Transcriptomic Architecture of the Adjacent Airway Field Cancerization in Non–Small Cell Lung Cancer

Earlier work by Slaughter et al. in patients with oral premalignant and cancer lesions suggested that histologically normal-appearing tissues adjacent to lesions display tumor-associated molecular abnormalities (1). Notably, Auerbach et al. demonstrated that cigarette smoke induces widespread histological changes and premalignant lesions in the bronchial epithelia in the lungs of smokers, suggestive of a field effect (2). This phenomenon, coined field cancerization (FC), was shown to be evident in various epithelial malignancies, including gastric, esophageal, hepatic, cervical, skin, and lung cancers (3–6) and was proposed to precede and explain the development of multiple primary and locally recurrent cancer (3,7). Previously, an analysis of histologically normal epithelium and premalignant and malignant epithelia from lung squamous cell carcinoma (SCC) patients indicated that multiple, sequentially occurring allele-specific chromosomal deletions commence early in the multistage pathogenesis of SCCs (8,9). Notably, 31% of histologically normal epithelium specimens had clones of cells with allelic loss at one or more regions examined, including loss of heterozygosity at chromosomal regions 3p and 9p (8,10). Belinsky et al. identified promoter methylation of p16, a common aberration in lung tumors (11), in at least one bronchial epithelial site from 44% of lung cancer cases examined (12). In addition, our group and others have demonstrated that mutations in the epidermal growth factor receptor (EGFR) and KRAS oncogenes were also found in histologically normal tissue adjacent to lung tumors (13,14). Global expression profiles have been described in bronchial epithelium of smokers, a portion of which exhibited cancer diagnostic properties (15–18), as well as in the field of injury of early-stage non–small cell lung cancer (NSCLC) patients who had their tumors surgically resected before airway transcriptome analysis (19). However, the adjacent airway FC in NSCLC has not yet been characterized at a whole-transcriptome level. In this study, we performed expression profiling of matched NSCLCs, uninvolved normal lung tissue, and multiple airways with varying distances from tumors to define the transcriptomic architecture of the adjacent airway FC.