Abstract 2502: Co-existing P53 and ARID1A mutations promote metastatic endometrial tumorigenesis

Abstract

Abstract P53 and ARID1A are frequently mutated across cancer but rarely in the same tumor. Uterine endometrial cancer displays the highest P53-ARID1A mutual exclusivity rate. The genetic basis underlying P53-ARID1A mutual exclusivity and the relationship between molecular programs imposed by either mutation have not been elucidated in vivo mouse models. Here, genetically engineered mice were used to discern both unique and overlapping roles of P53 and ARID1A in the endometrium. Endometrial epithelial hyperplasia is driven by P53 loss with oncogenic PIK3CAH1047R in the endometrial epithelium. Sorted hyperplastic endometrial epithelial cells were transcriptome profiled and compared to control cells and ARID1A-PIK3CA mutant endometrium. Both P53 and ARID1A mutations lead to activation of inflammatory pathways but differ on other gene expression programs, such as epithelial-to-mesenchymal transition. Gene expression patterns observed in the genetic mouse models are reflective of human tumors with respective genetic alterations. ARID1A co-regulates P53 transcriptional gene targets, and the P53 pathway is activated in ARID1A mutant endometrial tumors. Finally, TP53 and ARID1A mutations co-occur more frequently in metastatic lesions, and co-existing TP53-ARID1A mutations are viable in the endometrium and lead to invasive endometrial cancer. These data suggest P53 and ARID1A mutations stimulate shared and distinct tumorigenic programs in the endometrium and promote metastasis when existing simultaneously. We propose that ARID1A loss in P53 mutant endometrial cancer promotes metastasis. Citation Format: Jake J. Reske, Mike R. Wilson, Jeanne Holladay, John I. Risinger, Ronald L. Chandler. Co-existing P53 and ARID1A mutations promote metastatic endometrial tumorigenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2502.