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.
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MK, MD, AB, SM, and MS were supported by funding of the Deutsche Krebshilfe, Melanomverbund, grant number 109716.
MK, HL-W, MD, EW, GD, JK, TK, BN, JL, PZ, CM, HJS, LH, HB, SM, AB, and MS conceived and designed the work that led to the submission, acquired data, and played an important role in interpreting the results and approved the final version. SH, TT, JU, MZ, SK, MH, and AR supported the interpretation of the results and approved the final version.
Conflict of interest
MK has received honoraria from the Speakers Bureau of Roche Pharma AG and travel support from Novartis Pharma GmbH and Bristol-Myers Squibb GmbH (BMS). MZ has received speakers honoraria and honoraria for Medical Advisory Boards from BMS, Roche Pharma AG, MSD Sharp & Dohme GmbH (MSD), Amgen GmbH, Novartis Pharma GmbH, Pfizer Pharma GmbH, and Merck Serono GmbH as well as financial support for travel support from BMS and Amgen GmbH. TT has received honoraria from the Speakers Bureau of Roche Pharma AG and travel support from Novartis Pharma GmbH and BMS. CM has received travel support from MSD and Pfizer GmbH and Roche Pharma AG and received honoraria from Novartis Pharma GmbH. JU is on the advisory board or has received honoraria and travel support from Amgen, BMS, GlaxoSmithKline GmbH &nCo, LeoPharma, MSD, Novartis, Roche Pharma AG. AR received travel grants and honoraria from Roche Pharma AG, TEVA, MMS, MSD, Amgen, and Novartis Pharma GmbH and a research grant from Novartis Pharma GmbH. JL, HL-W, MD, EW, GD, JK, LH, SH, PZ, HJS, MH, SK, SM, AB, HB and MS declare that they have no conflict of interest.
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Kunz, M., Löffler-Wirth, H., Dannemann, M. et al. RNA-seq analysis identifies different transcriptomic types and developmental trajectories of primary melanomas. Oncogene 37, 6136–6151 (2018). https://doi.org/10.1038/s41388-018-0385-y
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