Large-Scale Effort Identifies New Genetic Mutations, Core Pathways
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), today reported the first results of its large-scale, comprehensive study of the most common form of brain cancer, glioblastoma (GBM). In a paper published 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.
More than 21,000 new cases of brain cancer are predicted in the United States this year, with more than 13,000 people likely to die from the disease. GBM, which is the type of brain cancer most often found in adults, is a very fast-growing type of tumor. Most patients with GBM die of the disease within approximately 14 months of diagnosis.
The TCGA network analyzed the complete sets of DNA, or genomes, of tumor samples donated by 206 patients with GBM. The work complements and expands upon a parallel study by Johns Hopkins researchers of 22 GBM tumors, which was also published today in the journal Science.
“These impressive results from TCGA provide the most comprehensive view to date of the complicated genomic landscape of this deadly cancer. The more we learn about the molecular basis of glioblastoma, the more swiftly we can develop better ways of helping patients with this terrible disease,” said NIH Director Elias A. Zerhouni, M.D. “Clearly, it is time to move ahead and apply the power of large-scale, genomic research to many other types of cancer.”
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.
The NCI and the NHGRI initiated TCGA in 2006 to accelerate understanding of the molecular basis of cancer through the application of current genome characterization technologies, including large-scale genome sequencing. TCGA was launched as a pilot program to determine the feasibility of a full-scale effort to potentially systematically explore the universe of genomic changes involved in all types of human cancer.
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.
The pathway mapping promises to be particularly informative for researchers working to develop therapeutic strategies that are aimed more precisely at specific cancers or that are better tailored to each patient’s particular subtype of tumor.
For example, a patient whose tumor has genetic alterations at one point in the CDK pathway might benefit from a drug that blocks CDK, while patients with mutations at another point in the same pathway might be predicted not to respond to such drugs. Similarly, while some drugs already used for GBM target the RTK pathway, the new findings suggest a need to tailor therapeutic cocktails to particular patterns of mutations in genes involved in that pathway.
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.
One particularly exciting finding with the potential for rapid clinical impact centers on the MGMT gene. Physicians already know patients with GBM tumors that have an inactivated, or methylated, MGMT gene respond better to temozolomide, an alkylating chemotherapy drug commonly used to treat GBM. By integrating methylation and sequencing data with clinical information about sample donors, TCGA’s multi-dimensional analysis found that in patients with MGMT methylation, alkylating therapy may lead to mutations in genes that are essential for DNA repair, commonly known as mismatch repair genes. Such mutations then lead to the subsequent emergence of recurrent tumors that contain an unusually high number of DNA mutations, and that may be resistant to chemotherapy treatment. If follow-up studies confirm such a mechanism, researchers say first- or second-line treatments for such GBM patients may involve therapies designed to target the results of combined loss of MGMT and mismatch-repair deficiency. The new findings also may help clinical researchers figure out the best ways to combine alkylating chemotherapy drugs with the next generation of targeted therapeutics.
“This represents another major step towards our ultimate goal of using information about the human genome to improve human health,” said NHGRI Acting Director Alan E. Guttmacher, M.D. “It’s thrilling to see what the cancer and genomics research communities can achieve through working together in a collaborative manner. I am confident that this paper is just the first of many exciting results that TCGA will generate.”
NCI’s Deputy Director Anna D. Barker, Ph.D., who co-leads the research program, said, “TCGA’s unprecedented multi-dimensional data on large numbers of high quality tumor and control samples offer new molecular insights that will most certainly inform the discovery of new cancer interventions.”
As in the Human Genome Project, TCGA data are being made rapidly available to the research community through a database, https://www.cancer.gov/about-nci/organization/ccg/research/structural-genomics/tcga. The database provides access to public data sets, and with required review and approval, allows researchers access to more in-depth data.
The TCGA Research Network members who chaired the large TCGA committee that wrote the Nature paper were Lynda Chin, M.D., and Matthew Meyerson, M.D., Ph.D., of Dana-Farber Cancer Institute and Harvard Medical School, Boston. Dr. Meyerson is also affiliated with the Broad Institute of MIT and Harvard, Cambridge, Mass.
For a full list of participants in the TCGA Research Network, go to https://www.cancer.gov/about-nci/organization/ccg/research/structural-genomics/tcga
NCI and NHGRI are two of the 27 institutes and centers at NIH, an agency of the U.S. Department of Health and Human Services.
For more details about The Cancer Genome Atlas, including Q&As, a graphic, a glossary, a brief guide to genomics and a media library of available images, please go to https://www.cancer.gov/about-nci/organization/ccg/research/structural-genomics/tcga.
For more information about cancer and the National Cancer Institute, please visit the NCI Web site at https://www.cancer.gov, or call NCI’s Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).
Additional information about NHGRI can be found at its Web site, https://www.genome.gov.