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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 harbour signatures of BRAF/MEK inhibitor resistance and M2 melanomas harbour signatures of anti-PD-1 antibody treatment resistance. Transcriptomic signatures suggest that the epigenetic regulators SMARCA2 and SMARCA4 are differentially involved in the epigenetic programming of the two melanoma types. Pseudotime dynamics of nevus and melanoma samples reflect 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE112509 | GEO | 2018/07/19

REPOSITORIES: GEO

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Project description:This study represents the first attempt to perform a profiling analysis of the intergenerational differences in the microRNAs (miRNAs) of melanocytic neoplasms in young adult and older adult groups. Our comparative miRNA profiling provides a novel characterization of the miRnomes of melanocytic neoplasms and melanomas of different age groups and identifies a set of potential diagnostic and potential clinico-pathologic biomarkers that may serve as targets for development of novel miR-based modalities in cancer diagnosis and treatment. An exploratory miRNA analysis of 666 miRs was conducted on formalin fixed and paraffin embedded tissues from 10 adults and 10 young adults including conventional melanoma and melanocytic neoplasms of uncertain biological significance. Age-matched benign melanocytic nevi were used as controls. The comparative profiling was intentionally performed at two extremes of age, i.e., less than 30 years (Mel 30) and greater than 60 years (Mel 60). Primary melanoma in patients greater than 60 years old was characterized by the increased expression of miRs regulating TLR-MyD88-NF-kappaB pathway (hsa-miR -199a), RAS/RAB22A pathway (hsa-miR-204); growth differentiation and migration (hsa-miR337), epithelial mesenchymal transition EMT (let-7b, hsa-miR-10b/10bSTAR(*)), invasion and metastasis (hsa-miR-10b/10bSTAR(*), hsa-miR-30a/e*, hsa-miR-29c*; cellular matrix components (hsa-miR-29c*); invasion-cytokinesis (hsa-miR 99b*) compared to melanoma of younger patients. miR 211 was dramatically downregulated in primary melanoma compared to nevi controls, decreased with increasing age and was among the miRs linked to metastatic processes and potentially targeting the inflammatory receptor CCR10; Primary melanoma in young adult patients was characterized by the increased expression of hsa-miR-449a and decreased expression of hsa-miR146b, hsa-miR 214*. Among the miRs expressed at higher levels in control nevi, compared to adult or young adult melanoma, was hsa-miR 574-3p. Only 2 miRs distinguished adult from young adult-pediatric nevi, hsa-miR374a* and has-miR-566. MiR 30a* appeared to be a strong marker of differentiation in clinical stages I-II adult and pediatric melanoma, and could predict classification of melanoma tissue in the two age groups. Furthermore, lymph node status in the two age groups was characterized by the statistically significant expression of hsa-miR-30a* and hsa-miR-204 (F-test, p-value <0.001).

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

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