RNA-seq analysis identifies different transcriptomic types and developmental trajectories of primary melanomas

Abstract

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.

Footprints of Sepsis Framed Within Community Acquired Pneumonia in the Blood Transcriptome

“…We assigned all genes within these regions to the respective state and further processed them in analogy to gene sets that provided GSZ-values for each sample [see also Ref. ( 29 ) for details]. Heatmap presentations were generated by standard R-functions including hierarchical clustering options.…”

MAPK-induced miR-29 targets MAFG and suppresses melanoma development

“…Thus, to analyze pri-miR-29 expression during melanomagenesis we performed RNA sequencing on four wildtype BRAF human melanocyte cell lines (Hermes1, Hermes2, Hermes3A, and Hermes4B) and five human melanoma cell lines (WM35, 1205Lu, WM164, SKMel28 and WM793) harboring the oncogenic BRAF V600E mutation. In addition, we interrogated pri-miR-29 expression in a publicly available RNAseq dataset (Kunz et al 2018) containing 23 nevi and 57 primary melanomas. In agreement with our observations, we found that there was a trend towards increased pri-miR-29b1~a expression in melanoma cell lines and primary melanomas compared to melanocyte cell lines and nevi, respectively ( Figure 3E and 3F).…”

Genomic analysis of metastatic melanoma in an adult with giant congenital melanocytic nevus

“…It is thought that bypass from a senescence program contributes to the malignant transformation of benign nevi, but the mechanism of this process remains only partly understood. Recently, gene expression profiling of benign nevi and melanomas characterized two transcriptomic types of melanocytic nevi and primary melanomas (Kunz et al, 2018). The two melanoma subtypes were associated with a high versus low rate of NRAS mutation and harbored gene expression signatures for BRAF/MEK and anti-PD-1 treatment resistance, respectively.…”