{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T05:10:45Z","timestamp":1788757845473,"version":"build-2803163510"},"reference-count":29,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2026,9,6]],"date-time":"2026-09-06T00:00:00Z","timestamp":1788652800000},"content-version":"vor","delay-in-days":248,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,1,1]],"date-time":"2026-01-01T00:00:00Z","timestamp":1767225600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Human Mutation"],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:p>Nonsmall cell lung cancer (NSCLC) is characterized by substantial heterogeneity in driver mutation backgrounds and tumor microenvironment (TME) phenotypes, yet the transcriptional regulatory states linking genotype context to immune\u2013stromal variation remain incompletely defined. In this study, we integrated mutation, transcriptomic, and clinical data from TCGA\u2010LUAD\/LUSC to construct a mutation\u2013expression\u2010matched NSCLC cohort and evaluated RUNX1 as a mutation context\u2013associated transcriptional\/regulatory state rather than as a recurrently mutated driver. Driver contexts were assessed using a prespecified six\u2010gene panel comprising EGFR, KRAS, TP53, STK11, KEAP1, and BRAF in the overall NSCLC cohort, the primary LUAD analysis, and a descriptive LUSC sensitivity analysis. The prespecified driver\u2010context\u2010negative operational group was defined as tumors without mutations in any of these six genes. RUNX1 mutation status was reported separately and did not contribute to this definition. Analyses included RUNX1 distributions, six\u2010gene overlap, the RUNX1 cutoff, comutation burden, model sample\u2010size audits, and adjusted context models. RUNX1 expression and inferred RUNX1 target\u2010gene\u2010set activity were evaluated across mutation contexts, whereas TME features were characterized using MCP\u2010counter, xCell, ssGSEA, and ESTIMATE. Single\u2010cell RNA sequencing and Visium spatial transcriptomic datasets were further used to localize RUNX1 expression, inferred target projections, and candidate TME\u2010supporting genes. RUNX1 was prioritized within a prespecified candidate\u2010screening framework and was significantly associated with the inferred RUNX1 target\u2010gene\u2010set readout. RUNX1 expression differences required interpretation in relation to histology and comutation structure. In the primary LUAD analysis, the KRAS\u2010mutant context was associated with higher RUNX1 expression, whereas the KEAP1\u2010mutant context was associated with lower expression. LUSC findings were retained as a descriptive sensitivity analysis and were not given the same inferential weight. Six\u2010gene overlap, comutation burden, the RUNX1 cutoff, and model sample\u2010size audits further showed that driver labels were nonmutually exclusive and that the prespecified driver\u2010context\u2010negative group was an operational reference rather than a biologically homogeneous subtype. RUNX1\u2010high and RUNX1\u2010low tumors displayed mutation context\u2013dependent immune and stromal differences, involving stromal\/cancer\u2010associated fibroblast, myeloid\/dendritic cell, endothelial, immune\u2010score, and tumor\u2010purity axes. Single\u2010cell analysis localized RUNX1\u2010associated signals and target\u2010gene projections across epithelial\u2010like and myeloid compartments, and spatial transcriptomics supported concordance between RUNX1 and selected TME\u2010supporting genes in NSCLC tissue sections. Public immune checkpoint inhibitor cohorts were limited by small sample size and incomplete annotations and did not support RUNX1 as a stable immunotherapy\u2010response predictor. Overall, these findings propose a mutation\u2010context\u2010aware RUNX1\u2013TME stratification framework and generate testable hypotheses for mechanistic validation and mutation\u2010annotated immunotherapy studies.<\/jats:p>","DOI":"10.1155\/humu\/6216101","type":"journal-article","created":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T04:20:35Z","timestamp":1788754835000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Association Between Mutation Context\u2013Associated RUNX1 Transcriptional States and Immune\u2013Stromal Heterogeneity in Nonsmall Cell Lung Cancer"],"prefix":"10.1155","volume":"2026","author":[{"given":"Jinyao","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuang","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingjing","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0438-6006","authenticated-orcid":false,"given":"Jing","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-8918-0655","authenticated-orcid":false,"given":"Huan","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,6]]},"reference":[{"key":"e_1_2_12_1_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature13385"},{"key":"e_1_2_12_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature11404"},{"key":"e_1_2_12_3_2","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.Cd-14-1236"},{"key":"e_1_2_12_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2015.375"},{"key":"e_1_2_12_5_2","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.Ccr-18-0163"},{"key":"e_1_2_12_6_2","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.Cd-18-0099"},{"key":"e_1_2_12_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtho.2021.10.013"},{"key":"e_1_2_12_8_2","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.27964"},{"key":"e_1_2_12_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2014.305"},{"key":"e_1_2_12_10_2","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.Cd-12-0095"},{"key":"e_1_2_12_11_2","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.2004088"},{"key":"e_1_2_12_12_2","doi-asserted-by":"publisher","DOI":"10.3390\/jcm9061694"},{"key":"e_1_2_12_13_2","doi-asserted-by":"publisher","DOI":"10.2147\/cmar.S168438"},{"key":"e_1_2_12_14_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-12159-9"},{"key":"e_1_2_12_15_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13148-020-00907-4"},{"key":"e_1_2_12_16_2","doi-asserted-by":"publisher","DOI":"10.1038\/s12276-020-00493-8"},{"key":"e_1_2_12_17_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13073-023-01164-9"},{"key":"e_1_2_12_18_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-48700-8"},{"key":"e_1_2_12_19_2","doi-asserted-by":"publisher","DOI":"10.1101\/gr.239244.118"},{"key":"e_1_2_12_20_2","doi-asserted-by":"publisher","DOI":"10.1101\/gr.240663.118"},{"key":"e_1_2_12_21_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkad841"},{"key":"e_1_2_12_22_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioadv\/vbac016"},{"key":"e_1_2_12_23_2","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.4463"},{"key":"e_1_2_12_24_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-016-1070-5"},{"key":"e_1_2_12_25_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-017-1349-1"},{"key":"e_1_2_12_26_2","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2105-14-7"},{"key":"e_1_2_12_27_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature08460"},{"key":"e_1_2_12_28_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms3612"},{"key":"e_1_2_12_29_2","doi-asserted-by":"publisher","DOI":"10.18332\/tid\/189490"}],"container-title":["Human 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