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

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 + 1208T/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.