Shared Gene Expression and Immune Pathway Changes Associated with Progression from Nevi to Melanoma

There is a need to identify molecular biomarkers of melanoma progression to assist the development of chemoprevention strategies to lower melanoma incidence. Using datasets containing gene expression for dysplastic nevi and melanoma or melanoma arising in a nevus, we performed differential gene expression analysis and regularized regression models to identify genes and pathways that were associated with progression from nevi to melanoma. A small number of genes distinguished nevi from melanoma. Differential expression of seven genes was identified between nevi and melanoma in three independent datasets. C1QB, CXCL9, CXCL10, DFNA5 (GSDME), FCGR1B, and PRAME were increased in melanoma, and SCGB1D2 was decreased in melanoma, compared to dysplastic nevi or nevi that progressed to melanoma. Further supporting an association with melanomagenesis, these genes demonstrated a linear change in expression from benign nevi to dysplastic nevi to radial growth phase melanoma to vertical growth phase melanoma. The genes associated with melanoma progression showed significant enrichment of multiple pathways related to the immune system. This study demonstrates (1) a novel application of bioinformatic approaches to aid clinical trials of melanoma chemoprevention and (2) the feasibility of determining a gene signature biomarker of melanomagenesis.

Features of skinfold thickness in men with benign nevi

Nevi, although benign neoplasms of the skin, but have a certain tendency to malignancy, which is influenced by various external and internal human factors. Predicting the risk of benign nevi against this background is an important topic for experimental research. The aim of the study was to establish the features of the skinfold thickness (SFT) in men of the first adult age with benign nevi. SFT was determined according to the Bunak scheme for men (aged 22-35 years) with melanocyte benign simple nevi (n=34), melanocyte benign dysplastic nevi (n=27), melanocyte benign congenital nevi (n=14) and non-melanocyte benign (n=17). The control group – SFT of 82 practically healthy men of the same age group was selected from the data bank of the Research Center of National Pirogov Memorial Medical University, Vinnytsya. Statistical processing of the results was performed in the license package “Statistica 5.5” using non-parametric evaluation methods. It was found that in practically healthy men higher than in patients – SFT on the anterior and posterior surfaces of the shoulder and thigh (in all groups of patients); SFT on the forearm, at the lower angle of the scapula, chest and shin (only in patients with melanocyte benign dysplastic nevi). Also in healthy men are found lower than in patients – SFT on the side (in all groups of patients); SFT in the abdomen (in patients with melanocyte benign simple and non-melanocyte benign nevi). When comparing SFT between patients with benign nevi, in most cases, lower values of SFT found in patients with melanocyte benign dysplastic nevi. The obtained results indicate the initial manifestations of abdominal (android) type of fat deposition in the body in patients with benign nevi (most pronounced in patients with melanocyte benign simple nevi).

Molecular Proof of a Clinical Concept: Expression of Estrogen Alpha-, Beta-Receptors and G Protein-Coupled Estrogen Receptor 1 (GPER) in Histologically Assessed Common Nevi, Dysplastic Nevi and Melanomas

Background and Objectives: Epidemiologic data show significant differences in melanoma incidence and outcomes between sexes. The role of hormonal receptors in the pathogenesis of melanocytic lesions remains unclear, thus we performed this study aiming to assess estrogen receptors expression in different melanocytic lesions. Materials and Methods: We performed a cross-sectional study that included 73 consecutively excised melanocytic lesions. Estrogen receptor alpha (ERα), beta (ERβ), and G-protein coupled estrogen receptor (GPER) expression was analyzed in melanocytes and keratinocytes of common nevi, dysplastic nevi, melanoma, healthy skin margin, and in sebaceous and sweat gland cells. Results: ERβ expression was higher in dysplastic nevi margin melanocytes compared to common nevi (p = 0.046) and in dysplastic nevi keratinocytes compared to melanoma keratinocytes (p = 0.021). ERβ expression was significantly higher in margin melanocytes compared to melanoma melanocytes (p = 0.009). No difference in ERβ expression was shown between melanocytes of three types of lesions. GPER expression was higher in nuclei and cytoplasm of dysplastic nevi (p = 0.02 and p = 0.036 respectively) and at the margin compared to melanoma. GPER expression was lower in sebaceous glands of tissue surrounding common nevi (p = 0.025) compared to dysplastic nevi. GPER expression was higher in skin margin tissue melanocytes (p = 0.016 nuclear, p = 0.029 cytoplasmic) compared to melanoma melanocytes. There were no differences in ERα expression between the melanocytic lesions. Conclusion: Further large-scale studies are warranted to investigate the potential role of ERβ and GPER in the pathogenesis of melanocytic lesions.

