Department of General, Visceral and Thoracic Surgery, University Medical Center of Hamburg-Eppendorf, Germany.
Lung Cancer. 2013 Jul;81(1):123-9. doi: 10.1016/j.lungcan.2013.03.007. Epub 2013 Mar 30.
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.
非小细胞肺癌（NSCLC）的进展取决于充足的血管生成。凝血酶诱导血小板上蛋白酶激活受体 1（PAR-1）的激活导致血小板分泌和聚集。这通过释放血管内皮生长因子（VEGF）和内皮抑素（ES）来影响细胞存活、凋亡和血管生成，ES 是一种有效的血管生成抑制剂。白细胞介素-8（IL-8）通过趋化因子 C-X-C 基序受体 2（CXCR-2）独立于 VEGF 途径诱导肿瘤血管生成。我们的目的是评估这些潜在治疗靶点的种系多态性作为手术治疗的 NSCLC 患者无病生存（DFS）和总生存（OS）的预后标志物。本研究共纳入 209 例白种人患者，于 1996 年至 2011 年期间接受治疗。从外周血白细胞中提取基因组 DNA。通过 TaqMan(®)基因分型检测或聚合酶链反应（PCR）后毛细管电泳，对 CXCR-2+1208C>T 和+785C>T、PAR-1-506Ins/del 和-14IvsA>T 和 ES+4349G>A 进行基因分型。卡方检验、Kaplan-Meier 估计器和 Cox 回归风险模型用于评估所选多态性的预后价值。PAR-1-14IvsA/A 基因型与晚期肿瘤分期相关（p=0.024），在单因素分析中，与鳞状细胞肺癌（SqCC）的中位 OS 较短相关（p=0.035）。CXCR-2+1208T/T 基因型与侵袭性肿瘤生物学相关（p=0.038），并且在 NSCLC 中，DFS 和 OS 较短（p=0.018，p=0.021），尤其是在 SqCC 中，DFS 和 OS 的阴性预测因子（p=0.045，p=0.041）。CXCR-2+1208C>T 多态性的基因分型可能是识别高风险 SqCC 亚组的有用工具。
