Abstract 2203: Implication of GPRC5A loss in lung carcinogenesis in patients with and without chronic obstructive pulmonary disease
Authors: Fujimoto Junya , Kadara Humam , Behrens Carmen , Liu Diane , Lee J Jack , Solis Luisa M. , Kim Edward , Sharafkhaneh Amir , Wistuba Ignacio I. , Reuben Lotan 
Published: June 2012

Abstract
Lung cancer is often associated with inflammation induced by cigarette smoke. In addition, chronic obstructive pulmonary disease (COPD), typically associated with inflammation, is a leading cause of morbidity and mortality in the United States and presents an increased risk of lung cancer development compared to patients without COPD. Mice with knockout of both alleles of the G-protein coupled receptor, family C, group 5, member A (Gprc5a) gene develop spontaneous lung adenomas and adenocarcinomas at a much higher incidence than their wild-type littermates, indicating that this gene is a novel lung-specific tumor suppressor gene. Interestingly, the majority of tumors in the Gprc5a knockout mice are associated with inflammatory cell infiltration, possibly due to increased NF-κB activation in mouse lung epithelial cells and tissues. Furthermore, the human GPRC5A can suppress NF-κB activation in human lung adenocarcinoma cells. Therefore, in the present study we investigated the expression patterns of GPRC5A in clinical specimens, including normal bronchial epithelia (NBE) of COPD patients with and without overt lung cancer as well as in non-small cell lung cancer (NSCLC) tumors by immunohistochemical (IHC) analysis. We performed IHC analysis of a tissue microarray (TMA) comprised of 311 lung adenocarcinomas and 166 squamous cell carcinomas (SCCs), as well as of normal bronchial epithelial specimens from 50 patients with COPD, which included 24 cancer-free cases and 26 cases with NSCLC (12, adenocarcinoma; 12, SCC; 2, bronchioalveolar carcinoma). Kruskal-Wallis test was used to compare GPRC5A levels among histology levels. All statistical tests were two-sided, and p values of 0.05 or less were considered to be statistically significant. Cytoplasmic GPRC5A expression was significantly higher in lung adenocarcinomas compared to SCCs (p&lt;0.001). Moreover, GPRC5A expression exhibited a positive correlation with never-smoking status (p=0.005). Interestingly, we noted a statistically significant inverse correlation between the expression of GPRC5A and that of NF-κB (p&lt;0.001), which we had previously found to be activated and elevated following loss of the GPRC5A tumor suppressor. Furthermore, analysis of two NBE obtained from each of 50 COPD patients demonstrated statistically significant decreased expression of GPRC5A in NBE of COPD patients with NSCLC compared to NBE from NSCLC-free COPD patients (p&lt;0.001). Our findings demonstrate that decreased GPRC5A expression may be associated with development of lung malignancies, especially in individuals with chronic lung inflammation, and pinpoints GPRC5A's potential suppressive effects on a lung tumor-promoting microenvironment. Assessment of GPRC5A's potential use as a risk factor for NSCLC development in COPD patients is warranted. Supported by the Samuel Waxman Cancer Research Foundation and by W81XWH-04-1-0142.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2203. doi:10.1158/1538-7445.AM2011-2203