Gene domino effect behind some types of tumors

WASHINGTON -- Scientists have mapped the cascade of genetic changes that turn normal cells in the brain and pancreas into two of the most lethal cancers. The result points to a new approach for fighting tumors and maybe even catching them sooner.

Genes blamed for one person's brain tumor were different from the culprits for the next patient, making the puzzle of cancer genetics even more complicated.

But today's research also found that clusters of seemingly disparate genes all work along the same pathways. So instead of today's hunt for drugs that target a single gene, the idea is to target entire pathways that most patients share. Think of delivering the mail to a single box at the end of the cul-de-sac instead of at every doorstep.

The three studies, published in the journals Science and Nature, mark a milestone in cancer genetics.

"This is the next wave," said Dr. Phillip Febbo of Duke University's Institute for Genome Sciences and Policy, who was not involved with the new research. "What's really important is that finding those common elements within the landscape suggests there are therapeutic interventions that can help the whole group."

Despite 30 years of laborious work, scientists until now have found only a fraction of the genetic alterations required to cause any of the 200 diseases that collectively are called cancer. Different tumors require a different domino effect of genetic changes to arise, and to determine their severity and even which treatments will work.

The new maps do not include just mutated genes. They cite missing ones, extra ones, and overactive or underactive ones, too, in the most comprehensive look ever at human tumors.

Teams led by Johns Hopkins University examined more than 20,000 genes in tumors taken from 24 pancreatic cancer patients and 22 patients with the most dangerous brain tumor, called glioblastoma multiforme. Separately, The Cancer Genome Atlas project -- a government-funded network of 18 medical centers -- analyzed 600 genes in glioblastomas from 206 patients.

IDH1 testing possible

The Hopkins teams found hundreds of genetic changes, including a particularly intriguing gene named IDH1. Twelve percent of glioblastoma patients, mostly young ones, harbored a mutated version that brought longer survival: a median of 3.8 years compared with the 1.1 years for patients without the mutation.

If additional study proves that effect, doctors soon might use an IDH1 test to help determine prognosis, said Hopkins' Dr. Victor Velculescu, who led the glioblastoma work. If so, the next question is whether certain drugs work better in those patients as well.

The bigger discovery involved cancer's genetic chaos. No tumors were identical. The typical pancreatic cancer contained 63 genetic alterations and the average brain tumor 60, Hopkins researchers reported in Science.

Fortunately, "genes don't work alone," said Hopkin's Dr. Kenneth Kinzler, who led the pancreatic work. Figure out which genes cluster in which pathways and "a simpler picture emerges."

The Hopkins team identified 12 core pathways that were abnormal in most pancreatic tumors. In Nature, The Cancer Genome Atlas researchers reported three core pathways at work in most glioblastomas.

The pathways do different things. Some allow damaged DNA to escape repair. Some switched off protective factors meant to suppress tumors.

Finding drugs that block those pathways will not be easy, said Dr. Bert Vogelstein of Hopkins and the Howard Hughes Medical Institute, who oversaw the research. They also may cause more side effects than current "targeted therapies" that work against only a specific gene defect.

But companies already are researching drugs to block a particular enzyme pathway implicated in the studies.

Also, pathway blockers should work in larger groups of patients, Vogelstein said. One particular pancreatic cancer pathway contains a variety of genes mutated in only a few people, but regardless of which gene ran amok, the whole pathway was broken in every tumor

studied.

"Even though it sounds complex, it's actually allowing us to simplify the complex into pathways that will allow us, I think, to truly understand cancer for the first time and take a much more rational approach to treatment," said Dr. Anna Barker of the National Cancer Institute, who co-directs the cancer atlas project. "I'm more optimistic."

Moreover, the work suggests possible ways to catch cancer earlier, by tracing mutant DNA floating through the bloodstream well before tumors themselves start to spread, Vogelstein added. "I don't think that's any longer science fiction."

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On the Net:

The Cancer Genome Atlas: http://cancergenome.nih.gov/