Ribosomal DNA copy number loss and sequence variation in cancer

PLoS Genet. 2017 Jun 22;13(6):e1006771. doi: 10.1371/journal.pgen.1006771. eCollection 2017 Jun.


Ribosomal DNA is one of the most variable regions in the human genome with respect to copy number. Despite the importance of rDNA for cellular function, we know virtually nothing about what governs its copy number, stability, and sequence in the mammalian genome due to challenges associated with mapping and analysis. We applied computational and droplet digital PCR approaches to measure rDNA copy number in normal and cancer states in human and mouse genomes. We find that copy number and sequence can change in cancer genomes. Counterintuitively, human cancer genomes show a loss of copies, accompanied by global copy number co-variation. The sequence can also be more variable in the cancer genome. Cancer genomes with lower copies have mutational evidence of mTOR hyperactivity. The PTEN phosphatase is a tumor suppressor that is critical for genome stability and a negative regulator of the mTOR kinase pathway. Surprisingly, but consistent with the human cancer genomes, hematopoietic cancer stem cells from a Pten-/- mouse model for leukemia have lower rDNA copy number than normal tissue, despite increased proliferation, rRNA production, and protein synthesis. Loss of copies occurs early and is associated with hypersensitivity to DNA damage. Therefore, copy loss is a recurrent feature in cancers associated with mTOR activation. Ribosomal DNA copy number may be a simple and useful indicator of whether a cancer will be sensitive to DNA damaging treatments.

MeSH terms

  • Animals
  • Cells, Cultured
  • DNA Copy Number Variations*
  • DNA Damage
  • Female
  • Humans
  • Leukemia / genetics*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred DBA
  • Mutation
  • PTEN Phosphohydrolase / genetics
  • PTEN Phosphohydrolase / metabolism
  • RNA, Ribosomal / genetics*
  • TOR Serine-Threonine Kinases / genetics
  • TOR Serine-Threonine Kinases / metabolism


  • RNA, Ribosomal
  • TOR Serine-Threonine Kinases
  • PTEN Phosphohydrolase

Grant support

Funding for this study was provided by the Stowers Institute for Medical Research. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.