ZIC1 gene drives distinct medulloblastoma types in different ways

A study published in Nature Genetics reveals new insights into how medulloblastoma, the most common malignant brain tumor of childhood, can arise as the cerebellum develops. Researchers discovered that the same gene, ZIC1, can drive highly similar cancers by distinct, context-dependent mechanisms. Led by researchers at Baylor College of Medicine, Texas Children’s Cancer Center, University of Toronto, St. Jude Children’s Research Hospital and Mayo Clinic College of Medicine and Science, these findings have direct implications for tumor prevention and treatment.

“Medulloblastoma arises from malignant transformation of developing neurons in the cerebellum,” said co-corresponding author Dr. Michael Taylor professor of pediatrics – hematology / oncology and neurosurgery at Baylor and Texas Children’s. He also is the Cyvia and Melvyn Wolff Chair of Pediatric Neuro-Oncology at Texas Children’s Cancer and Hematology Center. “Although many driver genes of medulloblastoma are well known, many others are less understood. In the current study, we investigate the ZIC1 gene, which plays crucial roles in the development of the central nervous system.”

The researchers worked with two types of human medulloblastoma, G4 and SHH, which are suspected to arise from a common cell of origin in the developing cerebellum. The team discovered that G4 and SHH medulloblastoma have mutations in ZIC1 gene that drive their growth, but they do it by different mechanisms.

Context is everything

“G4 medulloblastoma tumors have ZIC1 mutations that produce proteins that have lost their function. In contrast, SHH medulloblastoma tumors have ZIC1 mutations that produce proteins with a new function that is different from that of the original gene,” said co-corresponding author Dr. Paul A. Northcott, principal investigator in the Department of Developmental Neurobiology and director of the Center of Excellence in Neuro-Oncology Sciences at St. Jude. “Tumor-driving ZIC1 mutations in medulloblastoma are context dependent.”

“Distinct ZIC1 mutations affect cells of the rhombic lip area of the cerebellum where the tumors arise in diametrically opposed ways, suggesting that ZIC1 is a critical developmental regulator in both the normal and transformed rhombic lip,” Taylor said.

Supporting the role of ZIC1 mutations as true driver events of medulloblastoma, the researchers found that overexpression of ZIC1promotes malignancy in SHH medulloblastoma precursor cells.

“Identifying how mutations in the same gene drive different medulloblastoma groups has genuine consequences for developing treatments,” Northcott said. “Our findings highlight the importance of identifying the correct context before designing an approach to treating each medulloblastoma. In one subgroup, ZIC1 mutations produce active proteins that are potentially good targets to inhibit. In the other group, it's a loss-of-function mutation, therefore restoring its function would be a potential therapeutic avenue.”

For a complete list of the authors, their affiliations and the financial support for this project see the publication.