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

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

doi:10.1016/j.jgg.2025.03.006

Volume 52 Issue 11

Nov. 2025

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

doi: 10.1016/j.jgg.2025.03.006

a. State Key Laboratory of Genetic Engineering, National Clinical Research Center for Aging and Medicine, Huashan Hospital, Collaborative Innovation Center of Genetics and Development, Human Phenome Institute, Center for Evolutionary Biology, Shanghai Engineering Research Center of Industrial Microorganisms, School of Life Sciences, Fudan University, Shanghai 200438, China;
b. Center for Reproductive Medicine, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, China;
c. State Key Laboratory of Reproductive Regulation and Breeding of Grassland Livestock, Institutes of Biomedical Sciences, School of Life Sciences, Inner Mongolia University, Hohhot, Inner Mongolia 010070, China;
d. MOE Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai 200438, China

Funds:

This work was financially supported by the National Key R&D Program of China (2023YFC3603300, 2021YFA0909300), National Natural Science Foundation of China (92249302, 32370592, 32400437), and China Postdoctoral Science Foundation (BX20230073 and 2023M740709).

Received Date: 2024-12-17
Accepted Date: 2025-03-10
Rev Recd Date: 2025-03-06
Publish Date: 2025-03-17

Abstract

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 1333 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.
- Somatic variants,
- 3' UTR,
- Alternative polyadenylation,
- Cancer,
- Gene expression regulation

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References(48)

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