Mathewos Tessema1, Dereje D Tassew2, Christin M Yingling3, Kieu Do3, Maria A Picchi3, Guodong Wu3, Hans Petersen4, Scott Randell5, Yong Lin3, Steven A Belinsky3, Yohannes Tesfaigzi6. 1. Lung Cancer Program, Lovelace Respiratory Research Institute, Albuquerque, M, USA. Electronic address: mtessema@LRRI.org. 2. COPD Program, Lovelace Respiratory Research Institute, Albuquerque, NM, USA; Currently, Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, MA, USA. 3. Lung Cancer Program, Lovelace Respiratory Research Institute, Albuquerque, M, USA. 4. COPD Program, Lovelace Respiratory Research Institute, Albuquerque, NM, USA. 5. Department of Cell and Molecular Physiology, The University of North Carolina, Chapel Hill, NC, USA. 6. COPD Program, Lovelace Respiratory Research Institute, Albuquerque, NM, USA; Currently, Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, MA, USA. Electronic address: ytesfaigzi@bwh.harvard.edu.
Abstract
OBJECTIVES: Smoking is a common risk factor for chronic obstructive pulmonary disease (COPD) and lung cancer. Although COPD patients have higher risk of lung cancer compared to non-COPD smokers, the molecular links between these diseases are not well-defined. This study aims to identify genes that are downregulated by cigarette smoke and commonly repressed in COPD and lung cancer. MATERIALS AND METHODS: Primary human airway epithelial cells (HAEC) were exposed to cigarette-smoke-extract (CSE) for 10-weeks and significantly suppressed genes were identified by transcriptome array. Epigenetic abnormalities of these genes in lung adenocarcinoma (LUAD) from patients with or without COPD were determined using genome-wide and gene-specific assays and by in vitro treatment of cell lines with trichostatin-A or 5-aza-2-deoxycytidine. RESULTS: The ten most commonly downregulated genes following chronic CSE exposure of HAEC and show promoter hypermethylation in LUAD were selected. Among these, expression of CCNA1, SNCA, and ZNF549 was significantly reduced in lung tissues from COPD compared with non-COPD cases while expression of CCNA1 and SNCA was further downregulated in tumors with COPD. The promoter regions of all three genes were hypermethylated in LUAD but not normal or COPD lungs. The reduced expression and aberrant promoter hypermethylation of these genes in LUAD were independently validated using data from the Cancer Genome Atlas project. Importantly, SNCA and ZNF549 methylation detected in sputum DNA from LUAD (52% and 38%) cases were more prevalent compared to cancer-free smokers (26% and 15%), respectively (p < 0.02). CONCLUSIONS: Our data show that suppression of CCNA1, SNCA, and ZNF549 in lung cancer and COPD occurs with or without promoter hypermethylation, respectively. Detecting methylation of these and previously identified genes in sputum of cancer-free smokers may serve as non-invasive biomarkers for early detection of lung cancer among high risk smokers including COPD patients.
OBJECTIVES: Smoking is a common risk factor for chronic obstructive pulmonary disease (COPD) and lung cancer. Although COPD patients have higher risk of lung cancer compared to non-COPD smokers, the molecular links between these diseases are not well-defined. This study aims to identify genes that are downregulated by cigarette smoke and commonly repressed in COPD and lung cancer. MATERIALS AND METHODS: Primary human airway epithelial cells (HAEC) were exposed to cigarette-smoke-extract (CSE) for 10-weeks and significantly suppressed genes were identified by transcriptome array. Epigenetic abnormalities of these genes in lung adenocarcinoma (LUAD) from patients with or without COPD were determined using genome-wide and gene-specific assays and by in vitro treatment of cell lines with trichostatin-A or 5-aza-2-deoxycytidine. RESULTS: The ten most commonly downregulated genes following chronic CSE exposure of HAEC and show promoter hypermethylation in LUAD were selected. Among these, expression of CCNA1, SNCA, and ZNF549 was significantly reduced in lung tissues from COPD compared with non-COPD cases while expression of CCNA1 and SNCA was further downregulated in tumors with COPD. The promoter regions of all three genes were hypermethylated in LUAD but not normal or COPD lungs. The reduced expression and aberrant promoter hypermethylation of these genes in LUAD were independently validated using data from the Cancer Genome Atlas project. Importantly, SNCA and ZNF549 methylation detected in sputum DNA from LUAD (52% and 38%) cases were more prevalent compared to cancer-free smokers (26% and 15%), respectively (p < 0.02). CONCLUSIONS: Our data show that suppression of CCNA1, SNCA, and ZNF549 in lung cancer and COPD occurs with or without promoter hypermethylation, respectively. Detecting methylation of these and previously identified genes in sputum of cancer-free smokers may serve as non-invasive biomarkers for early detection of lung cancer among high risk smokers including COPD patients.
Authors: Shuguang Leng; Christine A Stidley; Randy Willink; Amanda Bernauer; Kieu Do; Maria A Picchi; Xin Sheng; Melissa A Frasco; David Van Den Berg; Frank D Gilliland; Christopher Zima; Richard E Crowell; Steven A Belinsky Journal: Cancer Res Date: 2008-04-15 Impact factor: 12.701
Authors: Mathewos Tessema; Christin M Yingling; Yushi Liu; Carmen S Tellez; Leander Van Neste; Stephen S Baylin; Steven A Belinsky Journal: Carcinogenesis Date: 2014-01-07 Impact factor: 4.944
Authors: Ruben D Ramirez; Shelley Sheridan; Luc Girard; Mitsuo Sato; Young Kim; Jon Pollack; Michael Peyton; Ying Zou; Jonathan M Kurie; J Michael Dimaio; Sara Milchgrub; Alice L Smith; Rhonda F Souza; Laura Gilbey; Xi Zhang; Kenia Gandia; Melville B Vaughan; Woodring E Wright; Adi F Gazdar; Jerry W Shay; John D Minna Journal: Cancer Res Date: 2004-12-15 Impact factor: 12.701
Authors: Shuguang Leng; Kieu Do; Christin M Yingling; Maria A Picchi; Holly J Wolf; Timothy C Kennedy; William J Feser; Anna E Baron; Wilbur A Franklin; Malcolm V Brock; James G Herman; Stephen B Baylin; Tim Byers; Christine A Stidley; Steven A Belinsky Journal: Clin Cancer Res Date: 2012-04-17 Impact factor: 12.531
Authors: Leah A Damiani; Christin M Yingling; Shuguang Leng; Paul E Romo; Jun Nakamura; Steven A Belinsky Journal: Cancer Res Date: 2008-11-01 Impact factor: 12.701
Authors: David S Shames; Luc Girard; Boning Gao; Mitsuo Sato; Cheryl M Lewis; Narayan Shivapurkar; Aixiang Jiang; Charles M Perou; Young H Kim; Jonathan R Pollack; Kwun M Fong; Chi-Leung Lam; Maria Wong; Yu Shyr; Rita Nanda; Olufunmilayo I Olopade; William Gerald; David M Euhus; Jerry W Shay; Adi F Gazdar; John D Minna Journal: PLoS Med Date: 2006-12 Impact factor: 11.069