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A widespread length-dependent splicing dysregulation in cancer

Sirui Zhang1, Miaowei Mao1, Yuesheng Lv2

  • 1CAS Key Laboratory of Computational Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China.

Science Advances
|August 17, 2022
PubMed

Insights

Cancer exhibits altered splicing, particularly excluding short exons. These cancer-associated short exons (CASEs) can predict survival and offer new diagnostic and therapeutic strategies.

Area of Science:

  • Molecular biology
  • Genomics
  • Cancer research

Background:

  • Alternative splicing dysregulation is a hallmark of cancer.
  • Common features and mechanisms of cancer splicing alterations are not fully understood.

Purpose of the Study:

  • To investigate length-dependent splicing regulation in cancer.
  • To identify common features of cancer-associated splicing events.
  • To develop clinical applications based on splicing alterations.

Main Methods:

  • Systematic transcriptome analysis of thousands of cancer patients.
  • Identification and characterization of cancer-associated short exons (CASEs).
  • Development of a CASE-based panel for cancer stratification and survival prediction.

Main Results:

  • Short exons are preferentially mis-spliced and excluded in cancers.
  • CASEs are conserved, encode low-complexity peptides, and are enriched in GTPase regulators and cell adhesion.
  • A CASE-based panel demonstrated reliable cancer stratification and survival prediction.
  • CASE mis-splicing is linked to elevated transcription and altered RNA binding proteins.

Conclusions:

  • A common, length-dependent splicing dysregulation pattern exists in cancer.
  • CASEs serve as potential biomarkers for cancer diagnosis, stratification, and prognosis.
  • Understanding CASE regulation offers new therapeutic avenues for cancer treatment.

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