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Engineering Artificial Factors to Specifically Manipulate Alternative Splicing in Human Cells
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3' untranslated region somatic variants connect alternative polyadenylation dysregulation in human cancers

Qiushi Xu1, Xiaomeng Cheng2, Qianru Li2

  • 1State 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; Center for Reproductive Medicine, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, China.

Journal of Genetics and Genomics = Yi Chuan Xue Bao
|March 19, 2025
PubMed

Insights

Somatic variants in cancer 3' untranslated regions (3' UTRs) can disrupt messenger RNA alternative polyadenylation (APA). This study identifies numerous variants linked to abnormal APA, revealing a new layer of gene regulation in cancer.

Area of Science:

  • Genomics
  • Molecular Biology
  • Cancer Research

Background:

  • Somatic variants in cancer genomes affect gene expression via various mechanisms.
  • The impact of 3' untranslated region (3' UTR) somatic variants on alternative polyadenylation (APA) has not been systematically evaluated.

Purpose of the Study:

  • To systematically investigate the effects of somatic variants in 3' UTRs on mRNA alternative polyadenylation (APA) across diverse cancer types.
  • To elucidate the mechanisms by which these variants alter APA and their functional consequences in cancer.

Main Methods:

  • Analysis of 10,199 tumor samples from 32 cancer types to identify somatic single nucleotide variants (SNVs) associated with 3' UTR APA.
  • Mechanistic investigation of SNV effects on cis-regulatory elements (e.g., poly(A) signals, UGUA motifs).
  • Validation using minigene assays and experimental determination of mRNA isoform stability.

Main Results:

  • Identified 1333 somatic SNVs linked to abnormal 3' UTR APA.
  • Demonstrated that these SNVs alter cis-regulatory elements, leading to changes in APA.
  • Confirmed SNV-induced aberrant APA in genes like RPS23 and CHTOP via minigene assays.
  • Found 62 affected genes with differential stability between tandem 3' UTR isoforms (e.g., HSPA4, UCK2).
  • Established SNV-driven abnormal APA as a regulatory mechanism for tumor suppressor HMGN2 in breast cancer.

Conclusions:

  • Somatic variants in 3' UTRs significantly impact mRNA alternative polyadenylation (APA).
  • This mechanism represents a critical pathway through which noncoding somatic variants exert functional effects in human cancers.
  • Abnormal 3' UTR APA is a newly identified layer of gene expression regulation in cancer.
Keywords:
3′ UTRAlternative polyadenylationCancerGene expression regulationSomatic variants

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