Two recent studies published in the Journal of the American Medical Association (JAMA) in July 2009 have revealed promising results in the ongoing fight against brain cancer. Studies led by investigators at the Northwestern Brain Tumor Institute have demonstrated that networks of altered genes work together cooperatively to drive GBM development and progression.
These published results have potential significance in two major clinical ways. First, the development of new therapeutics will need to consider the powerful influence of the interactions between genes and their expression. Secondly, understanding how the interactions of genes affects survival may offer a prognostic tool that can guide current and future brain tumor therapies.
Much research in the past twenty years has focused on the identification of genetic alterations in cancers. Mutation, an alteration of DNA in individual cells, is a critical step in the development of most forms of cancer. Altered levels at which specific genes are expressed are also critical in cancer development. By gaining a greater understanding of these alterations, scientists may be able to develop more effective treatments.
Advances in high-throughput DNA sequencing technologies have allowed scientists to more accurately identify the underlying genetic alterations responsible for cancer progression. The use of this technology may be crucial in finding a way to destroy a cancer at its origin. Researchers have already found many genes and genetic changes that are highly associated with specific types of cancer.
Glioblastoma multiforme (GBM) has proven to be quite difficult to treat due to its complex pattern of genetic alterations. In 2008, two complementary comprehensive reports were published by two groups of scientists (a consortium in The Cancer Genome Atlas Research Network, and at Johns Hopkins University) in which key gene and pathway alterations were found in GBM.
The two companion studies published by JAMA in July 2009 have expanded upon this previous work by demonstrating that networks of altered genes work together cooperatively to drive GBM development and progression.
Bredel et al. examined 45 glioblastoma samples and discovered 37 associations of gene alterations in 9 networking chromosomal regions. Twenty one of these 37 associations were confirmed by analyzing another set of over 200 GBMs from The Cancer Genome Atlas Project. They found that the chromosomal regions that exhibited tight associations with one another were more likely to function in the development and promotion of GBM tumors. The 11 most interactive genes that are vital contributors of cancer development and progression were labeled as "hub" genes. Many more "hub-interacting" genes with clear biological functions associated with tumors were also identified. In addition, they found within the 27 most interaction genes a set of 7 "landscape" genes that were associated with longer survival across several different GBM study populations.
The study by Yadav et al. looked at the functional relationship between two genes that were found to be highly interactive in previous study. A strong association was seen between an underexpression of the annexin A7 (ANXA7) gene and an overexpression of the epidermal growth factor receptor (EGFR) gene. Gene expression refers to the process in which information encoded by the DNA that makes up genes is used as a template to synthesize a functional product, such as a protein. Using genetically engineered cells, Yadav demonstrated that in fact the underexpression of the ANXA7 tumor suppressor gene results in increased EFGR functional signaling even without an increase in the amplification of the EGFR gene. Furthermore, the team demonstrated that underexpression of ANXA7 and overexpression of EGFR acts synergistically in the development of GBM tumors.
- Bredel et al. - A Network Model of a Cooperative Genetic Landscape in Brain Tumors
- Yadav et al. - Monosomy of Chromosome 10 Associated With Dysregulation of Epidermal Growth Factor Signaling in Glioblastomas
- Pasche et al. - One Step Forward Toward Identification of the Genetic Signature of Glioblastomas