POLE (DNA Polymerase Epsilon)

Without sequencing, 4 POLEmut cases would have been misclassified as either p53 abnormal or MMRd. There was no significant difference in biomarker results, molecular variants, or clinical outcomes between cases with aggressive or nonaggressive histopathologic features.

In reporting these neoplasms, we highlight that signet ring cells occasionally occur in primary endometrial carcinomas of endometrioid-type and, although numbers are small, there appears to be an association with MMR deficiency. These tumors have a propensity for high-stage at presentation.

The method of detection, such as immunohistochemistry or mutational analysis, has been debated for these molecular features. This article summarizes the current state of molecular pathology in endometrial cancer, including methods of testing, gaps in current approaches, molecular features with potential relevance, and therapeutic applicability.

Immunohistochemical markers based on The Cancer Genome Atlas (TCGA) classification show a strong correlation with established histopathological risk factors. Integrating molecular profiling into the routine diagnostic workup may improve prognostication and support personalized treatment strategies in EC.

This study refines the molecular landscape of POLEmut EC by demonstrating a potentially high prevalence of the V411L variant in the Chinese population and showing that the favorable prognosis of POLEmut EC remains largely consistent across different ethnic backgrounds and specific hotspot mutations in this real-world cohort. These findings support universal POLE testing to avoid overtreatment and provide a hypothesis-generating basis for large-scale, multi-center studies with longer follow-up to validate the distinct mutational spectrum across diverse Chinese regions and confirm the long-term prognostic stability of cases with multiple molecular classifiers.

P=N/A, N=264, Recruiting, Fondazione Policlinico Universitario Agostino Gemelli IRCCS

P=N/A, N=53, Completed, University of Saskatchewan | Recruiting --> Completed

P2, N=26, Completed, Memorial Sloan Kettering Cancer Center | Active, not recruiting --> Completed | Trial completion date: Jan 2027 --> Apr 2026 | Trial primary completion date: Jan 2027 --> Apr 2026

While POLE-mutated tumors overall retain an excellent prognosis, rare cases may follow an atypical and aggressive course. Improved molecular annotation and integrated risk-stratification models are needed to better identify this minority of higher-risk patients.

Immunohistochemistry-based TCGA classification, such as the ProMisE protocol, will not be able to detect these cases as the p53 IHC pattern is wild type and there are no distinguishing morphological features; this may be of relevance for analyzing ProMisE protocol-based clinical trials and outcomes studies. Long term outcome studies are needed to refine risk stratification and treatment decisions for this unique molecular class of endometrial cancers that further contributes to the evolving understanding that the clinical significance of TP53 mutation in endometrial cancer is complex and depends on co-existing molecular alterations.

P2, N=26, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Jan 2026 --> Jan 2027 | Trial primary completion date: Jan 2026 --> Jan 2027

We highlight the critical need to distinguish passenger mutations from true proofreading defects, as therapeutic benefit is strictly tethered to functional pathogenicity. Finally, we propose an integrated biomarker framework that moves beyond binary genomic screening toward a functional hierarchy of polymerase variants, providing a definitive roadmap for the next generation of precision immunotherapy in colorectal cancer.