{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T07:13:28Z","timestamp":1783581208347,"version":"3.55.0"},"reference-count":40,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T00:00:00Z","timestamp":1783468800000},"content-version":"vor","delay-in-days":188,"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>\n                    Environmental exposures are upstream determinants of molecular variation, yet exposure\u2010to\u2010biomarker gradients remain insufficiently quantified in harmonized multiomics cancer cohorts. Using TCGA lung adenocarcinoma as a model, we evaluated cumulative tobacco exposure and smoking history as determinants of variant\u2010derived biomarkers and tested whether integrating clinical, genomic, transcriptomic, and proteomic data improves identification of high tumor mutational burden (TMB). This secondary analysis used public cBioPortal\u2010linked TCGA data. Among 522 patients with clinical and molecular annotations, 302 ever\u2010smokers with nonmissing pack\u2010years, TMB, and covariates comprised the primary adjusted logistic\u2010regression cohort, and 250 cases had matched multiomics data for prediction modeling. Higher cumulative tobacco exposure was associated with greater odds of high TMB: Compared with pack\u2010year tertile 1, tertile 3 had an adjusted odds ratio of 2.28 (95% CI: 1.18, 4.41;\n                    <jats:italic>p<\/jats:italic>\n                    \u2009trend = 0.013), and each 10 pack\u2010year increment was associated with an odds ratio of 1.12 (95% CI: 1.02, 1.23). Smoking categories also showed strong gradients for TMB, total nonsynonymous mutation counts, and C &gt; A substitution fraction. Current smoking was positively associated with TP53 mutation and inversely associated with EGFR mutation relative to never\u2010smoking. High\u2010TMB tumors showed 201 differentially expressed transcripts and 15 differentially abundant proteins. Driver\u2010augmented models discriminated high TMB better than broader multiomics models, although integrated scores retained prognostic relevance. These findings support exposure\u2010aware biomarker development in lung adenocarcinoma. High TMB was defined as a cohort\u2010specific top\u2010quartile analytic endpoint rather than a universal clinical threshold. The findings support biomarker interpretation and hypothesis generation, not direct immunotherapy\u2010response prediction or a clinically deployable model.\n                  <\/jats:p>","DOI":"10.1155\/humu\/1906706","type":"journal-article","created":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T06:17:01Z","timestamp":1783577821000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["From Exposure to Biomarker: Cumulative Tobacco Burden and Integrated Multiomics Signatures of High Tumor Mutational Burden in Lung Adenocarcinoma\u2014A Secondary Analysis of the Cancer Genome Atlas"],"prefix":"10.1155","volume":"2026","author":[{"given":"Jin","family":"Wei","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qin","family":"Yangsong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruan","family":"Hongjia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhu","family":"Bingqiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-3901-8785","authenticated-orcid":false,"given":"Yang","family":"Conggao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,7,8]]},"reference":[{"key":"e_1_2_12_1_2","doi-asserted-by":"publisher","DOI":"10.1093\/aje\/kwf153"},{"key":"e_1_2_12_2_2","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.27339"},{"key":"e_1_2_12_3_2","doi-asserted-by":"publisher","DOI":"10.18295\/2075-0528.1488"},{"key":"e_1_2_12_4_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aag0299"},{"key":"e_1_2_12_5_2","doi-asserted-by":"publisher","DOI":"10.1080\/2162402X.2018.1494677"},{"key":"e_1_2_12_6_2","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2021.703143"},{"key":"e_1_2_12_7_2","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdy495"},{"key":"e_1_2_12_8_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMc1713444"},{"key":"e_1_2_12_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-018-0312-8"},{"key":"e_1_2_12_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejca.2020.02.038"},{"key":"e_1_2_12_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cels.2018.03.002"},{"key":"e_1_2_12_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2764"},{"key":"e_1_2_12_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.trsl.2015.08.001"},{"key":"e_1_2_12_14_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2760"},{"key":"e_1_2_12_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2018.03.023"},{"key":"e_1_2_12_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2018.02.052"},{"key":"e_1_2_12_17_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature13385"},{"key":"e_1_2_12_18_2","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-12-0095"},{"key":"e_1_2_12_19_2","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.2004088"},{"key":"e_1_2_12_20_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.2517-6161.1995.tb02031.x"},{"key":"e_1_2_12_21_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1467-9868.2005.00503.x"},{"key":"e_1_2_12_22_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.2517-6161.1972.tb00899.x"},{"key":"e_1_2_12_23_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-20-3991"},{"key":"e_1_2_12_24_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jss.2018.07.007"},{"key":"e_1_2_12_25_2","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.200801-142OC"},{"key":"e_1_2_12_26_2","doi-asserted-by":"crossref","unstructured":"MoorthiS. 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