Lack of major genome instability in tumors of p53 null rats

Roel Hermsen, Pim Toonen, Ewart Kuijk, Sameh A Youssef, Raoul Kuiper, Sebastiaan van Heesch, Alain de Bruin, Edwin Cuppen, Marieke Simonis

Research output: Contribution to journalArticlepeer-review

12 Citations (Scopus)

Abstract

Tumorigenesis is often associated with loss of tumor suppressor genes (such as TP53), genomic instability and telomere lengthening. Previously, we generated and characterized a rat p53 knockout model in which the homozygous rats predominantly develop hemangiosarcomas whereas the heterozygous rats mainly develop osteosarcomas. Using genome-wide analyses, we find that the tumors that arise in the heterozygous and homozygous Tp53C273X mutant animals are also different in their genomic instability profiles. While p53 was fully inactivated in both heterozygous and homozygous knockout rats, tumors from homozygous animals show very limited aneuploidy and low degrees of somatic copy number variation as compared to the tumors from heterozygous animals. In addition, complex structural rearrangements such as chromothripsis and breakage-fusion-bridge cycles were never found in tumors from homozygous animals, while these were readily detectable in tumors from heterozygous animals. Finally, we measured telomere length and telomere lengthening pathway activity and found that tumors of homozygous animals have longer telomeres but do not show clear telomerase or alternative lengthening of telomeres (ALT) activity differences as compared to the tumors from heterozygous animals. Taken together, our results demonstrate that host p53 status in this rat p53 knockout model has a large effect on both tumor type and genomic instability characteristics, where full loss of functional p53 is not the main driver of large-scale structural variations. Our results also suggest that chromothripsis primarily occurs under p53 heterozygous rather than p53 null conditions.

Original languageEnglish
Article numbere0122066
Pages (from-to)e0122066
JournalPloS one
Volume10
Issue number3
DOIs
Publication statusPublished - 2015
Externally publishedYes

Keywords

  • Animals
  • Animals, Genetically Modified
  • Comparative Genomic Hybridization
  • DNA Copy Number Variations
  • Disease Models, Animal
  • Female
  • Gene Knockdown Techniques
  • Genomic Instability
  • Heterozygote
  • Homozygote
  • Male
  • Mutation
  • Neoplasms/genetics
  • Rats
  • Telomere/metabolism
  • Tumor Suppressor Protein p53/deficiency

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