Genomic Profiling of Lung Adenocarcinoma in Never-Smokers. Issue 33 (20th November 2021)

• Record Type: Journal Article
• Authors: Devarakonda, Siddhartha; Li, Yize; Martins Rodrigues, Fernanda; Sankararaman, Sumithra; Kadara, Humam; Goparaju, Chandra; Lanc, Irena; Pepin, Kymberlie; Waqar, Saiama N.; Morgensztern, Daniel; Ward, Jeffrey; Masood, Ashiq; Fulton, Robert; Fulton, Lucinda; Gillette, Michael A.; Satpathy, Shankha; Carr, Steven A.; Wistuba, Ignacio; Pass, Harvey; Wilson, Richard K.; Ding, Li; Govindan, Ramaswamy
• Is Part Of: Journal of clinical oncology. Volume 39:Issue 33(2021)
• Page Start: 3747
• Page End: 3758
• Publication Date: 2021-11-20
• Subjects: Oncology -- Periodicals; Cancer -- Periodicals; Oncology; Medical Oncology; Cancérologie -- Périodiques; Cancer -- Périodiques; Cancérologie; Cancer; Oncology; Oncologia; Càncer; Periodicals; 616.994
• DOI: 10.1200/JCO.21.01691
• Languages: English
• ISSNs: 0732-183X

Abstract

Abstract : PURPOSE: 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. METHODS: 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. RESULTS: We observed a high prevalence of clinically actionable driver alterations in never-smoker LUADs compared with smoker LUADs (78%-92% v 49.5%; P < .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. CONCLUSION: 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. Abstract :