Abstract
BackgroundMalignant melanoma is the most lethal form of skin cancer with a variable clinical course even in patients with thin melanomas and localized disease. Despite increasing insights into melanoma biology, no prognostic biomarkers have yet been incorporated into clinical protocols. Reduced expression of the RNA binding motif protein 3 (RBM3) has been shown to correlate with tumour progression and poor prognosis in melanoma and several other cancer forms. In ovarian cancer, an inverse association was found between expression of RBM3 and the minichromosome maintenance 3 (MCM3) gene and protein. In melanoma, gene expression analysis and immunohistochemical validation has uncovered MCM3 as a putative prognostic biomarker. The aim of the present study was to examine the associations of MCM3 expression with clinical outcome and RBM3 expression in a prospective, population-based cohort of melanoma.MethodsImmunohistochemical MCM3 expression was examined in 224 incident cases of primary melanoma from the Malmö Diet and Cancer Study, previously analysed for RBM3 expression. Spearman´s Rho and Chi-Square tests were used to explore correlations between MCM3 expression, clinicopathological factors, and expression of RBM3 and Ki67. Kaplan Meier analysis, the log rank test, and univariable and multivariable Cox proportional hazards modelling were used to assess the impact of MCM3 expression on disease-free survival (DFS) and melanoma-specific survival (MSS).ResultsHigh MCM3 expression was significantly associated with unfavourable clinicopathological features and high Ki67 expression. A significant inverse correlation was seen between expression of MCM3 and RBM3 (p = 0.025). High MCM3 expression was associated with a reduced DFS (HR = 5.62) and MSS (HR = 6.03), and these associations remained significant in multivariable analysis, adjusted for all other factors (HR = 5.01 for DFS and HR = 4.96 for MSS). RBM3 expression remained an independent prognostic factor for MSS but not DFS in the multivariable model.ConclusionsThese findings provide validation of the utility of MCM3 expression as an independent biomarker for prognostication of patients with primary melanoma. Moreover, the inverse association and prognostic impact of MCM3 and RBM3 expression indicate a possible interaction of these proteins in melanoma progression, the functional basis for which merits further study.Virtual SlidesThe virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1814908129755401
Highlights
Malignant melanoma is an aggressive form of cancer with an increasing incidence and mortality worldwide [1]
An inverse association was observed between expression of RNA binding motif protein 3 (RBM3) and the minichromosome maintenance 3 (MCM3) gene and protein in human epithelial ovarian cancer (EOC) samples and in ovarian cancer cells, and high expression of MCM3 was demonstrated to be associated with poor prognosis in EOC, both at the mRNA and protein levels [16]
In contrast to RBM3 [12], there was no significant difference in MCM3 expression in paired primary melanoma and metastatic lesions (Spearmans Rho = 0.24; p = 0.205)
Summary
Malignant melanoma is an aggressive form of cancer with an increasing incidence and mortality worldwide [1]. We have previously demonstrated that high nuclear expression of the RNA binding motif protein 3 (RBM3) is associated with an improved outcome in several major cancer forms, i.e. breast, ovarian, colorectal and prostate cancer and malignant melanoma [10,11,12,13,14]. An inverse association was observed between expression of RBM3 and the minichromosome maintenance 3 (MCM3) gene and protein in human EOC samples and in ovarian cancer cells, and high expression of MCM3 was demonstrated to be associated with poor prognosis in EOC, both at the mRNA and protein levels [16]. Reduced expression of the RNA binding motif protein 3 (RBM3) has been shown to correlate with tumour progression and poor prognosis in melanoma and several other cancer forms. The aim of the present study was to examine the associations of MCM3 expression with clinical outcome and RBM3 expression in a prospective, population-based cohort of melanoma
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