The most significant gene alterations are linked to subtypes of medulloblastoma that currently have the best and worst prognosis. They were among 41 genes associated for the first time to medulloblastoma by the St. Jude Children’s Research Hospital – Washington University Pediatric Cancer Genome Project.

“This study provides new direction for understanding what drives these tumors and uncovers totally unexpected new drug targets. There are drugs already in development against these targets aimed at treating adult cancers and other diseases,” said Richard Gilbertson, M.D., Ph.D., St. Jude Comprehensive Cancer Center director.

This study found a high percentage of patients with wingless (WNT)-subtype medulloblastoma had mutations in the DDX3X gene. The investigators found evidence that mutated DDX3X is required to sustain the brain cells where WNT subtype tumors develop. The research also found evidence linking alterations in other genes, including CDH1 and PIK3CA, to the development and spread of the WNT subtype. “It is particularly exciting that these genes, or the pathways in which they work, are already the focus of drug development efforts. This opens up the possibility of using these drugs to treat medulloblastoma in new ways,” said Giles Robinson, M.D., St. Jude Department of Oncology research associate and one of the study’s first authors.

The results mark progress toward more targeted therapies against medulloblastoma and other cancers. While better use of existing drugs and improved supportive care have helped push long-term survival rates for childhood cancer to about 80 percent, drug development efforts have largely stalled for more than two decades, particularly against pediatric brain tumors.

"This study is a great example of the way whole-genome sequencing of cancer patients allows us to dig deep into the biology of certain tumors and catch a glimpse of their Achilles heel," said co-author Richard K. Wilson, Ph.D., director of The Genome Institute at Washington University School of Medicine in St. Louis. "These results help us better understand the disease and, as a result, we will be able to more effectively diagnose and treat these kids."

The findings are part of the Pediatric Cancer Genome Project, which launched in 2010 as a three-year effort to decipher the complete normal and tumor genomes of 600 young cancer patients with some of the most challenging tumors. The endeavor has already yielded important clues into the origin, spread and treatment response in childhood cancers of the blood, brain, eye and nervous system.

The findings add to mounting evidence from the Pediatric Cancer Genome Project that epigenetic changes play a pivotal role in fueling childhood cancer. Epigenetic mechanisms can serve as on-off switches, altering gene activity without changing the makeup of the gene. Such changes can lead to the unlimited cell growth of cancer.