The first 2 authors contributed equally to this article.
Genetic amplification of the vascular endothelial growth factor (VEGF) pathway genes, including VEGFA, in human osteosarcoma†
Version of Record online: 14 APR 2011
Copyright © 2011 American Cancer Society
Volume 117, Issue 21, pages 4925–4938, 1 November 2011
How to Cite
Yang, J., Yang, D., Sun, Y., Sun, B., Wang, G., Trent, J. C., Araujo, D. M., Chen, K. and Zhang, W. (2011), Genetic amplification of the vascular endothelial growth factor (VEGF) pathway genes, including VEGFA, in human osteosarcoma. Cancer, 117: 4925–4938. doi: 10.1002/cncr.26116
We thank Limei Hu and David Cogdell for performing the array comparative genomic hybridization experiments and Haixin Li and Jin Zhang for assisting with clinical data analysis. We thank Ms. Tamara Locke from the Department of Scientific Publication at The University of Texas MD Anderson Cancer Center for editing this article. We also thank Dr. Xishan Hao for his support of this project.
- Issue online: 19 OCT 2011
- Version of Record online: 14 APR 2011
- Manuscript Accepted: 16 FEB 2011
- Manuscript Revised: 2 FEB 2011
- Manuscript Received: 11 DEC 2010
- vascular endothelial growth factor A;
- gene amplification;
- fluorescent in situ hybridization;
- microarray-based comparative genomic hybridization
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. Cancer 2011;. © 2011 American Cancer Society.