• 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 Dubinett, Avrum E Spira, Erik A Ehli, Ignacio I Wistuba, and Paul Scheet.
• Department of Translational Molecular Pathology.
• Am. J. Respir. Crit. Care Med. 2019 Sep 15; 200 (6): 742750742-750.

AbstractRationale: 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.

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