Abstract
BACKGROUND: The P53 gene is the most common tumor-suppressor gene mutated in pancreatic ductal adenocarcinoma (PDAC). The gene's normal function is critical for regulation of replication, DNA repair, and apoptosis. The purpose of our study is to determine the impact of the various P53 mutation subtypes on survival in resected PDAC. METHODS: This is a retrospective cohort study assessing patients that underwent curative-intent resection for PDAC between the years of 2016-2022. Next generation sequencing (NGS) was performed on patient tumors. P53 tumor genotypes were grouped into wild-type (WT), gain-of-function (GOF) mutations (R175H, R248W, R248Q, R273H, R282W, G245S) and all other non-GOF mutations. RESULTS: The study included a total of 330 patients with resected PDAC. P53 mutations were found in tumors of 243 patients (74%), and 87 (26%) patients had WT P53. Among patients with mutant P53 tumors, 58 patients (24%) had a GOF mutation, and 185 patients (76%) had a non-GOF mutation. Survival analysis showed that non-GOF P53 mutations were associated with the shortest overall survival compared with WT and GOF (25.6 ± 2.4 months vs. 32.2 ± 3.6 months, vs. 36.2 ± 4.4 months, respectively. p = 0.038). Similarly, non-GOF mutations were associated with the shortest disease-free survival (14.6 ± 1.2 months, vs. 19.6 ± 3.5 months, vs. 18.3 ± 3.6 months, respectively. p = 0.039). CONCLUSIONS: Our data suggest that P53 mutations grouped by functional status may hold differential prognostic value regarding survival and recurrence of patients with PDAC. Further investigations are required to validate these findings.