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In-depth genomic data analyses revealed complex transcriptional and epigenetic dysregulations of BRAFV600E in melanoma.

Guo X, Xu Y, Zhao Z - Mol. Cancer (2015)

Bottom Line: 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.Further analyses suggested a complex mechanism driven by mutation BRAF (V600E) on melanoma tumorigenesis that disturbs specific cancer-related genes, pathways, and methylation modifications.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, TN, 37203, USA. xingyi.guo@vanderbilt.edu.

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.

Methods and 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.

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MITFandTGFB1dysregulated byBRAFV600Edriver mutation in primary tumor samples. Boxplots show significantly higher expressions of MITF but lower expressions of TGFB1 in BRAFV600E, as compared to BRAFWT samples.
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Fig3: MITFandTGFB1dysregulated byBRAFV600Edriver mutation in primary tumor samples. Boxplots show significantly higher expressions of MITF but lower expressions of TGFB1 in BRAFV600E, as compared to BRAFWT samples.

Mentions: We next examined whether BRAFV600E target genes were regulated by specific up-regulators (i.e., transcription factors). The top two up-regulators identified using the IPA tool were oncogene MITF and tumor suppressor TGFB1; both were significantly enriched among BRAFV600E target genes (p < 3.6 × 10−16 and p < 3.1 × 10−9 for MITF and TGFB1, respectively; Figure 2B). Previous studies revealed that the BRAF mutation hyper-activated the MAPK signaling pathway and led to MITF promotion [35-37], whereas TGFB1 was reported to be down-regulated in multiple cancers, including melanoma [38-40]. Consistently, our results showed that MITF expression was also significantly higher in BRAFV600E than in BRAFWT samples, whereas TGFB1 showed significantly lower expression in BRAFV600E than in BRAFWT (Wilcoxon test, p < 0.05 and p < 0.01 for MITF and TGFB1, respectively; Figure 3).Figure 3


In-depth genomic data analyses revealed complex transcriptional and epigenetic dysregulations of BRAFV600E in melanoma.

Guo X, Xu Y, Zhao Z - Mol. Cancer (2015)

MITFandTGFB1dysregulated byBRAFV600Edriver mutation in primary tumor samples. Boxplots show significantly higher expressions of MITF but lower expressions of TGFB1 in BRAFV600E, as compared to BRAFWT samples.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4373107&req=5

Fig3: MITFandTGFB1dysregulated byBRAFV600Edriver mutation in primary tumor samples. Boxplots show significantly higher expressions of MITF but lower expressions of TGFB1 in BRAFV600E, as compared to BRAFWT samples.
Mentions: We next examined whether BRAFV600E target genes were regulated by specific up-regulators (i.e., transcription factors). The top two up-regulators identified using the IPA tool were oncogene MITF and tumor suppressor TGFB1; both were significantly enriched among BRAFV600E target genes (p < 3.6 × 10−16 and p < 3.1 × 10−9 for MITF and TGFB1, respectively; Figure 2B). Previous studies revealed that the BRAF mutation hyper-activated the MAPK signaling pathway and led to MITF promotion [35-37], whereas TGFB1 was reported to be down-regulated in multiple cancers, including melanoma [38-40]. Consistently, our results showed that MITF expression was also significantly higher in BRAFV600E than in BRAFWT samples, whereas TGFB1 showed significantly lower expression in BRAFV600E than in BRAFWT (Wilcoxon test, p < 0.05 and p < 0.01 for MITF and TGFB1, respectively; Figure 3).Figure 3

Bottom Line: 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.Further analyses suggested a complex mechanism driven by mutation BRAF (V600E) on melanoma tumorigenesis that disturbs specific cancer-related genes, pathways, and methylation modifications.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, TN, 37203, USA. xingyi.guo@vanderbilt.edu.

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.

Methods and 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.

Show MeSH
Related in: MedlinePlus