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

Cell Rep. 2023 Aug 29;42(8):112840. doi: 10.1016/j.celrep.2023.112840. Epub 2023 Jul 28.

Abstract

3' untranslated region (3' UTR) somatic mutations represent a largely unexplored avenue of alternative oncogenic gene dysregulation. To determine the significance of 3' UTR mutations in disease, we identify 3' UTR somatic variants across 185 advanced prostate tumors, discovering 14,497 single-nucleotide mutations enriched in oncogenic pathways and 3' UTR regulatory elements. By developing two complementary massively parallel reporter assays, we measure how thousands of patient-based mutations affect mRNA translation and stability and identify hundreds of functional variants that allow us to define determinants of mutation significance. We demonstrate the clinical relevance of these mutations, observing that CRISPR-Cas9 endogenous editing of distinct variants increases cellular stress resistance and that patients harboring oncogenic 3' UTR mutations have a particularly poor prognosis. This work represents an expansive view of the extent to which disease-relevant 3' UTR mutations affect mRNA stability, translation, and cancer progression, uncovering principles of regulatory functionality and potential therapeutic targets in previously unexplored regulatory regions.

Keywords: 3' UTR; CP: Cancer; CP: Genomics; CRISPR-Cas9 base editing; IGF1R; ZWILCH; mRNA stability; mRNA translation; massively parallel reporter assay; prostate cancer; somatic mutation; untranslated region.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions / genetics
  • 5' Untranslated Regions
  • Genomics*
  • Humans
  • Mutation / genetics
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Regulatory Sequences, Nucleic Acid*

Substances

  • 3' Untranslated Regions
  • RNA, Messenger
  • 5' Untranslated Regions