Elucidation of abnormal RNA splicing and identification of driver events in U1 snRNA-mutant medulloblastoma

Abstract

This study aims to develop novel therapies for medulloblastoma, which has the poorest prognosis among pediatric tumors. Pediatric brain tumors are the leading cause of death among childhood cancers, and medulloblastoma has the poorest prognosis among them. The current standard of care is multidisciplinary treatment with surgery and radiation chemotherapy, but patients' quality of life is severely impaired due to side effects such as higher brain dysfunction, neurological disorders, and endocrine disorders. Despite these treatments, the prognosis is poor, and the development of new treatment methods is desired. The National Cancer Center Research Institute, Division of Brain Tumor Translational Research was the first in the world to discover the U1 small nuclear RNA (U1 snRNA) mutation by reanalyzing the entire genome data of medulloblastoma. This mutation is the most frequent genetic mutation in medulloblastoma reported to date. U1 snRNA recognizes various RNAs in the cell and processes them for proper RNA function. U1 snRNA mutations are thought to cause recognition of RNAs that are different from normal. These abnormalities are tumor-specific and thus may be promising therapeutic targets. However, previous analyses based on short-read sequencing have not yet elucidated which events among the wide range of abnormalities are involved in the pathogenesis of tumors, and this poses a challenge for therapeutic development. Therefore, this study will identify the true driver events produced in medulloblastoma by U1 snRNA mutations through long read sequencing and screening using a mouse model of brain tumors. This research will be conducted in collaboration with the National Cancer Center and the National Center of Neurology and Psychiatry. Both institutions have world-class research experience in medulloblastoma research. By collaborating and leveraging each other's strengths, we aim to identify the essential driver events of U1 snRNA-mutant medulloblastoma and provide a bridge to novel therapies.

Perspectives

• Identification of the true driver events of medulloblastoma development
• Development of novel therapies targeting the identified driver events
• Targeting tumor cell-specific changes is expected to lead to treatments with fewer side effects

Comments from principal researcher

The National Cancer Center Research Institute, Division of Brain Tumor Translational Research is conducting research to improve the treatment of malignant brain tumors by conducting sequencing, a technique for reading DNA and other sequences, analysis of various brain tumors and clarifying their pathophysiology. By identifying true driver events caused by U1 snRNA mutations, our research aims to develop novel therapies for medulloblastoma, which has the poorest prognosis among pediatric tumors.

Shared Researchers

• Hayato L Mizuno

The National Center of Neurology and Psychiatry, Department of Biochemistry & Cellular Biology