Uncoupling of gene expression from copy number presents therapeutic opportunities in aneuploid cancers

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Abstract

Uncoupling of mRNA expression from copy number (UECN) might be a strategy for cancer cells to a tolerate high degree of aneuploidy. To test the extent and role of UECN across cancers, we perform integrative multiomic analysis of The Cancer Genome Atlas (TCGA) dataset, encompassing ∼5,000 individual tumors. We find UECN is common in cancers and is associated with increased oncogenic signaling, proliferation, and immune suppression. UECN appears to be orchestrated by complex regulatory changes, with transcription factors (TFs) playing a prominent role. To further dissect the regulatory mechanisms, we develop a systems-biology approach to identify candidate TFs, which could serve as targets to disrupt UECN and reduce tumor fitness. Applying our approach to TCGA data, we identify 21 putative targets, 42.8% of which are validated by independent sources. Together, our study indicates that UECN is likely an important mechanism in development of aneuploid tumors and might be therapeutically targetable.

Original languageEnglish (US)
Article number100349
JournalCell Reports Medicine
Volume2
Issue number7
DOIs
StatePublished - Jul 20 2021

Keywords

  • CNVs
  • TCGA
  • aneuploidy
  • cancer biology
  • immune evasion
  • target discovery
  • transcriptional regulation

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

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