An exploratory analysis of driver gene alterations and their potential prognostic relevance in endometrial cancer with POLE exonuclease domain mutations

Abstract

Objective: Endometrial cancer represents a significant gynecologic malignancy affecting women globally, including Taiwan. This study aimed to analyze mutation patterns in endometrial cancer genes related to POLE exonuclease domain mutations and their association with patient prognosis.

Methods: We analyzed 100 endometrial cancer tissue samples from patients at MacKay Memorial Hospital (February 2014-February 2017). DNA sequencing was conducted on an Illumina MiSeq platform with subsequent QIAGEN CLC Workbench analysis. We applied Kaplan-Meier analysis and Fisher's exact test for statistical evaluations.

Results: Mutations in POLE were primarily located in the exonuclease domain, with 36 missense variants identified, of which 19 were in this specific domain. Tumors with POLE exonuclease domain mutations (POLEmut) exhibited a significantly higher tumor mutation burden (p < 0.0001), and Kaplan-Meier analysis revealed better overall survival for patients with POLEmut tumors compared to POLE wild-type tumors (POLEwt, p < 0.0388; HR: 3.624). In POLEmut cases, tumor suppressor genes showed scattered mutations with higher nonsense rates (TP53, PIK3R1, FBXW7; all p < 0.01), contrasting with oncogenes (PIK3CA, CTNNB1, KRAS). Mutations in tumor suppressor genes (TP53, PIK3R1, FBXW7) conferred significantly better survival outcomes in POLEmut cases compared to their POLEwt counterparts with identical gene mutations (HR: 3.929-6.598, all p < 0.05).

Conclusion: This exploratory study finds that POLE exonuclease domain mutations are associated with distinct mutational patterns that vary between tumor suppressor genes and oncogenes. These observations provide hypothesis-generating insights into potential mechanisms underlying the favorable prognosis of POLEmut tumors and may inform future molecular investigations in endometrial cancer.

Keywords: Driver genes; Endometrial cancer; POLE mutations; Prognosis; Tumor mutation burden.