Clinically relevant genes and regulatory pathways associated with NRASQ61 mutations in melanoma through an integrative genomics approach
Year: 2014
Type: article
Abstract: // Wei Jiang 1 , Peilin Jia 1,2 , Katherine E. Hutchinson 3 , Douglas B. Johnson 4,5 , Jeffrey A. Sosman 4,5 and Zhongming Zhao 1,2,3,4 1 Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA 2 Center for Quantitative Sciences, Vanderbilt University School of Medicine, Nashville, Tennessee, USA 3 Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA 4 Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee, USA 5 Department of Medicine/Division of Hematology-Oncology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA Correspondence: Zhongming Zhao, email: // Keywords : NRAS, melanoma, driver mutation, DNA methylation, gene expression, regulatory pathway Received : October 03, 2014 Accepted : December 09, 2014 Published : December 10, 2014 Abstract 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.
Source: Oncotarget
Institutions: Vanderbilt University, Vanderbilt-Ingram Cancer Center
Language: English
Topic: Melanoma and MAPK Pathways
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: diamond
Awards: Mapping the Genetic Architecture of Complex Disease via RNA-seq and GWAS, G457800531, SPORE in GI Cancer, SPORE in Breast Cancer, Investigating MicroRNAs and Their Regulatory Networks in Glioblastoma, Vanderbilt Clinical Oncology Research Career Development Award, Cancer Center Support Grant
OpenAlex ID: W1480100812