Case Report: Endometrial carcinoma harboring a rare POLE p.T278K variant and dual MSH6 frameshift variants
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Yuxuan Yang1, Huimei Luo1, Huixing Yan1
1Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Jinan, Shandong, China.
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.
