The role of cyclin D1 and Ki‐67 in the development and prognostication of thin melanoma

Abstract

Aims Despite their low individual metastatic potential, thin melanomas (≤1 mm Breslow thickness) contribute significantly to melanoma mortality overall. Therefore, identification of prognostic biomarkers is particularly important in this subgroup of melanoma. Prompted by preclinical results, we investigated cyclin D1 protein and Ki‐67 expression in in‐situ, metastatic and non‐metastatic thin melanomas. Methods and results Immunohistochemistry was performed on 112 melanoma specimens, comprising 22 in situ, 48 non‐metastatic and 42 metastatic thin melanomas. Overall, epidermal and dermal cyclin D1 and Ki‐67 expression were semiquantitatively evaluated by three independent investigators and compared between groups. Epidermal Ki‐67 expression did not differ statistically in in‐situ and invasive melanoma (P = 0.7). Epidermal cyclin D1 expression was significantly higher in thin invasive than in in‐situ melanoma (P = 0.003). No difference was found in cyclin D1 expression between metastatic and non‐metastatic invasive tumours. Metastatic and non‐metastatic thin melanomas did not show significant differences in epidermal expression of Ki‐67 and cyclin D1 (P = 0.148 and P = 0.611, respectively). In contrast, strong dermal expression of Ki‐67 was more frequent in metastatic than non‐metastatic samples (28.6 versus 8.3%, respectively, P = 0.001). The prognostic value of dermal Ki‐67 expression was confirmed by multivariate analysis (P = 0.047). Conclusion We found an increased expression of cyclin D1 in invasive thin melanomas compared to in‐situ melanomas, which supports a potential role of this protein in early invasion in melanoma, as suggested by preclinical findings. Moreover, our results confirm that high dermal Ki‐67 expression is associated with an increased risk of development of metastasis in thin melanoma and could possibly serve as a prognostic biomarker in clinical practice, especially if combined with additional methods.

Single Time Frame Overview of the Genetic Changes in Conjunctival Melanoma from Intraepithelial Disease to Invasive Melanoma: A Study of 4 Exenteration Specimens Illustrating the Potential Role of Cyclin D1

“…A much smaller number of background, cytologically normal melanocytes expressed Cyclin D1. Previous studies on skin have shown no staining in normal skin melanocytes compared to skin melanoma samples [7]. Case 3 showed no gains of 11q13 by aCGH or FISH, yet it showed the expression of Cyclin D1 protein in the in situ and invasive melanoma components.…”

Bergamottin Induces DNA Damage and Inhibits Malignant Progression in Melanoma by Modulating miR-145/Cyclin D1 Axis

“…It has been reported that expression of Cyclin D1 is elevated in the melanoma patients. 44 MiRNA-365 increases apoptosis and represses growth through modulating BCL2 and Cyclin D1 in melanoma cells. 45 RAF inhibitor LY3009120 stimulates BRAF or RAS mutant tumor to inhibition of CDK4/6 through abemaciclib by exceeding repression of phospho-RB and destruction of cyclin D1.…”

Prognostic and Clinicopathological Significance of CCND1/Cyclin D1 Upregulation in Melanomas: A Systematic Review and Comprehensive Meta-Analysis

“…The studies had a high (65.86%), moderate (17.07%), or low (17.07%) risk of bias (Figure 2) due to selective outcome reporting, lack of essential information in survival analysis (i.e., Kaplan-Meier courves or hazard ratios with confidence intervals), suspected data errors, or an inappropriate statistical analysis. [13][14][15][16]. Although considerable degrees of heterogeneity were reached for the alterations analyzed together, the subgroups were more homogeneous after applying the stratification by overexpression and amplification.…”

“…Although no studies have been designed to provide direct evidence of the other emerging functions of cyclin D1 in melanoma, some studies have observed an increase in cell migration after the activation of upstream regulators of cyclin D1 in melanomas [14,15]. Finally, the pro-proliferative activity of cyclin D1 has also been shown in melanomas in population-based studies, verified through the evaluation of the ki-67 proliferative index [16][17][18].…”