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

Abstract 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...

Full description

Saved in:
Bibliographic Details
Published in:Gynecologic oncology 2014-07, Vol.134 (1), p.15-19
Main Authors: Meng, Bo, Hoang, Lien N, McIntyre, John B, Duggan, Máire A, Nelson, Gregg S, Lee, Cheng-Han, Köbel, Martin
Format: Article
Language:English
Subjects:
Aged
Biomarkers, Tumor - genetics
Carcinoma, Endometrioid - enzymology
Carcinoma, Endometrioid - genetics
Carcinoma, Endometrioid - pathology
Cohort Studies
Disease-Free Survival
DNA Polymerase II - genetics
Endometrial cancer
Endometrial Neoplasms - enzymology
Endometrial Neoplasms - genetics
Endometrial Neoplasms - pathology
Endometrioid
Female
Hematology, Oncology and Palliative Medicine
Humans
Middle Aged
Mutation, Missense
Neoplasm Grading
Obstetrics and Gynecology
POLE
Poly-ADP-Ribose Binding Proteins
Prognosis
Protein Structure, Tertiary
Retrospective Studies
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Abstract 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.
ISSN:0090-8258
1095-6859
DOI:10.1016/j.ygyno.2014.05.006