Table 1.

Summary of Key Findings from Select Papers in the Field

Paper	Study Population	Tissue	Analytes	Significant Genes/Pathways	Major Findings
Slaughter et al. 1953 (41)	Oral cancer cases	Resected oral tumor	Histology	N/A	Non-malignant epithelium surrounding tumors is abnormal
Blomquist et al. 2009 (39)	Ever smokers undergoing bronchoscopy for suspect lung cancer	Bronchial Airway epithelial cells via bronchoscopy	mRNA	Antioxidant and DNA repair pathways (CAT, CEBPG, E2F1, ERCC4, ERCC5, GPX1, GPX3, GSTM3, GSTP1, GSTT1, GSTZ1, MGST1, SOD1, and XRCC1)	Variability in the expression of antioxidant, DNA repair and transcription factor genes in normal airway epithelium identifies the presence of lung cancer
Spira et al. 2007 (54)	Ever smokers undergoing bronchoscopy for suspect lung cancer	Bronchial Airway epithelial cells via bronchoscopy	mRNA	Inflammation (PLA2G4A, DEFB1, C6, FCGR3A, IL8, SERPINA1) Cell Cycle (PPBP, DUSP6, TOB1) Antioxidant (BACH2, DUOX1)	An 80-gene classifier derived from cytologically normal large airways of ever smokers can distinguish lung cancer vs. benign disease
Franklin et al. 1997 (43)	Lung premaligancy	Bronchial epithelial cells at multiple sites during autopsy	DNA	p53	A p53 tumor suppressor gene mutation was identified at several sites throughout the airway epithelium that exhibited only squamous metaplasia and mild to moderate atypia by histology.
Tang et al. 2005 (46)	Lung cancer cases	Resected lung tumor	DNA	EGFR mutations	EGFR mutations are found in normal epithelium of EGFR-positive lung cancer patients.
Kadara et al. 2014 (50)	Lung cancer cases	Resected lung tumor	mRNA	TGFBR2, VIPR1, NETO2, LAPTM4B	Histologically normal-appearing adjacent airway exhibits a gradient of tumor-associated gene expression that decreases with increasing distance from the tumor as well as a set of genes that are consistently altered regardless of tumor proximity
Silvestri et al. 2015 (57)	Ever smokers undergoing bronchoscopy for suspect lung cancer	Bronchial Airway epithelial cells via bronchoscopy	mRNA	Immune Response (BST1, CD177) Tumor related (TSPAN2, NOVA1, CDR1, MCAM) Xenobiotic Metabolism (EPHX3) Cell Cycle (SDC2, NKX3-1, CGREF1) Others (RPS4Y1, SLC7A11, CLND10, TKT, RUNX1T1, AKR1C2, CD177.2, ATP12A, GABBR1, CLND22, LYPD2, MIA, RNF150)	A 23-gene-expression classifier measured in cytologically normal mainstem bronchus improved the diagnostic performance of bronchoscopy for the detection of lung cancer.