The complete genetic blueprint for lethal pancreatic cancer and brain cancer and lethal was deciphered by Johns Hopkins Kimmel Cancer Center researchers.

New Genetic Blueprint for Lethal Cancers Found

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.

Isocitrate dehydrogenase 1 (IDH1) Gene Linked to Lethal Brain Cancers

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 gorrilla war than a conventional warbecause 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 gorilla 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.

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

About Pancreatic Cancer 

Pancreatic cancer is a malignant tumor of the pancreas. Each year about 37,680 individuals in the United States are diagnosed with this condition, and 34,290 die from the pancreatic cancer. In Europe more than 60,000 are diagnosed each year.

About 95 percent of pancreatic tumors are adenocarcinomas; the remaining 5 percent include other tumors of the exocrine pancreas (e.g., serous cystadenomas), acinar cell cancers, and pancreatic neuroendocrine tumors (such as insulinomas).

• Age
• Male gender
• African-American ethnicity
• Smoking. Cigarette smoking nearly doubles one's risk, and the risk persists for at least a decade after quitting. 
• Diets high in red meat
• Obesity
• Diabetes mellitus
• Chronic pancreatitis has been linked, but is not known to be causal
• Helicobacter pylori (H. Pylori)  infection
• Occupational exposure to certain pesticides, dyes, and chemicals related to gasoline
• Family history, 5-10% of pancreatic cancer patients have a family history of pancreatic cancer
• Gingivitis or periodontal disease.

Depending on the extent of the pancreatic cancer tumor at the time of diagnosis, the prognosis is generally regarded as poor, with <5% of those diagnosed still alive five years after diagnosis, and complete remission extremely rare.

Patients diagnosed with pancreatic cancer typically have a poor prognosis partly because pancreatic cancer usually causes no symptoms early on, leading to locally advanced or metastatic pancreatic cancer at time of diagnosis.

About Brain Cancer

All brain cancers are life threatening (malignant) because they have an aggressive and invasive nature. In the United States, the annual incidence of brain cancer generally is 15–20 cases per 100,000 people. Brain cancer is the leading cause of cancer-related death in patients younger than age 35.

There are two types of brain tumors: primary brain tumors that originate in the brain and metastatic (secondary) brain tumors that originate from cancer cells that have migrated from other parts of the body.

Primary brain cancer rarely spreads beyond the central nervous system, and death results from uncontrolled tumor growth within the limited space of the skull. Metastatic brain cancer indicates advanced disease and has a poor prognosis.

Exposure to vinyl chloride is an environmental risk factor for brain cancer. Vinyl chloride is a carcinogen, that is, a cancer-causing substance. It is used in manufacturing plastic products and is present in tobacco smoke.

Aside from a known association with exposure to vinyl chloride, there are no known chemical or environmental agents that lead to the development of brain tumors. Most incidents of brain cancer involve genetic mutations and deletions of tumor suppressor genes (i.e., genes that suppress the development of malignant cells). Studies show that people with a history of melanoma, lung cancer, breast cancer, colon cancer, or kidney cancer are at risk for secondary brain cancer.

Manufacturing and chemical plants may release vinyl chloride into the air or water, and it may leak into the environment as a result of improper disposal. People who work in these plants or live in close proximity to them have an increased risk for brain cancer.

About the Pancreatic Cancer and Brain Cancer Johns Hopkins Study

This year an estimated 38,000 people will develop pancreatic cancer in the United States, 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. 

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.

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.

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.

Under separate licensing agreements between The Johns Hopkins University and Genzyme, Beckman Coulter, and Exact Sciences corporations, Kenneth W. Kinzler, Bert Vogelstein, and Victor E. Velculescu are entitled to a share of royalties received by The Johns Hopkins University on sales of products related to research described in this paper. These authors and the university own Genzyme and Exact Sciences stock, which is subject to certain restrictions under university policy. The terms of these arrangements are managed by the university in accordance with its conflict-of-interest policies.