Clinicopathological features of pathogenic, non-pathogenic, and unknown significance (NP/US) POLE mutations in endometrial carcinomas: A study based on actual world

While 11 pathogenic mutations of the DNA polymerase epsilon ( POLE ) gene are recognized, the pathogenicity of additional mutations and their association with clinicopathological features remain unclear. This study investigates the clinicopathological features of endometrial carcinomas (ECs) with pathogenic, non-pathogenic, and unknown significance (NP/US) POLE mutations. 421 EC patients were included. Clinicopathological data, POLE gene mutation status, mismatch repair, and p53 protein statuses were collected. Pathogenic POLE mutations were identified in 56 ECs (13.3%) and NP/US POLE mutations in 58 ECs (13.8%). No recurrence or metastasis was observed in POLEmut EC patients with lymph node metastasis (LNM) and lymphovascular space invasion (LVSI). Although there were no significant differences in clinicopathological features between ECs with pathogenic POLE mutations and those with missense NP/US POLE mutations, ECs with missense NP/US POLE mutations had poorer disease-free survival ( P  = 0.047). ECs with a single missense NP/US POLE mutation at a non-hotspot site had a better prognosis in the first 36 months compared to the other molecular subtypes ( P  < 0.001). This study demonstrates that while ECs harboring missense NP/US POLE mutations exhibit a less favorable prognosis than those with pathogenic POLE mutations, tumors containing a individual missense NP/US POLE mutation localized to non-hotspot genomic regions show improved clinical outcomes relative to the other three molecular subtypes. Therefore, risk stratification for postsurgical treatment decisions in ECs with missense NP/US POLE mutations should combine traditional clinicopathological parameters.