Bronchial Epithelial Ki-67 Index Is Related to Histology, Smoking, and Gender, but Not Lung Cancer or Chronic Obstructive Pulmonary Disease York E. Miller, 1 Patrick Blatchford, 2 Dae Sung Hyun, 6 Robert L. Keith, 1 Timothy C. Kennedy, 3 Holly Wolf, 2 Tim Byers, 2 Paul A. Bunn, Jr., 4 Marina T. Lewis, 4,5 Wilbur A. Franklin, 5 Fred R. Hirsch, 4,5 and John Kittelson 2 1 Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, Denver Veterans Affairs Medical Center, Departments of 2 Preventive Medicine and Biometrics, 3 Medicine, HealthOne, and 4 Division of Medical Oncology, Department of Medicine, and 5 Department of Pathology, University of Colorado at Denver and Health Sciences Center, University of Colorado Comprehensive Cancer Center, Denver, Colorado; and 6 Catholic University of Daegu, Daegu, South Korea Abstract Purpose: To determine whether increased bronchial epithelial proliferation is associated with histology, smoking status, gender, age, chronic obstructive pul- monary disease (COPD), or lung cancer. Experimental Design: Cross-sectional study of 113 subjects undergoing white light and autofluores- cence bronchoscopy: 27 never smokers; 27 current or ex-smokers with normal spirometry; 31 current or ex- smokers with COPD; and 28 current, ex-, or never smokers with lung cancer. Ki-67 expresssion was determined by immunohistochemistry on all evalu- able biopsy sites without carcinoma. Relationships between Ki-67 index (percentage of epithelial cells expressing Ki-67), demographic variables, smoking, histology, and the presence of COPD and/or lung cancer were determined. Results: Results for both maximal and mean Ki-67 index are similar, so only the former are reported. Average maximal Ki-67 index was higher in current smokers than either ex-smokers or never smokers (48.0% versus 30.6% versus 22.6%; P < 0.001). Males had higher Ki-67 index than females (39.9% versus 23.6%; P < 0.001). Compared with subjects without disease (Ki-67 index = 30.0%), maximal Ki-67 index was not significantly elevated (P = 0.44) in subjects with either lung cancer (Ki-67 = 39.1%) or COPD (Ki-67 = 38.9%). Conclusions: Smoking status, bronchial histology, and gender were significantly associated with Ki-67 index. No increase in Ki-67 index was found in the nonma- lignant epithelium of patients with lung cancer or COPD. Although Ki-67 index may provide insight into the short-term effects of chemoprevention agents on cell proliferation, its lack of association with lung cancer or COPD raises question regarding its utility as a lung cancer risk biomarker. (Cancer Epidemiol Biomarkers Prev 2007;16(11):2425 – 31) Introduction Lung cancer is the leading cause of cancer death in the United States and the world (1). Eighty-five percent of lung cancer cases in the United States can be attributed to tobacco smoke. However, only one of nine smokers will develop lung cancer, so determination of lung cancer risk is extremely important. Smoking history, age, the presence of airflow obstruction [indicative of chronic obstructive pulmonary disease (COPD)], exposure to additional respiratory carcinogens, personal history of other smoking-related cancers, and family history of lung cancer are all simple historical or clinical features that can be used to further define risk (2-5). Reliable biomarkers of risk would be of great utility for developing early detection and prevention strategies. Many biomarkers of lung cancer risk have been proposed, but few have been comprehensively validated. Sputum cytology of moderate or worse atypia carries an increased risk, as described in several longitudinal cohort trials, with moderate atypia having a modestly elevated relative risk and severe atypia or carcinoma in situ having a highly elevated relative risk (6, 7). We recently reported that methylation of a panel of genes in the sputum is associated with an approximate 7-fold elevation in risk in an incident case control study (8). Uncontrolled cellular proliferation is a hallmark of cancer and a biologically plausible risk biomarker for preneoplastic epithelium (9-11). Ki-67 immunostaining has been used as an indicator of cellular proliferation for more than 20 years (12). The Ki-67 antigen is localized to the nucleus, currently incompletely biochemically char- acterized, and is expressed in all phases of the cell cycle except for G 0 (13). The percentage of epithelial cells expressing Ki-67, or Ki-67 index, is progressively Cancer Epidemiol Biomarkers Prev 2007;16(11). November 2007 Received 3/21/07; revised 7/13/07; accepted 8/21/07. Grant support: Specialized Program of Research Excellence in Lung Cancer (P50CA58187), Early Disease Research Network, Lung Cancer Biomarkers Chemoprevention Consortium, Cancer Center Support Grant (P30CA46934), Department of Veterans Affairs Career Development, and Merit Review Grants. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Requests for reprints: York E. Miller, Department of Medicine, University of Colorado, Pulmonary 111A, Denver Veterans Affairs Medical Center, 1055 Clermont Street, Denver, CO 80220. Phone: 303-393-2869; Fax: 303-393-4639. E-mail: york.miller@uchsc.edu Copyright D 2007 American Association for Cancer Research. doi:10.1158/1055-9965.EPI-07-0220 2425 Downloaded from http://aacrjournals.org/cebp/article-pdf/16/11/2425/2265031/2425.pdf by guest on 19 June 2022