POLE exonuclease domain mutation predicts long progression-free survival in grade 3 endometrioid carcinoma of the endometrium

Gynecol Oncol. 2014 Jul;134(1):15-9. doi: 10.1016/j.ygyno.2014.05.006. Epub 2014 May 16.


Objective: POLE exonuclease domain mutations were recently found to occur in a subset of endometrial carcinomas and result in defective proof-reading function during DNA replication. The aim of this study is to further characterize the clinical and pathologic significance of POLE exonuclease domain mutations in high-grade endometrial carcinomas.

Methods: We assessed for mutations in the exonuclease domain of POLE by Sanger sequencing in 53 grade 3 endometrioid, 25 serous, 16 clear cell and 5 dedifferentiated carcinomas. We correlated POLE mutation status with clinicopathologic features and molecular parameters. Univariate and multivariate survival analyses were performed using Kaplan-Meier and cox regression analyses.

Results: POLE exonuclease domain mutations were identified in 8 of 53 (15%) grade 3 endometrioid carcinomas and not in any other histotypes examined. Only 1 of the 8 grade 3 endometrioid carcinomas with POLE exonuclease domain mutation displayed deficient mismatch repair protein expression by immunohistochemistry (MSH6 loss), compared to 21 of 45 grade 3 endometrioid carcinomas with wild-type exonuclease domain. When analyzed together with published grade 3 endometrioid carcinomas by The Cancer Genome Atlas, the presence of POLE exonuclease domain mutation was associated with significantly better progression-free survival in univariate (p=0.025) and multivariate (p=0.010) analyses, such that none of the patients with POLE mutated tumors experienced disease progression

Conclusions: POLE exonuclease domain mutations occur in a subset of grade 3 endometrioid carcinomas and are associated with good clinical outcome. It can serve as an important prognostic molecular marker to guide the management of patients with grade 3 endometrioid carcinomas.

Keywords: Endometrial cancer; Endometrioid; POLE; Prognosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Biomarkers, Tumor / genetics
  • Carcinoma, Endometrioid / enzymology
  • Carcinoma, Endometrioid / genetics*
  • Carcinoma, Endometrioid / pathology*
  • Cohort Studies
  • DNA Polymerase II / genetics*
  • Disease-Free Survival
  • Endometrial Neoplasms / enzymology
  • Endometrial Neoplasms / genetics*
  • Endometrial Neoplasms / pathology*
  • Female
  • Humans
  • Middle Aged
  • Mutation, Missense*
  • Neoplasm Grading
  • Poly-ADP-Ribose Binding Proteins
  • Protein Structure, Tertiary
  • Retrospective Studies


  • Biomarkers, Tumor
  • Poly-ADP-Ribose Binding Proteins
  • DNA Polymerase II
  • POLE protein, human