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The SWI\/SNF ATPase subunits SMARCA2 and SMARCA4 are essential for chromatin dynamics, yet the clinicopathological and microenvironmental landscape of SMARCA2\/4-deficient esophageal adenocarcinoma (EAC) remains insufficiently defined. We analyzed 722 resected EACs from a large Western cohort. SMARCA2 and SMARCA4 status were assessed by immunohistochemistry, and tumors were classified as SMARCA-intact or SMARCA-deficient (complete loss of nuclear expression in tumor cells with internal controls). Molecular co-alterations were evaluated by immunohistochemistry and fluorescence in situ hybridization, including amplifications of\n                    <jats:italic>MET<\/jats:italic>\n                    ,\n                    <jats:italic>ERBB2 (HER2)<\/jats:italic>\n                    ,\n                    <jats:italic>EGFR<\/jats:italic>\n                    ,\n                    <jats:italic>PIK3CA<\/jats:italic>\n                    ,\n                    <jats:italic>MYC<\/jats:italic>\n                    ,\n                    <jats:italic>MDM2<\/jats:italic>\n                    ,\n                    <jats:italic>TERT<\/jats:italic>\n                    , and Y-chromosome loss (LOY). Several markers were available from prior works. Digital pathology workflows quantified CAF markers (SMA, PDGFR\u03b2, FAP, Periostin, Tenascin) and immune infiltrates (including CD4, CD8, FOXP3, CD20, MUM1, mast cell tryptase). Overall survival was examined using Kaplan\u2013Meier estimates and Cox regression models. SMARCA2\/4-deficient tumors accounted for 11.2% of the cohort (81\/722) and were enriched among patients aged\u2009\u2265\u200965 years. SMARCA-deficient EACs showed a significantly higher frequency of\n                    <jats:italic>MET<\/jats:italic>\n                    amplification (16.9%), particularly after neoadjuvant therapy. Within SMARCA-deficient tumors, PDGFR\u03b2-positive CAFs, increased plasma cell (MUM1+) and mast cell infiltrates correlated with a favorable outcome, whereas loss of Y-chromosome (LOY) identified an adverse-risk subgroup with particularly poor prognosis. This largest-to-date study defines SMARCA-deficient EAC as a distinct subtype characterized by frequent\n                    <jats:italic>MET<\/jats:italic>\n                    amplification and high-risk interaction with LOY, alongside prognostically relevant stromal-immune features, supporting refined biomarker-based risk stratification and therapeutic exploration.\n                  <\/jats:p>","DOI":"10.1038\/s41598-026-60346-8","type":"journal-article","created":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T02:05:29Z","timestamp":1785377129000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["SMARCA2 and SMARCA4-deficiency is associated with a distinct molecular and microenvironmental subtype of esophageal adenocarcinoma"],"prefix":"10.1038","volume":"16","author":[{"given":"Matteo","family":"Montalbano","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karl","family":"Knipper","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hans A.","family":"Schl\u00f6\u00dfer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bastian","family":"Grothey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reinhard","family":"Buettner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christiane Josephine","family":"Bruns","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Zander","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Su Ir","family":"Lyu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Quaas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,7,30]]},"reference":[{"issue":"3","key":"60346_CR1","doi-asserted-by":"publisher","first-page":"229","DOI":"10.3322\/caac.21834","volume":"74","author":"F Bray","year":"2024","unstructured":"Bray, F. et al. 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