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DNA study gives hope to children with brain cancer

A Canadian-led international effort has identified the genetic glitches behind one of the leading types of childhood brain cancer, giving scientists their first shot at designing less toxic treatments to battle the deadly disease.

Running the largest genetic study of childhood brain cancer ever undertaken, Toronto researchers have sequenced the DNA of brain tumours taken from 800 children worldwide and found a family of eight genes capable of spawning the malignancy known as medulloblastoma.

The disease, the result of primitive brain cells developing into tumours at the back of the head, is the leading cause of childhood cancer deaths - and cancer, after accidents, is the top killer of children.

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Researchers found that when the eight genes work properly, they tell the neurons in the rear part of an infant's brain when to stop growing. But when any one of the eight fouls up, this region remains in an immature state and never grows up. Cells multiply indefinitely and trigger tumours that kill 40 per cent of affected children within five years.

The genes are now a prime target for new treatments, and scientists are racing to test compounds that are already known to affect them.

The goal is particularly urgent because current therapies involve surgery and such high doses of radiation and chemotherapy that many children suffer permanent mental and physical damage as a result.

"Their IQs drop, they have a risk of developing secondary cancers - it's sort of like a deal with the devil; cures come at a very high price," said Michael Taylor, a pediatric neurosurgeon at Toronto's Hospital for Sick Children and senior author of the paper published online Sunday in Nature Genetics.

The genes had previously been known to be important in directing the growth of embryonic stem cells. As a result, the finding also adds intriguing evidence to the theory that cancer might be the result of rogue stem cells that never reach maturity.

"Our data support the idea that the tumour is coming from progenitor cells, that is they're half way to becoming a mature cell," said Dr. Taylor. "It's entirely consistent with the idea that [this cancer]is a failure of the development of the mature brain."

Mick Bhatia, director of the McMaster Cancer and Stem Cell Research Institute in Hamilton, called the report fantastic and said his lab had earlier done experiments showing some of these genes either tell a stem cell when to die or what to become.

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"Now here's a large number of tumours that they looked at from all these different people and they randomly come up with these same genes that happen to be critical to stem cells' fate - that's really provocative," said Dr. Bhatia, noting that tumour and stem cells share similar properties, such as the infinite capacity to multiply.

"This paper is fascinating, and it raises the question - do we have chemotherapy agents to target these genes?"

Children with medulloblastoma tend to be diagnosed around age seven, Dr. Taylor said, when they are old enough to describe symptoms, which include a persistent headache and vomiting. But a subset of cases can be detected in infancy, usually at an advanced stage, when the tumour results in a visual protrusion from the cerebellum, the hindbrain structure where medulloblastoma tumours grow. The cerebellum is involved in co-ordination, balance and motor control.

With current therapies, about 60 per cent of children survive beyond five years.

Dawson Dominick, who was diagnosed at age two, for example, is one of the success stories. But his road to survival was torturous. His parents, Scott and Josée Dominick, could only stand by as their 25-pound-toddler underwent a 10-hour surgery to remove the tumour, five aggressive rounds of chemotherapy, each one followed by a spinal tap and then a stem-cell transplant before their son was declared cancer free.

"Whatever we can do to help people in future, we wanted to do," Mr. Dominick said. "You never want anyone to go through this kind of thing."

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This form of brain cancer tends to be wildly different at the molecular level, which has made it especially tough to come up with a treatment that would combat all medulloblastoma tumours. As Dr. Taylor put it, "They're all Toyotas, but one might be a Sequoia and the other a Camry."

Earlier studies, meanwhile, did not have enough samples to spot common genetic patterns in the tumour cells. So in 2004, Dr. Taylor made a concerted effort to boost sample numbers.

"I did the typical Canadian thing and bought beer for my international collaborators," he joked. "When they were in a suitable frame of mind, I made them promise to send me frozen tissue samples from their tumours."

The barley-soaked tactic worked. Dr. Taylor and his team, including lead author Paul Northcott, have so far received 800 samples from all over the United States, Poland, Hungary, Russia, India, Brazil, Korea, Argentina, France, Germany and on it goes.

The Nature Genetics paper, however, is based on examinations of the first 212 tissue samples using technology that allowed researchers to conduct full DNA scans. Dr. Taylor said the old technology allowed scientists to spot suspicious "neighbourhoods" in the three-billion units of genetic code, but the new generation of equipment allows them to "see the street, the house and the bedroom in the house where things have gone wrong."

This way, researchers found that the culprit mutations sometimes involved the children carrying as many as 50 extra copies of a gene, or missing genes. But most striking is that the eight genes identified, which have so far been confirmed to play a role in 25 per cent of the cases, all impact the same pathway in the developing brain, Dr. Taylor explained - they hamper the signal that tells the cerebellum cells to stop growing.

Co-author Steve Scherer, a Sick Kids senior scientist involved with the DNA sequencing efforts, said the result is "quite precedent-setting," because it shows that rare variations in many different genes can impact the same function, and cause the same kind of cancer.

"I'm sure you will see this will be the story in other cancers," Dr. Scherer said.

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