Glioblastoma multiforme (GBM) was the first cancer type to be systematically studied by The Cancer Genome Atlas Research Network (TCGA) in 2008. In a new, complementary report, TCGA experts examined more than 590 GBM samples--the largest to date utilizing genomic characterization techniques and nearly 400 more than were examined in 2008--to identify several additional significantly mutated genes in GBM implicated in the regulation of chromatin modification. Chromatin is a combination of DNA and protein within a cell’s nucleus that is involved in regulating how genes are expressed.
GBM, the type of brain cancer most often found in adults, is a fast-growing and often fatal tumor. More than 23,000 new cases of brain cancer are predicted in the United States in 2013, with more than 14,000 people likely to die from the disease. Most patients with GBM die of the disease within approximately 15 months of diagnosis.
TCGA is a collaborative effort jointly funded and managed by the National Cancer Institute (NCI) and the National Human Genome Research Institute (NHGRI), both part of the National Institutes of Health (NIH). These new findings appeared October 10, 2013, in the journal Cell.
TCGA was established to generate a comprehensive catalogue of non-heritable genomic changes in over 25 different types of cancer. The initial observations in GBM provided a proof-of-concept that systematic genomic analyses could define core biological pathways, substantiate previous smaller-study observations and generate unanticipated insights.
At the start of the TCGA program, only several hundred GBM tumor samples were available for analysis, and technology to probe those samples was comparatively rudimentary. Since the inaugural TCGA publication on GBM, advances in genomic characterization technology have transformed the ability to characterize gene alterations with greater resolution and accuracy. For example, massively parallel sequencing technology that is able to read over 100 million sequences of DNA at a time is now part of the standard toolkit for characterization of tumors. Subsequent to the GBM study in 2008, TCGA has used these and newer technologies to describe the landscape of alterations in eight other tumor types.
This new research applied the advanced technologies to a larger set of high-quality samples. The report describes the identification of novel, significantly mutated genes in GBM, including LZTR1, ATRX, KEL and QKI, and revealed a pattern of mutations, not attributable to chance, among genes implicated in regulation of chromatin modification. Additionally, sequencing of whole genomes and messenger RNA detected several new mechanisms; one that changes the structure of the gene EGFR; one that reorganizes a region on chromosome 12 that contains the oncogenes MDM2 and CDK4; as well as detecting the presence of highly frequent point mutations, or a substitution of one base for another among the four bases that comprise DNA, in a non-coding region of the TERT gene.
The 2008 GBM study found biologically-relevant alterations in three core pathways. Additional research efforts to link these alterations to distinct subtypes of glioblastoma revealed that coordinated combinations of these alterations were enriched in different subtypes of the disease. In 2013, it is now evident that glioblastoma growth is driven by large signaling networks that have a functional redundancy that permit adaptation of the tumor in response to targeted molecular treatments. For example, the vast majority of GBM tumors have at least one known driver mutation in the PI3K pathway and close to half exhibit two or more such mutations. Thus, this new study provides a greatly needed comprehensive catalogue of molecular alterations in glioblastoma.
Additionally, based on integration of genomic alterations with metabolic activity, researchers demonstrated non-linear relationships between genomic alterations and signaling activities, challenging the concept of therapeutic inhibition of pathway components being equivalent to direct targeting of the mutated gene itself. “While this presents new challenges for therapies, it also provides an important understanding of how to develop better and more appropriately targeted drugs in the future,” said lead author Lynda Chin, M.D., University of Texas MD Anderson Cancer Center, Houston, and the Broad Institute of MIT and Harvard University Cambridge, Mass.
Brennan, C.W., Verhaak, R.G., McKenna, A., Campos, B., Noushmehr, H., Salama, S.R., Zheng, S., Chakravarty, D., Sanborn, J.Z., Berman, S.H., et al. The Somatic Genomic Landscape of Glioblastoma. Cell. October 10, 2013. doi: 10.1016/j.cell.2013.09.034.