Three epic studies, separately published in the September 4, 2008 issues of Science and Nature, aimed to improve our understanding of cancer genetics.
One of these studies, published in Nature, was conducted by 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 on the discovery of new genetic mutations in the most common form of brain cancer, glioblastoma multiforme (GBM). In this study, TCGA identified three previously unrecognized, high frequency mutations in GBM tumors, delineated core cell signaling pathways that are disrupted in GBM, and stumbled upon a potential resistance mechanism to a common chemotherapy used in brain cancer patients. The three previously unknown gene mutations were uncovered during the sequencing of 601 genes in GBM samples and matched control tissue. And these three mutations fell into three genes previously associated with uncontrolled tissue growth: NF1, ERBB2, and PIK3R1, the latter of which is a regulator of PI3K, a frequent target of cancer chemotherapy. By combining sequencing data with gene expression and DNA methylation patterns, the TCGA researchers were also able to delineate core biological pathways (CDK/cyclin/CDK inhibitor/RB, p53, and the RTK/RAS/PI3K pathways), which they found to be disrupted in GBM tumors, suggesting potential involvement in GBM pathogenesis. This study created the first gene map of GBM.
In other news, two separate studies published in Science in September 2008 reported on gene maps of GBM and pancreatic cancer. The studies represented a massive collaboration between the Johns Hopkins Kimmel Cancer Center, Duke University, and other research centers, in which 20,661 genes were sequenced from 24 patients with pancreatic cancer and 22 patients with glioblastoma. Every one of these tumors had a different set of profiles, further confounding the issue of “personalized” therapy. However, when the hundreds of cancer-associated mutations identified in these studies were examine more closely, many could be assigned to specific cell signaling pathways. For example, the researchers identified 12 core aberrant signaling pathways in pancreatic tumors, some of which were involved in either apoptosis or DNA repair—the disruption of which has been shown to lead to other forms of cancer.
“This perspective changes the way we think about solid tumors and their management, because drugs or other agents that target the physiologic effects of these pathways, rather than individual gene components, are likely to be the most useful approach for developing new therapies,” says Bert Vogelstein, MD, co-director of the Ludwig Center at Johns Hopkins and a Howard Hughes Medical Institute investigator.
Additionally, seventy genes identified in this study were found to be overexpressed on the tumor cell surface or in overexpressed in tumor secretions, increasing their potential as biomarkers in screening or diagnostic tests.
The significance of these studies has yet to be realized, but a greater systems approach to cancer drug design, whereby pathways and not individual proteins are targeted, would be a step in the right direction.
Filed Under: Genomics/Proteomics