3′ 非翻译区体细胞变异与人类癌症中选择性多腺苷酸化失调有关，这一成果由复旦大学倪挺团队经过不懈努力而取得。2025年3月17日出版的《遗传学报》发表了这项成果。

在这项研究中，课题组人员分析了32种癌症类型的10199个肿瘤样本，发现了1333个与3′  UTR APA异常相关的体细胞单核苷酸变异（SNV）。从机制上讲，这些3′  UTR SNV可以改变顺式调控元件，如poly(A)信号和UGUA基序，从而导致APA的变化。Minigene实验证实，包括RPS23和CHTOP在内的多个基因中的3′ UTR SNV可诱导APA异常。在受影响的基因中，62个在串联3′ UTR异构体之间表现出不同的稳定性，包括HSPA4和UCK2，实验分析证实了这一点。最后，研究小组确定SNV相关的APA异常图像在乳腺癌中作为肿瘤抑制基因HMGN2的另一层表达调控。总的来说，这项研究揭示了3′ UTR APA是介导人类癌症中体细胞非编码变异功能影响的关键机制。

研究人员表示，癌症基因组中的体细胞变异根据其特定位置通过多种机制影响基因表达。然而，关于位于3′ 非翻译区（3′ UTR）的体细胞变异对mRNA的选择性多聚腺苷化（APA）的影响的系统评估仍然缺乏。

附：英文原文

Title: 3′ untranslated region somatic variants connect alternative polyadenylation dysregulation in human cancers

Author: Ting Ni a c, Zhaozhao Zhao a d

Issue&Volume: 2025/03/17

Abstract: Somatic variants in the cancer genome influence gene expression through diverse mechanisms depending on their specific locations. However, a systematic evaluation of the effects of somatic variants located in 3′ untranslated regions (3′ UTRs) on alternative polyadenylation (APA) of mRNA remains lacking. In this study, we analyze 10,199 tumor samples across 32 cancer types and identify 1,333 somatic single nucleotide variants (SNVs) associated with abnormal 3′ UTR APA. Mechanistically, these 3′ UTR SNVs can alter cis-regulatory elements, such as the poly(A) signal and UGUA motif, leading to changes in APA. Minigene assays confirm that 3′ UTR SNVs in multiple genes, including RPS23 and CHTOP, induce aberrant APA. Among affected genes, 62 exhibit differential stability between tandem 3′ UTR isoforms, including HSPA4 and UCK2, validated by experimental assays. Finally, we establish that SNV-related abnormal APA usage serves as an additional layer of expression regulation for tumor-suppressor gene HMGN2 in breast cancer. Collectively, this study reveals 3′ UTR APA as a critical mechanism mediating the functional impact of somatic noncoding variants in human cancers.

DOI: 10.1016/j.jgg.2025.03.006

Source: https://www.sciencedirect.com/science/article/abs/pii/S1673852725000797