Researchers at the St. Jude Children’s Research Hospital and the Washington University Pediatric Cancer Genome Project have linked gene mutations not previously tied to cancer to the rare but deadly brain tumor diffuse intrinsic pontine glioma (DIPG). DIPG accounts for 10% to 15% of pediatric tumors of the brain and central nervous system. It aggressively attacks the brainstem and kills more than 90% of its victims within two years.

“We are hopeful that identifying these mutations will lead us to new selective therapeutic targets, which are particularly important since this tumor cannot be treated surgically and still lacks effective therapies,” Suzanne Baker, PhD, corresponding author of the January 29 paper in Nature Genetics and co-leader of the St. Jude Neurology and Brain Tumor Program, said in a statement. She holds the Sydney Schlobohm Chair of Research funded by the National Brain Tumor Society and is a member of the NBTS Scientific Advisory Council.

Dr. Baker and colleagues, in research partially funded by the NBTS, discovered that specific mutations in the HRF3A and HIST1H3B genes existed in almost 80% of the DIPG tumors they studied. These gene mutations also were present in pediatric glioblastoma tumors they studied, but not in other tumor types.

These genes encode histone proteins that organize the structure of DNA in cells and regulate how genes are expressed. In the pediatric tumor cells, their mutation is thought to interfere with these functions. The researchers are now trying to determine how the mutations are involved in development of these pediatric tumors.

The Pediatric Cancer Genome Project is an ambitious three-year project to sequence the normal and cancer genomes of 600 children with poorly understood, aggressive pediatric cancers, with the goal of finding new tools to diagnose, treat, or prevent diseases.

A re-analysis of clinical trial data shows that a combination of radiation and chemotherapy can double median survival time for some patients with a rare brain tumor, oligodendroglioma—from 7.3 to 14.7 years.

The affected patients are ones whose tumor has sections of chromosomes 1 and 19 deleted.
Principal Investigator Gregory Cairncross, MD, of the University of Calgary in Canada, says the re-analysis gives us “unequivocal evidence that the chromosomal structure of 1p and 19q co-deletion can be used as a marker to determine which patients will benefit from combined chemotherapy and radiation.” Dr. Cairncross has been an active advisor to the National Brain Tumor Society for several years.

An extra seven years would provide valuable family time for brain tumor patients. Moreover, such an increase in survival might be just enough time for researchers to develop a new therapy that could provide more time—or possibly a cure.

In the clinical trial, 286 patients with aggressive oligodendrogliomas received either radiotherapy alone or radiotherapy plus PCV chemotherapy (procarbazine, CCNU[lomustine], and vincristine).  In the first analysis (2006), when patients had been followed for three years, survival time amounted to 8.7 years for patients with the 1p19q deletion and 2.7 years for patients without the deletion.

In the re-analysis, after patients have now been followed more than 11 years, patients whose tumor has the deletion who received the combination treatment had overall survival times of 14.7 years compared to 7.3 years for the patients whose tumor did not have the co-deletion.

This news highlights the importance of Phase III clinical trials to produce actionable results. It also highlights the importance of tumor tissue collection and analysis for potential use in personalized medicine.