Abstract A042: Differences in gain-of-function and inhibitory effects amongst p53 mutants in vivo

Abstract The majority of p53 missense mutations identified in cancer patients are in the DNA-binding domain and are characterized as either structural or contact mutations. These missense mutations exhibit inhibitory effects on wild-type p53 activity. More importantly, these mutations also demonstrate gain-of-function (GOF) activities characterized by increased metastasis, poor prognosis, and drug resistance. To better understand the activities by which TP53 mutations, identified in Li-Fraumeni syndrome, contribute to tumorigenesis in vivo, we generated a novel germline p53R245W allele (contact mutation) and compared it to existing p53R172H (structural mutation) and p53R270H (contact mutation) alleles. Thymocytes from heterozygous mice showed all three hot-spot mutations exhibited similar inhibitory effects on wild type p53 transcription in vivo and tumors from these mice had similar levels of loss of heterozygosity. However, the overall survival of p53R245W/+ and p53R270H/+ mice, but not p53R172H/+ mice, was significantly shorter than that of p53+/- mice, demonstrating p53 mutation-specific GOF contributions to tumor development. Furthermore, p53R245W/+ and p53R270H/+ mice had more osteosarcoma metastases than p53R172H/+ mice, indicating that these two contact mutants have stronger GOF in driving osteosarcoma metastasis. Omics analyses using RNA-sequencing data from p53R172H/+, p53R245W/+, and p53R270H/+ primary osteosarcomas in comparison to p53+/- indicated GOF was mediated by distinct pathways among the three mutations. Thus, both the inhibitory effect of mutant over WT p53, and GOF activities of mutant p53 contributed to tumorigenesis in vivo. Targeting p53 mutant-specific pathways may be important for therapeutic outcomes in osteosarcomas. Citation Format: Shunbin Xiong, Dhruv Chachad, Yun Zhang, Jovanka Gencel-Augusto, Mario Sirito, Vinod Pant, Peirong Yang, Chang Sun, Guillermina Lozano. Differences in gain-of-function and inhibitory effects amongst p53 mutants in vivo [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr A042.