Enriching the Molecular De fi nition of the Airway " Field of Cancerization : " Establishing New Paradigms for the Patient at Risk for Lung Cancer

The "field of cancerization" refers to histologically normal-appearing tissue adjacent to neoplastic tissue that displays molecular abnormalities, some of which are the same as those of the tumor. Improving our understanding of these molecular events is likely to increase our understanding of carcinogenesis. Kadara and colleagues attempt to characterize the molecular events occurring temporally and spatially within the field of cancerization of patients with early-stage non–small cell lung cancer (NSCLC) following definitive surgery. They followed patients with bronchoscopies annually after tumor resection and extracted RNA from the serial brushings from different endobronchial sites. They then conducted microarray analysis to identify gene expression differences over time and in different sites in the airway. Candidate genes were found that may have biologic relevance to the field of cancerization. For example, expression of phosphorylated AKT and ERK1/2 was found to increase in the airway epithelium with time. Although there are limitations in the study design, this investigation demonstrates the utility of identifying molecular changes in histologically normal airway epithelium in lung cancer. In addition to increasing our understanding of lung cancer biology, studying the field of cancerization has the potential to identify biomarkers from samples obtained in a minimally invasive manner. Cancer Prev Res; 6(1); 4–7. 2012 AACR. Field of Cancerization In seminal studies defining histologic changes in oral malignancies, Slaughter and colleagues first used the term "field cancerization" to describe the histologically normalappearing tissue adjacent to neoplastic lesions that display molecular abnormalities, some of which are the same as those in the tumors (1). Since that time, investigators have attempted to define the underlyingmolecular events leading to field cancerization in several different epithelialmalignancies, including lung cancer (2, 3). In contrast to other common epithelial malignancies, there is not yet a clinical rationale to evaluate potential premalignant events in the patient at risk for lung cancer. Thus, carefully designed clinical investigations are required to harvest airway specimens that would not otherwise be collected in these individuals. In the absence of a critical mass of such studies, knowledge regarding themolecular changes thatoccur in theairwayepithelium in the setting of lung cancer is only fragmentary. However, it is generally accepted that there are alterations in the airway epithelium that mirror some of the changes seen in the lung cancer itself and that defining these changes could lead to the identification of biomarkers of lung cancer recurrence and provide a pathway for targeted chemoprevention. The field of cancerization theory has been tested and shown to be present in other epithelial cell malignancies, such as prostate, head and neck, colon, esophageal, and breast cancer (4–6). In fact, the concept of field of cancerizationhas led to the useof novel technologies to predict the risk of cancer based on testing of cells from the field. Lee and colleagues used aberrant DNA methylation patterns of 4 candidate genes in the normal esophageal mucosa adjacent to squamous carcinoma to develop a risk assessmentmodel that predicted the risk of finding squamous cell carcinoma of the upper aerodigestive tract at endoscopy (7). Damania and colleagues used anovel imaging technique, partialwave Authors' Affiliations: Division of Hematology Oncology, Department of Pediatrics, Mattel Children's Hospital at the University of California, Los Angeles (UCLA); Division of Pulmonary and Critical Care Medicine, Department of Medicine; Departments of Pathology and Laboratory Medicine and Medical and Molecular Pharmacology, David Geffen School of Medicine at UCLA; The Broad Stem Cell Research Center at UCLA, Los Angeles, California; Lung Cancer Research Program of the Jonsson Comprehensive Cancer Center, Los Angeles, California; The Pulmonary Center, Boston University Medical Center; Bioinformatics Program, Boston University; Section of Computational Biomedicine, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts; and Veterans' Affairs Greater Los Angeles Healthcare System, Los Angeles, California Corresponding Author: Steven M. Dubinett, Division of Pulmonary and Critical Care Medicine, David Geffen School of Medicine at UCLA, 37-131 Center for Health Sciences, 10833 Le Conte Avenue, Los Angeles, CA 90095. Phone: 310-267-2725; Fax: 310-267-2829; E-mail: sdubinett@mednet.ucla. edu doi: 10.1158/1940-6207.CAPR-12-047