title: C-X-C motif receptor 2, endostatin and proteinase-activated receptor 1 polymorphisms as prognostic factors in NSCLC.
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 + 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.
authors.affiliation: Department of General, Visceral and Thoracic Surgery, University Medical Center of Hamburg-Eppendorf, Germany.
authors.forename: Faik Güntac
authors.initials: FG
authors.lastname: Uzunoglu
authors.forename: Neda
authors.initials: N
authors.lastname: Yavari
authors.forename: Benjamin Alexander
authors.initials: BA
authors.lastname: Bohn
authors.forename: Michael Fabian
authors.initials: MF
authors.lastname: Nentwich
authors.forename: Matthias
authors.initials: M
authors.lastname: Reeh
authors.forename: Klaus
authors.initials: K
authors.lastname: Pantel
authors.forename: Daniel
authors.initials: D
authors.lastname: Perez
authors.forename: Tung Yu
authors.initials: TY
authors.lastname: Tsui
authors.forename: Maximilian
authors.initials: M
authors.lastname: Bockhorn
authors.forename: Oliver
authors.initials: O
authors.lastname: Mann
authors.forename: Jakob Robert
authors.initials: JR
authors.lastname: Izbicki
authors.forename: Harriet
authors.initials: H
authors.lastname: Wikman
authors.forename: Yogesh Kumar
authors.initials: YK
authors.lastname: Vashist
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000401:mortality / Q000601:surgery; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000401:mortality / Q000601:surgery; D015331:Cohort Studies; D018572:Disease-Free Survival; D043169:Endostatins / Q000235:genetics*; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000235:genetics* / Q000401:mortality / Q000601:surgery; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D016016:Proportional Hazards Models; D044463:Receptor, PAR-1 / Q000235:genetics*; D023063:Receptors, Interleukin-8B / Q000235:genetics*; D012189:Retrospective Studies
chemical_list: D014408:Biomarkers, Tumor; D043169:Endostatins; D044463:Receptor, PAR-1; D023063:Receptors, Interleukin-8B