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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.",{"@graph":69,"@context":123},[70,84,106],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":35,"@type":76,"position":81},"https://docshare.wps.com/document/healthcare/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/atm-immunohistochemistry-as-an-effective-screening-method-for-pole-variants-among-endometrial-carcinomas-lacking-mismatch-repair-deficiency-and-p53-abnormalities/352815/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/atm-immunohistochemistry-as-an-effective-screening-method-for-pole-variants-among-endometrial-carcinomas-lacking-mismatch-repair-deficiency-and-p53-abnormalities/352815.png","ImageObject",300,407,{"name":92,"@type":93},"Angel","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-30","2026-09-22",true,{"@type":102,"interactionType":103,"userInteractionCount":105},"InteractionCounter",{"@type":104},"ViewAction",12,{"@type":107,"mainEntity":108},"FAQPage",[109,115,119],{"name":110,"@type":111,"acceptedAnswer":112},"Why is an ATM IHC screening approach needed for POLE variants in endometrial carcinoma?","Question",{"text":113,"@type":114},"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.","Answer",{"name":116,"@type":111,"acceptedAnswer":117},"What did the study find about ATM staining patterns in POLE-mutated versus NSMP tumors?",{"text":118,"@type":114},"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.",{"name":120,"@type":111,"acceptedAnswer":121},"How accurate were the refined ATM IHC interpretations for identifying POLE variants?",{"text":122,"@type":114},"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.","https://schema.org",{"og:url":83,"og:type":125,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":127,"canonical":83},"index,follow",{"doc_id":129,"site_id":62},352815,1790247097,{"code":4,"msg":5,"data":132},{"doc_id":129,"user_id":133,"nickname":92,"user_avatar":134,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":135,"file_id":136,"file_url":137,"file_type":138,"file_size":139,"view_count":105,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":140,"language":141,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":142,"faqs":143,"seo_title":144,"seo_description":67,"update_tm":145,"read_time":146},687207412472,"https://ap-avatar.wpscdn.com/davatar_155a257f0dc6eb9ab79c44ca47cae57d","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)  \nORIGINAL ARTICLE  \nATM immunohistochemistry as an effective screening method for POLE variants among endometrial carcinomas lacking mismatch repair deficiency and p53 abnormalities  \nXinyi 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 *   \n1 Department of Pathology, Xijing Hospital, The Fourth Military Medical University, Xi ’an, PR China  \n2Department of Psychology and Brain Science, College of Letters and Science, University of California, Santa Barbara, CA, USA  \n*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  \nHospital, The Fourth Military Medical University, Xi’an, Shaanxi 710032, PR China. E-mail: [hupigeon@fmmu.edu.cn](hupigeon@fmmu.edu.cn)  \n†These authors contributed equally to this work.  \nAbstract  \nThe molecular classification of endometrial carcinomas (ECs) is now integrated into clinical practice. However,  \nidentification 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.  \nTargeted 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.  \nBased 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.  \nNotably, 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.  \nKeywords: endometrial carcinoma; ataxia telangiectasia mutated (ATM); immunohistochemistry; polymerase-ε ( POLE); no specific molecular profile (NSMP)  \nReceived 27 December 2025; Revised 15 February 2026; Accepted 3 March 2026 No conflicts of interest were declared.  \nIntroduction  \nEndometrial carcinoma (EC) is among the most common gynecological cancers in developed countries, an","cbCaigix2QXEoTeN","https://ap.wps.com/l/cbCaigix2QXEoTeN","pdf",30549417,15,"English","# Introduction\n## Molecular classification of endometrial carcinoma\n# Materials and methods (cohort and assays)\n## ATM immunohistochemistry evaluation\n## Targeted next-generation sequencing\n# Results\n## ATM staining patterns and POLE mutation status\n## Sequencing correlation with ATM alterations\n## Performance of null and subclonal loss patterns\n# Discussion\n## Proposed ATM IHC interpretation framework\n## Clinical screening implications","[{\"question\":\"Why is an ATM IHC screening approach needed for POLE variants in endometrial carcinoma?\",\"answer\":\"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.\"},{\"question\":\"What did the study find about ATM staining patterns in POLE-mutated versus NSMP tumors?\",\"answer\":\"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.\"},{\"question\":\"How accurate were the refined ATM IHC interpretations for identifying POLE variants?\",\"answer\":\"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.\"}]","ATM immunohistochemistry as an effective screening method for POLE variants among endometrial carcinomas lacking mismatch repair deficiency and p53 abnormalities | PDF",1790101515,38]