Case Report: Endometrial carcinoma harboring a rare POLE p.T278K variant and dual MSH6 frameshift variants
- 1Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Jinan
Abstract
Background: POLE -mutated endometrial carcinomas are associated with an excellent prognosis and have become an integral component of the molecular classification of endometrial carcinoma. However, the pathogenicity of many rare non-hotspot POLE exonuclease-domain variants remains uncertain, particularly when they occur in tumors harboring additional molecular alterations that may confound molecular classification.
Methods: Histopathologic findings and immunohistochemical expression of mismatch repair proteins and p53 were evaluated. Targeted next-generation sequencing of tumor tissue was performed to characterize genomic alterations, microsatellite instability, tumor mutational burden, and the mutational spectrum. The non-hotspot POLE p.T278K variant was evaluated using the León-Castillo scoring framework. MLH1 promoter methylation was assessed by methylation-specific PCR to further characterize the subclonal MLH1/PMS2 loss.
Case summary: A 59-year-old woman with endometrioid endometrial carcinoma underwent total hysterectomy with surgical staging. Targeted next-generation sequencing identified a rare non-hotspot POLE exonuclease-domain variant, c.833C>A (p.T278K), together with two MSH6 frameshift variants, c.3261del (p.F1088Sfs*2) and c.3261dup (p.F1088Lfs*5). The tumor demonstrated an ultramutated genomic profile with a tumor mutational burden of 370.0 mutations/Mb and an MSI-H phenotype. Immunohistochemistry demonstrated subclonal loss of MLH1, PMS2, and MSH6 with retained MSH2 expression; MLH1 promoter methylation was also detected.
Conclusion: This case adds clinicopathological and molecular evidence supporting the biological significance of the rare POLE p.T278K variant and illustrates a practical approach for interpreting uncommon POLE exonuclease-domain variants in endometrial carcinomas with multiple molecular classifiers. Accurate identification of the dominant molecular classifier is critical for appropriate molecular classification, prognostic assessment, and clinical management.
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BibTeX
@article{yang2026case,
title = {{Case Report: Endometrial carcinoma harboring a rare POLE p.T278K variant and dual MSH6 frameshift variants}},
author = {Yuxuan Yang and Huimei Luo and Huixing Yan and Haoping Yu and Xinyue Ma and Qiuli Teng and Longxin Zhang and Jinwen Ye and Zeng Yuan and Qing Zhang},
journal = {Frontiers in Oncology},
year = {2026},
month = oct,
doi = {10.3389/fonc.2026.1964637},
url = {https://www.frontiersin.org/articles/10.3389/fonc.2026.1964637/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Case Report: Endometrial carcinoma harboring a rare POLE p.T278K variant and dual MSH6 frameshift variants
AU - Yuxuan Yang
AU - Huimei Luo
AU - Huixing Yan
AU - Haoping Yu
AU - Xinyue Ma
AU - Qiuli Teng
AU - Longxin Zhang
AU - Jinwen Ye
AU - Zeng Yuan
AU - Qing Zhang
PY - 2026
DA - 2026/10/15
JO - Frontiers in Oncology
DO - 10.3389/fonc.2026.1964637
UR - https://www.frontiersin.org/articles/10.3389/fonc.2026.1964637/full
AB - Background: POLE -mutated endometrial carcinomas are associated with an excellent prognosis and have become an integral component of the molecular classification of endometrial carcinoma. However, the pathogenicity of many rare non-hotspot POLE exonuclease-domain variants remains uncertain, particularly when they occur in tumors harboring additional molecular alterations that may confound molecular classification. Methods: Histopathologic findings and immunohistochemical expression of mismatch repair proteins and p53 were evaluated. Targeted next-generation sequencing of tumor tissue was performed to characterize genomic alterations, microsatellite instability, tumor mutational burden, and the mutational spectrum. The non-hotspot POLE p.T278K variant was evaluated using the León-Castillo scoring framework. MLH1 promoter methylation was assessed by methylation-specific PCR to further characterize the subclonal MLH1/PMS2 loss. Case summary: A 59-year-old woman with endometrioid endometrial carcinoma underwent total hysterectomy with surgical staging. Targeted next-generation sequencing identified a rare non-hotspot POLE exonuclease-domain variant, c.833C>A (p.T278K), together with two MSH6 frameshift variants, c.3261del (p.F1088Sfs*2) and c.3261dup (p.F1088Lfs*5). The tumor demonstrated an ultramutated genomic profile with a tumor mutational burden of 370.0 mutations/Mb and an MSI-H phenotype. Immunohistochemistry demonstrated subclonal loss of MLH1, PMS2, and MSH6 with retained MSH2 expression; MLH1 promoter methylation was also detected. Conclusion: This case adds clinicopathological and molecular evidence supporting the biological significance of the rare POLE p.T278K variant and illustrates a practical approach for interpreting uncommon POLE exonuclease-domain variants in endometrial carcinomas with multiple molecular classifiers. Accurate identification of the dominant molecular classifier is critical for appropriate molecular classification, prognostic assessment, and clinical management.
SN - 2234-943X
ER -