Discrimination of Dysplastic Nevi from Common Melanocytic Nevi by Cellular and Molecular Criteria

Abstract

Dysplastic nevi (DNs), also known as Clark's nevi or atypical moles, are distinguished from common melanocytic nevi by variegation in pigmentation and clinical appearance, as well as differences in tissue patterning. However, cellular and molecular differences between DNs and common melanocytic nevi are not completely understood. Using cDNA microarray, quantitative RT-PCR, and immunohistochemistry, we molecularly characterized DNs and analyzed the difference between DNs and common melanocytic nevi. A total of 111 probesets (91 annotated genes, fold change > 2.0 and false discovery rate < 0.25) were differentially expressed between the two lesions. An unexpected finding in DNs was altered differentiation and activation of epidermal keratinocytes with increased expression of hair follicle-related molecules (keratin 25, trichohyalin, ribonuclease, RNase A family, 7) and inflammation-related molecules (S100A7, S100A8) at both genomic and protein levels. The immune microenvironment of DNs was characterized by an increase of T helper type 1 (IFNγ) and T helper type 2 (IL13) cytokines as well as an upregulation of oncostatin M and CXCL1. DUSP3, which regulates cellular senescence, was identified as one of the disease discriminative genes between DNs and common melanocytic nevi by three independent statistical approaches and its altered expression was confirmed by immunohistochemistry. The molecular and cellular changes in which the epidermal-melanin unit undergoes follicular differentiation as well as upregulation of defined cytokines could drive complex immune, epidermal, and pigmentary alterations.

Novel immune signatures associated with dysplastic naevi and primary cutaneous melanoma in human skin

“…CMN contained 380 unique DEGs, with enrichment for biological processes revolving around extracellular matrix organization, including endodermal cell differentiation, collagen catabolism and cell adhesion (Figure B). Previous work demonstrated that DN can be molecularly distinguished from CMN, with DN being characterized by dysplasia of the epidermal‐melanin unit and aberrant expression of hair follicle‐related proteins . Thus, we focused our analysis on molecular differences and similarities between DN and MM.…”

“…Tissue was never destroyed en bloc in the event that the pathologist thought diagnostic information was needed from the frozen sections. As described in our previous study, DN were classified by an experienced dermatopathologist using cytological and architectural features . Melanocytic nuclear atypia was noted if irregular, hyperchromatic or with prominent nucleoli.…”

Keratinocyte cadherin desmoglein 1 controls melanocyte behavior through paracrine signaling

“…Dsg1 regulates KC differentiation (Getsios et al, 2009;Harmon et al, 2013), (Jobe et al, 2016;Payne & Cornelius, 2002). In fact, CXCL1 was one of the most highly modified markers allowing discrimination between common melanocytic and dysplastic nevi (Eliades & Tsao, 2016;Mitsui et al, 2016). An altered inflammatory microenvironment contributes to the growth and invasion of transformed MCs and melanoma cells (Richmond, Yang, & Su, 2009).…”

A meta‑analysis of transcriptome datasets characterizes malignant transformation from melanocytes and nevi to melanoma

“…Next, by screening the full characteristics and the quality control, 312 datasets were excluded. Therefore, only 3 datasets from GEO were selected, with samples from melanocytes [GSE38312 (17), n=5], nevi [GSE53223 (18), n=5], and melanoma stages I, II and III [GSE15605 (19), n=40]. Primary melanomas at stage IV and metastatic melanoma samples were excluded to simplify the analysis of gene expression changes that occur during the early transformation of non-cancerous cells (melanocytes or nevi) to melanoma cells.…”