Epigenomic and genomic analysis of transcriptome modulation in skin cutaneous melanoma

Skin cutaneous melanoma (SKCM) is characterized by both epigenetic DNA methylation (MET) abnormalities and genomic copy number variations (CNVs). The resulting transcriptome dysregulation promotes progression of many cancers. In this study, DNA copy numbers and MET, as well as mRNA expression, were examined in 466 SKCM samples from The Cancer Genome Atlas. Our results indicate that CNVs-correlated (CNVcor) genes and MET-correlated (METcor) genes are coregulated to a remarkable degree. In addition, integrative multi-omics analysis of both METcor and CNVcor genes revealed four SKCM subtypes with differing prognoses; these subtypes were validated with independent data. Immune cell scores were markedly elevated in the iC1 subtype, which had the best prognosis. Immune cell infiltration correlated with DNA MET or CNV level in SKCM. In the iC3 subtype, which was associated with the most aggressive SKCM cases, FAM135B gene mutation frequencies were increased, while CD8A, GBP5, KIAA0040, and SAMHD1 expression were downregulated, suggesting that these genes play important roles in cancer development and immune responses. Taken together, the results of our epigenetic and genomic transcriptome modulation analysis improve our understanding of SKCM pathobiology and may aid in the development of more effective therapies.