title: In-depth genomic data analyses revealed complex transcriptional and epigenetic dysregulations of BRAFV600E in melanoma.
abstract: BACKGROUND
  The recurrent BRAF driver mutation V600E (BRAF (V600E)) is currently one of the most clinically relevant mutations in melanoma. However, the genome-wide transcriptional and epigenetic dysregulations induced by BRAF (V600E) are still unclear. The investigation of this driver mutation's functional consequences is critical to the understanding of tumorigenesis and the development of therapeutic strategies.
  
  
  RESULTS
  We performed an integrative analysis of transcriptomic and epigenomic changes disturbed by BRAF (V600E) by comparing the gene expression and methylation profiles of 34 primary cutaneous melanoma tumors harboring BRAF (V600E) with those of 27 BRAF (WT) samples available from The Cancer Genome Atlas (TCGA). A total of 711 significantly differentially expressed genes were identified as putative BRAF (V600E) target genes. Functional enrichment analyses revealed the transcription factor MITF (p < 3.6 × 10(-16)) and growth factor TGFB1 (p < 3.1 × 10(-9)) were the most significantly enriched up-regulators, with MITF being significantly up-regulated, whereas TGFB1 was significantly down-regulated in BRAF (V600E), suggesting that they may mediate tumorigenesis driven by BRAF (V600E). Further investigation using the MITF ChIP-Seq data confirmed that BRAF (V600E) led to an overall increased level of gene expression for the MITF targets. Furthermore, DNA methylation analysis revealed a global DNA methylation loss in BRAF (V600E) relative to BRAF (WT). This might be due to BRAF dysregulation of DNMT3A, which was identified as a potential target with significant down-regulation in BRAF (V600E). Finally, we demonstrated that BRAF (V600E) targets may play essential functional roles in cell growth and proliferation, measured by their effects on melanoma tumor growth using a short hairpin RNA silencing experimental dataset.
  
  
  CONCLUSIONS
  Our integrative analysis identified a set of BRAF (V600E) target genes. Further analyses suggested a complex mechanism driven by mutation BRAF (V600E) on melanoma tumorigenesis that disturbs specific cancer-related genes, pathways, and methylation modifications.
authors.affiliation: Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, TN, 37203, USA. xingyi.guo@vanderbilt.edu.|Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, 37232, USA. xingyi.guo@vanderbilt.edu.
authors.forename: Xingyi
authors.initials: X
authors.lastname: Guo
authors.affiliation: Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, TN, 37203, USA. yaomin.xu@vanderbilt.edu.|Department of Biostatistics, Vanderbilt University School of Medicine, Nashville, TN, 37203, USA. yaomin.xu@vanderbilt.edu.|Center for Quantitative Sciences, Vanderbilt University Medical Center, Nashville, TN, 37232, USA. yaomin.xu@vanderbilt.edu.
authors.forename: Yaomin
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, TN, 37203, USA. zhongming.zhao@vanderbilt.edu.|Center for Quantitative Sciences, Vanderbilt University Medical Center, Nashville, TN, 37232, USA. zhongming.zhao@vanderbilt.edu.|Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN, 37232, USA. zhongming.zhao@vanderbilt.edu.
authors.forename: Zhongming
authors.initials: Z
authors.lastname: Zhao
mesh_terms: D002471:Cell Transformation, Neoplastic / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics; D015536:Down-Regulation / Q000235:genetics; D044127:Epigenesis, Genetic / Q000235:genetics*; D057890:Epigenomics / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D023281:Genomics / Q000379:methods; D006801:Humans; D008545:Melanoma / Q000235:genetics*; D051739:Microphthalmia-Associated Transcription Factor / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D012878:Skin Neoplasms; D014158:Transcription, Genetic / Q000235:genetics*; D059467:Transcriptome / Q000235:genetics; D053773:Transforming Growth Factor beta1 / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics; D000096142:Cutaneous Malignant Melanoma
chemical_list: C497234:MITF protein, human; D051739:Microphthalmia-Associated Transcription Factor; C508960:TGFB1 protein, human; D053773:Transforming Growth Factor beta1; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf