BC Cancer Agency, Genome Sciences Centre, Vancouver, BC, V5Z 4S6, Canada.
Institute for Systems Biology, Seattle, 98109, WA, USA.
BMC Genomics. 2018 Jul 13;19(1):536. doi: 10.1186/s12864-018-4903-7.
Alternative polyadenylation (APA) results in messenger RNA molecules with different 3' untranslated regions (3' UTRs), affecting the molecules' stability, localization, and translation. APA is pervasive and implicated in cancer. Earlier reports on APA focused on 3' UTR length modifications and commonly characterized APA events as 3' UTR shortening or lengthening. However, such characterization oversimplifies the processing of 3' ends of transcripts and fails to adequately describe the various scenarios we observe.
We built a cloud-based targeted de novo transcript assembly and analysis pipeline that incorporates our previously developed cleavage site prediction tool, KLEAT. We applied this pipeline to elucidate the APA profiles of 114 genes in 9939 tumor and 729 tissue normal samples from The Cancer Genome Atlas (TCGA). The full set of 10,668 RNA-Seq samples from 33 cancer types has not been utilized by previous APA studies. By comparing the frequencies of predicted cleavage sites between normal and tumor sample groups, we identified 77 events (i.e. gene-cancer type pairs) of tumor-specific APA regulation in 13 cancer types; for 15 genes, such regulation is recurrent across multiple cancers. Our results also support a previous report showing the 3' UTR shortening of FGF2 in multiple cancers. However, over half of the events we identified display complex changes to 3' UTR length that resist simple classification like shortening or lengthening.
Recurrent tumor-specific regulation of APA is widespread in cancer. However, the regulation pattern that we observed in TCGA RNA-seq data cannot be described as straightforward 3' UTR shortening or lengthening. Continued investigation into this complex, nuanced regulatory landscape will provide further insight into its role in tumor formation and development.
可变多聚腺苷酸化（APA）导致信使 RNA 分子具有不同的 3'非翻译区（3'UTR），影响分子的稳定性、定位和翻译。APA 普遍存在，并与癌症有关。早期关于 APA 的报道集中在 3'UTR 长度修饰上，通常将 APA 事件特征化为 3'UTR 缩短或延长。然而，这种特征化过于简化了转录本 3'端的加工过程，无法充分描述我们观察到的各种情况。
我们构建了一个基于云的靶向从头转录物组装和分析管道，该管道整合了我们之前开发的切割位点预测工具 KLEAT。我们应用该管道阐明了 114 个基因在来自癌症基因组图谱（TCGA）的 9939 个肿瘤和 729 个组织正常样本中的 APA 谱。之前的 APA 研究尚未利用来自 33 种癌症类型的全套 10668 个 RNA-Seq 样本。通过比较正常和肿瘤样本组之间预测切割位点的频率，我们在 13 种癌症类型中鉴定出了 77 个肿瘤特异性 APA 调节事件（即基因-癌症类型对）；对于 15 个基因，这种调节在多种癌症中是反复出现的。我们的结果还支持了之前的一项报告，该报告表明在多种癌症中 FGF2 的 3'UTR 缩短。然而，我们鉴定出的超过一半的事件显示出对 3'UTR 长度的复杂变化，无法简单地归类为缩短或延长。
APA 的复发性肿瘤特异性调节在癌症中广泛存在。然而，我们在 TCGA RNA-seq 数据中观察到的调节模式不能简单地描述为 3'UTR 缩短或延长。对这种复杂而细微的调节景观的进一步研究将为其在肿瘤形成和发展中的作用提供进一步的见解。
