Driver mutations in normal airway epithelium elucidate spatiotemporal resolution of lung cancer

Humam Kadara, Smruthy Sivakumar, Yasminka Jakubek, F. Anthony San Lucas, Wenhua Lang, Tina McDowell, Zachary Weber, Carmen Behrens, Gareth E. Davies, Neda Kalhor, Cesar Moran, Randa El-Zein, Reza Mehran, Stephen G. Swisher, Jing Wang, Jianjun Zhang, Junya Fujimoto, Jerry Fowler, John V. Heymach, Steven DubinettAvrum E. Spira, Erik A. Ehli, Ignacio I. Wistuba, Paul Scheet

Research output: Contribution to journalArticlepeer-review

21 Scopus citations


Rationale: Uninvolved normal-appearing airway epithelium has been shown to exhibit specific mutations characteristic of nearby non–small cell lung cancers (NSCLCs). Yet, its somatic mutational landscape in patients with early-stage NSCLC is unknown. Objectives: To comprehensively survey the somatic mutational architecture of the normal airway epithelium in patients with early-stage NSCLC. Methods: Multiregion normal airways, comprising tumor-adjacent small airways, tumor-distant large airways, nasal epithelium and uninvolved normal lung (collectively airway field), matched NSCLCs, and blood cells (n = 498) from 48 patients were interrogated for somatic single-nucleotide variants by deep-targeted DNA sequencing and for chromosomal allelic imbalance events by genome-wide genotype array profiling. Spatiotemporal relationships between the airway field and NSCLCs were assessed by phylogenetic analysis. Measurements and Main Results: Genomic airway field carcinogenesis was observed in 25 cases (52%). The airway field epithelium exhibited a total of 269 somatic mutations in most patients (n = 36) including key drivers that were shared with the NSCLCs. Allele frequencies of these acquired variants were overall higher in NSCLCs. Integrative analysis of single-nucleotide variants and allelic imbalance events revealed driver genes with shared “two-hit” alterations in the airway field (e.g., TP53, KRAS, KEAP1, STK11, and CDKN2A) and those with single hits progressing to two in the NSCLCs (e.g., PIK3CA and NOTCH1). Conclusions: Tumor-adjacent and tumor-distant normal-appearing airway epithelia exhibit somatic driver alterations that undergo selection-driven clonal expansion in NSCLC. These events offer spatiotemporal insights into the development of NSCLC and, thus, potential targets for early treatment.

Original languageEnglish
Pages (from-to)742-750
Number of pages9
JournalAmerican Journal of Respiratory and Critical Care Medicine
Issue number6
StatePublished - Sep 15 2019

Bibliographical note

Publisher Copyright:
Copyright © 2019 by the American Thoracic Society


  • Allelic imbalance
  • Cancerization field
  • Deep targeted sequencing
  • Early-stage non–small cell lung cancer
  • Normal airway

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine


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