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Multi-level functional genomics reveals molecular and cellular oncogenicity of patient-based 3' untranslated region

Samantha L Schuster1, Sonali Arora2, Cynthia L Wladyka2

  • 1Molecular and Cellular Biology Graduate Program, University of Washington, Seattle, WA 98195, USA; Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA.

Cell Reports
|July 29, 2023
PubMed

Insights

Somatic mutations in the 3' untranslated region (3' UTR) of genes can drive cancer. This study found these mutations in prostate tumors significantly impact gene expression and patient outcomes, revealing new therapeutic targets.

Area of Science:

  • Genetics
  • Oncology
  • Molecular Biology

Background:

  • Somatic mutations in the 3' untranslated region (3' UTR) are an understudied mechanism of cancer gene dysregulation.
  • The functional impact of these 3' UTR mutations on mRNA stability and translation is largely unknown.

Purpose of the Study:

  • To investigate the significance of 3' UTR somatic mutations in advanced prostate cancer.
  • To identify functional 3' UTR variants and understand their role in oncogenesis and patient prognosis.

Main Methods:

  • Identification and analysis of 3' UTR somatic variants in 185 advanced prostate tumors.
  • Development and application of reporter assays to measure mutation effects on mRNA translation and stability.
  • CRISPR-Cas9 gene editing to validate the functional impact of specific variants.

Main Results:

  • Discovered 14,497 single-nucleotide mutations in 3' UTRs, enriched in oncogenic pathways and regulatory elements.
  • Identified hundreds of functional variants affecting mRNA stability and translation.
  • Demonstrated that specific 3' UTR mutations enhance cellular stress resistance and correlate with a poor patient prognosis.

Conclusions:

  • 3' UTR somatic mutations play a significant role in prostate cancer progression.
  • These mutations impact mRNA regulation and cellular functions, offering potential therapeutic targets.
  • This research expands the understanding of regulatory regions in cancer development.
Keywords:
3' UTRCP: CancerCP: GenomicsCRISPR-Cas9 base editingIGF1RZWILCHmRNA stabilitymRNA translationmassively parallel reporter assayprostate cancersomatic mutationuntranslated region

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