Features of total and longitudinal body sizes in men with benign nevi

The use of anthropometric markers to predict the onset or severity of the disease is key to solving the problem of preventive medicine and can be an indispensable tool in preventive examinations in schools, universities and industries. The purpose of the study was to establish total and longitudinal body sizes in men of the first mature age with benign nevi. Anthropometry (determination of total and longitudinal body sizes) was performed according to Bunak’s scheme for men (aged 22-35 years) patients with melanocytic benign simple nevi (n=34), melanocytic benign dysplastic nevi (n=27), melanocytic benign congenital nevi (n=14) and non-melanocytic benign nevi (n=17). As a control from the data bank of the research center of National Pirogov Memorial Medical University, Vinnytsya selected total and longitudinal body sizes of 82 practically healthy men of the same age group. Statistical processing of the obtained results was performed in the license package “Statistica 5.5” using non-parametric evaluation methods. It was found that the mass and surface area of the body in healthy men is lower than in patients (except for dysplastic nevi), and in patients with dysplastic nevi – lower than in patients with non-melanocytic nevi; the height of the suprathoracic, acromial and finger anthropometric points in healthy men is lower than in patients with nevi (except for the acromial point height in patients with dysplastic nevi), and the height of the pubic and acetabular anthropometric points – in healthy men is greater than in patients with simple (only pubic point) and dysplastic nevi; in addition, the height of the pubic and acetabular anthropometric points in patients with simple nevi is lower than in patients with non-melanocytic nevi and congenital nevi (only for the acetabulum height). Given the height of anthropometric points and the fact that body length between healthy and sick men has no significant or tendency differences, in sick men we observe a longer torso and shorter lower extremities (most pronounced in patients with simple and dysplastic nevi), which is a manifestation of “subpathological” constitutional types, which indicate a longer torso and shorter lower extremities.

Diffuse PRAME Expression Is Highly Specific for Thin Melanomas in the Distinction from Severely Dysplastic Nevi but Does Not Distinguish Metastasizing from Non-Metastasizing Thin Melanomas

Background: PReferentially expressed Antigen in MElanoma (PRAME) immunohistochemistry is increasingly used as diagnostic adjunct in the evaluation of melanocytic tumors. The expression and prognostic significance of PRAME in melanomas ≤1.0 mm and its diagnostic utility in the distinction from severely dysplastic compound nevi (SDN) have not been studied. Methods: We investigated and compared the immunohistochemical PRAME expression in 70 matched thin metastasizing and non-metastasizing melanomas and 45 nevi from patients with long-term follow-up (35 SDN and 10 unequivocally benign compound nevi). Results: Diffuse PRAME staining in >75% of lesional epidermal and dermal melanocytes identified 58.6% of thin melanomas but did not distinguish metastasizing from non-metastasizing melanomas (p = 0.81). A superficial atypical melanocytic proliferation of uncertain significance, in which the final diagnostic interpretation favored a SDN was the only nevus with diffuse PRAME expression (1/45). Melanomas and SDN with PRAME immunoreactivity exhibited different staining patterns. Most melanomas (67.6%) showed uniform PRAME expression in the in situ and invasive component, whereas most SDN (81.0%) showed a decreasing gradient with depth. Conclusion: Diffuse intraepidermal and dermal PRAME staining is highly specific for melanomas in the distinction from SDN. PRAME expression is not a prognostic biomarker in melanomas ≤1.0 mm.