Comprehensive Genetic Blueprints Revealed For Lethal Pancreatic, Brain Cancers

The studies, led by the same group who completed maps of the breast cancer and colorectal cancer genomes in 2007, are reported in two articles in the Sept. 5, 2008, issue of Science Express.

Believed to be the most comprehensive result to date for any tumor type, the new map evaluated mutations in virtually all known human protein-encoding genes, comprised of more than 20,000 genes, in 24 pancreatic cancers and 22 brain cancers.

A core set of regulatory gene processes and pathways, about a dozen for each tumor type, were found to be altered in the majority of tumors studied by the researchers. In pancreatic cancer, these 12 pathways, including those linked to DNA damage control, cell maturation, and tumor invasion, were altered in 67 percent to 100 percent of tumors.

"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, M.D., co-director of the Ludwig Center at Johns Hopkins and a Howard Hughes Medical Institute investigator.

In addition to the pathway discoveries, a number of individual mutated genes were identified, including 83 cancer genes in pancreatic cancer and 42 in the most lethal form of brain cancer, glioblastoma multiforme (GBM). Additionally, 70 genes that were dramatically overexpressed in either cancer encode proteins that are on the surface of cells or secreted, making them potential diagnostic and screening targets.

One gene, isocitrate dehydrogenase 1 (IDH1), was found to be frequently mutated in a subset of GBM brain cancers. The mutations were significantly more common in young GBM patients, and were associated with improved survival. IDH1 mutations were also found in nearly all cases of secondary GBMs (cancers that progress from pre-existing lower grade tumors), raising the possibility that this mutation may be a useful marker for identifying which low-grade brain tumors are most likely to develop into the lethal GBMs.

"Patients with IDH1 mutations seem to be different from other patients with GBM, both clinically and biologically," says Victor Velculescu, M.D., Ph.D., associate professor of oncology. "It is conceivable that these patients will ultimately benefit from different treatments, potentially by targeting IDH1."

"The landscape of human cancers is clearly more complex than has been previously appreciated. Fighting it is going to be more of a guerilla war than a conventional one because there are dozens of mutated genes in each tumor," says Kenneth W. Kinzler, Ph.D., co-director of the Ludwig Center at Johns Hopkins and professor of oncology. "Individually, these mutations don't seem formidable. But working together, they form an enemy that will require us to develop novel strategies to combat them, and the best long-term strategy may be early detection of tumors, when the number of guerilla warriors is still small and more easily handled."

To make their findings, the investigators integrated several methods of genetic analysis. They used high-density microarrays to identify copy number alterations (amplifications and deletions) and next-generation sequencing technologies to evaluate gene expression. They also developed novel statistical algorithms to integrate these complementary genetic analyses, as well as techniques to separate alterations likely to contribute to cancer initiation and progression from so-called passenger mutations, which accumulate harmlessly during cancer development.

Each project cost more than $4 million, with lead funding for the Goldman Pancreatic Cancer Genome Initiative coming from the Sol Goldman Charitable Trust and Lillian Goldman Charitable Trust. The Virginia and D. K. Ludwig Foundation provided lead funding for the brain cancer project. The Ludwig Brain Tumor Initiative represents the first formal collaboration of Ludwig Centers established by the Ludwig Fund in 2006.

This year an estimated 38,000 people will develop pancreatic cancer in the US, with overall survival rates less than 5 percent. Although fewer patients are diagnosed with brain cancers (approximately 20,000 cases per year in the United States), the results are equally catastrophic. "The main reasons we chose to focus on these cancers is because they are so deadly and have such limited treatment options. What we learn about these tumors may lead to improved diagnostic measures or therapies in the future," says Ralph Hruban, M.D., Director of the Sol Goldman Pancreatic Cancer Research Center at Johns Hopkins.

The Lustgarten Foundation provided significant funding for the pancreatic cancer research. Additional funding came from the Virginia and D.K. Ludwig Fund, Susan G. Komen Foundation, Michael Rolfe Pancreatic Cancer Foundation, Joseph C. Monastra Foundation, the family and friends of George Rubis, Viragh Family Foundation, Broad Foundation, Emerald Foundation, and National Institutes of Health.

Additional support for the brain cancer research came from the National Institutes of Health, Pew Charitable Trusts, Pediatric Brain Tumor Foundation Institute, Clayton Fund, Hirschhorn Foundation, Alex's Lemonade Stand Foundation, American Brain Tumor Association, American Society of Clinical Oncology, and Brain Tumor Research Fund.

Research participants in the pancreatic cancer study were Sian Jones, Xiaosong Zhang, D. Williams Parsons, Jimmy Cheng-Ho Lin, Rebecca J. Leary, Philipp Angenendt, Parminder Mankoo, Hannah Carter, Hirohiko Kamiyama, Antonio Jimeno, Seung-Mo Hong, Baojin Fu, Ming-Tseh Lin, Eric S. Calhoun, Mihoko Kamiyama, Kimberly Walter, Tatiana Nikolskaya, Yuri Nikolsky, James Hartigan, Douglas R. Smith, Manuel Hidalgo, Steven D. Leach, Alison P. Klein, Elizabeth M. Jaffee, Michael Goggins, Anirban Maitra, Christine Iacobuzio-Donahue, James R. Eshleman, Scott E. Kern, Ralph H. Hruban, Rachel Karchin, Nickolas Papadopoulos, Giovanni Parmigiani, I-Mei Su, Gary Gallia, Alex Olivi, Roger McLendon, B. Ahmed Rasheed, Stephen Keir, Dana Busam, Hanna Tekleab, Luis A. Diaz, Jr., Robert L. Strausberg, Suely Kazue Nagahashi Marie, Sueli Mieko Oba Shinjo, Hai Yan, Gregory L. Riggins, Darell D. Bigner, Rachel Karchin, Bert Vogelstein, Victor E. Velculescu, and Kenneth W. Kinzler.

Research participants in the brain cancer study are D. Williams Parsons, Siân Jones, Xiaosong Zhang, Jimmy Cheng-Ho Lin, Rebecca J. Leary, Philipp Angenendt, Parminder Mankoo, Hannah Carter, I-Mei Siu, Gary L. Gallia, Alessandro Olivi, Roger McLendon, B. Ahmed Rasheed, Stephen Keir, Tatiana Nikolskaya, Yuri Nikolsky, Dana A. Busam, Hanna Tekleab, Luis A. Diaz, Jr., James Hartigan, Doug R. Smith, Robert L. Strausberg, Suely Kazue Nagahashi Marie, Sueli Mieko Oba Shinjo, HaiYan, Gregory J. Riggins, Darell D. Bigner, Rachel Karchin, Nick Papadopoulos, Giovanni Parmigiani, Bert Vogelstein, Victor E. Velculescu, Kenneth W. Kinzler.