Abstract (Expand)
Recent studies revealed trajectories of mutational events in early melanomagenesis, but the accompanying changes in gene expression are far less understood. Therefore, we performed a comprehensive … RNA-seq analysis of laser-microdissected melanocytic nevi (n = 23) and primary melanoma samples (n = 57) and characterized the molecular mechanisms of early melanoma development. Using self-organizing maps, unsupervised clustering, and analysis of pseudotime (PT) dynamics to identify evolutionary trajectories, we describe here two transcriptomic types of melanocytic nevi (N1 and N2) and primary melanomas (M1 and M2). N1/M1 lesions are characterized by pigmentation-type and MITF gene signatures, and a high prevalence of NRAS mutations in M1 melanomas. N2/M2 lesions are characterized by inflammatory-type and AXL gene signatures with an equal distribution of wild-type and mutated BRAF and low prevalence of NRAS mutations in M2 melanomas. Interestingly, N1 nevi and M1 melanomas and N2 nevi and M2 melanomas, respectively, cluster together, but there is no clustering in a stage-dependent manner. Transcriptional signatures of M1 melanomas harbor signatures of BRAF/MEK inhibitor resistance and M2 melanomas harbor signatures of anti-PD-1 antibody treatment resistance. Pseudotime dynamics of nevus and melanoma samples are suggestive for a switch-like immune-escape mechanism in melanoma development with downregulation of immune genes paralleled by an increasing expression of a cell cycle signature in late-stage melanomas. Taken together, the transcriptome analysis identifies gene signatures and mechanisms underlying development of melanoma in early and late stages with relevance for diagnostics and therapy.
Authors: M. Kunz, H. Loffler-Wirth, M. Dannemann, E. Willscher, G. Doose, J. Kelso, T. Kottek, B. Nickel, L. Hopp, J. Landsberg, S. Hoffmann, T. Tuting, P. Zigrino, C. Mauch, J. Utikal, M. Ziemer, H. J. Schulze, M. Holzel, A. Roesch, S. Kneitz, S. Meierjohann, A. Bosserhoff, H. Binder, M. Schartl
Date Published: 12th Jul 2018
Publication Type: Not specified
Human Diseases: melanoma
PubMed ID: 29995873
Citation: Oncogene. 2018 Nov;37(47):6136-6151. doi: 10.1038/s41388-018-0385-y. Epub 2018 Jul 11.
