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This study aimed to comprehensively analyze the characteristics of this rare entity. A total of 738 surgical cases were enrolled, including 349 pure invasive mucinous adenocarcinoma (IMA), 61 mixed IMA\/NMA and 328 pure non-mucinous adenocarcinoma (NMA) cases. Using amplification refractory mutation system, immunohistochemistry, and DNA-\/RNA-based next-generation sequencing (DNA and RNA NGS), distinct molecular features were identified in mixed IMA\/NMA cases compared with IMA and NMA cases, particularly in\n                    <jats:italic>EGFR<\/jats:italic>\n                    ,\n                    <jats:italic>KRAS<\/jats:italic>\n                    , and\n                    <jats:italic>ALK<\/jats:italic>\n                    alterations and PD-L1 expression status. Paired analysis of the IMA and NMA components within mixed IMA\/NMA cases using DNA and RNA NGS revealed one to three shared genomic alterations between the two components in the same tumor. However, significant differences were observed in the levels of cancer-associated fibroblasts, protumor cytokines, MHC-II, coactivation molecules, T cells, and effector cells between the components. Similarly, multiplex immunofluorescence assay demonstrated that immune cell infiltration, including CD4\n                    <jats:sup>+<\/jats:sup>\n                    and CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells, was significantly higher in the NMA components compared to the IMA components. Postoperative follow-up revealed no significant difference in disease-free survival (DFS) or overall survival (OS) between NMA and mixed IMA\/NMA cases; however, both groups showed significantly shorter DFS (\n                    <jats:italic>P<\/jats:italic>\n                    \u2009=\u20090.011) and OS (\n                    <jats:italic>P<\/jats:italic>\n                    \u2009=\u20090.027) compared to IMA cases. Together, this study provides a comprehensive characterization of the molecular profiles, clonal relatedness, tumor heterogeneity, and surgical outcomes of mixed IMA\/NMA, which may inform diagnostic and therapeutic strategies for this rare LUAD subtype.\n                  <\/jats:p>","DOI":"10.1186\/s43556-026-00460-1","type":"journal-article","created":{"date-parts":[[2026,5,9]],"date-time":"2026-05-09T06:51:29Z","timestamp":1778309489000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Molecular characteristics, clonal relatedness and surgical outcomes of pulmonary mixed invasive mucinous and non-mucinous adenocarcinoma: a retrospective cohort study"],"prefix":"10.1186","volume":"7","author":[{"given":"Xinyi","family":"Shi","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yang","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nan","family":"Yao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bowen","family":"Xue","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lei","family":"Guo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Liming","family":"Xu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Changbin","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guiping","family":"Qin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jianming","family":"Ying","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yutao","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-2163-3335","authenticated-orcid":false,"given":"Weihua","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2026,5,9]]},"reference":[{"key":"460_CR1","doi-asserted-by":"publisher","unstructured":"Chen JW, Dhahbi J. 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Approval was granted by the Ethics Committee of the National Cancer Center\/National Clinical Research Center for Cancer\/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (NCC-007943). Informed consent was obtained from all individual participants included in the study.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"The authors affirm that human research participants provided informed consent for publication of the images in Figures and Tables.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"Authors Liming Xu and Changbin Zhu are employees of Amoy Diagnostics Co., Ltd. The other authors have no conflicts of interest to declare.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"65"}}