Deciphering the post-transcriptional mechanisms (PTM) regulating gene expression is critical to understand the dynamics underlying transcriptomic regulation in cancer. Alternative polyadenylation (APA)—regulation of mRNA 3′UTR length by alternating poly(A) site usage—is a key PTM mechanism whose comprehensive analysis in cancer remains an important open challenge. Here we use a method and analysis pipeline that sequences 3′end-enriched RNA directly to overcome the saturation limitation of traditional 5′–3′ based sequencing. We comprehensively map the APA landscape in lung cancer in a cohort of 98 tumor/non-involved tissues derived from European American and African American patients. We identify a global shortening of 3′UTR transcripts in lung cancer, with notable functional implications on the expression of both coding and noncoding genes. We find that APA of non-coding RNA transcripts (long non-coding RNAs and microRNAs) is a recurrent event in lung cancer and discover that the selection of alternative polyA sites is a form of non-coding RNA expression control. Our results indicate that mRNA transcripts from EAs are two times more likely than AAs to undergo APA in lung cancer. Taken together, our findings comprehensively map and identify the important functional role of alternative polyadenylation in determining transcriptomic heterogeneity in lung cancer.

破译转录后机制（PTM）调节基因表达对于理解癌症转录组调节的动态至关重要。替代多腺苷酸化 (APA)——通过交替使用 Poly(A) 位点来调节 mRNA 3'UTR 长度——是一种关键的 PTM 机制，其在癌症中的综合分析仍然是一个重要的开放挑战。在这里，我们使用直接对 3' 末端富集 RNA 进行测序的方法和分析流程，以克服传统 5'–3' 测序的饱和限制。我们全面绘制了来自欧洲裔美国人和非裔美国人患者的 98 个肿瘤/非相关组织队列中肺癌的 APA 情况。我们发现肺癌中 3'UTR 转录本的整体缩短，对编码和非编码基因的表达具有显着的功能影响。我们发现非编码RNA转录本（长非编码RNA和microRNA）的APA是肺癌中反复发生的事件，并发现替代polyA位点的选择是非编码RNA表达控制的一种形式。我们的结果表明，来自 EA 的 mRNA 转录本在肺癌中进行 APA 的可能性是 AA 的两倍。总而言之，我们的研究结果全面绘制并确定了替代多腺苷酸化在确定肺癌转录组异质性中的重要功能作用。