C-X-C motif receptor 2, endostatin and proteinase-activated receptor 1 polymorphisms as prognostic factors in NSCLC

• Published in: Lung cancer (Amsterdam, Netherlands) Vol. 81; no. 1; pp. 123 - 129
• Main Authors: Uzunoglu, Faik Güntac, Yavari, Neda, Bohn, Benjamin Alexander, Nentwich, Michael Fabian, Reeh, Matthias, Pantel, Klaus, Perez, Daniel, Tsui, Tung Yu, Bockhorn, Maximilian, Mann, Oliver, Izbicki, Jakob Robert, Wikman, Harriet, Vashist, Yogesh Kumar
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ireland Ltd 01.07.2013; Elsevier
• Subjects: Adult; Aged; Aged, 80 and over; Angiogenesis; Biological and medical sciences; Biomarkers, Tumor - genetics; C-X-C motif receptor 2; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - mortality; Carcinoma, Non-Small-Cell Lung - surgery; Carcinoma, Squamous Cell - genetics; Carcinoma, Squamous Cell - mortality; Carcinoma, Squamous Cell - surgery; Cohort Studies; Disease-Free Survival; Endostatin; Endostatins - genetics; Female; Hematology, Oncology and Palliative Medicine; Humans; Kaplan-Meier Estimate; Lung cancer; Lung Neoplasms - genetics; Lung Neoplasms - mortality; Lung Neoplasms - surgery; Male; Medical sciences; Middle Aged; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Pneumology; Polymorphism, Single Nucleotide; Polymorphisms; Prognosis; Proportional Hazards Models; Proteinase-activated receptor 1; Pulmonary/Respiratory; Receptor, PAR-1 - genetics; Receptors, Interleukin-8B - genetics; Retrospective Studies; Survival; Tumors; Tumors of the respiratory system and mediastinum; Angiogenesis; C-X-C motif receptor 2; Lung cancer; Endostatin; Proteinase-activated receptor 1; Polymorphisms; Survival; Lung disease; Prognosis; Enzyme; Respiratory disease; Malignant tumor; Peptidases; Hydrolases; Bronchus disease; Cancer; Non small cell carcinoma; Polymorphism; Biological receptor
• ISSN: 0169-5002; 1872-8332
• DOI: 10.1016/j.lungcan.2013.03.007

Abstract The progress of non-small cell lung cancer (NSCLC) is dependent on sufficient angiogenesis. Thrombin induced activation of proteinase-activated receptor 1 ( PAR-1 ) on platelets leads to platelet secretion and aggregation. This influences cell survival, apoptosis and angiogenesis by the release of VEGF and Endostatin (ES), a potent angiogenesis inhibitor. Interleukin-8 ( IL-8 ) induces tumor angiogenesis independent of the VEGF pathway through the chemokine C-X-C motif receptor 2 (CXCR-2). Our purpose was to evaluate germline polymorphisms of these potential therapy targets as prognostic markers for disease free survival (DFS) and overall survival (OS) in surgically treated NSCLC patients. In total 209 Caucasian patients, treated between 1996 and 2011, were included in this study. Genomic DNA was extracted from peripheral blood leucocytes. Genotyping of CXCR-2 +1208 C>T and +785 C>T, PAR-1 -506 Ins/del and -14 Ivs A>T and ES +4349 G>A was performed by TaqMan® genotyping assays or by polymerase chain reaction (PCR) followed by capillary electrophoresis. Chi-square test, Kaplan–Meier estimator and cox regression hazard model were used to assess the prognostic value of selected polymorphisms. The PAR-1 -14 Ivs A/A genotype was associated with advanced tumor stages ( p = 0.024) and, in univariate analysis, with shorter median OS in squamous cell lung carcinoma (SqCC, p = 0.035). The CXCR-2 +1208 T/T genotype was associated with aggressive tumor biology ( p = 0.038), and shorter DFS and OS ( p = 0.018, p = 0.021) in NSCLC and especially in SqCC a negative predictor for DFS and OS ( p = 0.045, p = 0.041). Genotyping of the CXCR-2 +1208 C>T polymorphism could be a useful tool to identify high-risk SqCC subgroups.