TP53Mutations Promote Immunogenic Activity in Breast Cancer

Abstract

Background. Although immunotherapy has recently achieved clinical successes in a variety of cancers, thus far there is no immunotherapeutic strategy for breast cancer (BC). Thus, it is important to discover biomarkers for identifying BC patients responsive to immunotherapy. TP53 mutations were often associated with worse clinical outcomes in BC whose triple-negative subtype has a high TP53 mutation rate (approximately 80%). To explore a potentially promising therapeutic option for the TP53-mutated BC subtype, we studied the association between TP53 mutations and immunogenic activity in BC. Methods. We compared the enrichment levels of 26 immune signatures that indicated activities of diverse immune cells, functions, and pathways between TP53-mutated and TP53-wildtype BCs based on two large-scale BC multiomics datasets. Moreover, we explored the molecular cues associated with the differences in immunogenic activity between TP53-mutated and TP53-wildtype BCs. Furthermore, we performed experimental validation of the findings from bioinformatics analysis. Results. Bioinformatics analysis showed that almost all analyzed immune signatures showed significantly higher enrichment levels in TP53-mutated BCs than in TP53-wildtype BCs. Moreover, in vitro experiments confirmed that mutant p53 could increase BC immunogenicity. Both computational and experimental results demonstrated that TP53 mutations could promote BC immunogenicity via regulation of the p53-mediated pathways including cell cycle, apoptosis, Wnt, Jak-STAT, NOD-like receptor, and glycolysis. Furthermore, we found that elevated immune activity was likely associated with a better survival prognosis in TP53-mutated BCs, but not necessarily in TP53-wildtype BCs. Conclusions. TP53 mutations may promote immunogenic activity in BC, suggesting that the TP53 mutation status could be a useful biomarker for stratifying BC patients responsive to immunotherapy.

Tumor Characterization in Breast Cancer Identifies Immune-Relevant Gene Signatures Associated With Prognosis

“…Besides, we tested whether the infiltration of immune cells is associated distinct mutations, and the results indicated that TP53 showed relatively obvious difference between the mutant and the wild type. These differences may illustrate that TP53 mutation may affect the immune microenvironment of breast cancer to a certain extent (the specific mechanism is not clear here), this is consistent with the conclusion of a recent study (Liu Z et al, 2019).…”

Pattern of nucleotide variants of TP53 and their correlation with the expression of p53 and its downstream proteins in a Sri Lankan cohort of breast and colorectal cancer patients

“…TP53 missense mutations are strongly associated with the strong immuno positivity of p53 protein in breast (pvalue = 0.001417) and breast and colorectal cancer combined (p-value = 8.104e-06). Several previous studies which observed an association between TP53 mutations and higher expression of p53 protein in various types of cancer [33,34] also support our findings. A larger study done on 7878 variants representing 60 distinct tumour sites from the IARC TP53 Database concludes that missense mutations are IHC positive while nonsense mutations, frameshift mutations and deletions were immunonegative [35].…”

Aberrant WNT/CTNNB1 Signaling as a Therapeutic Target in Human Breast Cancer: Weighing the Evidence

“…Finally, breast cancer is a systemic disease and the involvement of WNT signaling should be considered from this perspective as well. Both in mice and humans, loss of TP53 has recently been associated with the induction of WNT protein production, which may in turn stimulate the immune system to promote metastasis (Kim et al, 2019;Liu et al, 2019;Wellenstein et al, 2019). Likewise, cytokine signaling from the local bone microenvironment may promote metastatic colonization by initiating an autocrine WNT signaling loop in human breast cancer stem cells (Eyre et al, 2019).…”