future therapeutic targeting. Examination of transcriptome changes from benign states to early-, intermediate-, and late-category tumors using a unique set of 78 treatment-naive melanocytic tumors consisting of primary melanomas of the skin and benign melanocytic lesions.