Co-existing TP53 and ARID1A mutations promote aggressive endometrial tumorigenesis

PLoS Genet. 2021 Dec 23;17(12):e1009986. doi: 10.1371/journal.pgen.1009986. eCollection 2021 Dec.


TP53 and ARID1A are frequently mutated across cancer but rarely in the same primary tumor. Endometrial cancer has the highest TP53-ARID1A mutual exclusivity rate. However, the functional relationship between TP53 and ARID1A mutations in the endometrium has not been elucidated. We used genetically engineered mice and in vivo genomic approaches to discern both unique and overlapping roles of TP53 and ARID1A in the endometrium. TP53 loss with oncogenic PIK3CAH1047R in the endometrial epithelium results in features of endometrial hyperplasia, adenocarcinoma, and intraepithelial carcinoma. Mutant endometrial epithelial cells were transcriptome profiled and compared to control cells and ARID1A/PIK3CA mutant endometrium. In the context of either TP53 or ARID1A loss, PIK3CA mutant endometrium exhibited inflammatory pathway activation, but other gene expression programs differed based on TP53 or ARID1A status, such as epithelial-to-mesenchymal transition. Gene expression patterns observed in the genetic mouse models are reflective of human tumors with each respective genetic alteration. Consistent with TP53-ARID1A mutual exclusivity, the p53 pathway is activated following ARID1A loss in the endometrial epithelium, where ARID1A normally directly represses p53 pathway genes in vivo, including the stress-inducible transcription factor, ATF3. However, co-existing TP53-ARID1A mutations led to invasive adenocarcinoma associated with mutant ARID1A-driven ATF3 induction, reduced apoptosis, TP63+ squamous differentiation and invasion. These data suggest TP53 and ARID1A mutations drive shared and distinct tumorigenic programs in the endometrium and promote invasive endometrial cancer when existing simultaneously. Hence, TP53 and ARID1A mutations may co-occur in a subset of aggressive or metastatic endometrial cancers, with ARID1A loss promoting squamous differentiation and the acquisition of invasive properties.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / genetics
  • Adenocarcinoma / pathology
  • Animals
  • Carcinogenesis / genetics
  • Carcinoma in Situ / genetics
  • Carcinoma in Situ / pathology
  • Class I Phosphatidylinositol 3-Kinases / genetics
  • DNA-Binding Proteins / genetics*
  • Endometrial Hyperplasia / genetics
  • Endometrial Hyperplasia / pathology
  • Endometrial Neoplasms / genetics*
  • Endometrial Neoplasms / pathology
  • Endometrium / pathology
  • Epithelial-Mesenchymal Transition / genetics
  • Female
  • Gene Expression Regulation, Neoplastic / genetics
  • Humans
  • Mice
  • Mutation / genetics
  • Transcription Factors / genetics*
  • Tumor Suppressor Protein p53 / genetics*
  • Tumor Suppressor Proteins / genetics*


  • ARID1A protein, human
  • DNA-Binding Proteins
  • TP53 protein, human
  • TP63 protein, human
  • Transcription Factors
  • Tumor Suppressor Protein p53
  • Tumor Suppressor Proteins
  • Class I Phosphatidylinositol 3-Kinases
  • PIK3CA protein, human

Grants and funding

R.L.C. was supported by an Innovative Translational Grant from the Mary Kay Foundation ( (026-16). M.R.W. was supported by an American Cancer Society Postdoctoral Fellowship ( (PF-17-163-02-DDC). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.