Abstract
BACKGROUND: Medulloblastoma (MB) is the most common malignant pediatric brain tumor and exhibits high heterogeneity in genetic alterations and molecular subgroups. However, current treatment remains largely uniform, and more precise risk stratification is necessary to improve prognosis. Large-scale genomic studies have primarily focused on Western populations, while comprehensive data on Japanese patients remain limited due to low incidence. This study aimed to elucidate molecular genetic characteristics and prognostic factors in Japanese MB through integrative genomic and transcriptomic analyses. METHODS: Targeted DNA and RNA sequencing was performed on 200 cases from the Japanese Children’s Cancer Group (JCCG), and publicly available whole-genome and RNA sequencing data from 472 Western MB patients were analyzed for comparison. RESULTS: Known subgroup-specific driver mutations were identified in the Japanese cohort, and age-adjusted comparison with the Western cohort showed no significant differences in mutation frequencies, suggesting limited racial differences in MB pathogenesis. Deep sequencing detected subclonal mutations, including SMARCA4 in the WNT subgroup. Missense mutations in the MYC functional domain were observed in cases lacking MYC amplification; these are known drivers in hematological malignancies and may also play an oncogenic role in MB. MYC mutations were found in WNT and SHH subgroups, suggesting broader involvement beyond Group 3. Intron retention analysis revealed a non-canonical intronic ZMYM3 mutation in a Group 4 case, highlighting improved driver detection by integrating DNA and RNA data. Whole chromosomal aberrations correlated with better outcomes, supporting their role in risk classification. CONCLUSIONS: This study identified novel MYC alterations and emphasized the utility of RNA-integrated analysis. Cohort expansion may uncover additional diversity and aid in precision medicine development.