Genome Surveys Reveal Complexity of Brain Cancers
The most comprehensive studies to date of the molecular changes underlying brain cancer were published last week. The information significantly expands current knowledge about the genetic networks involved in this deadly disease and points to potential therapeutic strategies.
The Cancer Genome Atlas (TCGA) Research Network analyzed 206 glioblastoma (GBM) brain tumors using an integrated approach based on multiple types of genetic data and clinical information. Reporting their findings online in Nature, the researchers identified gene mutations not previously recognized in the disease and a core set of molecular pathways that are commonly deregulated in the cancer, frequently together.
An unexpected finding that could be translated into the clinic within the next few years, the research team said, was the discovery of a potential mechanism of resistance to temozolomide, a chemotherapy drug for brain cancer.
"This study demonstrates that an unbiased, comprehensive global search for alterations in a large collection of tumors can definitely yield valuable insights that were not anticipated," said Dr. Lynda Chin of Dana-Farber Cancer Institute, who co-chaired the TCGA committee that wrote the Nature paper with her colleague, Dr. Matthew Meyerson.
These are the first results from the TCGA pilot project, a collaborative effort funded by NCI and the National Human Genome Research Institute to establish the feasibility of using integrated genomic strategies to characterize the molecular alterations in cancer. NCI Deputy Director Dr. Anna Barker co-leads the research program, which includes investigators from 18 institutions and organizations.
The current project involved characterizing tumors for alterations in DNA copy number, gene expression, and DNA methylation status - an epigenetic change that regulates gene activity. The researchers also sequenced 601 genes in 91 of the GBM tumors.
The study highlights three genes involved in the disease - ERBB2, NF1, and TP53. In addition, three pathways - RB, p53, and RTK/RAS/PI3K - were interconnected and deregulated in most, if not all, of the GBM tumors analyzed. Combination therapies directed against these pathways may be an effective strategy for some patients, the researchers suggest.
"In study after study, we see that cancer-causing genes fall into certain pathways, and that these pathways can be altered in many different ways," said Dr. Meyerson. "And it is only by getting a comprehensive picture of these changes that you begin to understand the genetic landscape of these tumors."
The temozolomide finding involved the gene MGMT, which, when methylated (that is, inactivated), can predict sensitivity to the drug. The data suggest that in some patients with a methylated MGMT gene temozolomide could lead to resistance as well as to mutations in genes that are essential for repairing DNA.
"If confirmed, the finding would immediately give us a handle on how to design combination therapies to limit the development of secondary cancers and how to better use temozolomide," said Dr. Chin. "This finding is a good example of what you want to achieve with a cancer genome project," she added, because the insight was both unexpected and emerged only after diverse types of information were analyzed together.
The second study, co-led by Drs. Bert Vogelstein, Kenneth Kinzler, and Victor Velculescu of the Johns Hopkins Kimmel Cancer Center, analyzed nearly every human gene in 22 glioblastoma tumors. Their report, published online in Science, is accompanied by an analysis of 24 pancreatic cancers, another disease that, like brain cancer, needs new therapies and methods of early detection. The team has previously published genomic analyses of 11 breast and 11 colon tumors.
As in the TCGA study, the Johns Hopkins group integrated different types of genomic data and identified altered genes and pathways. A gene called IDH1, which was not previously associated with GBM, was altered in 18 of the 149 GBM tumors they analyzed.
The TCGA report and the complementary study by the Johns Hopkins investigators suggest that it will be possible to define cancer subtypes on the basis of activated pathways by developing multi-dimensional data on robust numbers of patient samples, noted Dr. Barker. "This level of understanding offers real hope for defining evidence-based therapies and diagnostics," she said.
TCGA is currently characterizing additional GBM cases and will obtain even more cases. "These results are not the final statement on this disease, but they do suggest that what we learn will lead us in new directions for patient care," said Dr. Daniela Gerhard of NCI's Office of Cancer Genomics.
—Edward R. Winstead