3' untranslated region somatic variants connect alternative polyadenylation dysregulation in human cancers.

IF 6.6 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Journal of Genetics and Genomics Pub Date : 2025-03-17 DOI:10.1016/j.jgg.2025.03.006

Qiushi Xu, Xiaomeng Cheng, Qianru Li, Peng Yu, Xiaolan Zhou, Yu Chen, Limin Lin, Ting Ni, Zhaozhao Zhao

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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.

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来源期刊

Journal of Genetics and Genomics 生物-生化与分子生物学

CiteScore

8.20

自引率

3.40%

发文量

4756

审稿时长

14 days

期刊介绍： The Journal of Genetics and Genomics (JGG, formerly known as Acta Genetica Sinica ) is an international journal publishing peer-reviewed articles of novel and significant discoveries in the fields of genetics and genomics. Topics of particular interest include but are not limited to molecular genetics, developmental genetics, cytogenetics, epigenetics, medical genetics, population and evolutionary genetics, genomics and functional genomics as well as bioinformatics and computational biology.