Lack of major genome instability in tumors of p53 null rats

Tumorigenesis is often associated with loss of tumor suppressor genes such as Tp53, genomic instability and telomere lengthening. Here we use a TP53 mutant rat model to illustrate that the tumors that arise in the heterozygous and homozygous genotype are fundamentally different. We investigated the p53 status and genomic integrity of tumors in heterozygous and homozygous Tp53C273X knockout rats and found that in all tumors p53 is fully inactivated. Strikingly, tumors from homozygous animals show very limited aneuploidy and a very low amount of CNV affected base pairs compared to the tumors from heterozygous animals. Also complex structural rearrangements such as chromothripsis and breakage-fusion-bridge cycles were never found in tumors from homozygous animals, while these where 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 ALT activity differences as compared to the tumors from heterozygous animals. Taken together our results demonstrate that host p53 status has a large effect on 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.