POLE (DNA Polymerase Epsilon)

The FIGO 2023 stage IA3 classification enables more precise risk stratification, particularly, in cases with low-grade tumors, estrogen receptor positivity, and favorable molecular profiles (POLE-mutated or p53 wild-type and non-specific molecular profile). However, it raises 2 critical issues: the need for appropriate staging surgery and the debate regarding the optimal grading system for ovarian endometrioid carcinoma.

POLE mutations, especially non-EDMs, are frequent in MSI-L CRC and often co-occur with MLH3, MSH3, KRAS, PIK3CA, and BRAF, highlighting their potential role in tumor biology and as biomarkers for personalized treatment. Functional validation and multicenter studies are needed.

However, due to small tumor sizes, NGS verification could not be performed on the remaining 4 PCR/CE-positive but Sanger-negative cases. The PCR/CE exhibits better sensitivity and detection capabilities than the Sanger sequencing in identifying POLE-exo* in EC samples, particularly in detecting low VAF.

However, endometrial carcinoma with pathogenic POLE mutations, without ultramutation, appear to retain the "POLE mutational signature" described in the literature. Additionally, clinical outcomes do not appear different; however, this phenomenon needs additional investigation.

Our results indicate that integrated morpho-molecular FIGO 2023 staging significantly impacts both stage and risk group stratification, and will benefit EC patients, particularly in high-grade early stage ECs, with potential treatment implications. Further comprehensive studies are needed to fully establish the implications of molecular classification in the FIGO 2023 staging system.

Endometrial carcinomas with SB-GN represent a distinct and aggressive tumor group characterized by solid growth pattern, prominent necrosis, frequent basaloid morphology, high rates of CTNNB1 mutations, and aberrant β-catenin staining. Our results demonstrate that endometrial carcinomas with SB-GN and PiMHECs share similar clinicopathologic and molecular profiles, supporting a unified biological spectrum.

However, omitting peritoneal cytology from prognostic assessment may risk undertreatment. Continued refinement in quantifying lympho-vascular space invasion (LVSI) and differentiating complex endometrial-myometrial junctions from genuine myometrial invasion remains a challenge.

DNA replication proteins interact with systemic inflammation and the TME in ccRCC, supporting their role as biomarkers and potential therapeutic targets.

Comprehensive genomic profiling assay was informative, allowing for correlation of MLH1 methylation and POLE genotype results with tumor mutation burden and mutational signature. Taken together, our data highlight the need for integrated approach in endometrial carcinoma biomarker testing, integrating NGS and MLH1 promoter methylation status, the latter of which benefits from assessing both regions C and D. Finding of MLH1 promoter methylation does not rule out either Lynch syndrome or ultramutated (POLE) carcinoma.

It also includes a concise summary of functional significance for each variant. PolED aims to assist in clinical decision-making, guide personalized therapy, and promote further research.

Given the ethnic origin of the Martinique population, these data suggest that CCNE1 amplification may be linked to African genetic heritage and could explain the over-incidence of non-endometrioid subtypes in these populations. Furthermore, our study contributes to addressing racial disparities in endometrial cancer outcomes by providing crucial insights into the genetic factors that may influence the prognosis of African-descended populations.

Identifying the subset of POLE mutations that cause LOP is critical to distinguish patients likely to respond to immunotherapy. Patients with CRC with LOP POLE mutant tumors experienced deep, sustained response to immunotherapy but were resistant to standard cytotoxic chemotherapy, in stark contrast to those with non-LOP POLE mutations.