Abstract
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.
Highlights
Incidence of skin cutaneous melanoma (SKCM), a common malignant skin tumor, has increased rapidly over the past decade [1]
MET, copy number variation (CNV), and messenger RNA (mRNA) expression profiles were obtained from 466 Skin cutaneous melanoma (SKCM) samples in TCGA
Six immune cell scores for samples in the iC1 subtype that had the best prognosis were markedly elevated compared to scores for samples in other subtypes (Figure 6A, 6B, p < 0.01). These results suggest that degree of immune cell infiltration or immune microenvironment in SKCM are correlated with DNA MET or CNV levels
Summary
Incidence of skin cutaneous melanoma (SKCM), a common malignant skin tumor, has increased rapidly over the past decade [1]. Novel treatments might help improve clinical outcomes, the prognosis for this disease remains poor due at least in part to the involvement and thickness of the lymph nodes and the ability of malignant cells to colonize distant organs [3, 4]. A comprehensive understanding of the molecular features of melanoma will help improve treatment efficacy. Large-scale multi-omics studies have greatly increased our understanding of genomic and epigenetic dysregulation in many diseases [5]. Epigenetic regulation in the form of DNA methylation (MET) contributes to many SKCM characteristics [7, 8]. DNA MET profiling studies indicate that epigenetic regulation influences biological and clinical aspects of cancer development [11, 12]. Some crucial cancer-related genes, such as LKB1, RB1, and RASSF1A, can regulate DNA MET, modulating gene function [13,14,15]
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