(Ivanhoe Newswire) Medulloblastoma, the most common pediatric brain cancer and leading killer of children with cancer, has been genetically decoded by scientists at the Johns Hopkins Kimmel Cancer Center. The genetic "map" is believed to be the first reported of a pediatric cancer genome.

The findings show that children with medulloblastoma have five- to tenfold fewer cancer-linked alterations in their genomes compared with their adult counterparts.

"These analyses clearly show that genetic changes in pediatric cancers are remarkably different from adult tumors. With fewer alterations, the hope is that it may be easier to use the information to develop new therapies for them," Victor Velculescu, M.D., Ph.D., associate professor of oncology at the Johns Hopkins Kimmel Cancer Center, was quoted as saying.

"We now know what many pieces of the medulloblastoma puzzle are," Bert Vogelstein, M.D., Clayton Professor of Oncology and co-director of the Ludwig Center at Johns Hopkins, was quoted as saying. "Now, we must figure out how to put the puzzle together and zero in on parts of the puzzle to develop new therapies. This is what scientists will be focused on for the next decade."

The Johns Hopkins team used automated tools to sequence hundreds of millions of individual chemicals called nucleotides, which pair together in a preprogrammed fashion to build DNA and, in turn, a genome. Combinations of these nucleotide letters form genes, which provide instructions that guide cell activity. Alterations in the nucleotides, called mutations, can create coding errors that transform a normal cell into a cancerous one. The scientists at Johns Hopkins have previously mapped genome sequences for pancreatic, adult brain, breast, and colon cancers with similar methods.

For the study, scientists sequenced nearly all protein-encoding genes in 22 samples of pediatric medulloblastoma and compared these sequences with normal DNA from each patient to identify tumor-specific changes or mutations. Each tumor sample had an average of 11 mutations. There were 225 mutations in all.

Then, the investigators searched through a second set of 66 medulloblastomas, including some samples from adults, to find how these mutations altered the proteins made by the genes.

The team found that most of the mutations stay within a few gene families or pathways. The most common pathway ordered the way long strands of DNA, that make up chromosomes, are twisted and shaped into dense packets that open and close depending on when genes need to be activated. Such a process is regulated by chemicals that operate outside of genes, termed "epigenetic" by scientists. Within the epigenetic pathway, two commonly mutated genes were both involved in how molecules called histones wrap around DNA.

"These epigenetic changes may be more important than we thought in childhood cancers," Will Parsons, M.D., Ph.D., formerly of Johns Hopkins and now an assistant professor at Texas Children's Cancer Center and Baylor College of Medicine, was quoted as saying.

Second to epigenetic pathways were gene mutations in pathways such as Hedgehog and Wnt that control tissue and organ development in humans and other animals. Both pathways have previously been linked to childhood medulloblastoma.

"It's a particular challenge to treat children with brain cancer," says Dr. Parsons, "because our most effective treatments, surgery and radiation therapy, can cause significant side effects, including cognitive disabilities and hormone abnormalities. For our youngest patients, the effects can be potentially devastating."

"As oncologists, we're working to understand how specific genetic changes found in patients' cancers should guide their treatment," Dr. Parsons said. "Any information that allows us to understand a patient's prognosis or provides clues about therapies that might work best in a patient is crucial and will help us provide better care."

SOURCE: Science, published online December 2010

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