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Cancer Genome Scientists Discover 100 More Mutated Genes

Major study offers clues to a cure

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HealthDay Reporter

WEDNESDAY, March 7, 2007 (HealthDay News) -- Cancer is a disease of genes gone awry, but new insights into the "cancer genome" could point the way to effective treatments, an international team of researchers reports.

Scientists taking part in the Cancer Genome Project say they've identified more than 100 mutated genes that help drive 210 different cancer types.

Each mutation could prove a promising new target for drug research, the scientists say.

"Looking at this set of genes may actually provide clues as to what is causing cancer and to also provide opportunities to think about developing therapeutic strategies against it," said the project's co-leader, Andrew Futreal of the Wellcome Trust Sanger Institute in Cambridge, England.

He and team co-leader Michael Stratton, also of the Wellcome Trust Sanger Institute, spoke to reporters at a special press conference Tuesday on the findings. The findings were expected to be published in the March 8 issue of the journal Nature.

According to the researchers, scientists have already uncovered about 350 cancer genes over the past few decades, usually through laborious single-gene experiments that took a long time to complete.

"However, the advent of the complete, finished human genome sequence has offered up a new strategy for finding cancer genes," Stratton explained. The strategy is simple, he said: to sequence (map) the genomes of human cancer cells and then compare them to the genome of a healthy cell, looking out for any suspicious aberrations in DNA.

But since the full human genome contains more than 3 billion letters of code, the Cancer Project has been forced to narrow its focus, at least for now. Researchers have homed in on a family of 500 "protein kinase" genes that have long been implicated in cancer.

"This set of genes is known to regulate key functions in virtually all cell processes of growth, differentiation -- telling cells to divide, telling cells to live or die," Futreal said. So, when a specific kinase gene gets mutated, formerly healthy cells can start dividing uncontrollably or refuse to undergo normal programmed cell death. The result is cancer.

"What we have done is looked at the 1.3 million letters of (genetic) code that constitute those 500 kinases, in more than 200 cancer samples -- cancers of many different types," Stratton said. The cancers studied included malignancies of the colon, breast, stomach, brain, kidney and testes, among others.

The result: 1,007 newly discovered kinase gene mutations that occurred in cancerous cells but not in healthy cells.

"When we analyzed those 1,000 mutations in more detail, what we find is quite surprising," Stratton said. "We find evidence for approximately 100 new cancer genes from within those 1,000 mutations."

The number of new cancer genes is smaller than the number of mutations because many of the cancer-associated mutations proved to be what scientists call "passenger mutations."

Passenger mutations "appear not to have anything to do with the causation of the cancer, they've just really hitchhiked along for the ride," Stratton said.

However, 150 of the mutations were so-called "drivers" -- genes that "drive the cell to stop behaving normally and to start behaving in that abnormal fashion that we call a cancer," Stratton said. Those 150 driver mutations are spread throughout about 100 different genes, the researchers said.

Cancers were not similar in terms of the number or type of kinase mutations they contained, Stratton noted. Some cancers (such as lung tumor cells) had a wide number of mutations, probably due to exposure to cigarette smoke or other DNA-altering carcinogens. But other malignancies relied on much fewer genetic flaws. Testicular cancer, for example, "has very few [kinase] mutations at all -- we were hardly able to find any," Stratton said.

Still, Stratton and Futreal said they were surprised at the number and variety of cancer-linked genes uncovered. This suggests that cancer research will get more complex before clearer patterns of causality emerge.

"There may be a period of greatly evolving complexity that we have to get through, which will only be sorted out by doing larger numbers and across more genes," Futreal said

He added that cancer probably stems not just from defects in individual genes but from mutations that upset interconnected gene pathways. "Because the way that these things function is that one kinase turns on another one, which then turns on another one," and so on, Futreal said.

Getting a handle on which genes and genetic pathways are at fault in particular cancers will be key to finding drugs or other treatments that can "fix" the problem and cure the disease, the researchers said.

But similar gene research into kinase activity has already produced Gleevec, the cancer "wonder drug" that has given new life to patients with chronic myelogenous leukemia, a formerly deadly blood cancer. Gleevec targets the defective kinase pathway responsible for CML, the researchers pointed out.

Another expert agreed. Dr. Len Lichtenfeld, deputy chief medical officer for the American Cancer Society, said work like the Cancer Genome Project "puts the future into focus."

He said that even though this type of research can uncover a seemingly "overwhelming" amount of new information, "the reality is that learning about these genetic changes and analyzing them carefully will lead to several things -- new targets for therapy and a better understanding of the cancer cell process."

And things may turn out to be simpler, rather than more complex. "We may well discover that even though we may have 100 or more (cancer) genes, the number of pathways that are really critically important that we have to interrupt may be a smaller number," Lichtenfeld said. "You may end up targeting one point or two or three points in a pathway for that particular cancer."

And because kinase genes are only a miniscule portion of the total cancer genome, the discoveries announced this week are likely just the tip of the iceberg.

"The analysis over the long haul will provide more clues on the key processes that have gone awry in cancers, moving away from the kinases into the rest of the genome," Futreal said.

According to Lichtenfeld, all of this bodes well for the future of cancer medicine, which will become more tailored to the genetics of a particular patient and his or her particular tumor.

"We're going to be able to take a cancer specimen, analyze it, and follow those genetic changes that influence particular pathways," he said. "Then we'll use one, two, three or more targeted therapies, perhaps simultaneously, and be able to completely interrupt the flow of the cancer process."

More information

Visit the Wellcome Trust Sanger Institute for more on the Cancer Genome Project.

SOURCES: Len Lichtenfeld, M.D., deputy chief medical officer, American Cancer Society, Atlanta; March 6, 2007, Nature news teleconference with Andrew Futreal, Ph.D., and Michael Stratton, Ph.D., co-leaders, Cancer Genome Project, Wellcome Trust Sanger Institute, Cambridge, England

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