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.
|Number of pages||9|
|Journal||American Journal of Respiratory and Critical Care Medicine|
|State||Published - Sep 15 2019|
Bibliographical noteFunding Information:
*Co–first authors. ‡Equally contributing co–senior authors. Supported in part by Cancer Prevention and Research Institute of Texas (grant RP150079, P.S. and H.K.); NIH (grant R01HG005859, P.S.); Department of Defense lung cancer program (grant W81XWH-10-1-1007, H.K., S.D., A.E.S., and I.I.W.); The University of Texas Lung Specialized Programs of Research Excellence (grant P50CA70907); MD Anderson’s Institutional Tissue Bank Award (P30CA016672); and The University of Texas MD Anderson Cancer Center Core Support Grant, Tissue Biorepository and Pathology Facility (P30CA16672).
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