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Therapies such as BRAF inhibitors have become standard treatment for melanoma patients whose tumors harbor activating BRAFV600 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 NRASQ61-mutated melanomas with pan-negative melanomas. Surprisingly, we found dominant hypomethylation (98.03%) in NRASQ61-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 NRASQ61 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 NRASQ61 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 NRASQ61 melanomas and the identification of NRASQ61-linked pathways will be useful for the development of targeted therapies against melanomas harboring NRASQ61 mutations.

Clinically relevant genes and regulatory pathways associated with NRASQ61 mutations in melanoma through an integrative genomics approach