Expression of DNA methyltransferase 1 is a hallmark of melanoma, correlates with response to BRAF and MEK inhibition and with proliferation in melanocytic tumors.

Expression of DNA methyltransferase 1 is a hallmark of melanoma, correlates with response to BRAF and MEK inhibition and with proliferation in melanocytic tumors. Am J Pathol. 2020 Jul 14;: Authors: Gassenmaier M, Rentschler M, Fehrenbacher B, Eigentler TK, Ikenberg K, Kosnopfel C, Sinnberg T, Niessner H, Bösmüller H, Wagner NB, Schaller M, Garbe C, Röcken M Abstract Aberrant DNA methylation is an epigenetic hallmark of melanoma and hypomethylating drugs with immunomodulatory activity are currently investigated in clinical trials. DNA methyltransferase 1 (DNMT1) is the major maintenance methyltransferase but its expression in melanocytic tumors is unknown. We analyzed DNMT1 expression in primary melanocytes, melanoma cell lines and 83 melanocytic tumors and explored its association with proliferation, mutational status and response to BRAF and MEK inhibition. We found that DNMT1 expression increased incrementally from nevi (mean fluorescence intensity (MFI) 48.1, interquartile range (IQR) 41.7 - 59.6) to primary melanomas (MFI 68.8, IQR 58.4 - 77.0) and metastatic melanomas (MFI 87.5, IQR 77.1 - 114.5; P < 0.001). DNMT1 expression correlated with Ki67 expression (Spearman correlation 0.483; P < 0.001) and was independent of the BRAF mutational status (P = 0.55). In BRAF mutant melanoma, DNMT1 was downregulated during response to BRAF and MEK inhibition and was again upregulated upon drug resistance in vitro and in vivo. Degr...
Source: The American Journal of Pathology - Category: Pathology Authors: Tags: Am J Pathol Source Type: research