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

Jiang W, Jia P, Hutchinson KE, Johnson DB, Sosman JA, Zhao Z - Oncotarget (2015)

Bottom Line: However, analogous therapies for inhibiting NRAS mutant signaling have not yet been well established.We identified 1,150 and 49 differentially expressed genes and microRNAs, respectively.Finally, we identified 52 downstream regulatory cascades of three hypomethylated and up-regulated genes (PDGFD, ZEB1, and THRB).

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.

ABSTRACT
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.

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Related in: MedlinePlus

Starburst plot integrating alterations in DNA methylation and gene expressionThe x-axis is the difference in DNA methylation levels (ΔM); the y-axis is the difference in gene expression (log2FC); green nodes represent the hypomethylated/up-regulated genes; red nodes represent the hypermethylated/down-regulated genes.
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Figure 3: Starburst plot integrating alterations in DNA methylation and gene expressionThe x-axis is the difference in DNA methylation levels (ΔM); the y-axis is the difference in gene expression (log2FC); green nodes represent the hypomethylated/up-regulated genes; red nodes represent the hypermethylated/down-regulated genes.

Mentions: In order to identify DNA methylation events with potential biological function, we integrated DNA methylation analysis with gene expression analysis. We first calculated the Spearman's rank correlation coefficient between DNA methylation and gene expression for DM CpG sites and their corresponding genes. We found that the hypermethylated loci displayed a stronger inverse relationship with the expression of their corresponding genes than the hypomethylated probes (Fig. S5). The average correlation coefficient was −0.31 for hypermethylated loci and −0.04 for hypomethylated loci. Next, we deeply analyzed the correlation distribution in different gene regions (Fig. S6). For both hypermethylation and hypomethylation, we observed a higher correlation in regions near the TSS (TSS1500, TSS200, 5′UTR, and 1stExon) and a lower correlation in regions far away from the TSS (gene body and 3′UTR). In the above DM loci analysis, we found that the hypermethylated and hypomethylated loci were most commonly observed in promoters and gene bodies, respectively. Thus, these results were consistent with the previous findings that promoter methylation levels negatively correlated with gene expression, while positive correlations were observed between DNA methylation levels in gene bodies and gene expression [48-50]. In the following analysis, we focused on the inverse relationship between DNA methylation and gene expression changes to identify potentially important factors and their regulatory pathways that correlated with NRASQ61 signaling. We obtained 112 genes that were concordantly hypomethylated and up-regulated in NRASQ61-mutant samples, and 9 genes that were concordantly hypermethylated and down-regulated in this sample group (Fig. 3).


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

Jiang W, Jia P, Hutchinson KE, Johnson DB, Sosman JA, Zhao Z - Oncotarget (2015)

Starburst plot integrating alterations in DNA methylation and gene expressionThe x-axis is the difference in DNA methylation levels (ΔM); the y-axis is the difference in gene expression (log2FC); green nodes represent the hypomethylated/up-regulated genes; red nodes represent the hypermethylated/down-regulated genes.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4385866&req=5

Figure 3: Starburst plot integrating alterations in DNA methylation and gene expressionThe x-axis is the difference in DNA methylation levels (ΔM); the y-axis is the difference in gene expression (log2FC); green nodes represent the hypomethylated/up-regulated genes; red nodes represent the hypermethylated/down-regulated genes.
Mentions: In order to identify DNA methylation events with potential biological function, we integrated DNA methylation analysis with gene expression analysis. We first calculated the Spearman's rank correlation coefficient between DNA methylation and gene expression for DM CpG sites and their corresponding genes. We found that the hypermethylated loci displayed a stronger inverse relationship with the expression of their corresponding genes than the hypomethylated probes (Fig. S5). The average correlation coefficient was −0.31 for hypermethylated loci and −0.04 for hypomethylated loci. Next, we deeply analyzed the correlation distribution in different gene regions (Fig. S6). For both hypermethylation and hypomethylation, we observed a higher correlation in regions near the TSS (TSS1500, TSS200, 5′UTR, and 1stExon) and a lower correlation in regions far away from the TSS (gene body and 3′UTR). In the above DM loci analysis, we found that the hypermethylated and hypomethylated loci were most commonly observed in promoters and gene bodies, respectively. Thus, these results were consistent with the previous findings that promoter methylation levels negatively correlated with gene expression, while positive correlations were observed between DNA methylation levels in gene bodies and gene expression [48-50]. In the following analysis, we focused on the inverse relationship between DNA methylation and gene expression changes to identify potentially important factors and their regulatory pathways that correlated with NRASQ61 signaling. We obtained 112 genes that were concordantly hypomethylated and up-regulated in NRASQ61-mutant samples, and 9 genes that were concordantly hypermethylated and down-regulated in this sample group (Fig. 3).

Bottom Line: However, analogous therapies for inhibiting NRAS mutant signaling have not yet been well established.We identified 1,150 and 49 differentially expressed genes and microRNAs, respectively.Finally, we identified 52 downstream regulatory cascades of three hypomethylated and up-regulated genes (PDGFD, ZEB1, and THRB).

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus