{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T13:44:28Z","timestamp":1792071868300,"version":"4.4.0"},"reference-count":40,"publisher":"American Society of Clinical Oncology (ASCO)","issue":"33","content-domain":{"domain":["ascopubs.org"],"crossmark-restriction":true},"short-container-title":["JCO"],"published-print":{"date-parts":[[2021,11,20]]},"abstract":"<jats:sec>\n                    <jats:title>PURPOSE<\/jats:title>\n                    <jats:p>Approximately 10%-40% of patients with lung cancer report no history of tobacco smoking (never-smokers). We analyzed whole-exome and RNA-sequencing data of 160 tumor and normal lung adenocarcinoma (LUAD) samples from never-smokers to identify clinically actionable alterations and gain insight into the environmental and hereditary risk factors for LUAD among never-smokers.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS<\/jats:title>\n                    <jats:p>We performed whole-exome and RNA-sequencing of 88 and 69 never-smoker LUADs. We analyzed these data in conjunction with data from 76 never-smoker and 299 smoker LUAD samples sequenced by The Cancer Genome Atlas and Clinical Proteomic Tumor Analysis Consortium.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>We observed a high prevalence of clinically actionable driver alterations in never-smoker LUADs compared with smoker LUADs (78%-92% v 49.5%; P &lt; .0001). Although a subset of never-smoker samples demonstrated germline alterations in DNA repair genes, the frequency of samples showing germline variants in cancer predisposing genes was comparable between smokers and never-smokers (6.4% v 6.9%; P = .82). A subset of never-smoker samples (5.9%) showed mutation signatures that were suggestive of passive exposure to cigarette smoke. Finally, analysis of RNA-sequencing data showed distinct immune transcriptional subtypes of never-smoker LUADs that varied in their expression of clinically relevant immune checkpoint molecules and immune cell composition.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSION<\/jats:title>\n                    <jats:p>In this comprehensive genomic and transcriptome analysis of never-smoker LUADs, we observed a potential role for germline variants in DNA repair genes and passive exposure to cigarette smoke in the pathogenesis of a subset of never-smoker LUADs. Our findings also show that clinically actionable driver alterations are highly prevalent in never-smoker LUADs, highlighting the need for obtaining biopsies with adequate cellularity for clinical genomic testing in these patients.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1200\/jco.21.01691","type":"journal-article","created":{"date-parts":[[2021,9,30]],"date-time":"2021-09-30T16:11:05Z","timestamp":1633018265000},"page":"3747-3758","update-policy":"https:\/\/doi.org\/10.1200\/crossmark","source":"Crossref","is-referenced-by-count":119,"title":["Genomic Profiling of Lung Adenocarcinoma in Never-Smokers"],"prefix":"10.1200","volume":"39","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2693-3848","authenticated-orcid":false,"given":"Siddhartha","family":"Devarakonda","sequence":"first","affiliation":[{"name":"Division of Oncology, Washington University School of Medicine, St Louis, MO"},{"name":"Siteman Cancer Center, St Louis, 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