PTHP-07. Clinical and Molecular Characteristics of Japanese Medulloblastoma, SHH-Activated

BACKGROUND Medulloblastomas (MBs) are categorized into four molecular subgroups: WNT, SHH, Group 3, and Group 4, as defined by the WHO classification. SHH-activated MB (SHH-MB) is more common in infants and adults, and genetically characterized by alterations in SHH pathway-related genes such as PTCH1, SMO, and SUFU. In this study, we have summarized the results of molecular analysis of Japanese MBs collected by the Japanese Pediatric Molecular Neuro-oncology Group (JPMNG) study and analyzed the clinical and molecular characteristics of SHH-MB. METHODS We enrolled 267 cases of MBs from 44 centers participating in the JPMNG study. Central histopathological diagnosis was performed by three neuropathologists, and molecular genetic diagnosis was conducted using the NanoString nCounter system or DNA methylation array, and we also examined pathogenic variants (PVs) and copy number aberrations (CNAs). RESULTS Among 243 analyzable cases, 60 (25%) were classified as SHH-MB. SHH-MB was predominant in children under 3 years (38.3%) and showed a slight male predominance. Desmoplastic/nodular (D/N) and MBEN histologies were frequent. In this study, all cases were negative for PVs of CTNNB1 (58/58: 100%). PVs of TERT promoter (11/58: 13.8%) were observed in the majority of adult cases (6/7: 85.7%). Regarding PVs of TP53, 12.1% (8/58) were detected by Sanger sequencing, and 17.8% (8/45) were detected by methylation array or microarray. While PTCH1 PVs were fewer than previously reported (20% vs. 43%), PTEN alterations were more common (22.2% vs. 7%). No clear prognostic differences were observed with SUFU or SMO PVs. CONCLUSIONS The SHH-MB cases in this Japanese cohort generally aligned with international data, though notable differences in the frequency of some genetic alterations were observed. These findings suggest that ethnic variability may influence molecular profiles of MBs, while certain features remain conserved. Such insights may inform the development of subgroup-specific therapies.