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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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Significant signaling pathways associated with NRASQ61 mutationsA) Heat map of enrichment p-values for significantly-associated pathways through combination analysis of DM genes, DE genes, and DE miRNAs. B) The “melanoma pathway” in KEGG.
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Figure 2: Significant signaling pathways associated with NRASQ61 mutationsA) Heat map of enrichment p-values for significantly-associated pathways through combination analysis of DM genes, DE genes, and DE miRNAs. B) The “melanoma pathway” in KEGG.

Mentions: In order to identify pathways associated with NRASQ61 mutation status, we performed an integrated functional analysis of DM genes, DE genes, and DE miRNAs. First, we used the Database for Annotation, Visualization and Integrated Discovery (DAVID) resources [25, 26] to find the pathways that enriched with DM genes or DE genes. Next, we employed the DNA Intelligent Analysis (DIANA) miRPath tool [27] to identify the pathways affected by DE miRNAs. At a significance level of p<0.05, we found 16, 10, and 49 significant pathways for DM genes, DE genes, and DE miRNAs, respectively. To incorporate information from multiple levels, we used Fisher's method to combine the three p-values for each pathway (Fig. 2A). In the sorted pathway list according to combined p-values, we found the most significantly-associated pathway is the MAPK signaling pathway, which is well-known to be dysregulated in most melanomas. This pathway was significant in all the pathway analyses of DM genes (p-value: 0.0026), DE genes (p-value: 0.0047) and DE miRNAs (p-value: 1.11×10−16). Current therapeutics are mainly focused on inhibitors of MAPK members, such as BRAF (vemurafenib) and MEK (trametinib) [28]. Both the “Pathways in cancer” and the “Melanoma pathway” were also in the top 5 significant pathways, demonstrating the capability of our approach to capture relevant pathways.


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)

Significant signaling pathways associated with NRASQ61 mutationsA) Heat map of enrichment p-values for significantly-associated pathways through combination analysis of DM genes, DE genes, and DE miRNAs. B) The “melanoma pathway” in KEGG.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 2: Significant signaling pathways associated with NRASQ61 mutationsA) Heat map of enrichment p-values for significantly-associated pathways through combination analysis of DM genes, DE genes, and DE miRNAs. B) The “melanoma pathway” in KEGG.
Mentions: In order to identify pathways associated with NRASQ61 mutation status, we performed an integrated functional analysis of DM genes, DE genes, and DE miRNAs. First, we used the Database for Annotation, Visualization and Integrated Discovery (DAVID) resources [25, 26] to find the pathways that enriched with DM genes or DE genes. Next, we employed the DNA Intelligent Analysis (DIANA) miRPath tool [27] to identify the pathways affected by DE miRNAs. At a significance level of p<0.05, we found 16, 10, and 49 significant pathways for DM genes, DE genes, and DE miRNAs, respectively. To incorporate information from multiple levels, we used Fisher's method to combine the three p-values for each pathway (Fig. 2A). In the sorted pathway list according to combined p-values, we found the most significantly-associated pathway is the MAPK signaling pathway, which is well-known to be dysregulated in most melanomas. This pathway was significant in all the pathway analyses of DM genes (p-value: 0.0026), DE genes (p-value: 0.0047) and DE miRNAs (p-value: 1.11×10−16). Current therapeutics are mainly focused on inhibitors of MAPK members, such as BRAF (vemurafenib) and MEK (trametinib) [28]. Both the “Pathways in cancer” and the “Melanoma pathway” were also in the top 5 significant pathways, demonstrating the capability of our approach to capture relevant pathways.

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