Junya Fujimoto1, Humam Kadara2, Melinda M Garcia2, Mohamed Kabbout2, Carmen Behrens2, Diane D Liu3, J Jack Lee3, Luisa M Solis4, Edward S Kim2, Neda Kalhor4, Cesar Moran4, Amir Sharafkhaneh5, Reuben Lotan6, Ignacio I Wistuba7. 1. Department of Thoracic/Head and Neck Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas. Electronic address: jfujimot@mdanderson.org. 2. Department of Thoracic/Head and Neck Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas. 3. Department of Biostatistics and Applied Mathematics, University of Texas M.D. Anderson Cancer Center, Houston, Texas. 4. Department of Pathology, University of Texas M.D. Anderson Cancer Center, Houston, Texas. 5. Department of Medicine, Section of Pulmonary, Critical Care and Sleep Medicine, Baylor College of Medicine, Houston, Texas. 6. Department of Thoracic/Head and Neck Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas; Deceased. 7. Department of Thoracic/Head and Neck Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas; Department of Pathology, University of Texas M.D. Anderson Cancer Center, Houston, Texas.
Abstract
INTRODUCTION: Understanding oncogenes and tumor suppressor genes expression patterns is essential for characterizing lung cancer pathogenesis. We have previously demonstrated that mGprc5a/hGPRC5A is a lung-specific tumor suppressor evidenced by inflammation-mediated tumorigenesis in Gprc5a-knockout mice. The implication of GPRC5A in human lung cancer pathogenesis, including that associated with inflammatory chronic obstructive pulmonary disease (COPD), a risk factor for the malignancy, remains elusive. METHODS: We sought to examine GPRC5A immunohistochemical expression in histologically normal bronchial epithelia (NBE) from lung disease-free never- and ever-smokers (n = 13 and n = 18, respectively), from COPD patients with (n = 26) and without cancer (n = 24) and in non-small cell lung cancers (NSCLCs) (n = 474). Quantitative assessment of GPRC5A transcript expression in airways (n = 6), adjacent NBEs (n = 29) and corresponding tumors (n = 6) from 6 NSCLC patients was also performed. RESULTS: GPRC5A immunohistochemical expression was significantly lower in tumors compared to uninvolved NBE (p < 0.0001) and was positively associated with adenocarcinoma histology (p < 0.001). GPRC5A airway expression was highest in lung disease-free NBE, decreased and intermediate in NBE of cancer-free COPD patients (p = 0.004) and further attenuated and lowest in epithelia of COPD patients with adenocarcinoma and SCC (p < 0.0001). Furthermore, GPRC5A mRNA was significantly decreased in NSCLCs and corre sponding NBE compared to uninvolved normal lung (p = 0.03). CONCLUSIONS: Our findings highlight decreased GPRC5A expression in the field cancerization of NSCLC, including that associated with lung inflammation. Assessment of the use of GPRC5A expression as a risk factor for NSCLC development in COPD patients is warranted.
INTRODUCTION: Understanding oncogenes and tumor suppressor genes expression patterns is essential for characterizing lung cancer pathogenesis. We have previously demonstrated that mGprc5a/hGPRC5A is a lung-specific tumor suppressor evidenced by inflammation-mediated tumorigenesis in Gprc5a-knockout mice. The implication of GPRC5A in humanlung cancer pathogenesis, including that associated with inflammatory chronic obstructive pulmonary disease (COPD), a risk factor for the malignancy, remains elusive. METHODS: We sought to examine GPRC5A immunohistochemical expression in histologically normal bronchial epithelia (NBE) from lung disease-free never- and ever-smokers (n = 13 and n = 18, respectively), from COPDpatients with (n = 26) and without cancer (n = 24) and in non-small cell lung cancers (NSCLCs) (n = 474). Quantitative assessment of GPRC5A transcript expression in airways (n = 6), adjacent NBEs (n = 29) and corresponding tumors (n = 6) from 6 NSCLCpatients was also performed. RESULTS:GPRC5A immunohistochemical expression was significantly lower in tumors compared to uninvolved NBE (p < 0.0001) and was positively associated with adenocarcinoma histology (p < 0.001). GPRC5A airway expression was highest in lung disease-free NBE, decreased and intermediate in NBE of cancer-free COPDpatients (p = 0.004) and further attenuated and lowest in epithelia of COPDpatients with adenocarcinoma and SCC (p < 0.0001). Furthermore, GPRC5A mRNA was significantly decreased in NSCLCs and corre sponding NBE compared to uninvolved normal lung (p = 0.03). CONCLUSIONS: Our findings highlight decreased GPRC5A expression in the field cancerization of NSCLC, including that associated with lung inflammation. Assessment of the use of GPRC5A expression as a risk factor for NSCLC development in COPDpatients is warranted.
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