During pre-mRNA maturation 3′ end processing can occur at different polyadenylation sites in the 3′ untranslated region (3′ UTR) to give rise to transcript isoforms that differ in the length of their 3′ UTRs. Longer 3′ UTRs contain additional cis-regulatory elements that impact the fate of the transcript and/or of the resulting protein. Extensive alternative polyadenylation (APA) has been observed in cancers, but the mechanisms and roles remain elusive. In particular, it is unclear whether the APA occurs in the malignant cells or in other cell types that infiltrate the tumor. To resolve this, we developed a computational method, called SCUREL, that quantifies changes in 3′ UTR length between groups of cells, including cells of the same type originating from tumor and control tissue. We used this method to study APA in human lung adenocarcinoma (LUAD). SCUREL relies solely on annotated 3′ UTRs and on control systems such as T cell activation, and spermatogenesis gives qualitatively similar results at much greater sensitivity compared to the previously published scAPA method. In the LUAD samples, we find a general trend toward 3′ UTR shortening not only in cancer cells compared to the cell type of origin, but also when comparing other cell types from the tumor vs. the control tissue environment. However, we also find high variability in the individual targets between patients. The findings help in understanding the extent and impact of APA in LUAD, which may support improvements in diagnosis and treatment.

中文翻译：

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构成肿瘤组织的大多数细胞类型中 3' UTR 的缩短表明蛋白质代谢中的替代聚腺苷酸化

在 pre-mRNA 成熟过程中，3' 末端加工可发生在 3' 非翻译区 (3' UTR) 的不同多聚腺苷酸化位点，以产生 3' UTR 长度不同的转录本亚型。较长的 3' UTR 包含额外的顺式- 影响转录本和/或所得蛋白质命运的调控元件。已在癌症中观察到广泛的替代聚腺苷酸化 (APA)，但其机制和作用仍然难以捉摸。特别是，尚不清楚 APA 是发生在恶性细胞中还是发生在浸润肿瘤的其他细胞类型中。为了解决这个问题，我们开发了一种称为 SCUREL 的计算方法，它可以量化细胞组之间 3' UTR 长度的变化，包括来自肿瘤和对照组织的相同类型的细胞。我们使用这种方法研究了人肺腺癌 (LUAD) 中的 APA。SCUREL 完全依赖于带注释的 3' UTR 和 T 细胞激活等控制系统，与之前公布的 scAPA 方法相比，精子发生以更高的灵敏度给出了定性相似的结果。在 LUAD 样本中，我们发现 3' UTR 缩短的一般趋势不仅在癌细胞中与起源细胞类型相比，而且在比较来自肿瘤的其他细胞类型与对照组织环境时也是如此。然而，我们还发现患者之间的个体目标存在很大差异。这些发现有助于了解 APA 在 LUAD 中的范围和影响，这可能有助于改进诊断和治疗。