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Here, it is innovatively discovered that 120\u00a0\u00b5g mL\n                    <jats:sup>\u22121<\/jats:sup>\n                    DEE exposure for 20 weeks, original bronchial epithelial cells exhibit abnormal morphology, form colonies in soft agar, and readily develop the lumps under the subcutaneous tissue of immunodeficient mice, which are pathologically confirmed as lung squamous cell carcinoma. Whole genome sequencing and RNA sequencing identify DEE\u2010induced mutational signatures (DBS3, ID1\/ID2), associated with polymerase epsilon (POLE) exonuclease domain mutations and mismatch repair (MMR) deficiency. Besides, 52 exonic mutations, 734 copy number variations (CNVs), and 2519 differentially expressed genes (DEGs) are discovered which are enriched in the suppressed DNA damage repair pathways and the activated lung cancer related signaling pathways including JAK\u2010STAT, PI3K\u2010Akt, MAPK in the DEE\u2010induced malignant transformed cells. Further assays confirm DEE\u2010induced malignant transformed cells harbor both POLE and MMR defects, leading to high mutation burden and genomic instability. Additionally, POLE deficiency exacerbates DEE\u2010induced DNA damage and genomic instability, promoting the cell malignant transformation. This study highlights the importance of gene\u2010environment interaction in carcinogenesis and emphasizes the critical role of POLE deficiency in DEE\u2010induced malignant transformation of lung cells.\n                  <\/jats:p>","DOI":"10.1002\/advs.202415943","type":"journal-article","created":{"date-parts":[[2025,7,13]],"date-time":"2025-07-13T12:17:58Z","timestamp":1752409078000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["POLE Deficiency Exacerbates Diesel Engine Exhaust\u2010Induced Genomic Instability and Malignant Transformation of Bronchial Epithelial Cells"],"prefix":"10.1002","volume":"12","author":[{"given":"Pimei","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Blood Transfusion The Affiliated Hospital of Qingdao University Qingdao University Qingdao Shandong 266000 China"},{"name":"School of Public Health Qingdao University Qingdao Shandong 266021 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhaoxu","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Blood Transfusion The Affiliated Hospital of Qingdao University Qingdao University Qingdao Shandong 266000 China"},{"name":"School of Public Health Qingdao University Qingdao Shandong 266021 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiang","family":"Ju","sequence":"additional","affiliation":[{"name":"Department of Blood Transfusion The Affiliated Hospital of Qingdao University Qingdao University Qingdao Shandong 266000 China"},{"name":"School of Public Health Qingdao University Qingdao Shandong 266021 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nuo","family":"Xu","sequence":"additional","affiliation":[{"name":"School of Public Health Qingdao University Qingdao Shandong 266021 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xian","family":"Chen","sequence":"additional","affiliation":[{"name":"School of Public Health Qingdao University Qingdao Shandong 266021 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongguang","family":"Chen","sequence":"additional","affiliation":[{"name":"School of Public Health Qingdao University Qingdao Shandong 266021 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuaishuai","family":"Yang","sequence":"additional","affiliation":[{"name":"School of Public Health Qingdao University Qingdao Shandong 266021 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Ji","sequence":"additional","affiliation":[{"name":"School of Public Health Qingdao University Qingdao Shandong 266021 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6618-2447","authenticated-orcid":false,"given":"Yanjie","family":"Zhao","sequence":"additional","affiliation":[{"name":"School of Public Health Qingdao University Qingdao Shandong 266021 China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,6,29]]},"reference":[{"key":"e_1_2_9_1_1","unstructured":"F. 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