Carlos Camps1,2,3,4,5, Eloísa Jantus-Lewintre6,7,8,9, Alejandro Herreros-Pomares10,11, Paula Doria12, Sandra Gallach1,2,3, Marina Meri-Abad4, Ricardo Guijarro1,3,13,14, Silvia Calabuig-Fariñas1,2,3,15. 1. Centro de Investigación Biomédica en Red Cáncer, CIBERONC, Madrid, Spain. 2. Molecular Oncology Laboratory, Fundación Investigación Hospital General Universitario de Valencia, Valencia, Spain. 3. TRIAL Mixed Unit, Centro de Investigación Príncipe Felipe-Fundación Investigación del Hospital General Universitario de Valencia, Valencia, Spain. 4. Department of Medical Oncology, Hospital General Universitario de Valencia, Valencia, Spain. 5. Department of Medicine, Universitat de València, Valencia, Spain. 6. Department of Biotechnology, Universitat Politècnica de València, Valencia, Spain. jantus_elo@gva.es. 7. Centro de Investigación Biomédica en Red Cáncer, CIBERONC, Madrid, Spain. jantus_elo@gva.es. 8. Molecular Oncology Laboratory, Fundación Investigación Hospital General Universitario de Valencia, Valencia, Spain. jantus_elo@gva.es. 9. TRIAL Mixed Unit, Centro de Investigación Príncipe Felipe-Fundación Investigación del Hospital General Universitario de Valencia, Valencia, Spain. jantus_elo@gva.es. 10. Department of Biotechnology, Universitat Politècnica de València, Valencia, Spain. herreros_ale@gva.es. 11. Centro de Investigación Biomédica en Red Cáncer, CIBERONC, Madrid, Spain. herreros_ale@gva.es. 12. Persona Biomed Spain S.L., Valencia, Spain. 13. Department of Surgery, Universitat de València, Valencia, Spain. 14. Department of Thoracic Surgery, Hospital General Universitario de Valencia, Valencia, Spain. 15. Department of Pathology, Universitat de València, Valencia, Spain.
Abstract
BACKGROUND: Mutations and deregulations in components of the Hedgehog (Hh) pathway have been associated with cancer onset and tumor growth in different malignancies, but their role in non-small cell lung cancer (NSCLC) remains unclear. This study aims to investigate the expression pattern of the main components of the Hh pathway in tumor and adjacent normal tissue biopsies of resected NSCLC patients. METHODS: The relative expression of GLI1, PTCH1, SHH, and SMO was analyzed by quantitative polymerase chain reaction (PCR) in a cohort of 245 NSCLC patients. Results were validated in an independent cohort of NSCLC patients from The Cancer Genome Atlas (TCGA). RESULTS: We found that SMO and GLI1 were overexpressed in the tumor compared with normal-paired tissue, whereas PTCH1 and SHH were underexpressed. In addition, patients with higher expression levels of PTCH1 presented better outcomes. A gene expression score, called the Hedgehog Score, was calculated using a multivariable model including analyzed components of the Hh signaling pathway. NSCLC patients with a high Hedgehog Score had significantly shorter relapse-free survival (RFS) and overall survival (OS) than patients with a low score, especially at stage I of the disease. Similarly, patients in the adenocarcinoma (ADC) subcohort had shorter RFS and OS. Multivariate Cox analysis exhibited that the Hedgehog Score is an independent prognostic biomarker for OS in both the entire training cohort and the ADC subcohort. The Hedgehog Score was validated in an independent cohort of NSCLC patients from TCGA, which confirmed its prognostic value. CONCLUSIONS: Our results provide relevant prognostic data for NSCLC patients and support further studies on the Hh pathway.
BACKGROUND: Mutations and deregulations in components of the Hedgehog (Hh) pathway have been associated with cancer onset and tumor growth in different malignancies, but their role in non-small cell lung cancer (NSCLC) remains unclear. This study aims to investigate the expression pattern of the main components of the Hh pathway in tumor and adjacent normal tissue biopsies of resected NSCLC patients. METHODS: The relative expression of GLI1, PTCH1, SHH, and SMO was analyzed by quantitative polymerase chain reaction (PCR) in a cohort of 245 NSCLC patients. Results were validated in an independent cohort of NSCLC patients from The Cancer Genome Atlas (TCGA). RESULTS: We found that SMO and GLI1 were overexpressed in the tumor compared with normal-paired tissue, whereas PTCH1 and SHH were underexpressed. In addition, patients with higher expression levels of PTCH1 presented better outcomes. A gene expression score, called the Hedgehog Score, was calculated using a multivariable model including analyzed components of the Hh signaling pathway. NSCLC patients with a high Hedgehog Score had significantly shorter relapse-free survival (RFS) and overall survival (OS) than patients with a low score, especially at stage I of the disease. Similarly, patients in the adenocarcinoma (ADC) subcohort had shorter RFS and OS. Multivariate Cox analysis exhibited that the Hedgehog Score is an independent prognostic biomarker for OS in both the entire training cohort and the ADC subcohort. The Hedgehog Score was validated in an independent cohort of NSCLC patients from TCGA, which confirmed its prognostic value. CONCLUSIONS: Our results provide relevant prognostic data for NSCLC patients and support further studies on the Hh pathway.
Authors: Tien Peng; David B Frank; Rachel S Kadzik; Michael P Morley; Komal S Rathi; Tao Wang; Su Zhou; Lan Cheng; Min Min Lu; Edward E Morrisey Journal: Nature Date: 2015-10-05 Impact factor: 49.962