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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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Downstream regulatory cascades of PDGFD, ZEB1, and THRBGreen nodes represent down-regulated genes, and red nodes represent up-regulated genes.
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Figure 4: Downstream regulatory cascades of PDGFD, ZEB1, and THRBGreen nodes represent down-regulated genes, and red nodes represent up-regulated genes.

Mentions: We used our previously proposed bioinformatics approach based on Breadth-First-Search algorithm [51] to identify the regulatory cascades that might be affected by aberrant DNA methylation of the 121 above-identified genes (112 hypomethylated/up-regulated and 9 hypermethylated/down-regulated). First, the curated TF and miRNA coordinated regulatory network was constructed through the integration of information from five databases (TRANSFAC [52], TransmiR [53], miRTarBase [54], miRecords [55], and TarBase [56]). This network was used as background network here, which was comprised of TFs, miRNAs and their experimentally validated target genes. 17 of the 121 genes were included in this background network. Next, we mapped all DE genes and DE miRNAs into this network and extracted all DE nodes and their neighbors. In addition, we eliminated the nodes that had outdegree of 0 and were not DE, because we preferred to focus on upstream genes, which might play a critical and causal role. Through these procedures, we constructed a subnetwork associated with NRASQ61 mutations. In this subnetwork, 5 of the 17 genes were included, and three of the genes (PDGFD, ZEB1, and THRB) had non-zero outdegrees, which indicated that these three genes were regulators of downstream gene expression. All three genes were hypomethylated and up-regulated in NRASQ61-mutant melanoma, indicating that they might contribute to oncogenicity in this subtype. Finally, 52 regulatory cascades originating from PDGFD, ZEB1, and THRB were identified through our previous approach (Fig. 4) [51].


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)

Downstream regulatory cascades of PDGFD, ZEB1, and THRBGreen nodes represent down-regulated genes, and red nodes represent up-regulated genes.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 4: Downstream regulatory cascades of PDGFD, ZEB1, and THRBGreen nodes represent down-regulated genes, and red nodes represent up-regulated genes.
Mentions: We used our previously proposed bioinformatics approach based on Breadth-First-Search algorithm [51] to identify the regulatory cascades that might be affected by aberrant DNA methylation of the 121 above-identified genes (112 hypomethylated/up-regulated and 9 hypermethylated/down-regulated). First, the curated TF and miRNA coordinated regulatory network was constructed through the integration of information from five databases (TRANSFAC [52], TransmiR [53], miRTarBase [54], miRecords [55], and TarBase [56]). This network was used as background network here, which was comprised of TFs, miRNAs and their experimentally validated target genes. 17 of the 121 genes were included in this background network. Next, we mapped all DE genes and DE miRNAs into this network and extracted all DE nodes and their neighbors. In addition, we eliminated the nodes that had outdegree of 0 and were not DE, because we preferred to focus on upstream genes, which might play a critical and causal role. Through these procedures, we constructed a subnetwork associated with NRASQ61 mutations. In this subnetwork, 5 of the 17 genes were included, and three of the genes (PDGFD, ZEB1, and THRB) had non-zero outdegrees, which indicated that these three genes were regulators of downstream gene expression. All three genes were hypomethylated and up-regulated in NRASQ61-mutant melanoma, indicating that they might contribute to oncogenicity in this subtype. Finally, 52 regulatory cascades originating from PDGFD, ZEB1, and THRB were identified through our previous approach (Fig. 4) [51].

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