January 24, 2011

Genome code cracked for most common pediatric brain cancer

Scientists at the Johns Hopkins Kimmel Cancer Center have deciphered the genetic code for medulloblastoma, the most common pediatric brain cancer and a leading killer of children with cancer. The genetic “map” is believed to be the first reported of a pediatric cancer genome and was published online in the Dec. 16 issue of Science Express.

Notably, the findings show that children with medulloblastoma have five- to 10-fold fewer cancer-linked alterations in their genomes compared with their adult counterparts, the scientists said.

“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,” said Victor Velculescu, associate professor of oncology at the Johns Hopkins Kimmel Cancer Center.

“We now know what many pieces of the medulloblastoma puzzle are,” added Bert Vogelstein, Clayton Professor of Oncology and co-director of the Ludwig Center at Johns Hopkins. “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 congregate within a few gene families or pathways. The most prevalent 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 involved in how molecules called histones wrap around DNA.

“These epigenetic changes may be more important than we thought in childhood cancers,” said Will Parsons, formerly of Johns Hopkins and now an assistant professor at Texas Children’s Cancer Center and Baylor College of Medicine.

Mutations in MLL2 and MLL3 were identified in 16 percent of the entire set of 88 medulloblastoma samples. Add to this three other epigenetic alterations found by the scientists in the genome scan, and the total set accounts for 20 percent of mutations in all the brain cancer samples.

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.

Cancer is the leading cause of death by disease in children in the United States, and more children die of brain tumors than any other type of cancer. Medulloblastoma is the most common malignant brain tumor in children, occurring in about 400 children per year in the United States.

“It’s a particular challenge to treat children with brain cancer,” said 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.”

Yet Parsons is encouraged by the study’s findings. “As oncologists, we’re working to understand how specific genetic changes found in patients’ cancers should guide their treatment. 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.”

The study was funded primarily through the National Cancer Institute’s Cancer Genome Characterization Initiative, as well as the Virginia and D.K. Ludwig Fund for Cancer Research, Alex’s Lemonade Stand Foundation, American Brain Tumor Association, Brain Tumor Research Fund at Johns Hopkins, Hoglund Foundation, Ready or Not Foundation, Children’s Brain Tumor Foundation, Pediatric Brain Tumor Foundation Institute, an AACR Stand Up To Cancer–Dream Team Translational Cancer Research Grant, Johns Hopkins Sommer Scholars Program, National Institutes of Health, National Science Foundation and Department of Defense. Parsons is a Graham Cancer Research Scholar at the Texas Children’s Cancer Center.

Additional Johns Hopkins scientists involved in the study are Meng Li, Xiaosong Zhang, Sian Jones, Rebecca J. Leary, Jimmy Cheng-Ho Lin, Simina M. Boca, Hannah Carter, Josue Samayoa, Chetan Bettegowda, Gary L. Gallia, George I. Jallo, Zev A. Binder, Peter C. Burger, Gregory J. Riggins, Rachel Karchin, Nick Papadopoulos and Kenneth W. Kinzler.

Under licensing agreements between The Johns Hopkins University and Beckman Coulter, Vogelstein, Kinzler and Velculescu are entitled to a share of royalties received by the university on sales of products related to research described in this paper. Papadopoulos, Vogelstein, Kinzler and Velculescu are co-founders of Inostics and Personal Genome Diagnostics and are members of their scientific advisory boards. Papadopoulos, Vogelstein, Kinzler and Velculescu own Inostics and Personal Genome Diagnostics stock, which is subject to certain restrictions under university policy. The terms of these arrangements are managed by The Johns Hopkins University in accordance with its conflict-of-interest policies.