BRAFV600E induces reversible mitotic arrest in human melanocytes via microrna-mediated suppression of AURKB

Benign melanocytic nevi frequently emerge when an acquired BRAFV600E mutation triggers unchecked proliferation and subsequent arrest in melanocytes. Recent observations have challenged the role of oncogene-induced senescence in melanocytic nevus formation, necessitating investigations into alternative mechanisms for the establishment and maintenance of proliferation arrest in nevi. We compared the transcriptomes of melanocytes from healthy human skin, nevi, and melanomas arising from nevi and identified a set of microRNAs as highly expressed nevus-enriched transcripts. Two of these microRNAs—MIR211-5p and MIR328-3p—induced mitotic failure, genome duplication, and proliferation arrest in human melanocytes through convergent targeting of AURKB. We demonstrate that BRAFV600E induces a similar proliferation arrest in primary human melanocytes that is both reversible and conditional. Specifically, BRAFV600E expression stimulates either arrest or proliferation depending on the differentiation state of the melanocyte. We report genome duplication in human melanocytic nevi, reciprocal expression of AURKB and microRNAs in nevi and melanomas, and rescue of arrested human nevus cells with AURKB expression. Taken together, our data describe an alternative molecular mechanism for melanocytic nevus formation that is congruent with both experimental and clinical observations.

Role of CALLA/CD10 Expression in Progression of Melanocytic Tumors: A Study in Egypt

BACKGROUND: Although most of melanocytic lesions can be diagnosed using morphology, there is a significant subset of lesions that are difficult to diagnose. These are a source of anxiety for patients, clinicians, and pathologists. This arouses the possible benefits of using ancillary techniques to solve this problem. CD10 is a zinc-dependent metalloproteinase, its expression is known to be associated with biological aggressiveness in various malignancies. AIM: This research observes the efficacy of CD10 in the progression of melanocytic tumors as well as the differential diagnosis between nevus and melanoma. METHODS: The material of this study included 49 paraffin blocks of Egyptian melanocytic tumors. CD10 expression either membranous and/or cytoplasmic in tumor cells was considered positive and scored, based on the percentage of cells stained and compared to Ki67 expression as a prognostic marker. RESULTS: In benign melanocytic nevi, only 16.7% of cases showed positive expression, all were + 1 score, compared to 82.6% of melanoma cases, mostly +1 score followed by +3 score and finally +2 score. The difference in CD10 expression among melanocytic tumors showed a highly statistically significant correlation between nevus and melanoma cases as well as in Spitz nevi versus other nevi. Another highly statistically significant correlation was observed between CD10 expression and both Ki67 expression and ulceration. CONCLUSION: CD10 expression was significantly higher expressed in melanomas rather than nevi with highly statistically significant positive relation with Ki67 and ulcer formation which supports its role as a potential biomarker in the development of malignant melanoma and marker of aggression.

Correlation of MET and PD-L1 Expression in Malignant Melanoma

The proto-oncogene MET, the hepatocyte growth factor (HGF) receptor, is a transmembrane receptor tyrosine kinase (RTK) with a prominent role in tumor metastasis and resistance to anti-cancer therapies. Melanoma demonstrates relatively frequent MET aberrations, including MET gene amplification. Concurrently, programmed death-ligand 1 (PD-L1), with its ability to evade anti-tumor immune responses, has emerged as a prominent therapeutic target in melanoma and other malignancies and its expression is used as a predictive biomarker of response to immunotherapy. We performed immunohistochemistry analysis of MET and PD-L1 in 18 human melanoma cell lines derived from both primary and metastatic lesions, and in a human melanoma tissue microarray containing one hundreds melanocytic lesions, including primary cutaneous melanomas, primary mucosal melanomas, metastatic melanomas and benign melanocytic nevi as controls. After color deconvolution, each core was segmented to isolate staining and calculate the percentage of positive cells. Overall, MET expression was higher in tumors with increased PD-L1 expression. Moreover, a robust correlation between MET and PD-L1 expression was found in samples from metastatic melanoma and not in primary cutaneous or mucosal melanoma. These data suggest that relative expression levels of these proteins in combination is a marker of advanced disease and testing for expression of these markers should be considered in patients with melanoma.

Correlation of MET and PD-L1 expression in malignant melanoma

Background: The proto-oncogene MET, the hepatocyte growth factor (HGF) receptor, is a transmembrane receptor tyrosine kinase (RTK) with a prominent role in tumor metastasis and resistance to anti-cancer therapies. Melanoma demonstrates relatively frequent MET aberrations, including MET gene amplification. Concurrently, PD-L1, with its ability to evade anti-tumor immune responses, has emerged as a prominent therapeutic target in melanoma and other malignancies and its expression is used as a predictive biomarker of response to immunotherapy. Methods: We performed immunohistochemistry analysis of MET and PD-L1 in 18 human melanoma cell lines derived from both primary and metastatic lesions; we then performed the same analysis in a human melanoma tissue microarray (TMA) containing 100 melanocytic lesions, including 42 cutaneous malignant melanomas, 20 mucosal melanoma, 21 metastatic melanomas and 17 benign melanocytic nevi as controls. After color deconvolution, TMA cores were identified and segmented to isolate staining and calculate the percentage of positive cells in each core. Results: Overall, MET expression was higher in metastatic lesions and it was higher in tumors with increased PD-L1 expression. Moreover, a positive correlation between MET and PD-L1 expression was found in metastatic melanoma. Conclusions: These data suggest that testing for expression of these markers should be conducted in patients with melanoma with metastatic disease and selective therapies targeting these proteins should be considered for advanced disease.

A clinico-pathological study of pigmented cutaneous lesions: a one-year prospective study in a tertiary care hospital

Background: Pigmented lesions are group of lesions which have melanocytic proliferation with very common clinical presentation. Diagnosing these pigmented lesions and differentiating cutaneous melanocytic lesions from non-melanocytic lesions poses a great challenge for the pathologist.Methods: A Prospective study was conducted for one year from June 2016 to June 2017 sent to the Department of Pathology, Andhra Medical College, Visakhapatnam, a tertiary care centre in southern India consisting of 44 pigmented lesions. Specimens were formalin fixed and the tissue was adequately processed for histopathological examination. The sections were stained routinely with hematoxylin and eosin stain and examined under light microscopy.Results: Out of 44 cases, 24 cases were cutaneous melanocytic lesions which include benign naevi 22 (50%) and 2 (4.6%) malignant melanoma cases. The other 20 cases were cutaneous non melanocytic lesions which include 5 (11.4%) pigmented seborrheic keratosis, 6 (13.7%) pigmented basal cell carcinoma, 1 (2.3%) pigmented actinic keratosis and 8 (18%) cases of naevus sebaceous. Most common effected age group was <21 years (31.81%), male: female ratio is 1:2 and most common site involved was face 29 cases (65.9%). Most common pigmented lesions were benign melanocytic nevi 22 (50%) followed by naevus sebaceous 8 (18%) cases. 32 (72.71%) cases were consistent with both clinico-histopathological correlation.Conclusions: Benign melanocytic nevi are most common lesions obtained, seborric keratosis and pigmented basal cell carcinoma were most common mimickers of melanocytic lesions, hence a careful histopathological diagnosis is important.