Cancer 2011 Nov;117 (21): 4925-38. [IF:5.131]
Genetic amplification of the vascular endothelial growth factor (VEGF) pathway genes, including VEGFA, in human osteosarcoma.
Yang J , Yang D , Sun Y , Sun B , Wang G , Trent JC , Araujo DM , Chen K , Zhang W .
Department of Bone and Soft Tissue Tumor, Tianjin Medical University Cancer Hospital and Institute, Tianjin, China.
天津医科大学附属肿瘤医院
Abstract
Osteosarcoma is the most common primary tumor of bone. It is a highly vascular and extremely destructive malignancy that mainly affects children and young adults. The authors conducted microarray-based comparative genomic hybridization (aCGH) and pathway analyses to gain a systemic view of pathway alterations in the genetically altered genes. Recurrent amplified and deleted genes that were detected by aCGH were subjected to an analysis based on the Kyoto Encyclopedia of Genes and Genomes to identify the altered pathways. Among the enriched pathways, vascular endothelial growth factor (VEGF) pathway genes collectively were amplified, and alterations of this pathway were validated by fluorescence in situ hybridization (FISH) and immunohistochemistry analyses in 58 formalin-fixed, paraffin-embedded osteosarcoma archival tissues that had clinical follow-up information. The pathway enrichment analyses of the aCGH data revealed that VEGF pathway genes, including the VEGFA gene itself, were amplified significantly in osteosarcoma. Genetic amplification of the VEGFA gene, both focally and in larger fragment, was validated by FISH analysis. It is noteworthy that amplification of the VEGFA gene and elevated expression of the VEGFA protein were associated significantly with microvascular density and adverse tumor-free survival in patients with osteosarcoma. The authors report for the first time that VEGF pathway genes, including the VEGFA gene, are amplified in osteosarcoma. Amplification of the VEGFA gene is not only an important mechanism for elevated VEGFA protein expression but also is a poor prognostic factor for tumor-free survival. Combined classification of VEGFA gene amplification and positive VEGFA protein expression may provide a more accurate stratification method of selecting anti-VEGF therapy for patients with osteosarcoma.
摘要
骨肉瘤是最常见的原发性骨肿瘤。它是一种富含血管的、具有极大破坏性的恶性肿瘤，主要多发于儿童和年轻成人。作者进行基于基因芯片的比较基因组杂交（aCGH）和（信号）通路分析，获得了基因改变中的通路改变的系统性的认识对aCGH检测到的周期性扩增和删除的基因进行了基于京都基因与基因组的分析，以确定改变的通路。在增强的通路中，血管内皮生长因子（VEGF）通路基因的表达集中增强，并且通路的这种改变被附带临床随访资料的58福尔马林固定、石蜡包埋的骨肉瘤存档组织的荧光原位杂交（FISH）和免疫组化分析结果证实 。aCGH数据的通路增强分析显示，VEGF通路的基因，包括VEGFA基因本身，在骨肉瘤中扩增显著。 FISH分析验证了局灶性及大片段的VEGFA基因的扩增。值得注意的是，VEGFA基因扩增和VEGFA蛋白质表达升高与微血管密度和骨肉瘤患者的无瘤生存显著相关。作者首次报道了VEGF通路的基因包括VEGFA基因在骨肉瘤中扩增。 VEGFA基因扩增不仅是VEGFA蛋白表达升高的重要机制，也是无瘤生存的一个不良的预后因素。VEGFA基因扩增的综合分类和VEGFA蛋白表达阳性可为骨肉瘤患者的抗VEGF治疗的选择提供更准确的分层方法。
