Genetic Mutations Linked to Deadly Cancers

Findings of 3 studies focus on brain and pancreatic tumors

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Genetic Mutations Linked to Deadly Cancers

By
HealthDay Reporter

THURSDAY, Sept. 4, 2008 (HealthDay News) -- Potentially groundbreaking discoveries involving genetic mutations of two deadly cancers -- the brain cancer glioblastoma and pancreatic cancer -- may lead to new treatments and even cures, researchers say.

"These studies represent the most complete genetic analysis to date of any tumor type and provide a detailed genetic map of these deadly cancers," Kenneth Kinzler, a professor of oncology at Johns Hopkins University, and co-author of the study on pancreatic cancer, said during a teleconference Wednesday.

These findings are important, because genetic mutations are involved in the development of all cancers, Kinzler said. Kinzler's study of the genetic makeup of pancreatic cancer is published in the Sept. 4 online edition of Science.

Pancreatic cancer is diagnosed in 38,000 people, and brain cancer strikes 21,000 people each year in the United States. Only about 5 percent survive these cancers, the researchers said.

For the pancreatic cancer study, the researchers looked at genes in 24 people with the disease. "Analysis of 20,000 genes in 24 pancreatic cancers provided a global overview of the molecular landscape that was previously unknown to this tumor type," Kinzler said.

The researchers found 63 genetic alterations in these pancreatic cancers. However, genes do not work alone; they work together in what are called pathways. When looked at this way, Kinzler's group found 12 altered pathways.

"This really is a new perspective on the changes that drive tumor progression and suggests that we need to rethink the optimal way of diagnosing, categorizing and treating cancer," Kinzler said.

In the second report, published in the same issue of Science, co-author Dr. Victor Velculescu, an assistant professor of oncology at Johns Hopkins University, and colleagues studied 20,000 genes from 22 patients with glioblastoma multiforme (GBM), the same type of cancer diagnosed in Sen. Edward Kennedy earlier this year.

"We found that a typical GBM contains approximately 60 genetic alterations," Velculescu said during the teleconference. "Some of these changes affected many of the same pathways as those in pancreatic cancer. But many were new and appeared to affect the processes that appear to relate to the development of GBM."

One of the important discoveries about GBM was that about 12 percent of patients have an alteration in one gene -- called IDH1 -- that had never before been implicated in any type of cancer. Patients with this particular gene alteration tended to be younger and survive longer, Velculescu said.

"GBMs used to be thought of as one disease. It is now clear that they are two," Velculescu said.

In another paper on genetic alterations involving GBM tumors, researchers also reported finding alterations that appear to be responsible for the brain cancer.

Dr. Matthew Meyerson, of the Dana-Farber Cancer Institute and Harvard Medical School, and colleagues found three major gene mutations in glioblastoma, namely NF1 (a tumor suppressor gene), ERBB2 (a protein tyrosine kinase gene), and PIK3R1 (a lipid kinase gene) among 206 GBM patients.

"These findings will guide glioblastoma therapies," Meyerson said. "Cancer genome projects can discover important new cancer-causing alterations, with clinical implications. We are on our way to understanding what causes cancer in detail," he said.

Meyerson's findings were published in the Sept. 4 online issue of the journal Nature.

The findings from all three studies could have important treatment and diagnostic implications, Dr. Bert Vogelstein, the Clayton Professor of Oncology and Pathology at Johns Hopkins University and a co-author of the Science paper on GBM, said during a teleconference.

The findings suggest that most solid tumors, particularly those of the brain and pancreas, won't respond to treatments that target a single gene, Vogelstein said. "Our work suggests that it may be more productive to screen for drugs that act against the core pathways that are disregulated in most cancers," he said.

Vogelstein said more effort needs to be placed on prevention and early detection, rather than looking for cures. This emphasis should include new ways of detecting alterations in the genetic pathways of tumors. Also, ways need to be found to detect genetic alterations when cancers are still curable, he said.

It takes many years for cancers to develop, and gene alterations could be detected long before tumors grow and spread to other parts of the body, Vogelstein noted.

"Almost all tumors, probably even those of the brain and pancreas, would be curable if they could be caught early," Vogelstein said. "One focus of future research should be to emphasize early detection using the genes and pathways that have been discovered to play a role in these tumor types," he said.

Dr. Len Lichtenfeld, deputy chief medical officer at the American Cancer Society, noted that genetic alterations may be different in different cancers and even among people with the same cancers.

"This [new research] reinforces the thought that we will eventually get to a point where we will be able to take a specimen from an individual's cancer and look at the genetic changes in the cancer and use that information and apply it to treatment that would be specific for that person's cancer," Lichtenfeld said.

However, one cancer geneticist said the new studies were too small to offer any firm conclusions.

"It's a bit disappointing that so many of the mutations in these genes have already been known. There seems to be a paucity of really new findings," said Dr. Charis Eng, the Sondra J. and Stephen R. Hardis Chair of Cancer Genomic Medicine at the Cleveland Clinic and a professor at the University of Cambridge in the United Kingdom.

"Sample sizes need to be increased, clinical annotation has to be better," she added. "This has to be done in a true international collaboration. Even then, I think, we will come up with more questions than answers."

More information

For more on cancer and genetics, visit the American Cancer Society.

SOURCES: Sept. 3, 2008, teleconference with Bert Vogelstein, M.D., Clayton Professor of Oncology and Pathology, Victor Velculescu, M.D., Ph.D., assistant professor of oncology, and Kenneth Kinzler, Ph.D., professor of oncology, all with Johns Hopkins University, Baltimore; Len Lichtenfeld, M.D., deputy chief medical officer, American Cancer Society, Atlanta; Charis Eng, M.D., Ph.D., Sondra J. and Stephen R. Hardis Chair of Cancer Genomic Medicine, Cleveland Clinic, and professor, University of Cambridge, England; Sept. 4, 2008, Science, online; Sept. 4, 2008, Nature, online

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