Mutated p53 results in altered type I interferon pathway expression and signaling in endometrial cancer.

INTRODUCTION

p53 status is prognostic in endometrial cancer (EC). Missense TP53 mutations typically produce an aberrant p53 overexpression phenotype by immunohistochemistry (IHC), and truncating mutations generally result in a p53 null phenotype. Given the role of p53 in modulation of the innate immune response through the type I interferon pathway (IFN-I), we hypothesized that IFN-I pathway expression and engagement would differ by p53 IHC status.

METHODS

Multiplex IHC assessed a convenience sample of 50 specimens (p53wild-type = 25; p53mut overexpressed = 15; p53mut null = 10) for IFN-I pathway components. Quantitative digital analysis and TCGA validation through single sample gene set enrichment analysis (GSEA) was performed. Clinicopathologic data was abstracted for correlative analysis.

RESULTS

Expression of several IFN-I pathway components (ADAR1, STING, MDA5, RIG-I) differed significantly by p53 status. Expression of all components was directionally consistent: p53mut overexpressed samples demonstrated the highest expression levels, and null samples demonstrated the lowest. Pathway substrate availability was assessed with K1 (an antibody for double-stranded RNA) was significantly increased in p53mut overexpressed samples. Pairwise Pearson correlation coefficients revealed signaling alterations by p53 status: DHX9 emerged as a central hub with increased network density in p53mut overexpressed tumors. GSEA confirmed findings, with significant divergence noted in IFN-I gene expression by missense versus truncated samples. Univariate analysis revealed high PKR IHC expression was associated with reduced odds of recurrence (OR 0.13, 95% CI: 0.03-0.68, p = 0.02).

CONCLUSION

p53mut overexpressed EC reveals patterns of IFN-I expression that reflect a chronic inflammatory state, whereas p53mut null tumors demonstrate an immunosuppressed state. These hypothesis-generating findings warrant further study in an expanded clinical cohort.