Annalyn M Welp, Alex R Mabry, Caleb L Lines, Premal H Thaker, David G Mutch, Mary M Mullen, Jason D Weber
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.
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.