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Next Generation Sequencing of human BRAF melanoma cell lines treated with vemurafenib for 20 days

ABSTRACT: Purpose: The goals of this study are to compare NGS-derived transciptomes from human melanoma cell lines before and after vemurafenib in order to compare to a mouse model of melanoma using doxycycline that permits control of mutant BRAF expression. Treatment with doxycycline leads to loss of mutant BRAF expression and tumor regression, but tumors reoccur after a prolonged period of dormancy. Results: We found conserved expression changes in histone methyltransferase genes (HMT), including Enhancer Of Zeste 2 Polycomb Repressive Complex 2 Subunit (EZH2), Suppressor Of Variegation 3-9 Homolog 1(SUV39H1), Suppressor Of Variegation 3-9 Homolog 2 (SUV39H2), ASH2 Like, Histone Lysine Methyltransferase Complex Subunit (ASH2L), SET And MYND Domain Containing 2 (SYMD2), and Protein arginine methyltransferase 5 (PRMT5) and histone deacetylases (HDACs) HDACS 7, 9,10, and 11.

ORGANISM(S): Homo sapiens

PROVIDER: GSE152699 | GEO | 2020/07/15

REPOSITORIES: GEO

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Project description:Melanoma is the deadliest form of skin cancer with rising incidence and mortality rates. Oncogenic mutation in BRAF gene is the single most frequent genetic alteration in human melanoma; however, this event per se is not sufficient to produce melanoma in vivo. We have investigated whether epigenetic changes, specifically aberrant DNA methylation and dysregulation of gene expression, alone or in combination with this genetic event, are involved in the genesis of human melanoma. We have constructed the whole M-bM-^@M-^XM-bM-^@M-^Xof primary human melanomas in relation to their BRAF mutational status. Our methylation profiling identified a large number of hyper- or hypomethylated genes in melanoma tumors, many of which being novel and having the potential to serve as biomarkers. Gene ontology analysis revealed that gene categories involved in neuronal cell morphology and development, and skin and neurological disorders were highly enriched. Frequently methylated targets included developmental regulatory transcription factors and homeobox genes, which are mostly subjected to bivalent histone marking and Polycomb occupancy in embryonic stem cells. Notably, several genes involved in the MEK-ERK and the PI3K pathways, two of the most frequently perturbed pathways in human melanoma, showed extensive methylation changes. Gene expression profiling identified a long list of dysregulated genes, many of which being involved in melanocytes development and differentiation, and showing concomitant aberrant DNA methylation. Sub-typing of the melanoma tumors based on BRAF mutational status revealed that tumors with a mutated BRAF had distinctive and more pronounced changes in both DNA methylation and gene expression profiles than tumors carrying the wildtype BRAF. The differentially compromised methylome and transcriptome of melanomas (dependent on BRAF mutation) deserves special attention because many epigenetic alterations, including DNA methylation-mediated regulation of gene expression, are potentially reversible. The dichotomous integrity of epigenome in human melanoma holds great promise for the field of personalized medicine. Methylome: Eleven primary human melanoma speciemens versus five normal human melanocyte samples. Transcriptome: Ten primary human melanoma speciemens versus four normal human melanocyte samples

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Next Generation Sequencing of human BRAF melanoma cell lines treated with vemurafenib for 20 days

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