The Jackson Laboratory, Bar Harbor, Maine 04609, USA.
Cancer Res. 2009 Dec 15;69(24):9422-30. doi: 10.1158/0008-5472.CAN-09-2236.
Molecular cancer diagnostics are an important clinical advance in cancer management, but new methods are still needed. In this context, gene expression signatures obtained by microarray represent a useful molecular diagnostic. Here, we describe novel probe-level microarray analyses that reveal connections between mRNA processing and neoplasia in multiple tumor types, with diagnostic potential. We now show that characteristic differences in mRNA processing, primarily in the 3'-untranslated region, define molecular signatures that can distinguish similar tumor subtypes with different survival characteristics, with at least 74% accuracy. Using a mouse model of B-cell leukemia/lymphoma, we find that differences in transcript isoform abundance are likely due to both alternative polyadenylation (APA) and differential degradation. While truncation of the 3'-UTR is the most common observed pattern, genes with elongated transcripts were also observed, and distinct groups of affected genes are found in related but distinct tumor types. Genes with elongated transcripts are overrepresented in ontology categories related to cell-cell adhesion and morphology. Analysis of microarray data from human primary tumor samples revealed similar phenomena. Western blot analysis of selected proteins confirms that changes in the 3'-UTR can correlate with changes in protein expression. Our work suggests that alternative mRNA processing, particularly APA, can be a powerful molecular biomarker with prognostic potential. Finally, these findings provide insights into the molecular mechanisms of gene deregulation in tumorigenesis.
分子癌症诊断是癌症管理方面的重要临床进展，但仍需要新的方法。在这种情况下，通过微阵列获得的基因表达谱代表了一种有用的分子诊断方法。在这里，我们描述了新的探针级微阵列分析，这些分析揭示了多种肿瘤类型中 mRNA 处理与肿瘤发生之间的联系，具有诊断潜力。我们现在表明，mRNA 处理的特征差异，主要是在 3'-非翻译区，定义了分子特征，可以区分具有不同生存特征的相似肿瘤亚型，准确率至少为 74%。使用 B 细胞白血病/淋巴瘤的小鼠模型，我们发现转录本亚型丰度的差异可能是由于可变多聚腺苷酸化（APA）和差异降解所致。虽然 3'-UTR 的截断是最常见的观察模式，但也观察到了延长转录本的基因，并且在相关但不同的肿瘤类型中发现了不同的受影响基因组。具有延长转录本的基因在与细胞间黏附和形态相关的本体论类别中过表达。对人类原发性肿瘤样本的微阵列数据分析的分析揭示了类似的现象。对选定蛋白质的 Western blot 分析证实，3'-UTR 的变化可以与蛋白质表达的变化相关。我们的工作表明，替代的 mRNA 处理，特别是 APA，可以成为具有预测潜力的强大分子生物标志物。最后，这些发现为肿瘤发生中基因失调的分子机制提供了深入的了解。
