ATM immunohistochemistry as an effective screening method for POLE variants among endometrial carcinomas lacking mismatch repair deficiency and p53 abnormalities

Sep 22, 2026

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Molecular classification of endometrial carcinomas is now used clinically, but identifying polymerase-ε (POLE) variants still depends on DNA sequencing, limiting broad uptake. This study evaluates whether immunohistochemistry (IHC) for mismatch repair (MMR) deficiency and p53, together with ataxia telangiectasia mutated (ATM) staining, can screen patients likely to carry POLE variants. Analysis of 24 POLE-pathogenic cases and matched no-profile controls shows POLE-mutated tumors have higher non-diffuse ATM staining patterns and enriched ATM truncating variants. A refined ATM IHC interpretation frame demonstrates high specificity and predictive value for POLE variant identification, supporting confirmatory sequencing prioritization.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages15

Reading Time38 min

AccessFree to download

Introduction

Molecular classification of endometrial carcinoma

Materials and methods (cohort and assays)

ATM immunohistochemistry evaluation

Targeted next-generation sequencing

Results

ATM staining patterns and POLE mutation status

Sequencing correlation with ATM alterations

Performance of null and subclonal loss patterns

Discussion

Proposed ATM IHC interpretation framework

Clinical screening implications

The Journal of Pathology: Clinical Research J Pathol Clin Res March 2026; 12: e70086 Published online in Wiley Online Library (wi[leyonlinelibrary.com](leyonlinelibrary.com). DOI: 10.1002/2056-4538.70086)[).](leyonlinelibrary.com). DOI: 10.1002/2056-4538.70086)[ DOI: 10.1002/2056-4538.70086](leyonlinelibrary.com). DOI: 10.1002/2056-4538.70086) ORIGINAL ARTICLE ATM immunohistochemistry as an effective screening method for POLE variants among endometrial carcinomas lacking mismatch repair deﬁciency and p53 abnormalities Xinyi Huang 1†, Yingmei Wang 1†, Wenjing Ni 1†, Luyang Zhong2, Yang Qin 1 , Shujun Zeng 1 , Hong Xu 1 , Yuling Qu 1 , Peizhen Hu 1 * and Jing Zhang 1 * 1 Department of Pathology, Xijing Hospital, The Fourth Military Medical University, Xi ’an, PR China 2Department of Psychology and Brain Science, College of Letters and Science, University of California, Santa Barbara, CA, USA *Correspondence to: Jing Zhang, No. 169, Changle West Road, Department of Pathology, Xijing Hospital, The Fourth Military Medical University, Xi’an, Shaanxi 710032, [PR China. E-mail:](PR China. E-mail: jzhang@fmmu.edu.cn)[ jzhang@fmmu.edu.cn](PR China. E-mail: jzhang@fmmu.edu.cn); Peizhen Hu, No. 169, Changle West Road, Department of Pathology, Xijing Hospital, The Fourth Military Medical University, Xi’an, Shaanxi 710032, PR China. E-mail: [hupigeon@fmmu.edu.cn](hupigeon@fmmu.edu.cn) †These authors contributed equally to this work. Abstract The molecular classiﬁcation of endometrial carcinomas (ECs) is now integrated into clinical practice. However, identiﬁcation of polymerase-ε (POLE) variants remains reliant on DNA sequencing, which limits broader implementation. Given the strong prognostic value of pathogenic POLE mutations and the established efﬁcacy of immunohistochemistry (IHC) for detecting mismatch repair (MMR) deﬁciency and p53 abnormalities, there is a clear need for IHC-based screening strategies to identify patients likely to carry POLE variants and prioritize them for conﬁrmatory sequencing. In this study, we analyzed 24 cases with POLE pathogenic mutations (POLEmut ECs), 3 with benign POLE variants, and 32 matched cases with no speciﬁc molecular proﬁle (NSMP) from a cohort of 378 ECs. IHC evaluation of the ataxia telangiectasia mutated (ATM) protein revealed that POLEmutated ECs (with pathogenic or benign POLE variants) exhibited signiﬁcantly higher frequencies of non-diffuse positive staining patterns, including null, heterogeneous positive, and subclonal loss, compared with NSMP cases. Targeted next-generation sequencing of all exons across 474 cancer-related genes in the 27 POLE-mutated ECsand 20 NSMP cases with ATM non-diffuse positive staining patterns conﬁrmed that POLE-mutated ECs typically had high tumor mutational burden and were enriched for ATM truncating variants. ATM molecular alterations, including various variant subtypes and multisite mutations, also closely correlated with these staining patterns. Based on these ﬁndings, we reﬁned the ATM IHC interpretation framework to integrate staining patterns with sequencing data for improved molecular correlation. Speciﬁcally, the null and subclonal loss patterns showed high speciﬁcity (96.9%), positive predictive value (94.1%), and accuracy (79.7%) for identifying POLE variants. Notably, the null pattern appeared exclusively in ECs with pathogenic POLE mutations. These results suggest that ATM IHC staining is an effective screening tool for identifying patients who may beneﬁt from conﬁrmatory POLE sequencing among those lacking MMR deﬁciency or p53 abnormalities. Keywords: endometrial carcinoma; ataxia telangiectasia mutated (ATM); immunohistochemistry; polymerase-ε ( POLE); no speciﬁc molecular proﬁle (NSMP) Received 27 December 2025; Revised 15 February 2026; Accepted 3 March 2026 No conﬂicts of interest were declared. Introduction Endometrial carcinoma (EC) is among the most common gynecological cancers in developed countries, an

FAQs

Why is an ATM IHC screening approach needed for POLE variants in endometrial carcinoma?

POLE variant detection currently relies on DNA sequencing, which constrains routine clinical implementation. The study builds on the prognostic value of POLE pathogenic mutations and the limitations of sequencing-only workflows by exploring ATM IHC patterns as a screening tool.

What did the study find about ATM staining patterns in POLE-mutated versus NSMP tumors?

POLE-mutated endometrial carcinomas showed significantly higher frequencies of non-diffuse ATM staining patterns, including null, heterogeneous positive, and subclonal loss, compared with NSMP cases.

How accurate were the refined ATM IHC interpretations for identifying POLE variants?

The null and subclonal loss patterns showed high specificity (96.9%), positive predictive value (94.1%), and accuracy (79.7%) for identifying POLE variants, with the null pattern appearing exclusively in cases carrying pathogenic POLE mutations.

Sep 22, 2026

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