{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T15:55:34Z","timestamp":1774626934103,"version":"3.50.1"},"reference-count":70,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T00:00:00Z","timestamp":1774569600000},"content-version":"vor","delay-in-days":26,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,3,1]],"date-time":"2026-03-01T00:00:00Z","timestamp":1772323200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82072869"],"award-info":[{"award-number":["82072869"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100015401","name":"Key Research and Development Projects of Shaanxi Province","doi-asserted-by":"publisher","award":["2024GX\u2010YBXM\u2010123"],"award-info":[{"award-number":["2024GX\u2010YBXM\u2010123"]}],"id":[{"id":"10.13039\/501100015401","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["pathsocjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Pathology CR"],"published-print":{"date-parts":[[2026,3]]},"abstract":"Abstract<\/jats:title>\n \n The molecular classification of endometrial carcinomas (ECs) is now integrated into clinical practice. However, identification of polymerase\u2010\u03b5 (\n POLE<\/jats:italic>\n ) variants remains reliant on DNA sequencing, which limits broader implementation. Given the strong prognostic value of pathogenic\n POLE<\/jats:italic>\n mutations and the established efficacy of immunohistochemistry (IHC) for detecting mismatch repair (MMR) deficiency and p53 abnormalities, there is a clear need for IHC\u2010based screening strategies to identify patients likely to carry\n POLE<\/jats:italic>\n variants and prioritize them for confirmatory sequencing. In this study, we analyzed 24 cases with\n POLE<\/jats:italic>\n pathogenic mutations (\n POLE<\/jats:italic>\n mut ECs), 3 with benign\n POLE<\/jats:italic>\n 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\n POLE<\/jats:italic>\n \u2010mutated ECs (with pathogenic or benign\n POLE<\/jats:italic>\n variants) exhibited significantly higher frequencies of non\u2010diffuse positive staining patterns, including null, heterogeneous positive, and subclonal loss, compared with NSMP cases. Targeted next\u2010generation sequencing of all exons across 474 cancer\u2010related genes in the 27\n POLE<\/jats:italic>\n \u2010mutated ECs and 20 NSMP cases with ATM non\u2010diffuse positive staining patterns confirmed that\n POLE<\/jats:italic>\n \u2010mutated ECs typically had high tumor mutational burden and were enriched for\n ATM<\/jats:italic>\n truncating variants.\n ATM<\/jats:italic>\n 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\n POLE<\/jats:italic>\n variants. Notably, the null pattern appeared exclusively in ECs with pathogenic\n POLE<\/jats:italic>\n mutations. These results suggest that ATM IHC staining is an effective screening tool for identifying patients who may benefit from confirmatory\n POLE<\/jats:italic>\n sequencing among those lacking MMR deficiency or p53 abnormalities.\n <\/jats:p>","DOI":"10.1002\/2056-4538.70086","type":"journal-article","created":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T14:45:37Z","timestamp":1774622737000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["ATM<\/scp>\n immunohistochemistry as an effective screening method for\n \n POLE<\/i>\n <\/scp>\n variants among endometrial carcinomas lacking mismatch repair deficiency and p53 abnormalities"],"prefix":"10.1002","volume":"12","author":[{"given":"Xinyi","family":"Huang","sequence":"first","affiliation":[{"name":"Department of Pathology, Xijing Hospital The Fourth Military Medical University Xi'an PR China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yingmei","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pathology, Xijing Hospital The Fourth Military Medical University Xi'an PR China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wenjing","family":"Ni","sequence":"additional","affiliation":[{"name":"Department of Pathology, Xijing Hospital The Fourth Military Medical University Xi'an PR China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luyang","family":"Zhong","sequence":"additional","affiliation":[{"name":"Department of Psychology and Brain Science, College of Letters and Science University of California Santa Barbara CA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yang","family":"Qin","sequence":"additional","affiliation":[{"name":"Department of Pathology, Xijing Hospital The Fourth Military Medical University Xi'an PR China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shujun","family":"Zeng","sequence":"additional","affiliation":[{"name":"Department of Pathology, Xijing Hospital The Fourth Military Medical University Xi'an PR China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hong","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Pathology, Xijing Hospital The Fourth Military Medical University Xi'an PR China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuling","family":"Qu","sequence":"additional","affiliation":[{"name":"Department of Pathology, Xijing Hospital The Fourth Military Medical University Xi'an PR China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peizhen","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Pathology, Xijing Hospital The Fourth Military Medical University Xi'an PR China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7719-6943","authenticated-orcid":false,"given":"Jing","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Pathology, Xijing Hospital The Fourth Military Medical University Xi'an PR China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2026,3,27]]},"reference":[{"key":"e_1_2_8_2_1","first-page":"10","article-title":"Cancer statistics, 2025","volume":"75","author":"Siegel RL","year":"2025","journal-title":"CA Cancer J Clin"},{"key":"e_1_2_8_3_1","first-page":"229","article-title":"Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"74","author":"Bray F","year":"2024","journal-title":"CA Cancer J Clin"},{"key":"e_1_2_8_4_1","volume-title":"Female Genital Tumours WHO Classification of Tumours Series, Volume 4","author":"WHO 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