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Comprehensive characterization of somatic variants associated with intronic polyadenylation in human cancers

Zhaozhao Zhao1, Qiushi Xu1, Ran Wei1,2

  • 1State Key Laboratory of Genetic Engineering, Collaborative Innovation Center of Genetics and Development, Human Phenome Institute, School of Life Sciences and Huashan Hospital, Fudan University, Shanghai 200438, P.R. China.

Nucleic Acids Research
|September 11, 2021
PubMed

Insights

Somatic single nucleotide variants (SNVs) near splice sites can cause abnormal intronic polyadenylation (IPA), a novel mechanism affecting gene expression in cancer. This finding impacts understanding of cancer-related gene mutations and their functional consequences.

Area of Science:

  • Genomics
  • Molecular Biology
  • Cancer Research

Background:

  • Somatic single nucleotide variants (SNVs) in cancer genomes can alter gene expression.
  • While SNVs near splice sites are known to cause abnormal splicing, other mechanisms remain unexplored.

Purpose of the Study:

  • To investigate novel mechanisms by which somatic SNVs affect gene expression in cancer.
  • To identify and characterize SNVs associated with abnormal intronic polyadenylation (IPA).

Main Methods:

  • Analysis of RNA sequencing and exome data from 4,998 cancer patients across ten cancer types.
  • Identification of somatic SNVs near splice sites associated with IPA.
  • Minigene assays to validate the functional impact of SNVs on IPA.

Main Results:

  • 152 somatic SNVs associated with IPA were identified, predominantly near donor splice sites.
  • IPA-associated SNVs were enriched in tumor suppressor genes (TSGs) like PTEN and CDH1.
  • Genomic features like GC content and intron length differentiated IPA from intron retention.

Conclusions:

  • Abnormal intronic polyadenylation (IPA) is a novel mechanism through which somatic SNVs impact gene expression in human cancers.
  • Understanding SNV-associated IPA provides new insights into cancer development and potential therapeutic targets.

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