Abstract 4781: Integrated epigenomic profiling reveals widespread demethylation in melanoma and reveals CSF-1 receptor as an aberrant regulator of malignant growth and invasion

Epigenetic alterations can direct carcinogenesis by leading to transcriptional changes and inducing genomic instability. We analyzed the methylome of malignant melanoma and observed widespread loss of DNA methylation that was found to preferentially occur outside of CpG islands. Demethylation was seen to occur early during carcinogenesis, was independent of mutational status and correlated with genomic instability. Parallel transcriptomic analyses revealed that various immune and cancer associated pathways were overexpressed and were associated with promoter demethylation. The CSF1-receptor (CSF1R) was aberrantly overexpressed and hypomethylated in nearly all cases and was strikingly expressed via an aberrant upstream promoter in 10% of melanomas. shRNA mediated knockdown and inhibition of CSF1R kinase via a clinically relevant inhibitor, PLX3397, led to decreased 3D growth and invasiveness. Co-inhibition of CSF1R and BRAF resulted in synergistic blockade of BRAF-mutant melanoma xenograft growth. Thus, widespread epigenetic changes are seen in melanoma and CSF1R is a potential therapeutic target in this disease. Citation Format: Yongkai Mo, Orsolya Giricz, Caroline H. Hu, Kimberly B. Dahlman, Sanchari Bhattacharyya, Hoa Nguyen, Bernice Matusow, Tushar Bhagat, Rafe Shellooe, Elizabeth Burton, James Tsai, Chao Zhang, Gaston Habets, Yu Shyr, John Greally, Yiting Yu, Gideon E. Bollag, Richard Stanley, Jeffrey Trent, Paraic A. Kenny, Brian L. West, Jeffrey Sosman, Amit K. Verma. Integrated epigenomic profiling reveals widespread demethylation in melanoma and reveals CSF-1 receptor as an aberrant regulator of malignant growth and invasion. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4781. doi:10.1158/1538-7445.AM2014-4781