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

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

基金项目:

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). The authors sincerely thank the participants for their help and willingness to participate in this study.

详细信息

通讯作者:
Ting Ni,E-mail:tingni@fudan.edu.cn

Zhaozhao Zhao,E-mail:zhaozzbio@126.com

计量
- 文章访问数: 6
- HTML全文浏览量: 3
- PDF下载量: 0
- 被引次数: 0
出版历程
- 收稿日期: 2024-12-17
- 录用日期: 2025-03-10
- 修回日期: 2025-03-06
- 网络出版日期: 2025-07-11

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

Qiushi Xu^a,b,
Xiaomeng Cheng^a,
Qianru Li^a,
Peng Yu^a,
Xiaolan Zhou^a,
Yu Chen^a,
Limin Lin^a,
Ting Ni^{a,c
, ,},
Zhaozhao Zhao^{a,d
, ,}

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:

摘要

摘要:
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
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

HTML全文

参考文献(0)

施引文献

资源附件(0)

访问统计

点击查看大图

计量

文章访问数: 6
HTML全文浏览量: 3
PDF下载量: 0
被引次数: 0

姓名
邮箱
手机号码
标题
留言内容
验证码

留言板

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

doi: 10.1016/j.jgg.2025.03.006

通讯作者:
Ting Ni,E-mail:tingni@fudan.edu.cn

Zhaozhao Zhao,E-mail:zhaozzbio@126.com

计量

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

计量

目录

留言板

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

doi: 10.1016/j.jgg.2025.03.006

通讯作者: Ting Ni,E-mail:tingni@fudan.edu.cn Zhaozhao Zhao,E-mail:zhaozzbio@126.com

计量

出版历程

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

计量

出版历程

目录

通讯作者:
Ting Ni,E-mail:tingni@fudan.edu.cn

Zhaozhao Zhao,E-mail:zhaozzbio@126.com