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Metastatic potential of melanomas defined by specific gene expression profiles with no BRAF signature

机译：由无BRAF签名的特定基因表达谱定义的黑色素瘤的转移潜力

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The molecular biology of metastatic potential in melanoma has been studied many times previously and changes in the expression of many genes have been linked to metastatic behaviour. What is lacking is a systematic characterization of the regulatory relationships between genes whose expression is related to metastatic potential. Such a characterization would produce a molecular taxonomy for melanoma which could feasibly be used to identify epigenetic mechanisms behind changes in metastatic behaviour. To achieve this we carried out three separate DNA microarray analyses on a total of 86 cultures of melanoma. Significantly, multiple testing correction revealed that previous reports describing correlations of gene expression with activating mutations in BRAF or NRAS were incorrect and that no gene expression patterns correlate with the mutation status of these MAPK pathway components. Instead, we identified three different sample cohorts (A, B and C) and found that these cohorts represent melanoma groups of differing metastatic potential. Cohorts A and B were susceptible to transforming growth factor-beta (TGF beta)-mediated inhibition of proliferation and had low motility. Cohort C was resistant to TGF beta and demonstrated high motility. Meta-analysis of the data against previous studies linking gene expression and phenotype confirmed that cohorts A and C represent transcription signatures of weakly and strongly metastatic melanomas, respectively. Gene expression co-regulation suggested that signalling via TGF beta-type and Wnt/beta-catenin pathways underwent considerable change between cohorts. These results suggest a model for the transition from weakly to strongly metastatic melanomas in which TGF beta-type signalling upregulates genes expressing vasculogenic/extracellular matrix remodelling factors and Wnt signal inhibitors, coinciding with a downregulation of genes downstream of Wnt signalling.
机译：先前已经对黑素瘤的转移潜力进行了分子生物学研究，并且许多基因表达的变化与转移行为有关。缺乏对表达与转移潜能有关的基因之间调节关系的系统表征。这样的表征将产生用于黑色素瘤的分子分类学，其可以被可行地用于鉴定转移行为变化背后的表观遗传机制。为了实现这一目标，我们对总共86种黑色素瘤培养物进行了三个单独的DNA芯片分析。重要的是，多次测试校正显示，先前描述基因表达与BRAF或NRAS中激活突变相关性的报道是不正确的，并且没有基因表达模式与这些MAPK途径组分的突变状态相关。相反，我们确定了三个不同的样本队列（A，B和C），并发现这些队列代表具有不同转移潜能的黑色素瘤组。队列A和队列B易受转化生长因子-β（TGFβ）介导的增殖抑制，并且运动能力低。队列C对TGFβ耐药，并显示出高运动能力。对有关链接基因表达和表型的先前研究进行的数据荟萃分析证实，队列A和C分别代表了弱转移性和强烈转移性黑素瘤的转录特征。基因表达的共调节提示，通过TGFβ型和Wnt /β-catenin途径的信号转导在人群之间发生了相当大的变化。这些结果提示了从弱转移性黑色素瘤向强烈转移性黑色素瘤过渡的模型，其中TGFβ型信号上调表达血管生成/细胞外基质重塑因子和Wnt信号抑制剂的基因，同时下调Wnt信号下游基因的表达。

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