Abstract
Pancreatic ductal adenocarcinoma (PDAC) has a high mortality rate and poor prognosis. KRAS, TP53, CDKN2A, and SMAD4 are driver genes of PDAC and 30–75% patients have mutations in at least two of these four genes. Herein, we analyzed the relationship between these genes and prognosis of 762 patients in the absence of coexisting mutations, using data from three independent public datasets. Interestingly, we found that compared with mutations in other driver genes, TP53 mutation plays a significant role in leading to poor prognosis of PDAC. Additionally, we found that snoRNA-mediated rRNA maturation was responsible for the progression of cancer in PDAC patients with TP53 mutations. Inhibition of STRAP, which regulates the localization of SMN complexes and further affects the assembly of snoRNP, can effectively reduce maturation of rRNA and significantly suppress progression of TP53-mutant or low p53 expression pancreatic cancer cells in vitro and in vivo. Our study highlighted the actual contribution rate of driver genes to patient prognosis, enriching traditional understanding of the relationship between these genes and PDAC. We also provided a possible mechanism and a new target to combat progression of TP53-mutant PDAC patients.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest human malignancies [1], with >95% mortality rate and a 5-year survival rate of less than 9% [2]
When analyzing the effects of TP53, SMAD4, and CDKN2A mutations on the prognosis of patients, we first analyzed the overall survival of patients with mutations in only one of the three driver genes based on the activation of KRAS and found that only patients with TP53 mutations were significantly different from the control group (Figure 1B)
It is of great significance to search for the key factors that affect the prognosis of PDAC patients and effective adjuvant treatment measures for clinical treatment
Summary
Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest human malignancies [1], with >95% mortality rate and a 5-year survival rate of less than 9% [2] It is known as the “king of cancer” due to its high degree of malignancy and currently the fourth leading cause of cancer-related deaths in the United States [2], and is expected to become the second within the decade [3]. Other studies [22, 23] showed that the higher the number of mutations occurring in these driver genes, the worse the prognosis, especially in patient with mutations in more than three genes. To explore the actual contribution rate of the four-driver genes to this disease, we analyzed the influence of mutation in a single gene on the prognosis of patients based on extensive sample sequencing data derived from public databases. This study explored the possible mechanism affecting prognosis of PDAC and investigated potential novel adjuvant therapeutic targets in vitro and in vivo
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