Xia Zheng, Donehower Lawrence A, Cooper Thomas A, Neilson Joel R, Wheeler David A, Wagner Eric J, Li Wei
1] Division of Biostatistics, Dan L Duncan Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA [2] Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
1] Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas 77030, USA [2] Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas 77030, USA.
Nat Commun. 2014 Nov 20;5:5274. doi: 10.1038/ncomms6274.
Alternative polyadenylation (APA) is a pervasive mechanism in the regulation of most human genes, and its implication in diseases including cancer is only beginning to be appreciated. Since conventional APA profiling has not been widely adopted, global cancer APA studies are very limited. Here we develop a novel bioinformatics algorithm (DaPars) for the de novo identification of dynamic APAs from standard RNA-seq. When applied to 358 TCGA Pan-Cancer tumour/normal pairs across seven tumour types, DaPars reveals 1,346 genes with recurrent and tumour-specific APAs. Most APA genes (91%) have shorter 3'-untranslated regions (3' UTRs) in tumours that can avoid microRNA-mediated repression, including glutaminase (GLS), a key metabolic enzyme for tumour proliferation. Interestingly, selected APA events add strong prognostic power beyond common clinical and molecular variables, suggesting their potential as novel prognostic biomarkers. Finally, our results implicate CstF64, an essential polyadenylation factor, as a master regulator of 3'-UTR shortening across multiple tumour types.
可变聚腺苷酸化（APA）是调控大多数人类基因的一种普遍机制，其在包括癌症在内的疾病中的作用才刚刚开始被认识到。由于传统的APA分析方法尚未被广泛采用，全球范围内关于癌症APA的研究非常有限。在此，我们开发了一种新型生物信息学算法（DaPars），用于从标准RNA测序中从头识别动态APA。当应用于七种肿瘤类型的358对TCGA泛癌肿瘤/正常样本时，DaPars揭示了1346个具有复发性和肿瘤特异性APA的基因。大多数APA基因（91%）在肿瘤中的3'非翻译区（3'UTR）较短，可避免微小RNA介导的抑制作用，包括谷氨酰胺酶（GLS），这是一种肿瘤增殖的关键代谢酶。有趣的是，所选的APA事件除了常见的临床和分子变量外，还具有很强的预后预测能力，表明它们作为新型预后生物标志物的潜力。最后，我们的结果表明，关键的聚腺苷酸化因子CstF64是多种肿瘤类型中3'UTR缩短的主要调节因子。
