Global changes in processing of mRNA 3' untranslated regions characterize clinically distinct cancer subtypes.
Global changes in processing of mRNA 3' untranslated regions characterize clinically distinct cancer subtypes.
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DOI：
10.1158/0008-5472.can-09-2236
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发表时间：
2009-12-15
期刊：
影响因子：
11.2
通讯作者：
Graber JH
中科院分区：
文献类型：
--
作者：
Singh P;Alley TL;Wright SM;Kamdar S;Schott W;Wilpan RY;Mills KD;Graber JH
分子癌症诊断是癌症治疗的重要临床进展，但仍需要新的方法。在这种背景下，通过微阵列获得的基因表达特征代表了一种有用的分子诊断。在这里，我们描述了新的探针级微阵列分析，揭示了多种肿瘤类型中mRNA处理和肿瘤形成之间的联系，具有诊断潜力。我们现在发现，在mRNA处理过程中的特征差异，主要是在3‘-非翻译区，定义了能够区分具有不同生存特征的相似肿瘤亚型的分子特征，准确率至少为74%。使用B细胞白血病/淋巴瘤的小鼠模型，我们发现转录异构体丰度的差异可能是由于交替多聚腺苷基化(APA)和差异降解。虽然3‘-UTR截断是最常见的观察模式，但也观察到了转录本延长的基因，在相关但不同的肿瘤类型中发现了不同的受影响基因组。带有拉长转录本的基因在与细胞-细胞黏附和形态相关的本体论类别中被过度表达。对来自人类原发肿瘤样本的微阵列数据的分析发现了类似的现象。对选定蛋白质的蛋白质印迹分析证实，3‘-非编码区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加工，特别是APA，可能是一个具有预后潜力的强大的分子生物标记物。最后，这些发现为肿瘤发生中基因去调控的分子机制提供了洞察力。
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.