Absence of VHL gene alteration and high VEGF expression are associated with tumour aggressiveness and poor survival of renal-cell carcinoma.
Absence of VHL gene alteration and high VEGF expression are associated with tumour aggressiveness and poor survival of renal-cell carcinoma.
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VHL 基因改变的缺失和 VEGF 的高表达与肾细胞癌的肿瘤侵袭性和较差的生存率相关。
DOI：
10.1038/sj.bjc.6605298
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发表时间：
2009-10-20
影响因子：
8.8
通讯作者：
中科院分区：
文献类型：
--
作者：
von Hippel-Lindau基因（VHL）改变是散发性透明细胞肾细胞癌（CCRCC）的常见事件，可导致高度血管化的肿瘤。血管内皮生长因子（VEGF）是参与血管生成的主要因子，但VHL失活和VEGF表达的预后意义仍存在争议。本研究的目的是分析VHL基因和表观遗传学改变，VHL表达和VEGF肿瘤或血浆表达之间的关系，并分析其各自的预后价值与CCRCC患者。共对102例CCRCC患者进行了前瞻性分析。通过测序、多重连接依赖性探针扩增（MLPA）和甲基化特异性MLPA确定VHL的改变。免疫组化法检测pVHL和VEGF的表达。采用酶联免疫吸附法（ELISA）测定血浆VEGF水平。VHL基因突变70例，缺失76例，启动子区甲基化14例。总的来说，至少有一个VHL基因变异发生在91例（89.2%）。VEGF肿瘤和血浆表达似乎在VHL改变的情况下降低。中位无进展生存期和CCRCC特异性生存期在野生型VHL或改变的VHL和高VEGF表达的患者中显著降低，因此，这代表了CCRCC中肿瘤侵袭性的两个标志物。根据VHL和VEGF状态对CCRCC进行分层可能有助于定制治疗策略。
The von Hippel–Lindau gene (VHL) alteration, a common event in sporadic clear-cell renal-cell carcinoma (CCRCC), leads to highly vascularised tumours. Vascular endothelial growth factor (VEGF) is the major factor involved in angiogenesis, but the prognostic significance of both VHL inactivation and VEGF expression remain controversial. The aims of this study were to analyse the relationship between VHL genetic and epigenetic alterations, VHL expression and VEGF tumour or plasma expression, and to analyse their respective prognostic value in patients with CCRCC. A total of 102 patients with CCRCC were prospectively analysed. Alterations in VHL were determined by sequencing, Multiplex Ligation-dependent Probe Amplification (MLPA) and methylation-specific MLPA. Expression of pVHL and VEGF was determined by immunohistochemistry. Plasma VEGF was measured by enzyme-linked immunosorbent assay (ELISA). VHL mutation, deletion and promoter methylation were identified in 70, 76 and 14 cases, respectively. Overall, at least one VHL-gene alteration occurred in 91 cases (89.2%). Both VEGF tumour and plasma expression appeared to be decreased in case of VHL alteration. Median progression-free survival and CCRCC-specific survival were significantly reduced in patients with wild-type VHL or altered VHL and high VEGF expression, which, therefore, represent two markers of tumour aggressiveness in CCRCC. Stratifying CCRCCs according to VHL and VEGF status may help tailor therapeutic strategy.
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