Abstract
TP53 mutation is a critical driver mutation that affects the carcinogenesis and prognosis of patients with pancreatic cancer (PC). Currently, there is no driver mutation-derived signature based on TP53 mutational status for prognosis and predicting therapeutic response in PC. In the present study, we characterized the TP53 mutational phenotypes in multiple patient cohorts and developed a prognostic TP53-associated signature based on differentially expressed genes between PC samples with mutated TP53 and wild-type TP53. Comprehensive investigations were carried out in prognostic stratification, genetic variation, immune cell infiltration, and efficacy prediction of chemotherapy and targeted therapy. We found that TP53 mutation commonly occurred as a survival-related driver mutation in PC. In total, 1,154 differentially expressed genes were found between two distinct TP53 mutational phenotypes. A five-gene TP53-associated signature was constructed in The Cancer Genome Atlas (TCGA) cohort by least absolute shrinkage and selection operator (LASSO)–Cox analysis and proven to be a robust prognostic predictor, which performed well in three independent Gene Expression Omnibus (GEO) validating cohorts. Remarkably, patients in the low-risk group were characterized with decreased tumor mutation burden and activity of immunity, with favorable prognosis. Higher fractions of macrophages M0 and impaired CD8 + T cells were observed in patients in the high-risk group, suggesting immunosuppression with poor survival. Patients in the high-risk group also demonstrated enhanced response to specific chemotherapeutic agents, including gemcitabine and paclitaxel. Several targeted inhibitors, like histamine receptor inhibitor, were screened out as promising drugs for PC treatment. Collectively, the TP53-associated signature is a novel prognostic biomarker and predictive indicator of PC. The signature could contribute to optimizing prognostic stratification and guide effective PC treatments.
Highlights
Pancreatic cancer (PC) is an aggressive and lethal malignancy with a dismal 5 years survival rate of 4% and 47,050 cancer-related deaths in 2020 (Klint et al, 2010; Siegel et al, 2020)
A significant association was observed between TP53 mutational status and prognosis in a deleterious direction (p = 6.723e-04, log-rank test), indicating that pancreatic cancer (PC) patients with TP53 mutation had worse prognosis than patients without TP53 mutation (Figure 1B)
The oncogenic role of TP53 mutation has been well documented, currently, there is a lack of a prognostic and therapeutically predictive biomarker based on the TP53 mutational status in PC
Summary
Pancreatic cancer (PC) is an aggressive and lethal malignancy with a dismal 5 years survival rate of 4% and 47,050 cancer-related deaths in 2020 (Klint et al, 2010; Siegel et al, 2020). The tumor suppressor gene TP53 is one of the frequent pan-cancer mutated genes, linked to unfavorable prognosis in multiple cancers and more than 500 million deaths (Kandoth et al, 2013). Occurring in about 70% of examples, TP53 mutation often leads to an oncogenic process and is associated with aggressive and metastatic phenotypes (Makohon-Moore and IacobuzioDonahue, 2016; Hashimoto et al, 2019). The tumor-suppressive effect of TP53 and the prevalence of TP53 mutation have encouraged the development of precise therapy targeting TP53 network in cancers. P53 induction was associated with peptide processing and major histocompatibility complex (MHC)-I surface expression, it might prevent the cytotoxic T lymphocytes (CTLs) from killing tumor cells (Wang et al, 2013)
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