Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, AB, Canada.
Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada.
Gynecol Oncol. 2014 Jul;134(1):15-9. doi: 10.1016/j.ygyno.2014.05.006. Epub 2014 May 16.
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.
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.
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
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.
POLE 外切核酸酶结构域突变最近在一部分子宫内膜癌中发现，导致 DNA 复制过程中校对功能缺陷。本研究旨在进一步探讨 POLE 外切核酸酶结构域突变在高级别子宫内膜癌中的临床病理意义。
我们通过 Sanger 测序评估了 53 例 3 级子宫内膜样癌、25 例浆液性癌、16 例透明细胞癌和 5 例去分化癌中外切核酸酶结构域 POLE 的突变情况。我们将 POLE 突变状态与临床病理特征和分子参数相关联。采用 Kaplan-Meier 和 Cox 回归分析进行单变量和多变量生存分析。
8 例（15%）3 级子宫内膜样癌中存在 POLE 外切核酸酶结构域突变，而其他检查的组织类型均未见。8 例 POLE 外切核酸酶结构域突变的 3 级子宫内膜样癌中，只有 1 例免疫组化显示错配修复蛋白表达缺失（MSH6 缺失），而 45 例野生型外切核酸酶结构域的 3 级子宫内膜样癌中有 21 例存在该缺失。当与 The Cancer Genome Atlas 公布的 3 级子宫内膜样癌一起进行分析时，POLE 外切核酸酶结构域突变的存在与无病生存的显著改善相关（单变量分析，p=0.025；多变量分析，p=0.010），因此没有 POLE 突变肿瘤的患者发生疾病进展。
POLE 外切核酸酶结构域突变发生在一部分 3 级子宫内膜样癌中，与良好的临床结局相关。它可以作为指导 3 级子宫内膜样癌患者管理的重要预后分子标志物。
