title: Lack of major genome instability in tumors of p53 null rats.
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.
authors: Hubrecht Institute, KNAW and University Medical Center Utrecht, Uppsalalaan 8, 3584 CT Utrecht, The Netherlands.
authors: Roel
authors: R
authors: Hermsen
authors: Hubrecht Institute, KNAW and University Medical Center Utrecht, Uppsalalaan 8, 3584 CT Utrecht, The Netherlands.
authors: Pim
authors: P
authors: Toonen
authors: Hubrecht Institute, KNAW and University Medical Center Utrecht, Uppsalalaan 8, 3584 CT Utrecht, The Netherlands.
authors: Ewart
authors: E
authors: Kuijk
authors: Dutch Molecular Pathology Center. Department of Pathobiology, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 1, 3584 CL Utrecht, The Netherlands.
authors: Sameh A
authors: SA
authors: Youssef
authors: Dutch Molecular Pathology Center. Department of Pathobiology, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 1, 3584 CL Utrecht, The Netherlands.
authors: Raoul
authors: R
authors: Kuiper
authors: Hubrecht Institute, KNAW and University Medical Center Utrecht, Uppsalalaan 8, 3584 CT Utrecht, The Netherlands.
authors: Sebastiaan
authors: S
authors: van Heesch
authors: Dutch Molecular Pathology Center. Department of Pathobiology, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 1, 3584 CL Utrecht, The Netherlands.
authors: Alain
authors: A
authors: de Bruin
authors: Hubrecht Institute, KNAW and University Medical Center Utrecht, Uppsalalaan 8, 3584 CT Utrecht, The Netherlands.
authors: Edwin
authors: E
authors: Cuppen
authors: Hubrecht Institute, KNAW and University Medical Center Utrecht, Uppsalalaan 8, 3584 CT Utrecht, The Netherlands.
authors: Marieke
authors: M
authors: Simonis
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D055028:Comparative Genomic Hybridization; D056915:DNA Copy Number Variations; D004195:Disease Models, Animal; D005260:Female; D055785:Gene Knockdown Techniques; D042822:Genomic Instability; D006579:Heterozygote; D006720:Homozygote; D008297:Male; D009154:Mutation; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology; D051381:Rats; D016615:Telomere / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism
chemical_list: D016159:Tumor Suppressor Protein p53