Clinically relevant genes and regulatory pathways associated with NRAS(Q61) mutations in melanoma through an integrative genomics approach

Therapies such as BRAF inhibitors have become standard treatment for melanoma patients whose tumors harbor activating BRAF(V600) mutations. However, analogous therapies for inhibiting NRAS mutant signaling have not yet been well established. In this study, we performed an integrative analysis of DNA methylation, gene expression, and microRNA expression data to identify potential regulatory pathways associated with the most common driver mutations in NRAS (Q61K/L/R) through comparison of NRAS(Q61)-mutated melanomas with pan-negative melanomas. Surprisingly, we found dominant hypomethylation (98.03%) in NRAS(Q61)-mutated melanomas. We identified 1,150 and 49 differentially expressed genes and microRNAs, respectively. Integrated functional analyses of alterations in all three data types revealed important signaling pathways associated with NRAS(Q61) mutations, such as the MAPK pathway, as well as other novel cellular processes, such as axon guidance. Further analysis of the relationship between DNA methylation and gene expression changes revealed 9 hypermethylated and down-regulated genes and 112 hypomethylated and up-regulated genes in NRAS(Q61) melanomas. Finally, we identified 52 downstream regulatory cascades of three hypomethylated and up-regulated genes (PDGFD, ZEB1, and THRB). Collectively, our observation of predominant gene hypomethylation in NRAS(Q61) melanomas and the identification of NRAS(Q61)-linked pathways will be useful for the development of targeted therapies against melanomas harboring NRAS(Q61) mutations.