Abstract
Medulloblastoma (MB) is the most common childhood malignant brain tumor. DNA methylation profiling has rapidly advanced our understanding of MB pathogenesis at the molecular level, MBs can be sub-grouped according to methylation patterns from FPPE samples into Wingless (WNT-MB), Sonic Hedgehog (SHH-MB), Group 3 (G3) and Group 4 (G4) WNT-MB and SHH-MB subgroups are characterized by gain-of function mutations that activate oncogenic cell signalling whilst G3/G4 tumors show recurrent chromosomal alterations. each subgroup has distinct clinical outcomes, the ability to subgroup SA-FPPE samples holds significant prognostic and therapeutic value. We performed the first assessment of MB-DNA methylation patterns in Saudi Arabian SA cohort using archival biopsy materials (FPPE n=49). Of the 41 materials available for methylation assessments, 39 could be classified into the major DNA methylation subgroups (SHH, WNT, G3 and G4). Methylation analysis was able to reclassify tumors that could not be sub-grouped through NGS testing, highlighting its improved accuracy for MB molecular classifications. Independent assessments demonstrate clinical relationships of the subgroups, exemplified by the high survival rates observed for WNT tumors. Surprisingly, the G4 subgroup did not conform to previously identified phenotypes, with a high prevalence in females, high metastatic rates and a large number of tumor-associated deaths. DNA methylation profiling enables the robust sub-classification of four disease sub-groups in SA-MB patients. Moreover, the incorporation of DNA methylation biomarkers can significantly improve current disease-risk stratification schemes, particularly concerning the identification of aggressive G4 tumors. These findings have important implications for future clinical disease management in MB cases across the Arab world.