Department of Clinical Sciences, Division of Pathology, Lund University, Skåne University Hospital, 221 85, Lund, Sweden.
Diagn Pathol. 2012 Jul 17;7:82. doi: 10.1186/1746-1596-7-82.
Malignant 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.
Immunohistochemical 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).
High 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.
These 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.
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恶性黑色素瘤是皮肤癌中最致命的一种，即使是在患有薄型黑色素瘤和局限性疾病的患者中，其临床病程也具有可变性。尽管对黑色素瘤生物学的认识不断加深，但尚未有任何预后生物标志物纳入临床方案。RNA 结合基序蛋白 3（RBM3）的表达降低已被证明与黑色素瘤和其他几种癌症形式的肿瘤进展和预后不良相关。在卵巢癌中，发现 RBM3 的表达与微小染色体维持蛋白 3（MCM3）基因和蛋白呈负相关。在黑色素瘤中，基因表达分析和免疫组织化学验证揭示了 MCM3 作为一种潜在的预后生物标志物。本研究的目的是在一项前瞻性、基于人群的黑色素瘤队列中，检查 MCM3 表达与临床结局和 RBM3 表达的相关性。
对来自马尔默饮食与癌症研究的 224 例原发性黑色素瘤病例进行 MCM3 的免疫组织化学表达分析，这些病例先前已分析 RBM3 的表达。使用 Spearman's Rho 和卡方检验探索 MCM3 表达与临床病理因素、RBM3 和 Ki67 表达之间的相关性。Kaplan-Meier 分析、对数秩检验以及单变量和多变量 Cox 比例风险模型用于评估 MCM3 表达对无病生存（DFS）和黑色素瘤特异性生存（MSS）的影响。
高 MCM3 表达与不良的临床病理特征和高 Ki67 表达显著相关。MCM3 表达与 RBM3 表达呈显著负相关（p = 0.025）。高 MCM3 表达与 DFS（HR = 5.62）和 MSS（HR = 6.03）降低相关，并且在调整所有其他因素的多变量分析中，这些相关性仍然显著（DFS 的 HR = 5.01，MSS 的 HR = 4.96）。在多变量模型中，RBM3 表达仍然是 MSS 的独立预后因素，但不是 DFS。
这些发现为 MCM3 表达作为原发性黑色素瘤患者预后的独立生物标志物的效用提供了验证。此外，MCM3 和 RBM3 表达的反比关系和预后影响表明这些蛋白质在黑色素瘤进展中可能存在相互作用，其功能基础值得进一步研究。
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