In its Nature paper, the TCGA Research Network describes the interim results of its analyses of GBM, the first type of cancer to be studied in the TCGA pilot. The pioneering work pulled together and integrated multiple types of data generated by several genome characterization technologies from investigators at 18 different participating institutions and organizations. The data include small changes in DNA sequence, known as genetic mutations; larger-scale changes in chromosomes, known as copy number variations and chromosomal translocations; the levels of protein-coding RNA being produced by genes, known as gene expression; patterns of how certain molecules, such as methyl groups, interact with DNA, known as epigenomics; and information related to patients' clinical treatment.

"This type of comprehensive, coordinated analysis of unprecedented multi-dimensional data is made possible by advanced technologies utilized by teams of scientists driven to solve complex questions,"said NCI Director John E. Niederhuber, M.D. "It will now fall to a dedicated cadre of laboratory scientists to turn this important information into new life-saving therapies and diagnostics for cancer.


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, such as gene expression and DNA methylation patterns, 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.

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