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Genetic amplification of the vascular endothelial growth factor (VEGF) pathway genes, including VEGFA, in human osteosarcom

2011-11-01 22:16:05

Cancer; 2011 Nov; 117(27):4925-38


Jilong Yang, Da Yang, Yan Sun, Baocun Sun, Guowen Wang, Jonathan C. Trent, Dejka M. Araujo, Kexin Chen, and
Wei Zhang



Abstract



BACKGROUND:



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.



METHODS:



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.



RESULTS:



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.



CONCLUSIONS:



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.



Introduction



Osteosarcoma is the most common primary tumor of bone and affects approximately 1500 individuals per year in the United States (Surveillance, Epidemiology, and End Results database, National Cancer Institute). According to the latest statistics of Tianjin Cancer Registry Center in 2006, in Tianjin, the third largest city of China, there were 56 patients with osteosarcoma among the population of 9488,900. Osteosarcoma affects primarily those in the second decade of life, and the incidence has a steady, gradual decrease thereafter. Because survival rates in patients with metastatic osteosarcoma have not improved significantly in recent years, identifying the key genetic and molecular events in the development of osteosarcoma is critical to the development of effective therapeutics. Increased vascular endothelial growth factor A (VEGFA) expression has been associated with osteosarcoma development and metastasis. Furthermore, inhibition of VEGF signaling has resulted in the suppression of both tumor-induced angiogenesis and tumor growth. Several preclinical and clinical studies have provided evidence that antiangiogenic therapies, such as antibodies and small-molecule inhibitors against the VEGF-VEGF receptor (VEGFR) axis, are promising strategies in the treatment of osteosarcoma. Several transcriptional factors, including hypoxia-inducible factor 1, alpha subunit (HIF-1A) and retinoblastoma 1 (RB1), have reportedly activate VEGF expression and angiogenesis in cancer cells. However, although numerous studies have reported chromosomal and gene aberrations in human osteosarcoma, to our knowledge, no genetic aberrations of the VEGF pathway have been reported in this tumor type. In the current study, we interrogated genome-wide, microarray-based comparative genomic hybridization (aCGH) profiling data on osteosarcoma by using pathway analysis and observed that VEGF pathway genes, including VEGFA, were amplified. We also investigated the clinical significance of VEGFA gene amplification in osteosarcoma.



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