Genomic Profiling of Lung Adenocarcinoma in Never-Smokers.


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.

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.

We observed a high prevalence of clinically actionable driver alterations in never-smoker LUADs compared with smoker LUADs (78%-92% <i>v</i> 49.5%; <i>P</i> < .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% <i>v</i> 6.9%; <i>P</i> = .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.

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.

  • Carr SA
  • Devarakonda S
  • Ding L
  • Fulton L
  • Fulton R
  • Gillette MA
  • Goparaju C
  • Govindan R
  • Kadara H
  • Lanc I
  • Li Y
  • Martins Rodrigues F
  • Masood A
  • Morgensztern D
  • Pass H
  • Pepin K
  • Sankararaman S
  • Satpathy S
  • Waqar SN
  • Ward J
  • Wilson RK
  • Wistuba I
Pub Med ID
Appears In
J Clin Oncol, 2021, 39 (33)