Brain Tumors-New Genetic Pathways

Comprehensive Study of Brain Tumors

New Genetic Mutations, Core Pathway

“The Cancer Genome Atlas (TCGA) Research Network, a collaborative effort funded by the National Cancer Institute (NCI) and the National Human Genome Research Institute (NHGRI) of the National Institutes of Health (NIH), reported the first results of its large-scale, comprehensive study of the most common form of brain cancer, glioblastoma (GBM). “Sept. 4, 2008, in the advance online edition of the journal Nature, the TCGA team describes the discovery of new genetic mutations and other types of DNA alterations with potential implications for the diagnosis and treatment of GBM.

Among the TCGA findings are the identification of many gene mutations involved in GBM, including three previously unrecognized mutations that occur with significant frequency; and the delineation of core pathways disrupted in this type of brain cancer. Among the most exciting results is an unexpected observation that points to a potential mechanism of resistance to a common chemotherapy drug used for brain cancer.

“… The more we learn about the molecular basis of glioblastoma, the more swiftly we can develop better ways of helping patients,” said NIH Director Elias A. Zerhouni, M.D.

Like most cancers, GBM arises from changes that accumulate in cells’ DNA over the course of a person’s life – changes that may eventually lead to the cells’ uncontrolled growth. However, until recently, scientists have understood little about the precise nature of these DNA changes and their impact on key biological pathways that are important to the development of new interventions.

TCGA researchers sequenced 601 genes in GBM samples and matched control tissue, uncovering three significant genetic mutations not previously reported to be common in GBM. The affected genes were: NF1, a gene previously identified as the cause of neurofibromatosis 1, a rare, inherited disorder characterized by uncontrolled tissue growth along nerves; ERBB2, a gene that is well-known for its involvement in breast cancer; and PIK3R1, a gene that influences activity of an enzyme called PI3 kinase that is deregulated in many cancers. PI3 kinase already is a major target for therapeutic development. The discovery of frequent mutations in the PIK3R1 gene means that GBM patients’ responses to PI3 kinase inhibitors may be dictated by whether or not their tumors have mutated versions of the gene.

The TCGA team combined sequencing data with other types of genome characterization information… to generate an unprecedented overview that delineated core biological pathways potentially involved in GBM. The three pathways, each of which was found to be disrupted in more than three-quarters of GBM tumors, were: the CDK/cyclin/CDK inhibitor/RB pathway, which is involved in the regulation of cell division; the p53 pathway, which is involved in response to DNA damage and cell death; and the RTK/RAS/PI3K pathway, which is involved in the regulation of growth factor signals.

The three pathways were interconnected and coordinately deregulated in most of the GBM tumors analyzed. Therefore, combination therapies directed against all three pathways may offer an effective strategy, the TCGA researchers state.

As in the Human Genome Project, TCGA data are being made rapidly available to the research community through a database, http://cancergenome.nih.gov/dataportal. The database provides access to public datasets, and with required review and approval, allows researchers access to more in-depth data.

Additional information about NHGRI can be found at its Web site,” http://www.genome.gov.

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