UM lab collaborates on international study revealing origin of pediatric brain tumour

An international research team has uncovered the first indication that a type of medulloblastoma may be preventable by identifying how and where these tumours develop during human fetal brain development.

Medulloblastoma, an aggressive type of pediatric brain tumour, exists in a pre-malignant form at birth after initially developing during the first or second trimester of pregnancy, according to the study.

Because medulloblastomas typically present during childhood, at around seven years of age, the team’s discovery is the first indication that there could be a window of several years during which a medulloblastoma could be prevented from ever occurring. The findings were published today in the prestigious journal Nature.

Four leading research groups partnered in the study, including groups at:

• The University of Manitoba (led by Dr. Tamra Werbowetski-Ogilvie, professor of biochemistry and medical genetics in the Max Rady College of Medicine, researcher with the Children’s Hospital Research Institute of Manitoba and scientist with the CancerCare Manitoba Research Institute);
• The National Cancer Center in Tokyo (led by Dr. Hiromichi Suzuki, chief and principal investigator in the division of brain tumor translational research);
• The Seattle Children’s Research Institute (led by Dr. Kathleen Millen, professor and principal investigator at the Center for Integrative Brain Research);
• The Hospital for Sick Children (SickKids) in Toronto (led by Dr. Michael Taylor, pediatric neurosurgeon and senior scientist in the developmental and stem cell biology program at SickKids and professor of surgery at the University of Toronto).

Brain tumours are the deadliest form of childhood cancer and account for 20 per cent of all new pediatric cancer cases. Treatment for medulloblastoma currently consists of aggressive surgery, high doses of chemotherapy and/or radiation of the whole brain and spinal cord. Up to 40 per cent of patients still succumb to the disease, while survivors must deal with the long-term toxicities associated with chemotherapy and radiation.

Medulloblastoma is comprised of multiple subgroups and the study focused on the most common and least well understood subgroup, called Group 4. The goal was to identify how and where Group 4 tumours arise during embryonic development.

The researchers collected medulloblastoma samples from children’s hospitals around the world and used several sequencing technologies to successfully identify genetic variations that can cause Group 4 medulloblastomas.

They found that these genetic variations were effectively “stalling” normal cellular differentiation in a specific cell type only present during early fetal development of the human cerebellum. This “stalling” of normal cellular differentiation results in a pre-malignant form of the tumour that then resides in the brain after birth, a finding which may be generalizable to the other forms of medulloblastoma.

The researchers note that the cell type they identified is far more common, and is found in a region of the developing cerebellum that is more structurally complex, in humans than in other mammals. They say this could mean medulloblastoma is a direct consequence of the evolved complexity of the human cerebellum.

“This project was a beautiful example of teamwork, where each lab contributed an important piece of the puzzle,” said UM’s Werbowetski-Ogilvie. “Working as a team over the last 18 months has led us in exciting new directions.

“Now that we can pinpoint where these tumours come from, we can develop better models of the disease that will then be used for extensive drug testing. This may even allow for earlier detection, so this research is very exciting and opens a lot of new opportunities.”

Crucially, the team’s findings show that medulloblastomas originate much earlier in pregnancy than previously thought. Clinicians may have a window of opportunity between birth and symptom onset to detect medulloblastomas before they develop, and possibly to prevent them from turning into deadly brain tumours. This is thought to be the first time that medulloblastoma has been identified as potentially preventable.

This work was supported by the National Institutes of Health, Stand Up To Cancer, Canadian Institutes of Health Research, Fonds de Recherche du Québec – Santé, Natural Sciences and Engineering Research Council of Canada, CancerCare Manitoba Foundation, National Cancer Center Research and Development Funds and SickKids Foundation.

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