Canadian researchers have pinpointed a family of eight genes that are mutated in patients with the most common form of childhood brain cancer, and they hope their discovery will lead to a more targeted means of treating the devastating disease.

Brain tumours are the leading cause of cancer-related death in children. Although about 60 per cent of children diagnosed with medulloblastoma now survive at least five years, they are often left with severe physical and neurological disabilities from both the cancer and the treatment.

'Once we've worked out what the genetic abnormalities are in medulloblastoma or any of these kinds of cancers, then we can start targeting the correct things to develop therapies that kill cancer but don't hurt kids.'— Dr. Michael Taylor

That's because as the tumour grows, it damages the child's still-maturing brain, explained principal researcher Dr. Michael Taylor, a pediatric neurosurgeon at Toronto's Hospital for Sick Children. Then the treatment — a combination of surgery to remove the tumour, chemotherapy and sometimes radiation — "does horrible things to the developing and growing brain."

"And as a result, these kids even when they survive, they frequently have cognitive problems, they have neurological disabilities ... they have growth problems and they have secondary cancers," Taylor said.

"So even when we win, it's a pyrrhic victory."

In the study, published online Sunday in the journal Nature Genetics, researchers analyzed more than 200 medulloblastomas that had been surgically removed from children. They discovered eight mutated genes from a group responsible for turning off growth-promoting genes in the brain.

Perpetual adolescence for cells

"So we think what happens when one of these eight genes is mutated is that the cells are growing normally and they're dividing like they're supposed to be when the brain is developing," Taylor said. "But when one of these genes becomes defective through mutation, they don't know when to stop."

"So they're stuck in a perpetual adolescence and they just keep dividing and dividing and dividing, until eventually they form a brain tumour."

When healthy, the genes make a protein that causes DNA in cells to wind up super tight, much like thread coiled around a spool, said Taylor. This tight winding normally shuts off growth-promoting genes once the brain is fully grown.

But when the aberrant genes are present, the DNA fails to be snugly wound, he said. "So as a result, genes that should be turned off when [brain] growth is done are not turned off."

Drug design potential

This discovery offers hope for treatment with far less collateral damage than is currently possible, because other genes involved in DNA winding have already been successfully targeted by drugs.

Followup studies in Taylor's lab will include testing of drugs to see if any are able to halt the out-of-control division of cells that keeps the tumour growing, in effect making them reach a mature state and stop running amok.

"We think if we could design drugs that target this pathway … they would kill tumour cells without affecting the normal growing brain the way current treatments do," he said. "You don't have to see too many kids melting away — despite optimal surgery, radiation and chemotherapy — to realize that we need to make things better for these kids and their families."

Medulloblastoma is primarily a disease of very young children and is particularly deadly among babies under 18 months of age, says the Canadian Cancer Society. In Canada, about 40 children a year are diagnosed with this type of tumour.

"This discovery is very promising and may help researchers develop better, more targeted treatments so that more of these children will survive and fewer will suffer debilitating side-effects," Dr. Christine Williams of the Canadian Cancer Society Research Institute said in a statement.

Scott and Josee Dominick's five-year-old son Dawson was diagnosed at age two with medulloblastoma, which develops in the cerebellum at the back of the brain. The tumour and treatment have left Dawson with some cognitive and balance problems, as well as diminished hearing. But his father said the effects could have been much worse.

Still, he concedes it has been difficult for the family from Orangeville, Ont.

'Great stride'

"It's just been a struggle. Your whole world gets turned upside-down in a blink of an eye."

The genetic discovery is a "great stride" forward, said Dominick. "Hopefully they'll get down the right path where they'll be able to make it a lot easier on families in the future."

Oncologist Dr. Rod Rassekh, an expert in childhood cancer at the Child & Family Research Institute at B.C. Children's Hospital, said cure rates for brain tumours are lagging those of other pediatric cancers, such as some forms of leukemia.

Rassekh, who was not involved in this study, called the researchers' approach of looking at the genetic basis for medulloblastoma "very powerful."

"What we need to do is use strong science like they use in this paper for finding novel ways of treating," he said from Vancouver. "And part of finding novel ways is to understand why these cancers occur in the first place."

Taylor said rapid advances in gene-sequencing technology are accelerating the pace of research into cancer genetics, and he predicts scientists will understand the full genetic underpinnings for a number of rare pediatric cancers over the next five to 10 years.

"And once we've worked out what the genetic abnormalities are in medulloblastoma or any of these kinds of cancers, then we can start targeting the correct things to develop therapies that kill cancer but don't hurt kids."