POLE exonuclease domain mutation predicts long progression-free survival in grade 3 endometrioid carcinoma of the endometrium.
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.
Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, AB, Canada.
Bo
B
Meng
Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada.
Lien N
LN
Hoang
Department of Oncology, University of Calgary and Translational Laboratory, Tom Baker Cancer Centre, Calgary, AB, Canada.
John B
JB
McIntyre
Department of Pathology and Laboratory Medicine, University of Calgary and Calgary Laboratory Services, Calgary, AB, Canada.
Máire A
MA
Duggan
Department of Gynecologic Oncology, Tom Baker Cancer Centre and University of Calgary, Calgary, AB, Canada.
Gregg S
GS
Nelson
Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, AB, Canada. Electronic address: chlee2@ualberta.ca.
Cheng-Han
CH
Lee
Department of Pathology and Laboratory Medicine, University of Calgary and Calgary Laboratory Services, Calgary, AB, Canada.
Martin
M
Köbel
D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics; D018269:Carcinoma, Endometrioid / Q000201:enzymology / Q000235:genetics* / Q000473:pathology*; D015331:Cohort Studies; D004257:DNA Polymerase II / Q000235:genetics*; D018572:Disease-Free Survival; D016889:Endometrial Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology*; D005260:Female; D006801:Humans; D008875:Middle Aged; D020125:Mutation, Missense; D060787:Neoplasm Grading; D000075223:Poly-ADP-Ribose Binding Proteins; D017434:Protein Structure, Tertiary; D012189:Retrospective Studies
D014408:Biomarkers, Tumor; D000075223:Poly-ADP-Ribose Binding Proteins; D004257:DNA Polymerase II; C119525:POLE protein, human
Endometrial cancer; Endometrioid; POLE; Prognosis